VictorJuiz/thesis huggingface dataset:
Inhibition of Oxidation-Induced Misfolding of Mutant SOD1 in ALS using Small Molecules

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neurons resulting in progressive paralysis that eventually leads to the death of an afflicted individual. In a majority of ALS cases, the cause of onset is unknown, but a small subset of ALS cases are linked to mutations in the protein Cu, Zn superoxide dismutase (SOD1). Despite extensive research in this area, few treatments for ALS have been developed. Since the description of the disease by Jean-Martin Charcot in the mid-nineteenth century, only one drug, Riluzole has been approved in the management of this disease. We propose investigating therapeutic treatments of ALS by looking for small molecules that have the potential to stabilize the native structure of mutant SOD1 and prevent its misfolding and aggregation. We started our investigation by first devising a method to optimize the purification of wildtype and mutant SOD1 in our lab. We constructed a fusion protein of SOD1 linked to a yellow fluorescent protein, a hexahistidine tag, and a tobacco etch virus (TEV) cleavage site and showed that both wildtype and mutant SOD1 purified from this construct was active and metallated. We used our purified protein to explore the results of an in silico binding screen searching for SOD1 native-state binders. We discovered the flavonoid, epigallocatecin-3-gallate (EGCG) was able to inhibit the misfolding and aggregation of the ALS-causing mutation A4V-SOD1 exposed to oxidative stress. Additionally, we have evidence that the inhibitory effect of EGCG occurs through the stabilization of the dimer interface of mutant SOD1, rather than the anti-oxidant properties of this molecule. This is the first report of EGCG having anti-aggregation properties in an ALS model and these results implicate the potential therapeutic value of EGCG within the field of SOD1-ALS.

Keywords: ALS
EGCG
SOD1
Advisor: Chakrabartty, Avijit
Bispecific Radioimmunoconjugates for Molecular Imaging and Radioimmunotherapy of HER2 Overexpressing Breast Cancer

The HER2 receptor is overexpressed in approximately 20% of breast cancer (BC) cases, and is the target for multiple therapies. One challenge in treating HER2+ BC is that a large proportion of patients demonstrate resistance to therapy. Upregulation of other members of the HER family, plays an important role in resistance to HER2-targeted therapies. The hypothesis was that bispecific radioimmunoconjugates (bsRICs) developed against HER2 and another member of the HER receptor family would be able to successfully target cells expressing one or more receptor for molecular imaging and radioimmunotherapy of BC. Trastuzumab Fab fragments were conjugated to heregulin (HRG) or epidermal growth factor (EGF) with a 24-mer polyethylene glycol (PEG) linker, and labeled with 111In or 177Lu. 111In-DTPA-Fab-PEG24-HRG and 111In-DTPA-Fab-PEG24-EGF demonstrated the ability to specifically bind to one or both receptors on cancer cell lines, and demonstrated higher binding than monospecific agents recognizing HER2, HER3 or EGFR. SPECT imaging was performed on mice bearing tumour xenografts, and optimal tumour uptake was found 48 hr after injection. Biodistribution studies showed tumour: blood uptake ratios of 6-8. The cytotoxicity of 111In-DTPA-Fab-PEG24-EGF and 177Lu- DOTA-Fab-PEG24-EGF was evaluated through clonogenic assays which revealed specific cell killing. Radiation absorbed doses to tumours and normal tissues were estimated and compared for 111In and 177Lu-labeled bsRICs. The maximum injected amount of 177Lu-DOTA-Fab-PEG24-EGF which caused no observable adverse effects (NOAEL) was identified to be 11.1 MBq. Mice bearing trastuzumab-sensitive or resistant tumours were treated with 111In and 177Lu-labeled bsRICs and 177Lu-bsRICs were found to inhibit tumour growth more effectively than 111In-bsRICs due to a 9.3-fold higher radiation absorbed dose (55.0 vs. 5.9 Gy, respectively). These results suggest that bsRICs may be useful for imaging and radioimmunotherapy of HER2-positive BC co-expressing HER3 or EGFR. Co-expression of these receptors in HER2+ tumours is associated with resistance to HER2-targeted therapies.

Keywords: Bispecific Antibodies
Breast Cancer
HER2
Nuclear Imaging
Radioimmunotherapy
Trastuzumab
Advisor: Reilly, Raymond M
Coming Full Circle - The Lifelong Journey of Becoming: An Exploration of Resilient Processes and Outcomes among Aboriginal Crown Wards of the Ontario Child Welfare System

Abstract Research on cultural identity clearly indicates that a healthy cultural identity is associated with positive outcomes including increased self-esteem, increased academic achievements, and higher reports of satisfying family interactions. This retrospective study explored the perceptions of culture, identity, and resilience among Aboriginal former Crown Wards of the Ontario government. Each participant in this research study reflected on the influence of their experiences of intergenerational trauma and being a Crown Ward in the development of their cultural identities. Overall findings indicate the importance of spirituality, culture, having purpose and meaning in life and acceptance of multiple identities, as they are critical elements of resiliency processes for former Aboriginal Crown Wards.

Keywords: Aboriginal
child welfare
culture
identity
qualitative
resilience
Advisor: Fallon, Barbara A.
Augmenting Probabilistic Matrix Factorization Models for Rare Users

Recommender systems are used for user preference prediction in a variety of contexts. Most commonly known for movie suggestion from the Netflix competition, these systems have evolved to cover generic product recommendation, friend suggestion, and even online dating. Matrix Factorization is a common model employed for several reasons. Among them, they scale well, are easily learned, and can be adapted to different contexts. Many extensions of the baseline Probabilistic Matrix Factorization model have been proposed in the literature, and as expected, all perform better than the baseline with reported test results. We review several of these extensions, notably: constraints based on similar rating patterns among users, allowing for nonconstant variance / precision in the model, introducing personal information on the users as constraints, and including user networks in the model. These models are extended to the Bayesian framework where necessary. We illustrate how these extensions perform overall, and for sets of users defined by different number of ratings at training time. In particular, we highlight the benefit of many of these extensions for infrequent users (those with few or no ratings in the system). This is particularly important as these users are the most common in the recommendation framework. In the case of user networks, we additionally study the robustness of the model in the presence of random links. This reflects the true state of user networks in applications such as Facebook, where social ties may not convey similar taste in preferences. In addition, we provide the first direct comparison of the performance of the models learned from Gibbs sampling and variational inference. Limitations of the variational algorithm are outlined for multiple models, with proposals given for alleviating overfitting.

Advisor: Salakhutdinov, Ruslan
Different But Equal? A Developmental Analysis of Variability in Adolescents' Understandings of Social Justice

Coming of age in an increasingly diverse social world, contemporary youth must make sense of the complexities of social differences and the disparities that exist between privileged and marginalized groups. This mixed methods study had two main objectives: (1) to examine adolescents’ understandings of social justice through their social awareness and perspective taking in the areas of racism, sexism, and classism; and (2) to assess whether these understandings varied as a function of cognitive (critical thinking, moral judgment) and affective (empathy) skills. Ninety-eight adolescents in Grades 9 and 12, evenly divided by sex, race/ethnicity, and socioeconomic status, completed a questionnaire measuring their awareness of social (in)justice in society at large and also participated in a semi-structured interview designed to assess their perspective-taking in hypothetical peer conflicts depicting these problems. Results showed that adolescents were moderately aware of social injustice overall, demonstrating greatest awareness of classism and least awareness of sexism. Qualitative analyses of interview responses revealed five levels of perspective taking, signifying increasingly mature interpretations of group differences. On average, participants assumed a `nominal` perspective that was naïve to social disparities and emphasized concerns about ‘equality’ over ‘equity’. Perspective taking was most sophisticated in the area of racism and least regarding sexism. Variability was also observed across grade, social location, and cognitive and affective skills. As expected, older adolescents demonstrated more mature understandings of social justice than younger adolescents. Furthermore, age-related differences were larger among adolescents attending higher SES schools. Minority youth showed greater awareness of racism than majority participants. Females demonstrated more mature understandings of sexism than males, and adolescents attending higher SES schools showed more mature understandings of classism than their lower SES counterparts. In addition, controlling for the effects of grade moral judgment predicted both social awareness and perspective taking, having the greatest effect in the area of classism and weakest in the area of sexism. Similarly, adolescents’ empathy levels predicted perspective taking in the area of sexism. These findings underline the importance of fostering adolescents’ understandings of social justice for the development of attitudes and behaviours that promote equity among all members of society.

Keywords: Adolescence
Adolescent Development
Adolescent Social Cognition
Awareness
Social Justice
Social Perspective Taking
Advisor: Arnold, Mary Louise
Exploring the Relationships among Attachment, Emotion Regulation, Differentiation of Self, Negative Problem Orientation, Self-esteem, Worry, and Generalized Anxiety

This study attempted to provide preliminary empirical support for an emerging model of generalized anxiety disorder (GAD) stemming from an emotion-focused therapy (EFT) perspective, which views GAD as reflecting negative self-organizations and emotion dysregulation as a function of attachment injuries (Watson Greenberg, in press). It has done so by examining negative early attachment experiences and attachment styles, as representing attachment injuries; differentiation of self, negative problem orientation, and self-esteem, as representing negative self-organization; and emotion dysregulation, and by investigating the relationships among these variables and their contribution to generalized anxiety and worry. Following on suggestion of previous research (Ruscio, 2002; Ruscio Borkovec, 2004; Ruscio et al., 2001) indicating that worry, while characteristic of GAD, exists independently of GAD and therefore would benefit from being studied in its own right, this study examined worry and generalized anxiety separately. Cross-sectional data was collected from 218 participants who completed self-report questionnaires assessing demographics and variables of interest. Results indicated that negative early attachment experiences are significantly and positively related to generalized anxiety and worry. Findings from correlational analysis demonstrated that negative early experiences with fathers were associated with worry in adulthood whereas negative early experiences with both parents as well as perceptions of unfair family interactions were related to generalized anxiety symptoms. Multiple mediation analysis using PROCESS (Hayes, 2012) revealed a different pattern of mediation for insecure adult attachment and worry than for insecure adult attachment and generalized anxiety. Negative problem orientation and differentiation of self mediated the relationship between insecure adult attachment and worry, whereas negative problem orientation and self-esteem mediated the relationship between insecure adult attachment and generalized anxiety. Implications of these findings for the understanding of GAD are discussed.

Advisor: Watson, Jeanne C
From Plant Properties To Forest Function In Temperate Mixed Angiosperm-conifer Old Growth

Ecosystem functions are the processes that cycle matter among vegetation, soils and the atmosphere. These processes are conventionally modelled as the physiological response of homogeneous plant cover driven by abiotic conditions over large areas. However, efforts invested in understanding how structural complexity within these homogeneous pixels influences ecosystem functions, especially the abundance and distribution of tree species, have led to substantial improvements in predictive accuracy. The ecosystem consequences of adaptive variation among plants were explored in a 13 ha old-growth plot located in Central Ontario's mixed conifer-angiosperm forest. Topography, soil moisture and soil nitrogen were found to structure the distribution of tree species: Conifers dominated the less fertile, xeric lake margin and tolerant hardwoods dominated the richer mesic interior. Patterns in functional composition reflected the trade-offs that have influenced the evolution of plant traits, especially the Leaf Economics Spectrum. Functional composition based on species-level traits, more than acclimation of growth rates along environmental gradients, translated into variability in stand structure and consequently biomass and productivity. Functional diversity was positively correlated with productivity. Rates of litter production and decomposition were quantified along the conifer-angiosperm gradient. Functional composition of litter assemblages accurately predicted decomposition rates and dominated temperature and moisture effects. Organic-horizon dynamics that resulted from coevolved green-leaf and litter properties have presumably acted to stabilize relative abundances in these plant-soil systems, through cultivation of nutrient levels more beneficial to existing assemblages than invaders. Functional diversity was negatively correlated with decomposition, which has likely favored conifers in mixed-species communities. Impacts of tree ontogeny on soil respiration were investigated for the hyper-dominant species, Acer saccharum Marsh. Following an intense rainfall, soil respiration was especially amplified in tree root zones. Post-rain root-zone fluxes increased with tree size, implying that ontogenetic processes have contributed soil-carbon dynamics. A trait-based perspective has linked adaptive variation among trees to ecosystem function. Important diversity effects on productivity and decomposition were detected, implying that increased representation of community structure in ecosystem models can lead to improved predictions. Investigating relationships between community and ecosystem processes in remaining old-growth forests is necessary to evaluate the potential functioning of degraded landscapes.

Keywords: Acclimation
Adaptation
Biodiversity
Biogeochemistry
Ecosystem
Productivity
Advisor: Thomas, Sean C
Regulation of Phagocyte Immunity by Lipid Signals

Phagocytosis, the process by which relatively large particles are internalized into a membrane-bound compartment known as the phagosome, is paramount to both fighting infection and maintaining tissue homeostasis. Professional phagocytes routinely contend with a large assortment of targets, ranging from small pathogenic bacteria to large fungal networks. Non-professional and professional phagocytes also cooperate in the daunting yet critical task of clearing hundreds of billions of apoptotic cells on a daily basis. By promptly removing effete cells, phagocytes prevent secondary necrosis and the onset of autoimmunity, aid in tissue remodelling during wound healing, and orchestrate morphogenesis throughout development. To carry out these functions, phagocytes must be able to effectively find, engulf and dispose of their prey. In this dissertation, I focus on the phagocytic response from the conceptual stages of: 1) capture, 2) uptake and 3) degradation-all presented as self-contained chapters-while placing particular emphasis on the mechanisms by which glycerophospholipids and diacylglycerols regulate these processes. I provide evidence that phosphatidic acid, which is uniquely enriched in the plasmalemma of professional phagocytes, facilitates the continuous membrane ruffling that underlies the uptake of particulate and fluid-phase antigen. Similarly, I argue that phosphatidylinositol-3,4,5-trisphosphate biosynthesis signals actin remodelling during the uptake of large particles, thereby mediating the orderly progression of pseudopodia around large targets. I then discuss the role of diacylglycerol kinases in controlling deployment of the NADPH oxidase, thus fine-tuning the compromise between eliciting effective antimicrobial responses and preventing oxidative damage to the host. Notably, phosphoinositide signalling is often subverted by invading microorganisms in order to avoid phagocyte recognition. The final study in this thesis, also a self-contained chapter, describes a phosphoinositide-centric mechanism by which gliotoxin, an Aspergillus fumigatus mycotoxin, precludes macrophage immune defences.

Keywords: Actin
Cytoskeleton
Macrophages
Phagocytosis
Phosphoinositides
Virulence
Advisor: Grinstein, Sergio
Mental Health Counselling in Family Health Teams: A Narrative Inquiry

The purpose of this study was to examine the experiences of seven mental health counsellors as they come to understand counselling within a family health team setting. Semi-structured qualitative interviews were held with each participant and a narrative analysis yielded meta-themes of professional background, professional practice and interprofessional practice which aided in formulating an integrative model of mental health counselling within this setting. In conceptualizing counselling in this setting, participant told stories of facilitators and barriers to providing care and the process by which they came to understand these dynamics. Systemic issues of hierarchy in medicine and funding models are also discussed. This study adds to the discussion on mental health counselling in family health teams in southern Ontario and provides additional insight into recommendations for counselling practice within interprofessional teams.

Keywords: Counselling
Family Health Teams
Mental Health
Advisor: Stewart, Suzanne
Understanding How Critical Growth Parameters Affect Algal Biofilm Growth and Internal Lipid Concentrations

Due to their relatively fast growth rates and high concentrations of specific biocompounds, algal biofilms have great potential for the production of valuable bioproducts. This thesis investigates the critical factors affecting algal biofilm growth rates and their internal lipid concentrations. Results of this thesis have implications for operation of algal biofilm culturing systems. The main factors investigated in this thesis were how nutrient supplies (carbon dioxide, nitrogen and silicon concentrations), light orientation, and photon flux density affects algal biofilm growth and internal lipid concentrations. This was accomplished by growing algal biofilms on glass and polycarbonate growth coupons in culturing systems that facilitated control over the main factors affecting growth. Two separate biofilm culturing systems were developed and utilized to test distinct research objectives. Biofilms were grown for 14-26 days, harvested from growth coupons several times per week, lyophilized to determine productivities (g/m2/d), and in some cases, exposed to chemical treatments to determine lipid content. Irradiating algal biofilms from either the water side, material side, or both sides, while maintaining a total photon flux density (PFD) of 100 μmol/m2/s, did not affect overall algal biofilm biomass productivities. When well-developed algal biofilms were starved of nitrogen and silicon, there was no accumulation of neutral lipids. Fatty acid methyl ester (FAME) concentrations increased from 5% to 8% (w/w) when PFDs were increased from 50 to 150 μmol/m2/s, however, further FAME accumulations were not observed beyond that PFD range. Algal biofilm starvation did, however, induce biofilm growth cessation and sloughing from the growth substratum. At fixed PFDs of 100 μmol/m2/s, increasing inorganic carbon concentrations from 0.04% to 2% (v/v) resulted in significant biomass productivity increases of 0.5 to 2.0 g/m2/d; however, no biomass productivity increases occurred when CO2 concentrations were incrementally increased from 2% to 12%. When PFDs and CO2 concentrations were simultaneously increased (from 50 to 440 μmol/m2/s and 0.04 to 7% CO2), there were significant increases in algae biofilm biomass productivities (from ~1 g/m2/d to 4.4 g/m2/d) i.e. there was an interaction effect. Maximal algal biofilm total FAME productivities were ~0.3 g/m2/d, comparable to the best terrestrial crops.

Keywords: Biofilm
Biofuel
Growth Parameter
Lipid
Microalgae
Productivity
Advisor: Allen, Grant D
Espie, George S
On the Scaling, Structure and Evolution of the Near to Intermediate Fields of the Round Turbulent Jet

This thesis concerns the structure of turbulence and energy budget equations in the near to intermediate fields of the turbulent, round free jet. A transport equation is proposed for turbulent round jet flows by generalising Kolmogorov's equation. This equation is of particular interest as it essentially represents an energy budget at different spatial scales. A novel equilibrium similarity analysis of the scale-by-scale energy budget equations for the jet is also performed and the possibility for a self-similar solution of the large-scale inhomogeneous terms is considered. The self-similar solution predicts a power-law decay for the turbulence kinetic energy as well as some other characteristics. The current analysis argues that the similarity assumptions in combination with the linear decay of the mean velocity are enough to predict a power-law decay of the mean energy, ⟨q2⟩. Importantly, the application of equilibrium similarity analysis is introduced to data obtained off the axis of the jet, what are the implications of using standard (stationary and flying) hot-wire techniques and tools as well as passive control. The theoretical solution is tested against new experimental data obtained in the downstream of a round turbulent jet. The present similarity form of the scale-by-scale budget equation is shown to be closely satisfied by the experimental data in the intermediate field of the jet.

Keywords: similarity analysis
transport equation
turbulence
turbulent jet
Advisor: Lavoie, Philippe
Pollard, Andrew