VictorJuiz/thesis huggingface dataset:
Kinase Inhibitors and Nucleoside Analogues as Novel Therapies to Inhibit HIV-1 or ZEBOV Replication

Without a vaccine for Human Immunodeficiency Virus type 1 (HIV-1), or approved therapy for treating Zaire Ebolavirus (ZEBOV) infection, new means to treat either virus during acute infection are under intense investigation. Repurposing tyrosine kinase inhibitors of known specificity may not only inhibit HIV-1 replication, but also treat associated inflammation or neurocognitive disorders caused by chronic HIV-1 infection. Moreover, tyrosine kinase inhibitors may effectively treat other infections, including ZEBOV. In addition, established nucleoside/nucleotide analogues that effectively inhibit HIV-1 infection, could also be repurposed to inhibit ZEBOV replication. In this work the role of two host cell kinases, cellular protoncogene SRC (c-SRC) and Protein Tyrosine Kinase 2 Beta (PTK2B), were found to have key roles during early HIV-1 replication in primary activated CD4+ T-cells ex vivo. siRNA knockdown of either kinase increased intracellular reverse transcripts and decreased nuclear proviral integration, suggesting they act at the level of pre-integration complex (PIC) formation or PIC nuclear translocation. c-SRC siRNA knockdown consistently reduced p24 levels of IIIB(X4) and Ba-L(R5) infection, or luciferase activity of HXB2(X4) or JR-FL(R5) recombinant viruses, prompting further drug inhibition studies of this kinase. Four c-SRC kinase inhibitors (dasatinib, saracatinib, KX2-391 and SRC Inhibitor-1) significantly reduced HXB2 and JR-FL infection in primary CD4+ T-cells. Thus, these potent c-SRC inhibitors should be further evaluated in humanized mouse models of HIV-1 infection. During 2014-16, the Ebola outbreak in West Africa prompted us to rapidly assess whether conventional nucleoside analogs could inhibit in vitro ZEBOV replication. Employing a new lifecycle model of ZEBOV infection in level 2 biocontainment, combinations of nucleoside analogues and interferons were found to synergistically inhibit ZEBOV replication. These included zidovudine, lamivudine and tenofovir, confirmed to show antiviral activity against fully infectious ZEBOV-GFP in level 4 biocontainment. Findings from this thesis provided the rationale for further preclinical development of nucleoside analogue combination treatments, and a phase II EVD trial evaluating recombinant interferon in Guinea. Pre-clinical results using c-SRC kinase inhibitors also suggest that this approach could also be effective in EVD.

Keywords: c-SRC
HIV-1
kinase
nucleoside analogue
PTK2B
ZEBOV
Advisor: Branch, Donald R
Properties of Stellar Remnants: Rotational and Magnetic Evolution of Their Progenitors

The rotation and magnetic evolution of stars is examined in detail. Advection of angular momentum by convective plumes is a source of differential rotation, which both reduces the angular momentum loss to stellar winds and spins up the inner regions. This spin up not only affects the rotation of the stellar remnant, but also facilitates the winding of magnetic field lines necessary to amplify a seed field. In radiative regions we demonstrate that an embedded magnetic field can effectively mix angular momentum, as well as sustain coupling with adjacent convective zones. In addition to the resulting angular momentum transport model, we consider a mechanism for rotationally-induced winding of a seed magnetic field. When this mechanism operates at a convective-radiative boundary which moves in a Lagrangian sense towards the convection zone, net helicity is left behind in the newly radiative material. We employ this model of angular momentum transport and helicity deposition in stellar models of a wide range of masses. Our aim is to gauge the effect on the evolution of rotation and the impact on the properties of stellar remnants. In low- and intermediate-mass stars we find a quantitative agreement between the predicted and observed core and surface rotation rates, during both the sub-giant and helium-burning phases. Continuing the evolution to the ejection of the envelope, we are able to reproduce the spin periods and magnetic fields of highly magnetic white dwarf remnants. We find similar success in massive stellar models, by being able to reproduce both the spin periods and magnetic fields of pulsars. And in progenitors of black holes with sufficiently high angular momentum pre-core-collapse, a portion of the infalling material can reach rotational support. This quenches the accretion onto the newly formed black hole, and may result in observable phenomena, such as high energy jets.

Keywords: Black holes
Magnetic fields
Neutron stars
Rotation
White dwarfs
Advisor: Thompson, Christopher
Examining Changes in Spatialized Geometry Knowledge for Teaching as Early Years Teachers Participate in Adapted Lesson Study

Background: Research suggests there is a crucial need for improved teaching of geometry and spatial reasoning in early years classrooms; however, limited teacher knowledge of geometry and spatial reasoning are noted to be significant challenges to this goal. Aims: This dissertation investigated teacher learning about spatialized geometry when participating in an adapted lesson study. The analyses focused on growth in teachers’ gains in knowledge of students, their knowledge of teaching, and growth in their content knowledge of spatialized geometry. Teacher perceptions of the adaptations to lesson study were also examined. Intervention: Teachers participated in an adapted lesson study, which added clinical interviews, exploratory lessons, and resource creation to the traditional Japanese lesson study model (goal setting, lesson design, lesson implementation, and lesson debriefing). Sample: This case study examined the learning of five teachers within one lesson group. Design and methods: Data included pre- and post-questionnaires and geometry inventories, video-recordings of nine meetings over seven months, and artifacts and videos from activities within the teachers’ own classes. Teacher learning was then analyzed through a new construct—spatialized geometry knowledge for teaching (SGKT)—which encompassed learning about students and teaching as well as about specific geometry concepts. Results: The teachers demonstrated substantial expansion of their SGKT including an increased awareness and knowledge of students’ strategies, challenges, and abilities to succeed in spatialized geometry tasks. The teachers also gained substantially increased knowledge for teaching as evidenced by their increased sophistication in designing and implementing quality geometric tasks. Finally, the teachers credited the expanded lesson study structure, in particular the addition of clinical interviews and exploratory lessons, for their considerable learning. Conclusion: The substantial learning about SGKT evidenced in this case study suggests that the adapted lesson study model has potential to address the limited geometry knowledge typically found in early years teachers.

Keywords: Geometry
Lesson Study
Professional Development
Spatial Reasoning
Teacher Learning
Advisor: Moss, Joan
A Superscalar Out-of-Order x86 Soft Processor for FPGA

Although FPGAs continue to grow in capacity, FPGA-based soft processors have grown very little because of the difficulty of achieving higher performance in exchange for area. Superscalar out-of-order processor microarchitectures have been used successfully for hard processors for many years, and promise large performance gains if they can also be used for FPGA soft processors. Out-of-order soft processor microarchitectures have so far been avoided due to the area increase and the expectation that a loss in clock frequency would more than offset the instructions-per-cycle (IPC) gains. This thesis presents the design of the microarchitecture and circuits of a two-issue (superscalar) out-of-order x86 FPGA soft processor. Our microarchitecture achieves 2.7 times the per-clock performance of a performance-tuned Nios II/f, Alteraâ s fastest (RISC-like, single-issue, pipelined) soft processor, and 0.8 times the frequency, for a total performance improvement of 2.2 times. The processor is projected to use around 28700 Stratix IV Adaptive Logic Modules (ALMs), which is 6.5 times the area of the Nios II/f, but still only a small fraction of a modern FPGA. In addition to performance improvements, our microarchitecture design is sufficiently complete and correct to boot most 32-bit x86 operating systems unmodified. We also design circuits for most of the components in the processor. These highly-optimized circuits are key to achieving high operating frequency despite the increased complexity of out-of-order execution. Through the design of our processor, we demonstrate that a high-performance processor microarchitecture can be implemented successfully on FPGAs. Beyond the proposed microarchitecture, the processor circuits presented in this thesis will enable new out-of-order soft processor microarchitectures of varying performance, cost, and instruction set, created from variations of our circuits.

Advisor: Rose, Jonathan
Betz, Vaughn
FAITH AND FEMINISM IN PAKISTAN: Religious Agency or Secular Autonomy?

Numerous post 9/11 ethnographic studies on Islamist/Muslim women have focused almost exclusively on their piety, spiritual drive, agency and subjectivities. Against this trend, the academic and political interest of Faith and Feminism is to recall attention to the political ideologies and routine struggles of women in Muslim majority contexts. This thesis tracks some epistemological tensions that define the growing antagonism between faith-based and secular feminist politics in Pakistan. It argues that there are serious limitations to the religious agency sometimes celebrated by scholars in Western academia as a manifestation of Muslim women’s imaginaries or subjectivities (Abu-Lughod 2013, Jamal 2013, Iqtidar 2011, Mahmood 2005). The influence of postsecularist scholarship that discredits secular feminisms and liberal aspirations is studied with reference to Pakistan. The thesis finds that such criticism relies on a forfeiture of equality and freedoms for Muslim women and minorities only and offers a rationalisation of patriarchy and conservatism. At the same time, this study also recognises the limitations and ineffectual strategies of liberal resistance to Islamic conservatism; the ideological tensions amongst feminists; and the futile dependence on popular culture as a mode of resistance. The post 9/11 developmental model of “donor-driven Islam” (as a strategy of embedding progressive Islam under the guise of servicing gender empowerment while promoting a communalised ‘Muslim human rights’) is found to hinge on postsecularist arguments. In contrast to the above trends, this thesis documents and analyses some examples of the nation-wide working women’s movements in Pakistan that were active through the decade of the “War on Terror” (2001 – 2013). These struggles and campaigns have been secular, or free of theological underpinnings, motivations, slogans or props, and have taken no recourse from faith or religious debates, yet they remain the direct targets of Islamist conservatism and militancy. The thesis argues for political investment in these movements of secular resistance for meaningful feminist progress.

Keywords: Feminism
Islam
Muslim women's agency
Pakistan
Secular autonomy
Advisor: Mojab, Shahrzad
McElhinny, Bonnie
Beyond 'Passion Versus Reason': Identifying Person and Feature Attributes that Predict Deontological and Consequentialist Moral Judgment

The Central Tension Principle asserts that characteristically deontological judgments are preferentially supported by automatic emotional responses, whereas characteristically consequentialist judgments are supported by conscious reasoning and cognitive control. Although a large body of research supports this claim, there are reasons to be skeptical. In Chapter 1 I will outline several criticisms of the Central Tension Principle and propose an alternate framework. In Chapter 2 I will demonstrate that consequentialist moral judgments vary as a function of attachment insecurity, a need to belong, discomfort caring for others, empathy for the group (or individual), and the desires of the people involved in the situation. These data support the idea that to understand moral judgment, one must move beyond the emotion vs. reason dichotomy and take into account other features of the situation. In addition, it highlights an emotional route to consequentialist judgment. In Chapter 3 I will demonstrate that deontological and consequentialist responders use equal amounts of emotional language overall when justifying a moral judgment, but deontological responders use more anger language and consequentialist responders use more sadness language. In Chapter 4 I will demonstrate that another feature that influences moral judgment is the amount of effort the protagonist exerts to arrive at a moral conclusion. I will provide evidence that when the actor exerts little effort, participants judge a deontological actor to be morally superior to a consequentialist actor, but at high effort, this difference is eliminated or attenuated. This effect is mediated by changes in the perceived moral character of the actor. Taken together, the accumulated data suggest ways in which the field may move beyond â emotion vs. reasonâ by highlighting the importance of features of the actor, features of the victims, and features of the beneficiaries.

Keywords: Moral judgment
Advisor: Plaks, Jason E
Inbar, Yoel
Corneal reinnervation to treat neurotrophic keratopathy

Patients lacking corneal sensation develop neurotrophic keratopathy (NK). NK is characterized by recurrent breakdown of the corneal epithelium, resulting in scarring of the cornea and permanent vision loss. Even with optimal ophthalmic management, corneal epithelial breakdown and vision loss in patients with advanced NK is inevitable. Conventional treatments protect the cornea from injury but fail to prevent vision loss as they do not address the underlying lack of corneal innervation. Success in treating other nerve palsies surgically with nerve grafts and transfers provides a strong rationale for investigating surgical reinnervation of the cornea in patients with NK. We demonstrate in a prospective clinical study that a novel surgical procedure to reinnervate the cornea improves corneal sensation and ocular surface health in patients with NK. Furthermore, we document reinnervation of the cornea using immunohistochemistry, magnetoencephalography and in vivo confocal microscopy of the cornea. We developed a novel rat model of NK and corneal reinnervation with nerve grafts and transfers to further investigate how foreign axons influence corneal epithelial healing. In this model, we demonstrated that corneal reinnervation improves corneal healing after injury, suggesting that the donor nerves that reinnervate the cornea contain neuromediators necessary to promote corneal epithelial healing. There are several challenges limiting axon regeneration and recovery when using nerve grafts and transfers. In the final chapter, investigation of retrograde neuronal death after neonatal peripheral nerve injury demonstrated that N-acetyl cysteine decreases motor neuron death but fails to prevent sensory neuron death after injury. The promising clinical results and animal studies presented as part of this thesis suggest reinnervation of the cornea with nerve grafts and transfers results in corneal reinnervation, restoring corneal sensation and nerve-derived trophic support, which in turn, improves corneal epithelial maintenance and repair after corneal injury in the context of NK. With this work, we have introduced an animal model that will allow investigation of the mechanisms by which corneal reinnervation influences the corneal epithelium and vision.

Keywords: Cornea
Corneal neurotization
Nerve Regeneration
Neurotrophic Keratopathy
Peripheral Nerve
Wound Healing
Advisor: Borschel, Gregory H
Neural Stem Cells in the Central Nervous System: Their Identification, Characterization and lineage Relationship

Adult neural stem cells (NSC) reside in the periventricular region along the entire neuaxis. It is thought that a subset of mature astrocytes, expressing glial fibrillary acidic protein (GFAP), known as definitive NSCs (dNSC) are responsible for neurogenesis within the adult forebrain. We have identified a novel population of a rare, primitive NSC (pNSC) expressing low level of the pluripotency marker, Oct4. Both dNSC and pNSC can be isolated in vitro using neurosphere assays and differentiate into glial and neuronal cell types. Transplantation studies of pure pNSCs into the anterior rostral migratory stream of mice produced migrating neuroblasts and neurons in the olfactory bulb suggesting a potential lineage relationship between pNSCs and downstream progenitor cells. Using transgenic mouse models whereby dNSCs are labeled using a Cre-Lox system then subsequently ablated using the thymidine kinase system under the GFAP promoter, we have shown that pNSCs are non-GFAP expressing and can give rise to dNSCs in the forebrain. By taking advantage of the unique marker expression of Oct4 in pNSCs, we used Oct4CreERT2;ROSAyfpfl/fl;GFAPtk mice to selectively label pNSCs followed by complete depletion of dNSCs. As predicted, some dNSCs that returned over time expressed YFP, revealing a direct contribution from pre-labeled Oct4 expressing pNSCs. Together, these findings confirm the NSC lineage relationship in vivo, whereby the dNSC lies downstream of the pNSC in the adult forebrain. In the non-neurogenic spinal cord niche, we have isolated pNSC and dNSC populations throughout development. We suggest a similar lineage relationship based on in vitro passaging experiments. Interestingly, the most abundant protein within mature myelin, myelin basic protein (MBP), inhibits proliferation which terminates NSC derived sphere formation in vitro. In a transgenic mouse model with conditional knock-out of MBP, the shiverer-/- mouse, there is a significant enhancement of the number of NSCs isolated both naively and following injury compared to littermate or non-injured controls respectively. In conclusion, we have identified two distinct NSC populations within the adult central nervous system that can be activated following injury but suppressed by MBP. Understanding the factors and conditions that impact these distinct populations of cells will shed light into developing novel stem cell-based regenerative medicine strategies.

Keywords: Adult
Adult Stem Cells
Myelin
Neural Stem Cells
Regenerative Medicine
Spinal Cord Injury
Advisor: Morshead, Cindi M
Investigating the Practices of Literacy Teacher Educators

Investigating the Practices of Literacy Teacher Educators Doctor of Philosophy 2017 Belinda Longe Graduate Department of Curriculum, Teaching and Learning University of Toronto Abstract This research investigated the practices of six literacy teacher educators and explored the influences on their teaching practices in their literacy courses. This qualitative case study involved two interviews for each participant and classroom observations for some of the participants over a three-year period. Four main findings emerged from this research. First, participants’ vision for teaching, and their vision for teaching literacy was not static. The participants’ visions evolved over time and was influenced by their teaching and research experiences. Second, the participants emphasized continuous learning as an integral part of their vision, both for themselves and for their student teachers. They recognized that in their role as literacy teacher educators, a commitment to on-going learning was essential and fostering that commitment to life-long learning in their student teachers was equally important. Third, the participants had a range of pedagogical approaches that they implemented, although there were some approaches that were common across participants. Fourth, the participants focused on infusing components of balanced literacy into their literacy course and many drew on children’s and young adult literature as a springboard for teaching literacy concepts. The analysis of the data includes a discussion of the conceptual framework for the study and gives a brief overview of the interconnectedness of the concepts of social constructivism, vision for teaching literacy, and the elements of a pedagogy of teacher education. Implications for literacy teacher educators include developing literacy courses that aim to broaden student teachers’ notion of what counts as literacy. Other implications include encouraging literacy teacher educators to remain responsive and adaptive in their literacy teaching, and creating opportunities for literacy teacher educators to regularly review, participate, and conduct scholarly research in the field of literacy teacher education, which could inform and improve their practice.

Keywords: Literacy
Literacy Teacher Educators
Student Teachers
Teacher Education
Advisor: Kosnik, Clare M.
Generating Evidence to Streamline the Clinical Pathway in Autism Spectrum Disorder Using Simulation Models: Cost-effectiveness Comparisons of Screening and Genetic Testing Strategies

The clinical pathway to diagnosis in autism spectrum disorder (ASD) is complex. The objective of this thesis was to estimate the health and monetary impact of changes in the provision of select ASD screening and diagnostic health services. First, a meta-analysis estimated that the Modified Checklist for Autism in Toddlers, a commonly used ASD screening tool, performed at a low-to-moderate accuracy among children with developmental delay (pooled sensitivity: 0.83, 95% credible interval [CrI] 0.75, 0.90; specificity: 0.51, 95% CrI: 0.41, 0.61; positive predictive values [PPV] in high-risk children: 0.55, 95% CrI: 0.45, 0.66; PPV in low-risk children: 0.07, 95% CrI: <0.01, 0.16) and its performance changed with patient characteristics. The second study evaluated the cost-effectiveness of universal or high-risk screening compared to standard care, surveillance monitoring, in ASD using discrete event simulation. Results demonstrated that universal screening would greatly burden the healthcare system by heightening demand for diagnostic services and increasing healthcare expenditure. High-risk screening, on the other hand, could be a cost-effective strategy, yielding incremental cost-effectiveness ratios (ICERs) of $1100-1900/child initiated treatment or diagnosed earlier. The last study compared the cost-effectiveness of genome (GS) or exome sequencing (ES) to chromosomal microarray (CMA) using a microsimulation model. The use of ES in children with syndromic features after a negative CMA could be cost-effective compared to CMA alone (ICERs $5800-6000/child with pathogenic variant). If CMA was to be replaced by sequencing, GS would be the more cost-effective option. Findings from this thesis indicate that strategic resource allocation is crucial in ASD. Given the network of health, psychosocial and educational services required by individuals with ASD, changes in one component can have a large impact on the wait time, resource use and expenditure on downstream services that can affect children without ASD and extend beyond the healthcare system.

Keywords: Autism spectrum disorder
Health economics
Health services
Advisor: Ungar, Wendy J