VictorJuiz/thesis huggingface dataset:
Transcriptome Studies in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a composite classification for a range of gastrointestinal disorders. The two most common forms of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). The chronicity of IBD has long-term consequences on the quality of life of affected individuals. However, therapies available today are applied with limited success. It is thought that interplay between environmental triggers and commensal bacteria can cause a dysregulated inflammatory response in genetically predisposed individuals, but the exact etiology is not understood. The objective of these studies was to identify the gene expression changes which associate with differential response to therapy and with recurrence of disease following surgery. The effects of genetic variation on gene expression were also evaluated. Tissue and blood samples were collected from eligible patients. Total RNA was extracted and measured on gene expression microarrays. The raw gene expression data were analyzed in a statistical framework against variables of interest in order to assess the significance of each association. Genes were evaluated individually as well as in biological networks. A few tens of genes were identified as differentially expressed in blood between UC patients who respond to intravenous corticosteroid therapy and those who do not. Some of these genes were also shown to have high predictive value. Differentially regulated genes were also found in UC patients who experience recurrence of disease after surgery, relative to those who remain disease-free. Specifically, gene networks responsible for the regulation of cellular transport were among the major players. A comparative analysis of genotype and gene expression in the human ileum indicated that the transcription of approximately 10% of genes is influenced by variations in the genome. Results from these studies have not only contributed to our understanding of disease mechanism, but could also have medical implications. With the advance of new and less costly transcriptome technologies on the clinical stage, panels of expression markers associated with therapy response and post-operative recurrence can be used as diagnostic and prognostic tools. Data on the relationship between genotype and gene expression are already shedding new light on the function of certain genetic IBD risk variants.

Keywords: Transcriptome
IBD
Advisor: Silverberg, Mark
Applications of Focused Ultrasound for Reducing Amyloid-β in a Mouse Model of Alzheimer's Disease

Focused ultrasound (FUS) can temporarily increase blood-brain barrier (BBB) permeability and locally deliver therapeutic agents to the brain. To date, applications of FUS for treatment of Alzheimer’s disease (AD) have not been explored. Here, I propose that FUS can facilitate a rapid reduction in amyloid-β peptide (Aβ) pathology in a mouse model of AD. Firstly, FUS was used to enhance delivery of an antibody directed against Aβ, which aggregates and forms extracellular plaques. FUS mediated the delivery of antibodies to the targeted right cortex by 4 hours post-treatment and antibodies remained bound to Aβ plaques for 4 days. At 4 days post-treatment, stereological quantification of plaque burden demonstrated a significant reduction of 23%. Secondly, FUS treatment alone resulted in a significant reduction in plaque load (13%). I then investigated effects of FUS that may contribute to Aβ plaque reduction, specifically the delivery of endogenous antibodies to the brain and, activation of microglia and astrocytes. Endogenous immunoglobulin was found bound to plaques within the treated cortex at 4 days post-FUS. Western blot analysis confirmed that immunoglobulin levels were increased significantly. Further, FUS led to a time-dependent increase in glial response. The expression of ionized calcium-binding adaptor molecule 1, a marker of phagocytic microglia, was increased at 4 hours and 4 days, and it was resolved by 15 days. Astrocytes had a slightly delayed response, with an increase in the expression of glial fibrillary acidic protein at 4 days, which declined by 15 days. After 4 days, microglia and astrocytes had significantly greater volumes and surface areas, signifying enhanced activation in the FUS-treated cortex, without an apparent increase in cell count. Co-localization of Aβ within activated glia revealed a significant increase in Aβ internalization following FUS. In conclusion, it was demonstrated that the delivery of exogenous antibodies by FUS, and FUS alone can lead to plaque reduction. Mechanisms by which FUS alone reduces plaque load may include entry of endogenous antibodies to the brain and the induction of a transient glial response. This work details acute effects of FUS that highlight the promise of this delivery method for AD treatment.

Keywords: Alzheimer's disease
focused ultrasound
immunotherapy
astrocytes
microglia
immunoglobulin
amyloid-β
mouse models
MRI
Advisor: Aubert, Isabelle
Hynynen, Kullervo
Development of Innovative Gas-assisted Foam Injection Molding Technology

Injection molding technology is utilized for a wide range of applications from mobile phone covers to bumper fascia of automotive vehicles. Foam injection molding (FIM) is a branched manufacturing process of conventional injection molding, but it was designed to take advantage of existing foaming technology, including material cost saving and weight reduction, and to provide additional benefits such as improvement in dimensional stability, faster cycle time, and so on. Gas-assisted injection molding (GAIM) is another supplemental technology of injection molding and offers several advantages as well. This thesis study takes the next step and develops innovative gas-assisted foam injection molding (GAFIM) technology, which is the result of a synergistic combination of two existing manufacturing technologies, FIM and GAIM, in order to produce a unique thermoplastic foam structure with proficient acoustic properties. The foam structure manufactured by GAFIM consists of a solid skin layer, a foam layer, and a hollow core; and its 6.4-mm thick sample outperformed the conventional 22-mm thick polyurethane foam in terms of the acoustic absorption coefficient. With respect to foaming technology, GAFIM was able to achieve a highly uniform foam morphology by completely decoupling the filling and foaming phases. Moreover, the additional shear and extensional energies from GAFIM promoted a more cell nucleation-dominant foaming behavior, which resulted in higher cell density and smaller cell sizes with both CO2 and N2 as physical blowing agents. Lastly, it provided more direct control of the degree of foaming because the pressure drop and pressure drop rate was controlled by a single parameter, that being the gas injection pressure. In summary, innovative, gas-assisted foam injection molding technology offers not only a new strategy to produce acoustically functioning thermoplastic foam products, but also technological advantages over the conventional foam injection molding process. Gas-assisted foam injection molding can become the bedrock for more innovative future applications.

Keywords: foaming
injection molding
gas-assisted injection molding
acoustic
thermoplastic polyurethane
Advisor: Park, Chul B.
Voicing Power through the Other: Elite Appropriations of Fable in the 1st-3rd Centuries CE

As a result of its association with marginalized groups, the genre of fable is sometimes presented as accurately reflecting the voice of the Other, although the fable has traditionally always been a vehicle for the elite to establish, explain and justify their positions. While the fable is increasingly associated with the Other from the 1st century CE, the genre is still appropriated by upper-class male authors as a means of defining their positions and constructing their own ideal political, social and literary worlds. This study will focus on the voicing of the Aesopic fable in the literature of the 1st-3rd centuries CE, primarily in authors and works that incorporate one clearly identifiable fable exemplum told at length in the text. Elite authors in this period used the fable as a means of communicating their views of behavioural expectations, not only by appropriating a genre that they have characterized as Other, but also by the voicing of fable through marginalized figures. This appropriation of the othered genre and voice allows for an exploration of boundaries that in the end will reaffirm the established order. The elite appropriation of fable as a means of social control over marginalized groups reflects an uneasiness about their own positions and the increasing social mobility beginning in the 1st century CE. This study of the appropriation of the othered genre will contribute to our understanding of how elite authors dealt with anxieties about potential and actual disruptions in their expectations of the socio-political reality.

Keywords: Fable
Slavery
Advisor: Mason, Hugh
Untangling the Temporal Dynamics of Bilateral Neural Activation in the Bilingual Brain

A persistent unanswered question in cognitive neuroscience has been what are the neural origins of human brain lateralization? Language is strongly lateralized to the left-hemisphere, however, lateralization varies with language experience. Bilinguals demonstrate a greater extent and variability of right-hemisphere involvement for language relative to monolinguals. Here, bilingualism is used as a lens into the conditions that drive brain lateralization. Why does bilingual language processing yields more robust bilateral neural activation relative to monolingual language processing? Neural activation and functional connectivity were measured to test hypotheses about the temporal dynamics of hemispheric recruitment during language processing in monolingual and bilingual children with varying ages of first bilingual language exposure. Hypothesis (1), The human brain is strongly left-hemisphere lateralized for language, but, when faced with the demands of two languages, additional right-hemisphere resources are recruited. Hypothesis (2), The human brain has the potential for enhanced dual hemispheric language processing that can be either potentiated or not based on early life bilingual versus monolingual language experience. If dual language experience places increased cognitive demands on the bilingual brain requiring additional right-hemisphere resources, asynchronous neural activation in left and right hemispheres was predicted. If dual language experience potentiates dual hemispheric language processing, synchronous neural activation in left and right hemispheres was predicted. Furthermore, only early-exposed bilinguals but not later-exposed bilinguals or monolinguals, would show synchronous neural activation across the hemispheres. Early experience with one language (monolinguals) or two languages at different times during a child's development (early-exposed bilinguals, later-exposed bilinguals) revealed differences in the time-course of activation across the two hemispheres' language areas, supporting Hypothesis (2). Monolinguals and later-exposed bilinguals showed asynchronous activation between the hemispheres. Early-exposed bilinguals showed synchronous activation between the hemispheres. The results provide a new view on how different experiences can drive lateralization in development and reveal the neural basis of bilateral activation in the bilingual brain. Synchronous temporal accessing of the hemispheres in bilinguals suggests early life bilingual language experience may support more equal and efficient hemispheric involvement, and, in turn, constitute the brain-based mechanism that makes possible the widely observed linguistic and cognitive advantages in young bilinguals.

Keywords: Cerebral asymmetry
Bilingualism
Advisor: Petitto, Laura-Ann
Parent materialistic values: Effects on domain parenting and adolescent moral development

Materialism, or the orientation towards viewing material goods and money as important for personal happiness, is detrimental in several ways: it is associated with psychological maladjustment and lowered well-being and also conflicts with pursuits of caring for and relating to others. Although research has found that materialism is associated with fewer and lower-quality relationships with others, no research to date has explored the effects of materialism on the parent-child relationship, and the resulting impact on the child&rsquo;s orientation towards others. These associations were explored in the present research. One hundred and five mothers and 76 fathers were assessed on measures of materialism (self-enhancement values and extrinsic aspirations) and parenting. Three domains of parenting were considered: control parenting (disciplinary strategies), protection parenting (responsiveness to child distress), and guided learning parenting (guidance through parent-child discussion). The 105 adolescents of these parents were assessed on indicators of moral development: prosocial and antisocial behavior, value internalization, prosocial moral reasoning, and empathy. It was hypothesized that parent materialism would predict lower levels of adolescent moral development and that this association would be mediated by parenting behaviors. This hypothesis was partially supported, but only for mothers. One measure of mother materialism - self-enhancement - related to adolescent prosocial behavior, while the other measure of mother materialism - extrinsic aspirations - related to adolescent approval orientation. Two mediators were identified for the mother self-enhancement/adolescent prosocial behavior link: mother operational-interfering style during moral discussions (guided learning parenting) and mother use of non-reasoning and punitive disciplinary strategies (control parenting). Beyond these links to adolescent moral development, both mother and father materialism were linked to negative parenting behaviors, including low responsiveness to adolescent distress, low empathy (in mothers), and high use of scolding and criticisms (in fathers). The results of this research indicate that when parents place high value on demonstrating power over others and achievement according to social standards at the expense of more prosocial values, adolescent moral development suffers, as mediated by the effect of materialism on parenting behaviors.

Keywords: Moral development
Parenting
Materialism
Advisor: Grusec, Joan
A Variationist Approach to Cross-register Language Variation and Change

The comparative method of variationist sociolinguistics has demonstrated that frequency changes are not reliable determinants of whether grammatical change is taking place. Frequency changes can be the result of extra-linguistic register changes, changes within the underlying grammar, or a combination (Szmrecsanyi, 2011; Tagliamonte, 2002). This work examines two variables known to vary along the written-to-spoken continuum — relative clause pronouns, and the genitive construction — across three registers of English and 100 years, with the goal of furthering our understanding of the relationship between spoken and written language. The s-genitive (i.e. Canada's government vs. the government of Canada) is on the rise in the 20th century (Hinrichs and Szmrecsanyi, 2007; Rosenbach, 2007). Statistical modeling confirms the press register leads this increase — a register change. Examination of internal linguistic constraints over time indicates simultaneous grammatical change, with the s–genitive increasing with certain inanimate subtypes. The WH-forms (who, which) of the relative pronouns have become increasingly restricted to written registers (e.g. Romaine, 1982; Tottie, 1997), leaving that as the variant used most for subject function in vernacular speech (D'Arcy and Tagliamonte 2010). Although who continues to be used for animates, which is shown to have lost any grammatical conditioning that it once had and to be undergoing lexical replacement by that for non-human subject antecedents. Unlike the genitives, though, examination of internal linguistic factors reveals no evidence of grammatical change. The methodology employed here provides a way to tease apart grammatical change from register change, with register-internal change shown to be a motivating factor in change from above. While the vernacular is ''the most systematic data for our analysis of linguistic structure'' (Labov, 1972a:208), it is not necessarily the most innovative, nor is it always the locus of change. With that in mind, this work provides a model of language change that integrates change across speech and writing.

Keywords: sociolinguistics
language variation
language change
grammatical change
register variation
register change
relative pronoun
genitive
corpus construction
Canadian english
Advisor: Tagliamonte, Sali A.
The Role of Perceptual Task Parameters in Children’s Inflexible Dimensional Switching

Children at a certain age often have difficulty in flexibly shifting attention between different representational schemes. One example of such cognitive inflexibility occurs in the Dimensional Change Card Sorting (DCCS) task in which 3-year-old children have difficulty switching between sorting dimensions. For instance, after initially sorting the cards by one dimension (e.g., colour) they are unable to sort the cards by a second dimension (e.g., shape). This finding has been primarily associated with problems in attention or inhibition. The present study investigated the role of perceptual information on children’s dimensional shift abilities by manipulating the perceptual characteristics of both task-relevant (the colour or shape of the images on the cards) and task-irrelevant (the background colour or shape of the actual cards themselves) aspects of the task materials between the pre- and post-switch experimental phases. Across three experiments better performance was observed when either task-relevant or task-irrelevant information was changed, with this improved performance occurring when these changes were salient enough to induce a stimulus novelty effect. Experiment 4 investigated yet another perceptual feature of the task; the degree of stimulus realism (abstractness) on children’s cognitive flexibility. Children successfully sorted the cards when three-dimensional stimuli were used but perseverated when using two-dimensional cards, providing evidence for the role of representational status of the stimuli in influencing children’s dimensional switching. Manipulations made to increase the salience of the task material as well as those resulting in reduction of similarity between the two phases of the tasks (or increased novelty) were used to enhance children’s cognitive flexibility. Overall, these findings highlight the critical role played by the perceptual information of the overall experimental context, and have important implications for theories of cognitive flexibility.

Keywords: Card Sorting Task
Executive Function
Advisor: Schmuckler, Mark
Characterization of Kallikrein-related Peptidase-8 in Normal Human Epidermis and Psoriasis

Kallikrein-8 (KLK8) is a relatively-uncharacterized epidermal protease. Although proposed to regulate wound-healing and barrier repair in KLK8-deficient mouse skin, KLK8-catalytic activity was never demonstrated in human epidermis and its regulators and targets remain largely unknown. KLK8 overexpression was reported in inflammatory skin diseases, but the underlying mechanisms are poorly understood. In this thesis, we elucidated for the first time KLK8-specific activity in normal human non-palmoplantar stratum corneum and sweat, and identified epidermal regulators and targets that augment its involvement in a skin-barrier proteolytic cascade. Given that inflammatory skin diseases have interlinked immune and epidermal roots, we hypothesized that epidermal KLK8 expression is distinctly regulated by the aberrant T-cell immunity implicated in the two common skin diseases, psoriasis and atopic dermatitis, independent of skin-barrier insults. We profiled secretion of KLK8 by normal human keratinocytes post-treatment with T-helper (Th1, Th17 and Th2) cell-derived cytokines, and investigated the effect of KLK8 overexpression on terminal keratinocyte differentiation and innate immunity gene expression. Our results show that TNFα and IL-17A synergistically induce potent KLK8 hyper-secretion, while IL4 and IL13 reduce its expression. TNFα and IL-17A overexpression and KLK8 hyperactivity resulted in hyperkeratosis and upregulation of keratinocyte innate defense genes’ expression mimicking psoriatic lesions. Consistently, KLK8 expression was reduced in lesional skin of atopic dermatitis patients and significantly elevated in lesional skin and sera of psoriatic patients. KLK8 levels correlated with psoriasis skin severity and were significantly reduced by effective treatment with biologic TNFα-blockers, correlating positively with psoriasis clearance. Thus, KLK8 is a new epidermal psoriasis therapeutic target. We performed high throughput screens of small molecule compound libraries to identify KLK8-specific inhibitors and discovered promising KLK8 small molecule inhibitors with IC50s in the nanomolar range. This thesis provides original findings corroborating KLK8 as an active serine protease in normal human skin and a down-stream epidermal respondent to TNFα and IL17A overexpression in psoriatic skin. Our novel KLK8-specific inhibitors may have future potential as topical barrier-enhancing agents in psoriasis.

Keywords: Kallikrein
Epidermis
Stratum corneum
Psoriasis
Advisor: Diamandis, Eleftherios P.
The "How" of Change in Emotion-focused Group Therapy for Eating Disorders

Currently, there is a limited understanding of change mechanisms across all treatment approaches for eating disorders (ED), particularly with regard to group psychotherapy. This presents one of the major obstacles in the development of more effective treatments. The purpose of this study was to extend current understanding of therapeutic processes in group psychotherapy for bulimic disorders. Thirty-one women were randomly assigned to either 16-weeks of Emotion-Focused Therapy (EFT) or Motivation/Education and Skill Building (M/ESB) as part another study at a participating outpatient ED program. The goals of this study were to: (1) evaluate the relationship between in-session processes; (2) compare these processes between two group treatments; (3) examine in-session differences as a function of client activity in group EFT; (4) and identify a pathway to change. As expected, the findings demonstrated that mid therapy emotional arousal was associated with higher levels of insight, and an increase in insight overtime was associated with an increase in therapeutic alliance. Arousal was not positively correlated with alliance. There was a significant interaction between group treatment x time: clients in EFT reported gains in insight overtime, as measured by post-session change measure, whereas clients’ scores in M/ESB did not change over the course of psychotherapy. Alliance increased significantly over the course of therapy in both groups. Contrary to expectations, clients in the EFT group did not report higher levels of arousal compared to the M/ESB group. The limited sample size in the control group precludes firm conclusions about group comparisons. When examining client activity within EFT, the results demonstrated that clients that were actively engaged in the chair-tasks reported higher post-session change scores, arousal, and alliance compared to when they were in the observing role; however, there was a significant upward trend on post-session change scores regardless of the client role. The pathway to change was partially supported: the observer-rated degree of resolution scores predicted a third of variance in post-session change scores; controlling for pre-treatment outcome scores, post-session change scores predicted variance at the outcome on several EDI-3 subscales. These preliminary findings are discussed in the context of psychotherapy process literature, highlighting limitations and future directions.

Keywords: emotion-focused therapy
eating disorders
psychotherapy process
mechanisms of change
group psychotherapy
Advisor: Watson, Jeanne