VictorJuiz/thesis huggingface dataset:
Determining the Roles of the Intrinsic versus the Extrinsic Pathway in Regulating Neuronal Programmed Cell Death In Vivo
Keywords: Neuronal Programmed Cell Death
Gene Knockout

Programmed cell death (PCD) is a highly evolved mechanism of cellular suicide that is aberrantly activated following neural injury. Two fundamental PCD signaling pathways termed the extrinsic (caspase-8-mediated) and intrinsic (caspase-9-mediated) pathways, have been described. While each pathway is initiated by distinct cellular stimuli, both pathways culminate in the activation of downstream executioner caspases. Previous efforts to isolate the in vivo contribution of each pathway have been hindered by the embryonic lethality of casp8 and casp9 null mice. In the present study, I overcame this obstacle to directly assess the contribution of each pathway following two well-characterized forms of acute neural injury; excitotoxic destruction of CA1 pyramidal neurons, and the loss of motor neurons following facial nerve transection. To determine the role of caspase-8, I constructed several lines of mice in which caspase-8 was conditionally ablated within the relevant neuronal populations. The results obtained from these animals definitively demonstrate that caspase-8 is not required by either motor neurons or CA1 pyramidal neurons to undergo PCD following injury. Therefore, these findings have provided the first direct experimental evidence to counter the widely held dogma of caspase-8 as the central effector of death receptor-mediated signaling within neurons. With respect to the intrinsic pathway, several lines of evidence suggest that the apoptosome predominantly regulates the death of motor neurons. I tested this hypothesis by performing facial axotomies in mice containing a point mutation introduced (“knocked in”) into the genomic locus of cytochrome c which abolishes its ability to activate the intrinsic pathway. Homozygous cytochrome c knock-in mice displayed a significant enhancement in motor neuron survival in comparison to control littermates following injury. However, the level of motor neuron protection differed from that previously reported in mice either overexpressing anti-apoptotic or lacking pro-apoptotic members of the Bcl-2 family. Therefore, the results of this study directly demonstrate the influence of the apoptosome on injury-induced neuronal PCD isolated from upstream Bcl-2 family-mediated effects. In addition, my results have provided the first evidence that activation of the apoptosome is required for the release of apoptosis inducing factor (AIF) from the mitochondria of injured motor neurons in vivo.
Neuroprotective Drug Delivery to the Injured Spinal Cord with Hyaluronan and Methylcellulose
Keywords: Drug Delivery
Spinal Cord Injury
Spinal Cord Blood Flow
CT Imaging
Tissue Diffusion
Fibroblast Growth Factor 2
Erythropoietin
Injectable
Intrathecal
Poly(ethylene glycol)
PEGylation
Dynamic Contrast Enhancement

Traumatic spinal cord injury (SCI) is a devastating condition for which there is no effective clinical treatment. Neuroprotective molecules that minimize tissue loss have shown promising results; however systemic delivery may limit in vivo benefits due to short systemic half-life and minimal passage across the blood-spinal cord barrier. To overcome these limitations, an injectable intrathecal delivery vehicle comprised of hyaluronan and methylcellulose (HAMC) was developed, and previously demonstrated to be safe and biocompatible intrathecally. Here, HAMC was determined to persist in the intrathecal space for between 4-7 d in vivo, indicating it as an optimal delivery system for neuroprotective agents to reduce tissue degeneration after SCI. HAMC was then investigated as an in vivo delivery system for two neuroprotective proteins: erythropoietin (EPO) and fibroblast growth factor 2 (FGF2). Both proteins demonstrated a diffusive release profile in vitro and maintained significant bioactivity during release. When EPO was delivered intrathecally with HAMC to the injured spinal cord, reduced cavitation in the tissue and significantly improved neuron counts were observed relative to the conventional delivery strategies of intraperitoneal and intrathecal bolus. When FGF2 was delivered intrathecally from HAMC, therapeutic concentrations penetrated into the injured spinal cord tissue for up to 6 h. Poly(ethylene glycol) modification of FGF2 significantly increased the amount of protein that diffused into the tissue when delivered similarly. Because FGF2 is a known angiogenic agent, dynamic computed tomography was developed for small animal serial assessment of spinal cord hemodynamics. Following SCI and treatment with FGF2 from HAMC, moderate improvement of spinal cord blood flow and a reduction in permeability were observed up to 7 d post-injury, suggesting that early delivery of neuroprotective agents can have lasting effects on tissue recovery. Importantly, the entirety of this work demonstrates that HAMC is an effective short-term delivery system for neuroprotective agents by improving tissue outcomes following traumatic SCI.
Developmental Plasticity of Language Representation in Healthy Subjects and Children with Medically Intractable Epilepsy
Keywords: language
plasticity
development
epilepsy

This thesis includes four studies designed to improve the ability to predict and assess language representation in healthy children and/or individuals with neurological disorders arising in childhood. In the first study, the role of pathology type on interhemispheric plasticity of language was determined by comparing lateralization in children with developmental, acquired, and tumour pathologies. Findings from 105 consecutive intracarotid sodium amobarbital procedures were retrospectively analyzed, revealing no lateralization differences between pathology groups. In the second study, a novel verb generation paradigm and magnetoencephalography (MEG) were used to determine the spatial-temporal characteristics of language expression in healthy subjects (n = 12) and children with neurological disorders (n = 4). Time-frequency and differential beamformer analyses revealed low-beta event-related desynchronization (ERD) in the left inferior frontal lobe for verb generation. The paradigm was well-tolerated by all subjects. The third study involved assessment of expressive language lateralization in 25 healthy subjects, aged 5-18 years, using two novel MEG paradigms: covert picture naming and verb generation. Novel analyses permitted objective quantification of ERD lateralization on an individual basis. For both tasks, left lateralization of frontal lobe ERD tended to increase with advancing age. Findings suggest that adult-typical left lateralization emerges from an early bilateral language network in normal development. In the fourth study, frontal lobe ERD lateralization for naming and verb generation was characterized in 14 children and adolescents with neurological disorders. Novel analyses permitted objective assessment of individual scans at multiple contrast time windows. In several cases, rapid hemispheric shifts in predominant frontal lobe ERD were observed through the response period. On an individual basis, the assessment protocol showed promise for future use in a presurgical context. These studies serve to advance the understanding of normal paediatric language representation, and improve the ability to predict and assess language lateralization in individuals who have experienced early neurological insults.
Soot Formation in Non-premixed Laminar Flames at Subcritical and Supercritical Pressures
Keywords: soot formation
high pressure combustion
laminar diffusion flames

An experimental study was conducted using axisymmetric co-flow laminar diffusion flames of methane-air, methane-oxygen and ethylene-air to examine the effect of pressure on soot formation and the structure of the temperature field. A liquid fuel burner was designed and built to observe the sooting behavior of methanol-air and n-heptane-air laminar diffusion flames at elevated pressures up to 50 atm. A non-intrusive, line-of-sight spectral soot emission (SSE) diagnostic technique was used to determine the temperature and the soot volume fraction of methane-air flames up to 60 atm, methane-oxygen flames up to 90 atm and ethylene-air flames up to 35 atm. The physical flame structure of the methane-air and methane-oxygen diffusion flames were characterized over the pressure range of 10 to 100 atm and up to 35 atm for ethylene-air flames. The flame height, marked by the visible soot radiation emission, remained relatively constant for methane-air and ethylene-air flames over their respected pressure ranges, while the visible flame height for the methane-oxygen flames was reduced by over 50 % between 10 and 100 atm. During methane-air experiments, observations of anomalous occurrence of liquid material formation at 60 atm and above were recorded. The maximum conversion of the carbon in the fuel to soot exhibited a strong power-law dependence on pressure. At pressures 10 to 30 atm, the pressure exponent is approximately 0.73 for methane-air flames. At higher pressures, between 30 and 60 atm, the pressure exponent is approximately 0.33. The maximum fuel carbon conversion to soot is 12.6 % at 60 atm. For methane-oxygen flames, the pressure exponent is approximately 1.2 for pressures between 10 and 40 atm. At pressures between 50 and 70 atm, the pressure exponent is about -3.8 and approximately -12 for 70 to 90 atm. The maximum fuel carbon conversion to soot is 2 % at 40 atm. For ethylene-air flames, the pressure exponent is approximately 1.4 between 10 and 30 atm. The maximum carbon conversion to soot is approximately 6.5 % at 30 atm and remained constant at higher pressures.
Data Quality By Design: A Goal-oriented Approach
Keywords: Data Quality
Database Design
Goal Oriented
Conceptual Modeling

A successful information system is the one that meets its design goals. Expressing these goals and subsequently translating them into a working solution is a major challenge for information systems engineering. This thesis adopts the concepts and techniques from goal-oriented (software) requirements engineering research for conceptual database design, with a focus on data quality issues. Based on a real-world case study, a goal-oriented process is proposed for database requirements analysis and modeling. It spans from analysis of high-level stakeholder goals to detailed design of a conceptual databases schema. This process is then extended specifically for dealing with data quality issues: data of low quality may be detected and corrected by performing various quality assurance activities; to support these activities, the schema needs to be revised by accommodating additional data requirements. The extended process therefore focuses on analyzing and modeling quality assurance data requirements. A quality assurance activity supported by a revised schema may involve manual work, and/or rely on some automatic techniques, which often depend on the specification and enforcement of data quality rules. To address the constraint aspect in conceptual database design, data quality rules are classified according to a number of domain and application independent properties. This classification can be used to guide rule designers and to facilitate building of a rule repository. A quantitative framework is then proposed for measuring and comparing DQ rules according to one of these properties: effectiveness; this framework relies on derivation of formulas that represent the effectiveness of DQ rules under different probabilistic assumptions. A semi-automatic approach is also presented to derive these effectiveness formulas.
The Global Person: A Political Liberal Approach to International Justice Theory Giving Moral Primacy to the Individual
Keywords: Rawls
international justice
toleration
human rights

John Rawls's The Law of Peoples has been criticized for focusing on the interests of peoples rather than individuals and for compromising individuals' fundamental human rights in order to tolerate nonliberal ideas of justice. This dissertation develops a new political liberal approach to international justice theory that responds to these concerns. This approach gives explicit moral primacy to the individual while also upholding the political liberal commitment to toleration. I do this by developing a political conception of the person specifically for international justice theory and a global original position of persons for working out principles of international justice. This involves the specification of an idea of freedom that is not parochially liberal and the development of a new political liberal human rights framework. This dissertation does not offer a defense of political liberalism as the right account of justice; the aim of this work is to consider whether a political liberal theory of international justice is able to give the individual moral primacy and to explore how it might do so.
Organizational Learning From Near Misses in Health Care
Keywords: Near Misses
Organizational Learning
Patient Safety

How clinicians detect and differentiate near misses from adverse events in health care is poorly understood. This study adopted a constructivist grounded theory approach and utilized document analysis and semi-structured interviews with 24 managers (middle and senior) and clinicians to examine the processes and factors associated with recognizing and recovering and learning from near misses in daily clinical practice. While safety science suggests that near misses are sources of learning to guide improvement efforts, the study identified how clinicians and managers cognitively downgrade and accept near misses as a routine part of daily practice. Such downgrading reduces the visibility of near misses and creates a paradoxical effect of promoting collective vigilance and increased safety while also encouraging violations in clinical practice. Three approaches to correcting and/or learning from near misses emerged: “doing a quick fix,” “going into the black hole,” and “closing off the swiss-cheese holes”; however, minimal organizational learning occurs. From these findings, two key paradoxes that undermine organization-level learning require further attention: (a) near misses are pervasive in everyday practice but many remain undetected and are missed learning opportunities, and (b) collective vigilance serves as both safety net and safety threat. Study findings suggest that organizational efforts are required to determine which near misses need to be reported. Organizations need to shift the culture from one of “doing a quick fix” to one that learns from near misses in daily practice; they should reinforce the benefits and reduce the risks of collective vigilance, and further encourage learning at the clinical microsystem level. Future research is required to provide insight into how individual, social, and organizational factors influence the recognition, recovery, and instructional value of near misses and safety threats in health care organizations’ daily practice.
Invariant Procedures for Model Checking, Checking for Prior-Data Conflict and Bayesian Inference
Keywords: invariance
P-value
model checking
checking for prior-data conflict
Bayesian inference
relative surprise

We consider a statistical theory as being invariant when the results of two statisticians' independent data analyses, based upon the same statistical theory and using effectively the same statistical ingredients, are the same. We discuss three aspects of invariant statistical theories. Both model checking and checking for prior-data conflict are assessments of single null hypothesis without any specific alternative hypothesis. Hence, we conduct these assessments using a measure of surprise based on a discrepancy statistic. For the discrete case, it is natural to use the probability of obtaining a data point that is less probable than the observed data. For the continuous case, the natural analog of this is not invariant under equivalent choices of discrepancies. A new method is developed to obtain an invariant assessment. This approach also allows several discrepancies to be combined into one discrepancy via a single P-value. Second, Bayesians developed many noninformative priors that are supposed to contain no information concerning the true parameter value. Any of these are data dependent or improper which can lead to a variety of difficulties. Gelman (2006) introduced the notion of the weak informativity as a comprimise between informative and noninformative priors without a precise definition. We give a precise definition of weak informativity using a measure of prior-data conflict that assesses whether or not a prior places its mass around the parameter values having relatively high likelihood. In particular, we say a prior Pi_2 is weakly informative relative to another prior Pi_1 whenever Pi_2 leads to fewer prior-data conflicts a priori than Pi_1. This leads to a precise quantitative measure of how much less informative a weakly informative prior is. In Bayesian data analysis, highest posterior density inference is a commonly used method. This approach is not invariant to the choice of dominating measure or reparametrizations. We explore properties of relative surprise inferences suggested by Evans (1997). Relative surprise inferences which compare the belief changes from a priori to a posteriori are invariant under reparametrizations. We mainly focus on the connection of relative surprise inferences to classical Bayesian decision theory as well as important optimalities.
Contemplative Teachers' Practical Knowledge: Towards Holistic Teacher Education
Keywords: contemplation
teachers' practical knowledge

The purpose of this study is to understand the significance of contemplative practice in fostering teachers’ personal practical knowledge. Teachers’ practical knowledge has been valued to make teaching relevant to students’ real life contexts. However, practical knowledge has been considered difficult to teach because of the diversity and dynamism of reality. Based on the conceptualization that teachers’ contemplative practice could support their practical knowledge development, this qualitative study was carried out through a review of the literature and exploration of direct experiences of four teachers who have linked their contemplative practices to their teaching. The literature review informs us that in order to develop teachers’ practical knowledge, attention, a sense of the whole, and a sense of context are critical. In addition, those qualities can be fostered by non-dual knowing or intuitive knowing which can be developed by contemplation, that is, the act of looking at something by paying attention without thinking of anything else and without premises or judgments. The exploration of the participants’ direct experiences shows that their contemplative practices performed a significant role in fostering personal practical knowledge of self, students, environment, subject matter, curriculum, and instruction and in making their teaching relevant to the students’ real lives from a holistic perspective.
Dancing about Architecture in a Performative Space: Discourse, Ethics and the Practice of Music Education
Keywords: Music
Education
Literature
Philosophy
Performativity
Ethics
Rhetoric

British singer/songwriter Elvis Costello once said, “Talking about music is like dancing about architecture – it’s a really stupid thing to want to do” (in Brackett, 1995, p. 157). In this thesis I talk not only about music but I also talk about talk about music, perhaps an even stupider thing to want to do. But I do so because recent critical discourses in musicology and music education suggest talk about music is an inherent part of music, such that if we talk about music at all we must additionally talk about talk about music. But in talking about talk about music we are called upon to talk about talk. Consequently this thesis divides into five parts. In Part I I talk about talk with a discussion of performativity. I outline three different conceptions of the performative, showing how ethics inheres in language, with talk about talk necessarily being talk about ethics to some extent. In Part II I talk about talk about music, showing how musicology has attempted to respond to this ethical dimension of talk with a “new” musicology. In Part III I write in a number of different genres, exploring the discursive norms governing genres of writing about music and musicians and how they impact what we take music to be. Thus I write in philosophical, ethnographic, genealogical, narratological, autobiographical and literary forms, concluding that literary writing on music and musicians acts as a meta-discourse on music, bringing multiple different discourses into dialogue within a single unified text. In Part IV I explore the implications of literary writing about music and musicians for the practice of music education with critical readings of four novels, concluding with the recommendation that a “Non-foundational approaches to music education” course be offered as part of music teacher education programs, in addition to the more traditional “Foundational approaches to music education” course. In Part V I provide two annotated bibliographies for teachers interested in teaching such a course and for those who simply wish to further their understanding of music and music education through critical engagement with literary texts about music and musicians.
Role of EphB Family Receptors in Regulating Axon Guidance in the Mammalian Central Nervous System
Keywords: Axon Guidance

Neural function depends on precise wiring of axon during development. Previous studies have demonstrated that the erythropoietin producing hepatocellular carcinoma (Eph) family of tyrosine receptor kinases is crucial for the proper development of a number of neural circuits in the mammalian central nervous system (CNS). Mice lacking Eph receptors have been shown to exhibit deficits in pathways which include the thalamocortical, callosal, retinal and corticospinal tract. Due to the large number of Eph family members, the relative contribution of each receptor to axon pathfinding and neural function remains elusive. In this thesis, I have addressed the function of EphA4, EphB2 and EphB3 in the regulating the formation of interhemispheric projections within the forebrain and motor axon connections within the spinal cord using EphA4, EphB2 and EphB3and combinatorial null mice. To perform a detailed examination of the process of axon guidance regulated by these receptors within the forebrain, high resolution magnetic resonance imaging (MRI), immunofluorescence and in vivo stereotactic fluorescent labeling were performed. This work resulted in the development and validation of MRI-based analytic tools performed using EphB2 mutants which we have previously shown to exhibit specific morphologic defects in the anterior commissure (AC). Analysis of EphA4 null mice using high resolution MRI revealed for the first time that in addition to errors of midline crossing, loss of EphA4 activity results in a positional reorganization of the rostral AC. Results demonstrate that while EphB2 and A4 each regulate distinct aspects of guidance within ACpp, these receptors also operate cooperatively to control the guidance of axons in the pars anterior of the AC, a pathway not been previously implicated in Eph-mediated guidance. With respect to the spinal cord, mice deficient in EphB2 and EphA4 display prominent axon guidance errors in the medial subsets of the lateral motor column (LMCm); neurons which normally innervate ventral limb musculature. Finally, I have addressed the functional effect which Eph mutants exhibit with respect to motor behavior by examining a detailed set of motor coordination parameters