VictorJuiz/thesis huggingface dataset:
Identification of New IRS1 Interactors in the Regulation of Insulin Signalling and Cell Proliferation
Keywords: Autophagy
Cell Proliferation
DCAF7
Insulin Signalling
IRS1
KLHL

Insulin is an essential hormone for the maintenance of whole-body glucose homeostasis, inducing glucose disposal in skeletal muscle and adipose tissue and inhibiting glucose production in the liver. Moreover, insulin signalling stimulates whole-body growth by promoting cell proliferation. Upon binding to the insulin receptor (IR), insulin acts through conserved signalling nodes, including insulin receptor substrate 1 (IRS1), AKT and Forkhead box O1 (FOXO1). When insulin signalling fails, insulin resistance develops, which is a key contributor to the development of type 2 diabetes mellitus (T2D). Insulin resistance correlates with various, potentially causative, altered cellular conditions, such as deficient autophagy. Irrespective of the causal condition, insulin resistance is usually associated with defects at key signalling nodes, IRS1 and AKT. IRS1 inhibitory serine phosphorylation and decreased protein content are common in insulin resistance, while insulin-stimulated AKT phosphorylation is decreased and often used as a measure of insulin sensitivity. Despite associations between insulin resistance and IRS1 dysregulation, how this arises is still debated. The work in this thesis focused on identifying regulators of IRS1 and characterizing their impact on downstream insulin signalling. First, we identified the KLHL9/KLHL13/CUL3 E3 Ubiquitin ligase complex as a new IRS1 interactor responsible for proteasomal targeting of IRS1 for degradation. This E3 complex contributes to the development of insulin resistance in a genetic cellular model of deficient autophagy. Second, we identified DCAF7 as a new interactor of IRS1 that when lacking leads to activation of FOXO1 downstream. We found that DCAF7 regulation of FOXO1 is important for cell proliferation and inhibition of hepatic glucose production. Together, our findings identify new interactors of IRS1 and reveal the importance of these interactors in the regulation of IRS1, AKT and FOXO1. In this way, our findings contribute to the overall mechanistic understanding of insulin signalling.
Negative Neuroplasticity in Moderate-to-severe Traumatic Brain Injury and Healthy Aging, and the Development of an Intervention to Attenuate Hippocampal-related Decline
Keywords: aging
intervention
neurodegeneration
neuroplasticity
traumatic brain injury

The present dissertation examined neurocognitive processes associated with negative neuroplasticity related to declines in enriching activities (i.e., new learning), neurally in patients with chronic moderate-to-severe traumatic brain injury (TBI), and behaviourally in healthy older adults. Additionally, it explored a potential avenue for offsetting negative neuroplasticity in older adults. In TBI, recent longitudinal studies show that neurodegeneration continues chronically, and is associated with negative environmental factors (e.g., low levels of enriching activities) that can lead to a cycle of negative neuroplasticity. Similarly, healthy aging involves degeneration and related cognitive declines, which are exacerbated by previous incidences of trauma (e.g., TBIs), while counterproductive environmental factors promote negative neuroplasticity. A region that is vulnerable to damage in both populations is the hippocampus (HPC), which also shows heightened experience-dependent neuroplasticity. Furthermore, the HPC is implicated in memory and navigation, domains that are negatively impacted by both TBI and aging. Although hippocampal degeneration has been previously described in TBI, Study 1 examined patterns of decline across all gray matter structures in patients with chronic moderate-to-severe TBI, finding that other structures also show decline and may be affected by negative neuroplasticity. Study 2 investigated injury- and age-related deficits in two hippocampal-dependent domains – spatial cognition and memory, finding broad age-related effects across all tasks, while TBI-related deficits were more specific to memory. The behavioural relationship between these domains was examined in younger and older adults. Although spatial cognition significantly predicted memory processes in younger adults, these two domains seem to become more independent with age. Finally, Study 3 assessed the feasibility and preliminary efficacy of a novel, remotely delivered intervention in healthy older adults, which behaviourally targets the HPC through allocentric navigation. Although retention rates suggest this population may need more initial support, compliance was encouragingly high. There was evidence of near- and some medium-transfer effects, but improvements did not generalize to memory. Together, this dissertation deepens our understanding of how negative neuroplastic processes may be manifested in affected populations (i.e., TBI and healthy older adults), how specific its effects may be in each population, and examines environmental enrichment as a way of counteracting this negative cycle.
Thickness of the Cerebral Cortex and Stress: A Multiscale Analysis
Keywords: Cortical Thickness
Gene Expression
Income Inequality
Lifespan
Neuroimage
Stress

The intricate relationship between stress and the brain varies spatially, across brain regions, and temporally, across the lifespan. It is hypothesized that stress, spanning from the molecular level to environmental level, will be related to cortical thickness and its underlying neurobiology. The research described in this thesis focuses on the neurobiology of cortical thickness and the potential relationship with psychiatric disorders, expression of stress-hormone receptor genes, and potential stress exposure from the socioeconomic environment. The first study investigated what neurobiological features contribute to the variation in cortical thinning during maturation, and how those features may be implicated in psychopathology. Here, dendritic- and myelin-related gene expression both contributed to regional variation in cortical thickness during development, and were also enriched for genes associated with several psychiatric disorders. For the next study, regional variations in expression of the cortisol binding glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2, respectively) were associated with cortical thickness across the lifespan. The association betweenthe profiles of gene expression and cortical thickness increased rapidly in strength during childhood and adolescence, plateaued in midlife, and decreased during late life. The final study investigated the relationship between cortical thickness and income inequality (in neighborhoods); it used expression of NR3C1 and androgen receptor (AR) in the cerebral cortex to aid interpretation of this relationship. Females, from low-income families living in neighbourhoods with high income-inequality had greater age-related reductions in cortical thickness when compared with females of differing economic conditions. The same group of females displayed a stronger negative association between cortical thinning and both NR3C1 and AR gene expression when compared with other low-income females. This body of research demonstrates how stress, spanning from the molecular level to environmental level, is related to cortical thickness. Overall, this contributes to the understanding of how stressors may contribute to spatial and temporal variations in brain structure, and contribute to the emergence of psychiatric disorders.
Brain Endocannabinoid Metabolism and Hippocampus Glutamate Metabolites in Young Adults with and without Psychotic Disorders: Multimodal Imaging with [11C]CURB Positron Emission Tomography and Proton Magnetic Resonance Spectroscopy
Keywords: cannabinoid
endocannabinoid
neuroimaging
positron emission tomography
psychosis
schizophrenia

The brain’s endocannabinoid neurotransmitter system, the primary target of cannabis, has been implicated in psychosis. The endocannabinoid anandamide is elevated in cerebrospinal fluid of patients with schizophrenia. Fatty acid amide hydrolase (FAAH) controls brain anandamide levels; however, it is unknown if FAAH is altered in vivo in psychosis or related to psychotic symptoms. The endocannabinoid system is a key regulator of neurotransmission throughout the brain including the hippocampus, a major site of glutamate dysfunction in schizophrenia. In vivo neuroimaging studies report alterations in cannabinoid CB1 receptors in psychotic disorders, however, no other endocannabinoid system target has been imaged in vivo in this population. Further, although the endocannabinoid system is related to functional brain activity, the relationship between regional endocannabinoid system markers and brain glutamate remains virtually unexplored. In this work we measured brain FAAH and hippocampal glutamate neurometabolites (glutamate and glutamate-glutamine) using [11C]CURB positron emission tomography (PET) and proton magnetic resonance spectroscopy (1H-MRS), respectively, in patients with psychotic disorders and healthy control participants. Brain FAAH availability did not differ between patients with psychotic disorders and healthy controls, however, low FAAH availability was associated with greater severity of positive dimension psychotic symptoms in patients. FAAH differed across brain regions, with the highest availability observed in hippocampus and striatum. Further, FAAH was higher in females than in males. Hippocampal glutamate metabolites did not differ between patients and healthy controls and were not significantly associated with psychotic symptoms. Combining imaging data from both modalities, we observed that higher FAAH was associated with higher hippocampal glutamate-glutamine and this effect did not differ between patients and healthy control participants or across brain regions. This report provides novel findings that expand the existing picture of endocannabinoid system function in young adults with and without psychotic disorders. Although FAAH did not differ between patients and healthy controls, its relation to psychotic symptom severity may indicate that FAAH serves as a state but not trait biomarker for psychotic symptoms. Regional brain FAAH was associated with hippocampal glutamate metabolite concentrations, providing evidence that the link between glutamate and FAAH activity observed in other species is conserved in humans.
Therapeutic Instrumental Music Training and Sensory-enhanced Motor Imagery in Chronic Post-stroke Upper-extremity Rehabilitation: A Randomized Controlled Trial
Keywords: affective responding
cognition
motor imagery
music
stroke
upper extremity rehabilitation

Objectives: To investigate the effectiveness of Therapeutic Instrumental Music Performance (TIMP) training, with or without motor imagery, in upper-extremity rehabilitation for individuals with chronic, post-stroke hemiparesis. Secondary objectives investigate effects of interventions on cognition and affect. Methods: Two baseline assessments, a minimum of one week apart; one final assessment. Nine interventions (3x/wk for 3 wks), facilitated by a qualified Neurologic Music Therapist. Thirty participants were randomized to one of three groups: 45 minutes of active TIMP; 30 minutes of TIMP followed by 15 minutes of metronome-cued motor imagery (TIMP+cMI); 30 minutes of TIMP followed by 15 minutes of motor imagery without cues (TIMP+MI). A selection of acoustic and electronic instruments was used. Results: Thirty participants completed the protocol, ten per arm [14 women; mean age= 55.9; mean time post-stroke= 66.9 months]. Pooled group baseline measures did not significantly differ. There were significant improvements from pre-test 2 to post-test for all groups on the Fugl-Meyer-Upper Extremity (FM-UE) and the Wolf Motor Function Test-Functional Ability Scale (WMFT-FAS), and for TIMP and TIMP+MI on the Motor Activity Log (MAL)-Amount of Use Scale. Comparing percent change differences between groups, TIMP (mean rank = 21.05) scored significantly higher than TIMP+cMI (mean rank = 11.00, p = .032) on the FM-UE. There were no significant percentage change differences between TIMP and TIMP+MI. The TIMP+MI group showed a significant change on the Trail Making Test (TMT)–Part B. The TIMP group showed a significant increase on the Multiple Affect Adjective Checklist (MAACL) Sensation Seeking scale and the Valence and Dominance portions of the Self-Assessment Manikin (SAM); TIMP+cMI showed respective increases and decreases in positive and negative affect on the MAACL, as well as an increase in Valence, Dominance, and Arousal portions of the SAM. There was no statistically significant association between cognitive and affective measures. Conclusions: Implementation of TIMP-based techniques led to significant improvements in paretic arm control. TIMP and TIMP+MI showed greater benefits than TIMP+cMI, suggesting that synchronizing internal and external cues during cMI may pose additional sensory integration challenges. TIMP+MI appeared to increase mental flexibility, while active TIMP interventions appeared to enhance positive affect. Trial Registration: ClinicalTrials NCT03246217
Exploring Targets of TET2-mediated Methylation Reprogramming as Potential Therapeutic Targets and Discriminators of Prostate Cancer Progression
Keywords: Biochemical recurrence
Disease modeling
Epigenetics
Prostate cancer
TET2
Therapeutic targets

Aberrant cytosine methylation is one of the most common alterations in cancer, with global hypomethylation and regional hypermethylation characterizing many different malignancies, including prostate cancer. In normal cells, master methylation regulators, the ten-eleven translocase (TET) family of enzymes, demethylate genes by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine. Although lowered expression of all three TETs is common in prostate cancer, TET2 in particular plays a central role through its interaction with – and repression by – the androgen receptor. Loss of TET2 is associated with decreased cancer-specific survival, while missense alterations of TET2 are linked to metastatic disease. In this thesis, genome-wide targets of TET2 were examined via integrative (hydroxy)methylation and expression analysis to first identify how locus-specific epigenetic patterns affect prostate cancer cells and phenotype. Subsequently, genes regulated by TET2 were assessed to determine their individual and combinatorial utility as potential tumor suppressors or oncogenic factors in disease. In contrast to the paradigm of universal hydroxymethylation loss in cancer, locus-specific intronic retention in genes related to basic cellular function and intergenic gain of hydroxymethylcytosine marks proximal to androgen-related genes was observed in 22Rv1 prostate cancer cell lines. CRISPR-Cas9 based TET2 knockout in prostate cells identified high-confidence genes specifically mediated by TET2 methylation reprogramming. Expression loss of three such genes – ASB2, NUDT10, and SRPX – or increased promoter methylation of NRG1 was significantly (p
Affective Indignities at Work: Exposing the Inequality of Feelings in Canadian Professional Workplaces
Keywords: Affect
Diversity and Inclusion
Emotion Work
Emotional Labour
South Asian Women
White Institutional Space

Despite the “talk” of diversity and inclusion, power in professional workplaces in Canada remains in the hands of a dominant white network. In order to devise effective strategies to achieve workplace equality, a deeper understanding of how power flows in professional workplaces is needed. In this thesis, I connect the framework of white institutional space, and the concept of feeling rules to explore how 20 foreign-trained South Asian (FTSA) women who occupied professional and/or managerial jobs in the Greater Toronto Area (GTA) conceptualized the power differences that produced and reproduced the form of workplace inequality they experienced. Based on a narrative analysis of the feeling rules experienced and navigated by FTSA women in the professional workplace, I conceptualize the workplace inequality they experienced in two interconnected ways to demonstrate the hegemonic nature of feelings in the professional workplace (i.e., the inequality of feelings). Firstly, through the structural lens afforded by connecting the concept of feeling rules and the framework of white institutional space, I argue that the cumulative impact of years of engaging in multidimensional emotional labour to constantly manage recurring racialized and gendered emotions is a form of workplace inequality. The emotions that FTSA women managed daily did not dissipate each day; instead they accumulated daily and as such are irreducible to invisible work (Daniels, 1987). Secondly, I use Ahmed’s (2004) critical concept of impression and the process of racialization to argue that the accumulation of racialized and gendered emotions through repeated performances of gratitude work, shame work, and empathy work, as directed by the five distinct feeling rules that FTSA women experienced–namely, to be hyper-pleasant, grateful, fearful, not angry, and not lonely–resulted in an intensification of emotions that produced affective associations that racialized their bodies. The impact of these affective associations on an FTSA woman’s bodily and embodied experiences in the workplace is a unique form of workplace inequality as it constrains her agentic actions. I have termed this form of workplace inequality affective indignities as it sustained the racialized relations of power in white institutional spaces that diminished the capacity of FTSA women to act.
Foaming Effects on Conductivity Percolation Threshold in Conductive Polymer Composites
Keywords: CNT alignment
computational modeling
conductive polymer composite foam
electrical conductivity
MWCNT

Conductive filler/polymer composite foams (CPC) with micro-/nano-scale bubbles have attracted much attention due to their various advantages. Understanding the evolution of electrical behavior in CPC foams is important for their functional application. This thesis investigated the foaming effects on the re-alignment of the conductive filler and the subsequent conductivity percolation threshold of CPC foams experimentally and theoretically. The polystyrene (PS) and multiwalled carbon nanotubes (MWCNTs) were selected as the model system for analysis. In the experimental approach, we prepared a series of PS/MWCNTs composite foams using solvent-mixing method to blend PS and MWCNTs followed by the conventional batch foaming. It was found that at a relatively low void fraction, the electrical conductivity can be increased, and the percolation threshold can be decreased. In the theoretical modeling, a novel resistive network model based on Monte Carlo simulation to directly predict the electrical conductivity of CPC foams was developed. The model predictions agreed very well with the experimental data for both the solid and foamed composites. At relatively low void fractions (up to ~30 %), the growth of bubbles with size comparable to the MWCNT length increased the conductivity. The methods and models developed in this work are useful tools for understanding the underlying mechanism of percolation behavior in CPC foams, as well as quantitative tools in the design of CPC foams. Furthermore, the approaches and strategies used to develop such computational model can provide guidelines and useful references for model simulation in other functional polymer composite foams, such as thermally conductive polymer composite foams.
Geriatric Traumatic Brain Injury: Outcomes, Costs and Quality of Care
Keywords: Clinical Care Pathways
Geriatric
Observational
Resource Use
Trauma Center
Traumatic Brain Injury

Observational data from an adult traumatic brain injury (TBI) cohort derived from a Level I Trauma Centre (TC) over an eight-year time horizon were analyzed using descriptive statistics and logistic regression in a series of four studies. The first study aimed to assess differences between younger and older TBI patients in injury presentation, hospital resource utilization and short-term outcomes. Older adults were found to have reduced odds for TBI in the presence of multisystem injury (TBI+), direct hospital transport, and trauma team activation (TTA). Older age was also associated with increased odds for assisted living disposition and hospital readmission. The second study sought to assess the impact of different factors related to older and younger patients and factors related to mortality after TBI. It was found that increasing age was associated with increased odds (OR: odds ratio) mortality, as was the presence of comorbidities, severity of injury and receiving surgery. The third study aimed to assess determinants of hospital length of stay (LOS) and associated costs for acute care medical treatment. It was found that the mean LOS was 6.4 days, with intensive care unit (ICU) admissions and alternate level of care (ALC) designated patients accounting for 23% and 13% of total hospital days. The six most influential determinants of acute care hospital LOS were discharge destination, hospital acquired complications, ICU management, Geriatric Trauma Consultation Service (GTCS) exposure, physician service, and TBI+ diagnosis. The mean acute care hospital cost for patients in the cohort was $20,148 CAN (SD: $32,800). TBI+ presentation accounted for 20% of all hospital bed-days and 23% of all hospital expenditures, despite its representation in only 10% of the entire cohort. The fourth study was designed to measure associations between GTCS and hospitalization outcomes for geriatric TBI patients. GTCS patients were matched to those without GTCS (UC: usual care) using propensity scores. GTCS management was significantly associated with increased rate of in-hospital complications, ICU- and ALC-management and prolonged total LOS Among GTCS survivors, there was significant increased disposition to in-patient rehabilitation (IR) (OR 1.37 CI 1.00-1.88), compared to UC patients.
Experiences of Secondary Long-term Occassional Teachers Seeking Permanent Employment in Ontario
Keywords: Equity
Hierarchy
Invisible Influence
Nepotism
Permanent Employment

This study analyses how Long-term Occasional Teachers (LTO) interface with permanent teachers, students and the administration as they seek to gain permanent employment. It also focuses on Internationally Educated Teachers (IETs) who are LTOs as they seek integration into the Ontario teaching workforce as permanent teachers. The study utilized a general qualitative research methodology with interviews to obtain participant data and is undergird by notions of Post-Fordism, communities of practice and equity education. Data were collected from 15 participants who self-identified as LTOs. Of the 15 LTOs 4 identified as IETs who sought employment as full-time teachers in Ontario. Findings reveal that (a) LTOs and in particular those who were internationally trained (IETs) felt that they were required to continuously reinvent themselves to become marketable for the Ontario education system; (b) their knowledge seems to be less appreciated than that of permanent contract teachers and; (c) there are challenges achieving permanent employment. This study also reports on the insecurities and low self-esteem caused by extended periods of job search as well as the impact of different forms of discrimination on their ability to obtain full time employment. This study relies on the extant literature on the experiences of LTOs and IETs to build greater awareness of the challenges they experience while seeking employment in Ontario as full-time teachers.