VictorJuiz/thesis huggingface dataset:
Minding the Gap: Understanding the Experiences of Racialized/Minoritized Bodies in Special Education
Keywords: special education
minorities
learning disabilities
anti-racist discursive framework
critical race theory

The issue of special education in the United States has been a contentious issue, at best, for the past 40 years. In Ontario, to a lesser extent, there have been issues of equal access to education for minoritized and racialized students. Special education in the Toronto area has not been without its issues surrounding parental advocacy, the use of assessments, and disproportionate number of English Language Learners in special education. This project examines how racialized and minoritized families understand special education practices and policies, specifically within the Toronto, York, Peel, and Halton Regions. The investigation is informed by nine interviews with students in grades 7 to 12, their respective mothers, and five special education administrators and educators. Students and parents identified themselves as Black, Latino/a, and South Asian. Within these categories, parents identified themselves as Somali, Trinidadian, Jamaican, and Punjabi-Sikh. Students were identified with a range of disabilities including learning, behavioural, and/or intellectual. This research focuses on ways to interrogate and examine the experiences of minoritized students and their parents by bringing forward otherwise silenced voices and understanding what it means to “speak out” against the process of identification and placement in special education. The findings of this investigation suggest a disconnect how policies and practices are implemented, and how, parents’ rights are understood. In particular, policies are inconsistently applied and are subject to the interpretation of educators and administrators, especially in relation to parental involvement and how much information should be released to families. The issue of language acquisition being read as a disability was also a noted concern. This investigation points to implications for teacher education programs, gaps in parental advocacy and notions of parental participation within schools, and re-examining special education assessments, practices, and policies.
Requirements for Notch Signaling in Positive Selection and Effector Function of CD8 T Cells
Keywords: CD8 T cells
Notch signaling
thymus
OP9 cells

The generation of the cytotoxic CD8 T cell response is dependent on the functional outcomes imposed by the intrathymic constraints of differentiation and self-tolerance. Although thymic function can be partly replicated in vitro using OP9-DL1 cell cultures to yield CD8 αβ T cell receptor (TCR)-bearing cells from hematopoietic progenitor cells, a comprehensive and functional assessment of entirely in-vitro generated CD8 T cells derived from bone marrow hematopoietic stem cells (BM-HSCs) has not been established and remains controversial. Here we demonstrate that a phenotypic, molecular, and functional signature of in vitro-derived CD8 T cells is akin to that of ex vivo CD8 T cells. Transfer of in vitro-derived CD8 T cells into syngeneic and immunodeficient host mice showed no graft-versus-host response, while a robust homeostatic proliferation was observed, respectively. These findings, along with a diverse and broad TCR repertoire expressed by the in vitro-derived CD8 T cells, allowed for the successful generation of antigen (Ag)-specific T cells to be obtained from an entirely in vitro-generated CD8 T cell pool, which calls for further tailoring of their use against viral infections or malignancies. Furthermore, I demonstrate that Notch signaling regulates the expression of the cytolytic molecule Granzyme A in CD8+ T cells. This is supported by the inability of Notch-deprived TCR-signaled CD8 T cells to express Granzyme A, while CD8 T cells that received Notch signals readily expressed Granzyme A, suggesting that Notch signaling is a prerequisite for induction of this cytolytic molecule. We further demonstrate that Notch signaling by OP9 cells allows for efficient differentiation of conventional effector CD8 T cells from SAP-/- BM-derived HSCs and restricts differentiation of innate CD8 T cells while allowing for differentiation of IL17-producing CD8 T cells from BM-HSCs isolated from Itk-/-Rlk-/- (DKO) mice. Moreover, we reveal that the process of positive and negative selection in vitro is constrained by peptide-MHC (pMHC) class I expressed by the OP9 cells and disclose that the commitment of DP precursors to the CD8 T cell lineage is facilitated by Notch signaling. Our findings further establish the requirement for Notch receptor-ligand interactions throughout intrathymic T cell differentiation.
Deep Brain Stimulation of the Subthalamic and Entopeduncular Nuclei in an Animal Model of Tardive Dyskinesia
Keywords: deep brain stimulation
subthalamic
entopeduncular
tardive dyskinesia
haloperidol
serotonin
dopamine

Deep brain stimulation (DBS) has emerged as a potential intervention for treatment-resistant tardive dyskinesia (TD). Despite promising case reports, no consensus exists regarding optimal stimulation parameters, neuroanatomical target for DBS in TD, or mechanisms underlying its anti-dyskinetic effects. We used vacuous chewing movements (VCMs) in rats treated chronically with haloperidol (HAL) as a TD model to address some of these issues. We show that acute DBS applied to the subthalamic nucleus (STN) or the entopeduncular nucleus (EPN) suppresses VCMs without affecting locomotor activity. Using immediate early gene mapping with zif268 as an index of neuronal activity, we found that STN-DBS induced decreases in activity throughout the basal ganglia, whereas EPN-DBS increased activity in projection regions. While chemical inactivation of the STN or EPN with the GABAA agonist muscimol also suppressed VCMs, muscimol infusion did not mimic the changes in neuronal activity induced by DBS, suggesting that DBS is not equivalent to functional inactivation. We next examined the contribution of serotonin (5-HT) and dopamine (DA) to the anti-dyskinetic effects of DBS. Decreasing 5-HT transmission pharmacologically or with serotonergic lesions decreased VCMs. Using microdialysis and zif268 mapping, we determined that STN- but not EPN-DBS decreased 5-HT release and activity of raphe neurons. However, when the decrease in 5-HT induced by STN-DBS was prevented by pre-treating rats with fluoxetine or fenfluramine, we found that decreasing 5-HT is not necessary for the anti-dyskinetic effects of DBS. STN-DBS transiently increased striatal DA release in intact rats only, whereas EPN-DBS had no effect on DA release. Moreover, pharmacologically elevating DA levels did not suppress VCMs. Together these findings lead us to conclude that increased DA release does not contribute to the anti-dyskinetic effects of DBS. Finally, we compared depressive- and anxiety-like behaviours induced by chronic DBS of the EPN and STN, since adverse psychiatric effects of DBS have become a significant clinical concern. STN-DBS but not EPN-DBS induced depressive-like behaviour in a learned helplessness task. We established that the chronic HAL VCM model preparation may be used to explore mechanisms underlying anti-dyskinetic and psychiatric effects of DBS, and provided the first investigations into these mechanisms.
Aesthetics of Social Work: Governing Risky Spaces and Youth Subjects through Techniques of Visuality
Keywords: youth policy
social welfare

In the wake of a rescaling of national state welfare responsibilities, urban centres, like the city of Toronto, have become new governance sightlines for managing the deleterious effects of a globalised restructuring of capitalist economies. Toronto is now trafficking its multicultural and “creative city” flare in regional and global markets to secure capital investment necessary to float its newly acquired fiscal responsibilities, including welfare and social services provisioning. And a host of local private-public partnerships have appeared as “shadow state” actors to assist in the suturing of disenfranchised communities to the operative logics of neo-liberal governance and globalised city aspirations. Social welfare and urban studies literature has not been attentive to the increasing reliance on visuality and the “aesthetic” more broadly in securing these desired social and economic outcomes. My ethnographically based dissertation picks up this analytical slack by inciting a two-fold intervention: First, I hone in on the efficacious properties of visual images produced within 3 different social policy spaces and their presumed roles in constituting the domains of social interaction and production. This analysis illustrates that different policy crafting experts understand the “aesthetic” as a remunerative technology of governance - for regulating the problematics of socio-economic and racialised difference, and for mediating rifts in the social fabric as fallout from welfare retrenchment. Second, I examine the ways in which certain normativised aesthetic sensibilities connected to neoliberal urbanism serve as both a calculative resource for re-defining certain spaces and subjects as problematic and thus controllable, and an interpellative mechanism for assembling moralized subjects around the dictates of responsibility and (self) empowerment. The dissertation argues that although these aesthetic governance strategies are resulting in a depoliticisation of communities, and a moralised segregation of compliant and non-compliant subjects played out along racialised /economic lines, there exists a level of disruption transpiring in the spaces of policy implementation. In situ attention to these disruptions, layered with a reflexive analytical restaging of these events and a critical analysis of deployed governance strategies are proposed as a grounding for social work, research and social policy praxis.
Structural Investigation of Biological and Semiconductor Nanostructures with Nonlinear Multicontrast Microscopy
Keywords: Nonlinear Optics
Laser Scanning Microscopy
Semiconductor Nanowires
Starch Biocrystals
Second Harmonic Generation
Third Harmonic Generation
Polarization Harmonic Microscopy
Imaging Photosynthetic Structures

Physical and functional properties of advanced nano-composite materials and biological structures are determined by self-organized atoms and molecules into nanostructures and in turn by microscopic organization of the nanostructures into assemblies of higher structural complexity. Therefore, microscopes are indispensable tools for structural investigations at various levels of organization. In this work, novel nonlinear optical microscopy methods were developed to non-invasively study structural organization at the nanoscopic and microscopic levels. Atomic organization of semiconductor nanowires, molecular organization of amylose biocrystallites in starch granules, and microscopic organization of several photosynthetic organisms was elucidated. The structure of ZnSe nanowires, key components in many modern nanodevices, was investigated using polarization harmonic generation microscopy. Based on nonlinear optical properties of the different crystal lattices, zinc blende and wurtzite nanowires were differentiated, and the three-dimensional orientation of the zinc blende nanowires could be found. The structure of starch granules, a model biocrystal, important in food as well as health sciences, was also investigated using polarization harmonic microscopy. The study was combined with ab initio calculations using the crystal structures of amylose A and B, revealing that second harmonic signals originate from the hydroxide and hydrogen bonds in the starch granules. Visualization of several photosynthetic organisms including the green algae, Chlamydomonas reinhardtii, two species of cyanobacteria, Leptolyngbya sp. and Anabaena sp., aggregates of light-harvesting pigment-protein complexes as well as chloroplasts from green plants were also explored, revealing that future nonlinear microscopy applications could include structural studies of cell walls, the Chlamydomonas eyespot, and photosynthetic membranes. In this study, several nonlinear optical microscopy modalities were developed for quantitative structural investigations of nano and micro-sized architectures. Non-invasive extraction of crystallographic information in microscopic samples will have a number of potential benefits, for example, in clinical applications, allowing observations of disease states inside tissues without the need for biopsy. Industrial nanotechnology will benefit from fast determination of nanostructures with nonlinear microscopy that will improve quality of nanodevices.
Development, Characterization and Validation of Trastuzumab-Modified Gold Nanoparticles for Molecularly Targeted Radiosensitization of Breast Cance
Keywords: Gold Nanoparticles
Radiation Therapy
Imaging
Antibodies
HER2
Trastuzumab
Radiosensitizer
Breast Cancer
Radionuclide
Nanomedicine
Nanoparticles
Molecular Targeting

The overexpression of the human epidermal growth factor receptor-2 (HER-2) in 20-25% of human breast cancers was investigated as a target for development of a gold nanoparticle (AuNP) based radiosensitizer for improving the efficacy of neoadjuvant X-radiation therapy of the disease. HER-2 targeted AuNPs were developed by covalently conjugating trastuzumab, a Health Canada approved monoclonal antibody for the treatment of HER-2-overexpressing breast cancer, to 30 nm AuNPs. Trastuzumab conjugated AuNPs were efficiently internalized by HER-2-overexpressing breast cancer cells (as assessed by darkfield microscopy and transmission electron microscopy) and increased DNA damage from X-radiation in these cells by more than 5-fold. To optimize delivery of AuNPs to HER-2-overexpressing tumors, high resolution microSPECT/CT imaging was used to track the in vivo fate of 111In-labelled non-targeted and HER-2 targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and non-specific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to non-targeted AuNPs. This phenomenon could be attributed to Fc-mediated recognition and subsequent sequestration of trastuzumab conjugated AuNP by the reticuloendothelial system (RES). Blocking of the RES did not increase tumor uptake of either HER-2 targeted or non-targeted AuNPs. Following i.t. injection, our results suggest that Au-NTs redistribute over time and traffick to the liver via the ipsilateral axillary lymph node leading to comparable exposure as seen with i.v. administration. In contrast, targeted AuNPs are bound and internalized by HER-2-overexpressing tumor cells following i.t. injection, with a lower proportion of AuNPs redistributing to normal tissues. In vivo, the combination of HER-2 targeted AuNPs injected i.t. and X-radiation (11 Gy) yielded a 46% decrease in tumor size over a 4 month period in contrast to an 11.5% increase in tumor size for X-radiation treatment alone. Toxicology studies (evaluated through complete blood cell counts, by serum transaminase and creatinine measurements and by monitoring the body weight) demonstrated no apparent normal organ toxicity from the combination of HER-2 targeted AuNPs and X-radiation. These results are promising for the clinical translation of HER-2-targeted AuNPs for radiosensitization of tumors to X-radiation.
Examination of Age Differences in Incentive Motivation and Impulsivity as Possible Contributing Factors to a Susceptibility to the Effects of Drugs of Abuse during Adolescence
Keywords: adolescence
addiction
impulsivity
reward
nicotine
rat
sex differences
conditioned reinforcement
self-administration
dopamine
glutamate
amphetamine
opioid
NMDA
incentive motivation
DRL
5-choice
sucrose
age differences

Rationale. Adolescence may be a period of susceptibility to the effects of drugs of abuse. This vulnerability may result from a convergence of psychological processes that contribute to drug addiction including impulsive action and incentive motivation during adolescence. Objectives. I examined age differences in incentive motivation, as measured by responding for a conditioned reinforcer (CR) previously paired with natural or drug rewards, and age and sex differences in impulsive action, as measured by responding on a differential reinforcement of low rates of responding (DRL) schedule or premature responding on the 2-Choice Serial Reaction Time Test (2-CSRTT), in Sprague-Dawley rats. The effects of drugs that affect these behaviours in adulthood and that act on neurochemical systems still developing during adolescence were also examined. Methods. In a first set of experiments (Chapter 3), I compared male adolescents and adults on responding for a CR previously paired with sucrose and the effect of amphetamine on this behaviour. In a second set of experiments (Chapter 4), I examined age differences in responding for a CR previously paired with passive or self-administered intravenous (IV) nicotine infusions. Subsequently, I investigated age and sex differences in responding on a DRL schedule in response to amphetamine (Chapter 5) and 2-CSRTT performance in response to amphetamine, nicotine and Ro 63-1908 (a glutamate N-Methyl-D-aspartic acid [NMDA] receptor subunit antagonist; Chapter 6). Results. Compared to adults, adolescents responded more for a CR previously paired with sucrose or passive, but not self-administered, IV nicotine infusions. Amphetamine only enhanced responding for a CR previously paired with sucrose. Adolescents responded more than adults on a DRL schedule, while adolescents made the most premature responses in the 2-CSRTT. No consistent sex differences were observed during the acquisition of either behaviour. Amphetamine increased premature responding most in adolescent males and adult females in the 2-CSRTT but not in responding on the DRL schedule. No consistent age or sex differences were observed for Ro 63-1908 or nicotine. Conclusions. Adolescents show enhanced impulsivity and incentive motivation than adults depending on the behavioural measure. Dopamine may contribute to age and sex differences in these behaviours.
Role of the Catecholamine and Limbic Systems in Narcolepsy/Cataplexy
Keywords: Narcolepsy
Cataplexy
Sleep
Amygdala
Dopamine
Noradrenalin

In this thesis I investigated the neural circuits that trigger cataplexy in mice. Specifically, I first addressed the theory that cataplexy is a REM sleep disorder. I then investigated a role for the noradrenergic and dopaminergic systems in murine cataplexy. Finally, I addressed the role of the amygdala in triggering cataplexy. From this work several specific conclusions can be drawn: 1. Cataplexy does not share a common executive mechanism with REM sleep, although the two may share a common mechanism that generates muscle atonia. Muscle tone during REM sleep and cataplexy is similar, however increasing REM sleep pressure does not increase cataplexy and positive affective stimuli that can increase cataplexy tend to decrease REM sleep. 2. Systemic manipulation of dopamine receptors can modulate cataplexy without affecting behavioral state. Specifically, manipulation of D2-like dopamine receptors at specific doses can modulate cataplexy while having no affect on sleep-wake state or sleep attacks, and manipulation of D1-like receptors potently affects sleep-wake state and sleep attacks without affecting cataplexy. 3. Systemic modulation of noradrenergic activity in orexin KO mice is sufficient to modulate cataplexy. Specifically, activation of excitatory α1 receptors reduces the occurrence of cataplexy while blockade of these receptors exacerbates it. 4. Withdrawal of an endogenous α1-mediated noradrenergic drive from motor neurons during wakefulness contributed to the loss of muscle tone during cataplexy. Re-establishing this excitatory drive exogenously alleviated cataplexy-dependant muscle atonia. 5. The amygdala is a critical part of the neural mechanism that triggers cataplexy in orexin KO mice. Ablation of the amygdala resulted in significant decreases in both baseline cataplexy and emotionally-induced cataplexy. The amygdala may trigger cataplexy through direct projections to brainstem areas that regulate muscle atonia.
Verdazyl Radicals as Substrates for Organic Synthesis
Keywords: verdazyl
radical
cycloaddition
heterocycle
rearrangement

Verdazyl radicals, discovered in 1963, are a family of exceptionally stable radicals defined by their 6-membered ring containing four nitrogen atoms. Verdazyl radicals are highly modular compounds with a large assortment of substitution patterns reported. Their stability and high degree of structural variability has been exploited in the fields of materials, inorganic, polymer and physical chemistry; however their deliberate use as starting materials towards organic synthesis had only been reported in recent years by the Georges lab. In 2008, the Georges group reported a disproportionation reaction that was observed to a occur with 6-oxoverdazyl radicals resulting in azomethine imines capable of undergoing 1,3-dipolar cycloaddition reactions. With this discovery, the door to using verdazyl radicals as substrates towards organic synthesis had been opened. Their utility in synthesis was soon discovered not to be limited to just the cycloadducts their azomethine imine derivatives could generate but also the increasing number of N-heterocycles that could be generated from these cycloadducts via unique rearrangement reactions, a major theme of this thesis. In addition, triphenyl verdazyl radicals, a distinct class of verdazyl radicals, has been shown to react with alkynes by direct radical addition and rearrangement to afford isoquinolines. As part of this thesis, a new synthetic methodology of generating 6-oxoverdazyl radicals is reported that does not rely on the use of phosgene or hydrazines. This new synthesis allows for the expansion of available alkyl substituents possible on N1 and N5 positions of 6-oxoverdazyl radicals, as well as, generation of unsymmetrical examples of 6-oxoverdazyl radicals with non-identical N1 and N5 alkyl substituents. Employing the new 6-oxoverdazyl radicals synthesized via this method, a study on the effects of different alkyl substituents on the disproportionation reaction of 6-oxoverdazyls was undertaken. Lastly, given the assortment of N-heterocyclic molecular scaffolds capable of being synthesised starting from verdazyl radicals as precursors, the applicability of verdazyl radicals in making a diversity oriented synthesis (DOS) based library was explored. In a group effort with other Georges lab members, a small library composed of various classes of verdazyl radical derived compounds was synthesized and non-specifically tested for cytotoxicity against acute myeloid leukemia and multiple myeloma cell lines in collaboration with The Princess Margaret Hospital. One example was shown to effectively kill cancer cells in both these lines in 250 μM concentration pointing out the potential of using verdazyl radical based chemistry in drug discovery.