VictorJuiz/thesis huggingface dataset:
Death Shapes Life: Characterizing the Role of p63 and p73 During Neural Development and Aging

The molecular mechanisms that regulate survival of embryonic neural precursors are still relatively ill-defined. Here, we have asked whether the p53 family member p63 plays any role during this developmental window, focusing upon the embryonic cerebral cortex. We show that genetic knockdown of p63 either in culture or in the embryonic telencephalon causes apoptosis of cortical precursors and newly-born cortical neurons, and that this can be rescued by expression of ΔNp63, but not TAp63 isoforms. This cortical precursor apoptosis is the consequence of deregulated p53 activity, since both basal precursor apoptosis and that induced by loss of p63 are rescued by coincident genetic silencing of p53. Finally, we demonstrate that the third p53 family member, ΔNp73, does not regulate survival of cortical precursor cells, but that it collaborates with ΔNp63 to ensure the survival of newly-born cortical neurons. Thus, the balance of ΔNp63 versus p53 determines the life versus death of embryonic cortical precursors. To assess if p63 plays a similar role in the adult brain, we examined mice haploinsufficient in p63 (p63+/-); we observed that aging, but not young, mice show deficits in short term memory and vertical exploratory behaviour. These results establish a foundation upon which the role of p63 in aging can be further characterized. Given the importance of p73 in aging and in preventing neurodegeneration, we aimed to create a conditional p73 knock out mouse (floxed p73). This mouse will allow for lineage-specific characterization of p73 function and will circumvent the reduced life span displayed by 4 mice lacking p73 (p73-/-). The work presented in this thesis has advanced our knowledge on the role of the p53 family members (p53, p63, and p73) in regulating survival and death in the nervous system. This knowledge will be important to understand neuropathology and to design appropriate therapeutic interventions.

Keywords: developmental biology
brain
Advisor: Miller, Freda
Genomic Exploration of Transcriptional Regulation and Evolution in Vertebrates

All cellular processes depend on the coordinate expression of genes and their interactions. Regulatory sequences encoded in the genome stipulate the necessary instructions interpreted by sequence-specific transcription factors (TFs) to control the spatial-temporal output of gene expression. Detection of cis-regulatory signals is challenging, owing to the lack of distinguishing features such as open reading frames and an overwhelming excess of spurious to functional TF binding site matching sequences embedded within the vast non-coding regions of vertebrate genomes. From an evolutionary standpoint, functional alterations in cis-regulatory architecture are thought to be important in diversifying morphology and physiology in the evolution of vertebrates, which share a similar body plan and complement of genes. Correspondingly, recent studies have highlighted the plasticity of cis-regulatory architecture organization over evolutionary time, finding associations with examples of both diverged and conserved patterns of gene expression. These observations underscore the gap in our collective knowledge with respect to the rules by which TFs recognize and bind their targets in vivo, as well as how this process evolves in vertebrates, and serve as a motivating basis for this thesis work. To begin, I probed the extent of conservation and divergence of sequence and expression profiles across tissues of diverse vertebrate species, identifying thousands of candidate genes with conserved expression by microarray analysis. However, corresponding conservation of non-exonic and potentially regulatory sequence was lacking, suggestive of binding site turnover over evolutionary time. Next, I analyzed the sequence specificity of a wide array of mouse and yeast TFs, finding great diversity and complexity in their binding preferences, with many factors recognizing multiple distinct motifs. Furthermore, comparative analysis of orthologous TFs suggest well conserved binding specificities. I also demonstrate the likely biological relevance of sequences highly preferred by these TFs by revealing distinctive signatures in their distribution and organization within putative regulatory regions in each genome. Lastly, I have begun to explore the organization of cis-regulatory sequences active in vertebrate tissues by high-throughput sequencing of open chromatin. Together, these data help illuminate the organization and evolution of vertebrate regulatory architectures, providing a useful toolkit for the testing of new models and hypotheses.

Keywords: comparative genomics
transcription regulation
bioinformatics
vertebrates
evolution
Advisor: Hughes, Timothy R.
Automatic Program Parallelization Using Traces

We present a novel automatic parallelization approach that uses traces. Our approach uses a binary representation of a program, allowing for the parallelization of programs even if their full source code is not available. Furthermore, traces can represent both iteration and recursion. We use hardware transactional memory (HTM) to ensure correct execution in the presence of dependences. We describe a parallel trace execution model that allows sequential programs to execute in parallel. In the model, traces are identified by a trace collection system (TCS), the program is transformed to allow the traces to execute on multiple processors, and the traces are executed in parallel. We present a framework with four components that, with a TCS, realizes our execution model. The grouping component groups traces into tasks to reduce overhead and make identification of successor traces easier. The packaging component allows tasks to execute on multiple processors. The dependence component deals with dependences on reduction and induction variables. In addition, transactions are committed in sequential program order on an HTM system to deal with dependences that are not removed. Finally, the scheduler assigns tasks to processors. We create a prototype that parallelizes programs and uses an HTM simulator to deal with dependences. To overcome the limitations of simulation, we also create another prototype that automatically parallelizes programs on a real system. Since HTM is not used, only dependences on induction and reduction variables are handled. We demonstrate the feasibility of our trace-based parallelization approach by performing an experimental evaluation on several recursive and loop-based Java programs. On the HTM system, the average speedup of the computational phase of the benchmarks on four processors is 2.79. On a real system, the average speedup on four processors is 1.83. Therefore, the evaluation indicates that trace-based parallelization can be used to effectively parallelize recursive and loop-based Java programs based on their binary representation.

Keywords: automatic parallelization
traces
Advisor: Abdelrahman, Tarek S.
Effects of a Short Work/Shorter Rest Intermittent Exercise on Muscle Metabolic Status, VO2, Hemoglobin Saturation and Performance

Effects of a Short Work/Shorter Rest Intermittent Exercise on Muscle Metabolic Status, VO2, Hemoglobin Saturation and Performance, PhD, 2010, Glen Robert Belfry, Exercise Science, University of Toronto. Abstract Many sports require short duration work periods and short duration rest periods (INT). This dissertation examines the engagement of aerobic and anaerobic energy systems in acute exercise with brief (10 seconds) work and recovery (5 seconds) and the effect of chronic exposure on those systems. The differences between INT and continuous exercise (CONT) of deoxygenated hemoglobin saturation (ΔHHb), the pattern of breath-by-oxygen uptake (VO2) and muscle metabolic status, including, [Pi], [Pi]/[PCr], and [H+] were studied in young healthy adults. The physiological and performance responses to a four week, 12 session cycle ergometer training regime of the CONT and INT protocols were observed. Fluctuations in VO2, ∆HHb, [PCr], and [H+] were observed within the work : recovery duty cycle of INT. Fluctuations of VO2, ΔHHb, and [PCr] may be a function of the priming effects of previous high intensity exercise, inhibition at the locus of metabolic control, and elevated blood flow over the recovery-work transitions. Fluctuations in oxidative phosphorylation were associated with concurrent fluctuations in [PCr]. [Pi] and [PCr] were greater in INT vs CONT, whereas no differences were observed for [H+] between conditions. Reduced [PCr] may be the most appropriate indicator of metabolic stress, not increased [Pi] or [H+]. Similar improvements in aerobic power were observed for CONT and INT training, whereas anaerobic performance was enhanced post-INT training. Collectively the findings indicate that a unique INT exercise protocol facilitates increased muscle blood flow versus continuous exercise, the temporal association of muscle metabolic status, ΔHHb, and pulmonary VO2 with work rate, the apt use of [PCr] as a proxy for metabolic stress, and when this unique INT bout is utilized as a training protocol, adaptations in both aerobic and anaerobic metabolism will occur.

Keywords: intermittent exercise
oxygen delivery utilization and muscle metabolic status
Advisor: Thomas, Scott
Application-oriented Networking through Virtualization and Service Composition

Future networks will face major challenges in accommodating emerging and future networked applications. These challenges include significant architecture and management issues pertaining to future networks. In this thesis, we study several of these challenges including issues such as configurability, application-awareness, rapid application-creation and deployment and scalable QoS management. To address these challenges, we propose a novel Application-Oriented Network (AON) architecture as a converged computing and communication network in which application providers are able to flexibly configure in-network resources on-demand. The resources in AON are virtualized and offered to the application providers through service-oriented approaches. To enable large-scale experimentation with future network architectures and applications, in the second part of this thesis, we present the Virtualized Application Networking Infrastructure (VANI) as a prototype of an Application-Oriented Network. VANI utilizes a service-oriented control and management plane that provides flexible and dynamic allocation, release, program and configuration of resources used for creating applications or performing network research experiments from layer three and up. Moreover, VANI resources allow development of network architectures that require a converged network of computing and communications resources such as in-network processing, storage and software and hardware-based reprogrammable resources. We also present a Distributed Ethernet Traffic Shaping (DETS) system used in bandwidth virtualization in VANI and designed to guarantee the send and receive Ethernet traffic rates in VANI, in a computing cluster or a datacenter. The third part of this thesis addresses the problem of scalable QoS and admission control in service-oriented environments where a limited number of instances of service components are shared among different application classes. We first use Markov Decision Processes to find optimal solutions to this problem. Next we present a scalable and distributed heuristic algorithm able to guarantee probability of successful completion of a composite application. The proposed algorithm does not assume a specific distribution type for services execution times and applications request inter-arrival times, and hence is suitable for systems with stationary or non-stationary request arrivals. We use simulations and experimental measurements to show the effectiveness of the proposed solutions and algorithms in various parts of this thesis.

Keywords: AON
SOA
VANI
Application-Oriented Network
Virtualized Application Networking Infrastructure
Advisor: Leon-Garcia, Alberto
The Role of the GLP-2 Receptor in Intestinal and Islet Adaptation to Changes in Nutrient Availability

GLP-2 is a potent intestinotrophic peptide that can increase mucosal growth, intestinal blood flow, and nutrient absorption when administered exogenously. We aimed to delineate the effects of endogenous GLP-2R signalling in conditions of nutrient deprivation and excess. Using a mouse with a targeted genetic deletion of the Glp2r gene (Glp2r-/-), we addressed the hypothesis that the known GLP-2R is required for intestinal adaptation to nutrient deprivation and excess. In Chapter 2, we demonstrate that Glp2r−/− mice fasted for 24 hours and re-fed for 24 hours failed to increase intestinal growth and jejunal crypt cell proliferation compared to littermate Glp2r+/+ mice. Administration of EGF to Glp2r−/− during the re-feeding period rescued this re-feeding defect. Wildtype mice re-fed for 30, 90, and 180 minutes following a 24 hour fast displayed increased jejunal mRNA levels of the ErbB ligands amphiregulin, epiregulin and HB-EGF. Treatment with the pan ErbB inhibitor CI-1033 inhibited induction of these ErbB ligands in jejunum of mice in association with prevention of crypt cell proliferation. Re-feeding also caused an increase in jejunal p-Akt levels and treatment with CI-1033 prevented increased p-Akt levels. Moreover, re-fed Glp2r−/− mice failed to increase ErbB ligands or p-Akt levels 90 minutes following re-feeding when compared to Glp2r+/+ littermates. Therefore, the GLP-2R is essential for re-feeding induced intestinal adaptation by activating the ErbB network and p-Akt to increase crypt cell proliferation. In Chapter 3, we show that the known GLP-2R is not required for intestinal adaptation to a perceived nutrient deprivation challenge (STZ-induced diabetes) or chronic nutrient excess (high-fat diet induced glucose intolerance). Although exogenous GLP-2 administration has been previously shown to stimulate glucagon secretion, glucose homeostasis was normal in STZ-diabetic and high fat fed Glp2r−/− mice. We also developed a third model of diabetes and glucose intolerance: ob/ob: Glp2r−/−. In the absence of GLP-2R signalling, ob/ob mice display improved oral but impaired intraperitoneal glucose tolerance, elevated fed and fasted glucose levels, increased circulating glucagon, decreased beta cell and increased alpha cell mass. Taken together, these results suggest that endogenous GLP-2R signalling is essential for intestinal and islet adaptation to conditions of nutrient deprivation and excess.

Keywords: GLP-2
Intestine
Advisor: Drucker, Daniel J.
Quality of Life of Adolescents Following Heart Transplantation

Despite the establishment of heart transplantation as a life-saving therapy for children and adolescents, little research has focused on the biopsychosocial impact of the transplant process. Few studies have captured the subjective experiences of young heart transplant recipients. This program of research examined how pediatric heart transplant recipients construct their worlds and the meanings they ascribe to their transplant experience. A grounded theory approach was implemented which guided data collection and analysis. A total of twenty-seven adolescents participated in semi-structured qualitative interviews. Findings illuminate pediatric heart transplantation to be a pervasive experience, with consequent impact on physical, psychological and social well-being. Participants described various biopsychosocial processes and experiences that occurred over the course of their transplant journey. Data analysis yielded themes of quality of life reflecting notions of temporality including: 1) the pre-transplant experience – a struggle to survive, 2) the transplant surgery and hospitalization – a difficult transition and 3) the post-transplant experience – an awakening and transformation. This research identifies that heart transplantation, which may contain elements of suffering and loss, may ultimately enhance young recipients’ overall quality of life. Results reveal the possibility that adolescent heart transplant recipients not only adapt to transplantation, but also potentially experience associated growth-enhancing experiences. An emergent theoretical model is presented, with implications for practice and research.

Keywords: pediatric heart transplant
qualitative
Advisor: West, Lori J.
Kant, Skepticism, and Moral Sensibility

In contrast to his rationalist predecessors, Kant insists that feeling has a pos- itive role to play in moral life. But the exact nature of this role is far from clear. As much as Kant insists that moral action must proceed from a feeling of respect, he maintains with equal insistence that the objective basis of acting from duty must come from practical reason alone, and that when we act from duty we must exclude sensibility from the determining grounds of choice. In what way, then, is respect for the law a feeling? And what place does this feeling have—if any—in Kant’s ethics? The aim of my dissertation is to answer these questions, in part through a close engagement with Kant’s second Critique. I provide a close reading of his claim that our recognition of the moral law must effect both painful and pleasurable feelings in us, and I argue that these feelings, for Kant, are meant to explain how the moral law can figure into the basis of a maxim. By showing why our recognition of the law must be painful from the perspective of self-love, but pleasurable from the perspective of practical reason, Kant is able to show how our desires can acquire normative direction. On my reading, then, the theory of moral sensibility we find in the second Critique addresses a rather troubling form of skepticism: skepticism about moral motivation.In the course of defending this claim, I provide an alternative reading of the development of Kant’s project of moral justification from Groundwork III to the second Critique. Against a wide-spread view in the literature, I suggest that what changes between these texts is not a direction of argument (from freedom to morality, or morality to freedom), but a methodological shift toward the concept of human sensibility. In the later work, I argue, Kant develops a novel approach to moral feeling from the perspective of the deliberating agent; and this in turn clears room in Kant’s ethics for a new kind of a priori knowledge—namely, knowledge of what the activity of practical reason must feel like. The broader aim of my dissertation is thus to put Kant’s work on meta-ethics and moral psychology in closer proximity.

Keywords: Kant
Ethics
Moral Psychology
Moral Motivation
Skepticism
Moral Feeling
Respect
Groundwork III
Critique of Practical Reason
Advisor: Franks, Paul
Racing Solidarity, Remaking Labour: Labour Renewal from a Decolonizing and Anti-racism Perspective

The study examines how Aboriginal workers and workers of colour experience union solidarity and explores the necessary conditions for the remaking of solidarity and the renewal of the labour movement. Grounded in anti-colonial discursive framework, the study analyzes the cultures and practices of labour solidarity through the lived experiences of Aboriginal activist and activists of colour within the Canadian labour movement. Utilizing the research methodologies of participatory action research, arts-informed research and critical autobiography, the research draws on the richness of the participants’ collective experiences and visual images co-created during the inquiry. The study also relies on the researcher’s self-narrative as a long time labour activist as a key part of the embodied knowledge production and sense making of a movement that is under enormous challenges and internal competing tension exacerbated by the neoliberal agenda. The findings reveal sense of profound gap between what participants experience as daily practices of solidarity and what they envisioned. Through the research process, the study explores and demonstrates the importance and potential of a more holistic and integrative critical education approach on anti-racism and decolonization. The study proposes a pedagogical framework on solidarity building with four interlinking components – rediscovering, restoring, reimagining and reclaiming – as a way to make whole for many Aboriginal activists and activists of colour within the labour movement. The pedagogy of solidarity offers a transformative process for activists to build solidarity across constituencies in the pursuit of labour renewal and social justice movement building.

Keywords: labour studies
anti-racism
solidarity and movement building
critical education
anti-racism education
race and class
inter-racial working class consciousness
decolonization
Aboriginal circle methodology
arts-informed research
social movement
Advisor: Jackson, Nancy
"Experience is the Best Teacher." Community Treatment Orders (CTOs) among Ethno-Racial Minority Communities in Toronto: A Phenomenological Study

Since de-institutionalization, numerous community based treatment modalities have been implemented to provide treatment for individuals diagnosed as seriously and persistently mentally ill. CTOs are a recent addition to the community mental health care system designed to provide outpatient mental health services to seriously mentally ill clients and using legal mechanisms to enforce a contractual obligation to participate in those services. Although there is a growing body of literature on CTOs and other mandated outpatient treatment programs for people diagnosed with mental illnesses, the research predominantly focuses on the perspectives of service providers and family members. Little attention has been given to how clients view the experience of receiving the treatment and no attention has been given to the experience of clients who are of ethno-racial minority background. As Ontario is a racially and ethnically diverse environment in which many people of minority backgrounds are placed on CTOs. This study, utilizing a phenomenological methodology, interviewed twenty-four participants of ethno-racial minority background who are either on CTOs or have been on a CTO in the past. The focus of the study was to explore the views and lived experience of the participants regarding the treatment. The outcome of the study showed that the participants did not experience the treatment as racially motivated but felt it was necessary and beneficial. The participants discussed the impact of power in the treatment process. Implications of the study were that it would enhance the mental health literature by providing an understanding of serious mental illness among individuals of ethno-racial minority background. The study would provide insight for policy makers and practitioners on providing effective support for the marginalized.

Keywords: serious mental illness
ethno-racial minority
community treatment orders
Advisor: Williams, Charmaine