VictorJuiz/thesis huggingface dataset:
Essays on Immigrant Mental Health: A Look at Health Reporting, Model Identification, and Policy Changes

Upon arrival to the host country, immigrants are, on average, physically healthier than the native-born population; however, it is unclear whether this health benefit extends to mental health or whether it applies to recent immigrant cohorts. This thesis seeks to understand the healthy immigrant effect with regards to mental health, by examining aspects of mental health reporting and immigrant mental health using both survey and administrative health data. The first chapter explores the potential role of stigma in mental health reporting by combining survey data, which may be subject to reporting biases, and administrative health data, an alternative source of data, which may be more objective. Results suggest that underreporting may be highest for the most stigmatizing conditions, such as schizophrenia and self-harm, followed by mood disorders, and lowest for physical health conditions, such as cancer and diabetes. The second chapter attempts to disentangle the role of length of stay, period, and cohort in explaining the healthy immigrant effect in mental health as measured by poor mental health and the presence of mood and/or anxiety disorders. Accounting for length of stay, period, and cohort effects is necessary to avoid biased results. Using orthogonal polynomial parameterization in the model, results suggest that period effects are insignificant and thus do not play a role in explaining immigrant mental health. Furthermore, mental health appears to decline the longer immigrants remain in Canada in the survey data, but not in the administrative data. These data sources may be measuring different aspects of health and health care utilization. The third chapter explores the presence of cohort effects in immigrant mental health by evaluating the impact of three policy changes associated with increasingly strict language requirements and applied differentially to cohorts of recent immigrants in each visa class. Results show that mental health care utilization decreased for immigrants who were most impacted by the policy compared to long-term residents, particularly following policies that coincided with periods of increased English proficiency as an entry requirement. This suggests that language proficiency may be associated with one’s own mental health and/or ability to access health care.

Keywords: Administrative health data
Healthy immigrant effect
Immigrant
Language proficiency
Mental health
Self-report data
Advisor: Laporte, Audrey
Methacrylic Acid Based Hydrogels for Enhanced Skeletal Muscle Regeneration

Skeletal muscles make up 40-50% of the human body’s mass and are used in most daily activities. While muscles have a remarkable ability to regenerate following small injuries, massive loss of muscle tissue, termed volumetric muscle loss (VML), results in the formation of scar tissue and persistent loss of function. The current treatment for these injuries, autologous tissues grafts, suffers from limited availability, donor site morbidity, infection, and necrosis. A novel method of enhancing skeletal muscle regeneration is through regenerative biomaterials, such as those containing methacrylic-acid (MAA). MAA-based materials have been found to promote wound healing, new vessel formation, and macrophage polarization; however, MAA has yet to be studied outside the skin. The goal of this thesis was to expand the applications of MAA-based materials from beyond the skin into skeletal muscle. In the first aim, the effects of MAA-poly(ethylene glycol) (MAA-PEG) hydrogels on immune cell recruitment and macrophage polarization were examined. Non-degradable hydrogels were found to damage muscle. Thus, degradable hydrogels with degradation rates of either 2 (fast-degrading) or 7 days (slow-degrading) were synthesized. When injected into the tibialis anterior muscle of mice, both slow and fast degrading hydrogels increased the expression of Tnfα, Il10, and pro-regenerative M2 macrophage markers. Moreover, the slow degrading hydrogel decreased the number of pro-inflammatory MHCII+ macrophages. An unbiased t-distributed stochastic neighbor embedding (tSNE) analysis suggested the involvement of additional immune cells (e.g., dendritic cells) in the effect of MAA on skeletal muscle. In the last aim, the ability of MAA-PEG and MAA-collagen hydrogels to promote functional regeneration after a VML injury was evaluated. The MAA-collagen hydrogel increased muscle regeneration both morphologically and functionally. Treatment with this hydrogel also enhanced vascularization and innervation of the injured muscle. These effects were attributed to the hydrogel’s immunomodulatory function as it reduced the recruitment of pro-inflammatory M1 macrophages (MHCII+CD206-). Moreover, the regenerative ability of MAA depended on the carrier material: the MAA-PEG hydrogel did not show the same regenerative potential in this context. It is hoped that the MAA-collagen hydrogel could be a simple treatment to restore muscle function to patients who would not otherwise recover.

Keywords: Hydrogel
Macrophage Polarization
Methacrylic Acid
Regenerative Medicine
Skeletal Muscle
Tissue Enginering
Advisor: Sefton, Michael V
The Kusamala Program for Primary Caregivers of Children with Severe Acute Malnutrition in Malawi

Children with severe acute malnutrition (SAM) with clinical co-morbidities who require nutritional rehabilitation unit (NRU) treatment are prone to poor long-term developmental and nutritional outcomes. The Kusamala Program is a four-day hospital-based counselling program for caregivers of children with SAM that integrates nutrition, water, sanitation and hygiene, and psychosocial stimulation, aimed at improving these outcomes. The objective of this research was to evaluate the effects of the Kusamala Program on child development and nutritional status in children with SAM six months after NRU discharge. Furthermore, we aimed to qualitatively understand perceptions and experiences of caregivers of children with SAM who participated in the intervention. We conducted a cluster-randomized controlled trial with caregivers and their children 6-59 months of age with SAM admitted to the Moyo NRU in Blantyre, Malawi. The primary outcome of the trial was child development according to Malawi Developmental Assessment Tool (MDAT) composite z-scores of gross motor, fine motor, language, and social domains. A qualitative component with focus group discussions and in-depth interviews was also completed with a subset of caregivers who participated in the trial. Sixty-eight caregivers and children were enrolled to clusters by week and randomized to the comparison arm and 104 to the intervention arm. There were no differences in child development, with mean MDAT composite z-scores in the comparison arm of -1.2 (95% CI: -2.1, -0.22) and in the intervention arm of -1.1 (95% CI: -1.9, -0.40) (p=0.93). The qualitative evaluation with 20 caregivers indicated that the three modules of the Kusamala Program were appropriate and that caregivers applied many of the lessons learned at home. In conclusion, the Kusamala Program did not result in improved developmental or nutritional outcomes, yet it was viewed positively by caregivers according to qualitative results. Future research should evaluate more intensive interventions for caregivers and children with SAM.

Keywords: child development
nurturing care framework
nutrition
psychosocial stimulation
SAM
severe acute malnutrition
Advisor: Bandsma, Robert HJ
The Glial Response to Focused Ultrasound-mediated Permeabilization of the Blood-brain Barrier: Evaluating the Potential Contribution of Microglia and Astrocytes to Pathology and Regeneration

Focused ultrasound in the presence of intravenous microbubbles (FUS) facilitates the non-invasive temporary permeabilization of the blood-brain barrier (BBB) for delivering therapeutics to the brain. FUS-mediated BBB modulation is known to activate microglia and astrocytes, which can exacerbate pathology or promote neuroprotection. I hypothesized that FUS induced a transient activation of microglia and astrocyte that is consistent with pro-regenerative functions. Firstly, I developed a method, MORPHological assessment of Outlier clusters (MORPHIOUS), to quantify microglial and astrocytic activation. MORPHIOUS is a machine learning tool that detects clusters of activated glia in histological sections by referencing control sample cell morphologies. As validation, identified clusters of activated microglia and astrocytes exhibited hallmark morphological and marker changes. Indeed, activated microglia were deramified and upregulated transforming growth factor beta 1 (Tgfβ1), and activated astrocytes were hypertrophic and expressed nestin. MORPHIOUS can therefore sensitively detect activated glia. Secondly, I used MORPHIOUS to characterize microglial and astrocytic activation from 1 to 30 days (D) post-FUS. Microglial activation peaked at 1D and was progressively attenuated between 4D and 30D post-FUS. Activated microglia predominantly colocalized with Tgfβ1, indicative of anti-inflammatory and neuroprotective functions; but not with the inflammation-associated cluster of differentiation 68. Astrocytic activation peaked at 4D and was significantly attenuated by 30D post-FUS. Activated astrocytes did not significantly proliferate or upregulate glial scar components. Thus, post-FUS glial activation was transient, and not indicative of pathology. Thirdly, to evaluate the regenerative potential of the brain environment post-FUS, I characterized neural progenitor cell (NPC) proliferation and oligodendrogenesis. NPC proliferation increased between 4D and 7D post-FUS and coincided with the activated astrocytic upregulation of insulin-like growth factor 2. Moreover, an increased proliferation of oligodendrocyte progenitors increased between 1D and 4D, promoted the number of newly developed oligodendrocytes at 30D. Therefore, post-FUS glial activation is permissive of broader brain regenerative programs. Collectively, this data supports my hypothesis by demonstrating that the FUS-mediated activation of microglia and astrocytes is transient, upregulates regenerative factors, and occurs alongside enhanced neurogenesis and oligodendrogenesis. This work positions FUS-mediated BBB permeabilization as a promising component of multimodal therapies, with potential to aid in the treatment of neurodegenerative disorders.

Keywords: Astrocytes
Blood-brain barrier
Brain Regeneration
Focused Ultrasound
Machine Learning
Microglia
Advisor: Aubert, Isabelle
Viral Infectivity Factors of Human Immunodeficiency Viruses: Functional Convergence Through Structural Divergence

The human immunodeficiency virus (HIV) causes the acquired immunodeficiency syndrome. Both HIV type 1 (HIV-1) and HIV type 2 (HIV-2) viruses encode for a powerhouse protein named viral infectivity factor (Vif). The HIV Vif encodes for several functionalities that are collectively aimed at disarming an immunological pathway in humans. The apolipoprotein B mRNA-editing catalytic polypeptide-like 3 (APOBEC3/A3) proteins embody this immunological pathway through their nucleic acid mutator activities that inactivate viral genomes. The HIV Vif is the “annihilator” of A3 proteins, since Vif is an E3 ubiquitin ligase substrate receptor that targets A3 proteins for poly-ubiquitination and degradation. The HIV Vif mediates its functionalities through structural determinants located in N- or C-terminal domains. The Vif C-terminal domain interfaces with Elongin B-Elongin C complex (EloB-EloC), and Cullin 5 (Cul5). Vif interactions with EloB-EloC and Cul5 link Vif to the ubiquitination machinery. The Vif N-terminal domain interfaces with A3 proteins using determinants unique to each A3 protein. For a VifN-term-A3 interface to form, Vif conformations need be stabilized via interactions with another protein called core-binding factor β (CBFβ). VifN-term-CBFβ interactions enhance Vif stability and are indispensable for other Vif-protein interactions. The HIV Vif protein acts as a structural hub that nucleates protein-protein interactions required for targeting A3 proteins. The present dissertation employed biochemical, biophysical, and structural methods to study structure-function relationships of HIV-1 and HIV-2 Vif proteins. HIV-1 and HIV-2 viruses have disparate evolutionarily histories and their respective Vif proteins have divergent sequences. Functionally, HIV-1 and HIV-2 Vif have converged (since both target A3 proteins). Structurally, we have begun to discover their differences. In the present dissertation, we generated the first soluble HIV-2 Vif species suitable for in vitro and structural studies. Additionally, we studied Vif-CBFβ, Vif-A3, Vif-Cul5, Vif-[EloB-EloC] and Vif-Vif interactions for HIV-1 Vif and/or HIV-2 Vif. We attempted crystallographic and microscopic studies of various Vif species and made key advances. Notably, we have now initiated cryo-electron microscopic studies of a self-associating HIV-2 Vif-CBFβ-EloB-EloC-Cul5 pentameric complex. Collectively, our studies revealed that HIV-1 and HIV-2 Vif proteins evolved divergent structures that bring about the same ultimate outcome – eliminating human A3 proteins.

Keywords: APOBEC
biophysics
HIV
protein-protein interactions
structural biology
viral infectivity factor
Advisor: Lee, Jeffrey E JEL
Phage Display for the Development of Synthetic Antibodies Targeting Receptor Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are single-pass transmembrane receptors that drive the growth and development of human tissue from embryo to adult. Overexpressed RTK family members are present on the surface of cancer cells, making them susceptible to targeting by therapeutic IgGs, molecules that exhibit high affinity and specificity, the ability to recruit the immune system, and the ability to disrupt RTK signaling. Two RTK sub-families, the Eph and ErbB families, have previously been linked to cancer development and progression. Epidermal growth factor receptor (EGFR), the first RTK discovered and a member of the ErbB family, has been extensively validated as tumourigenic and has been the target of four approved therapeutic IgGs. Unfortunately, resistance to existing therapies is common and occurs in 70-90% of patients. Conversely, the Eph receptor family, represented by EphA2 and EphA3 in this study, has been suggested to be either oncogenic or tumour-suppressive, and lacks approved therapeutics. The goal of this project was to examine the epitope-specific effects of these receptors through targeting with high affinity IgGs. I constructed RTK-biased phage-displayed Fab libraries and utilized them to develop hundreds of antibody clones, which were screened for optimal therapeutic and research characteristics. In the first data chapter, I describe the development of anti-Eph receptor IgGs and accompanying proliferation experiments on pancreatic and ovarian tumour cell lines expressing EphA2 and EphA3. I show that cellular Eph receptor context is critical in determining the pharmacological and proliferative response to Eph receptor antagonism, where co-targeting of EphA2 and EphA3 is the most effective therapeutic modality for the treatment of cancers expressing both receptors. In the second data chapter I present the development of two anti-EGFR IgGs, one that targets the same domain as all approved IgG therapeutics, and one that targets a novel epitope. Both IgGs are effective at reducing the proliferation of EGFR-expressing cancers. Importantly, I show that the two IgGs have non-identical anti-proliferative profiles in vitro, revealing a new modality for the treatment of EGFR-positive tumours. My work demonstrates the utility of phage display for the development of IgGs and the therapeutic potential of epitope-specific targeting of RTKs.

Keywords: Antibody
Cancer
Immunotherapy
Phage Display
Protein Engineering
Receptor Tyrosine Kinase
Advisor: Sidhu, Sachdev S
Boone, Charles M
Towards the Development of Preclinical Models and Subtype-Specific Therapeutics for Atypical Teratoid Rhabdoid Tumors

Atypical Teratoid Rhabdoid Tumor (ATRT) is a rare, devastating and largely incurable pediatric brain tumor diagnosed early in childhood. Use of intensive, high-dose chemotherapy and/or craniospinal irradiation has improved short-term survival for some patients, however, long-term survival rates remain dismal with 70-75% of children succumbing to their disease. Poor survival outcomes and treatment toxicity necessitate targeted and more efficacious therapeutics for children suffering from this disease. Genetic characterization of primary tumors has revealed that in addition to SNF5 loss of function, ATRTs comprise three molecular subtypes that differ at the level of global gene expression as well as DNA methylation, and are found in distinct anatomical compartments. In this thesis we describe the generation of a genetically engineered mouse model that recapitulates the spatial pattern of human disease upon targeted loss of Snf5 to putative cells of origin using the Cre lox recombination strategy (Chapters 1-4). We have also developed a robust drug screening strategy that employs a rigorous dose assessment methodology for high throughput analysis of a library of 477 kinase inhibitors against a panel of subtyped ATRT cell lines (Chapters 5-8). Using this methodology, we identified multiple kinase inhibitors which demonstrate therapeutic benefit in Group 2a/b ATRT. Numerous kinase targets showed subtype-specific expression, among which is ERBB2 that is exclusively expressed in Group 2a and Group 2b ATRTs. More broadly, we found that ATRT cell lines are highly sensitive to PI3K and MAPK signaling blockade, and that combinatorial inhibition of these signaling pathways acts synergistically to reduce cell viability. Lastly, we combined our drug screening strategy with radiation treatment and found that the multikinase inhibitor, dasatinib and MTOR inhibitors, rapamycin, everolimus and temsirolimus are capable of sensitizing Group 2a/b cells to radiation. This thesis work advances ATRT research on two important fronts: the much-needed development of preclinical models and the identification of novel, subtype-specific therapeutics.

Keywords: ATRT
Drug Screening
Genetics
Mouse Models
Radiation
Synergy
Advisor: Rutka, James T
Women Workers Behind the AI Revolution: The Production and Reproduction of Data Annotation Platforms

This thesis examines women’s conditions of work and social relations within transnational data annotation platforms, focusing on the gendered and racialized dynamics in this platform work. The proliferation of the Artificial Intelligence (AI) industry and machine learning companies fundamentally rely upon human labour of data annotation. The potential of platform technologies occupies the heart of debates on digitally mediated work and the disruption of traditional norms of workplaces and employment. The study focuses on the experiences of women who form a substantial part of the data annotation workforce. The labour force for this low-wage, piece work is primarily home-based workers in Global South countries, and India has emerged as a significant location for this work. As a feminist scholar, I center my attention on women’s lives and experiences, revealing the gendered and racialized dimensions of platform work and challenging typical notions of freedom, inclusion, and an available workforce. This qualitative study draws on field visits, arts-informed methods, and semi-structured interviews with home-based women data annotators living in India. The study also draws on interviews with key informants, including union organizers, and document analysis of State policy and platform company contracts. The study examines how platforms reproduce women’s proletarianization and diminish their political power inside the family. The study contributes to debates on worker organizing in the platform economy, adding dimensions of informal organizing amongst women data annotators in India and the possibilities of expanding the organizing agenda for platform work towards a more collective working-class struggle against the capitalist political economy.

Keywords: automation
data annotation
home-based work
Indian labour market
platform labour
women workers
Advisor: Mirchandani, Kiran
Partitioning and biodegradation of diethylenetriamine (DETA) and metal-DETA chelates, and their predicted behaviour in tailings management areas

Pyrrhotite (Po) is an unwanted mineral with low economic value which dilutes valuable mineral streams and contributes significantly to SO2 emissions during smelting. The most effective pyrrhotite rejection method is by using chelating agents, such as diethylenetriamine (DETA), during flotation. DETA improves the concentrate grade; however, its use results in stable chelates between DETA and metal ions: nickel and copper. Once in the tailings management area, DETA-metal chelates cannot be removed by hydroxide precipitation. DETA mobilizes the metal ions through the treatment area and into the environment, which is detrimental to the local flora and fauna.To effectively assess the implications of DETA in a mine tailings management area, DETA must be reliably detectable. An analytical method for DETA detection method was developed using cation exchange chromatography with conductivity detection without the need for preconcentration or derivatization. The limits of detection and quantification were 0.002 and 0.005 mM, respectively, in deionized water samples. This method also proved effective to detect DETA chelated with metals such as nickel and copper. The behaviour of DETA was modeled in a theoretical tailings management area using experimental sorption data along with geochemical modelling using OLI Studio software to 1) predict the concentration of DETA, Cu-DETA, and Ni-DETA in final effluent and 2) ascertain if copper and nickel concentrations would be expected to exceed regulated limits. Operational parameters were investigated to ascertain their influence on the model outputs. In all cases, except the case for dry stacking the DETA containing tailings, the concentration of metal in the final effluent exceeded regulated limits. These results strongly indicate the necessity for a DETA mitigation strategy. This thesis investigates the potential of biodegradation of DETA and metal-DETA chelates using a mixed bacterial culture. Cation and anion ion chromatography results were used to track the DETA degradation progress by measuring DETA, ammonium, and succinate concentrations. The biomass generated by the degradation process was observed using microscopy, quantified using qPCR, and bacteria genera were identified using 16S rRNA sequencing. Evidence of complete DETA degradation in the presence of an external energy source, succinate, was demonstrated for unchelated DETA and for Ni-DETA. DETA was demonstrated to be a nitrogen source.

Keywords: Biodegradation
Bioremediation
Chromatography
Diethylenetriamine
Pyrrhotite
Advisor: Bobicki, Erin R