VictorJuiz/thesis huggingface dataset:
Cell Polarity Protein SCRIBBLE Regulates Pregnancy-induced Alveologenesis In the Mammary Gland
Keywords: Mammary Gland
Polarity
Prolactin
Receptor trafficking
Scribble

SCRIBBLE (SCRIB) was identified as a regulator of epithelial cell polarity and morphogenesis in Drosophila. Subsequent studies in mammalian cells demonstrated that SCRIB regulates epithelial cell polarization, cell migration, and tumourigenesis. SCRIB also plays important roles during mammalian development where loss of SCRIB resulted in embryonic lethality and tissue- specific knockout studies identified SCRIB as a tumor suppressor in the prostate, lung, and mammary gland. However, the role SCRIB plays in adult epithelial tissues during physiological remodeling remains unknown. To address this question, we generated an inducible RNAi mouse model whereby SCRIB expression can be controlled in vivo. Since the mouse mammary gland undergoes morphological changes during pregnancy, we investigated the effects of inactivating SCRIB in adult mammary epithelial cells. Downregulation of SCRIB in adult mammary glands resulted in a significant decrease in development of alveolar buds and reduced epithelial content, in conjunction with a decrease in cell proliferation during pregnancy. Surprisingly, loss of SCRIB did not affect the differentiation or polarization of alveolar structures. Mechanistically, SCRIB knockdown attenuated prolactin- induced activation of the JAK2/STAT5 signaling pathway, a critical mediator of pregnancy- induced cell proliferation. Thus, in contrast to the previously reported role for SCRIB in the virgin gland as a negative regulator of proliferation, these studies identify SCRIB as a positive regulator of pregnancy-induced alveologenesis in the adult mammary gland. The attenuation of prolactin responsiveness in SCRIB knockdown cells was attributable to decreased cell surface accumulation of the prolactin receptor (PRLR). In SCRIB knockdown cells, PRLR partially co-localized with the Golgi apparatus and recycling endosome. Using an unbiased mass spectrometry approach, we found that SCRIB controlled levels of multiple cell surface proteins. Collectively, the studies in this dissertation identify SCRIB as a positive regulator of prolactin-initiated proliferation of mammary epithelial cells during pregnancy and steady state cell surface levels of PRLR.
The Role of Standing and Travelling Waves in Stratosphere-troposphere Coupling
Keywords: Fourier analysis
general circulation
stratosphere-troposphere coupling

Upward wave activity flux in the mid-latitudes is a strong control on the strength and temperature of the stratospheric polar vortex in the Northern Hemisphere winter. In this thesis, the variability of upward wave activity flux is studied using the ideas of linear interference. This framework separates meteorological fields into a zonally asymmetric climatology-â the stationary waveâ and a wave anomaly. Fluxes are then decomposed into a linear term that measures the spatial coherence of the anomaly and the climatology and an additional nonlinear term. In order to determine the structure of the wave anomalies that interfere with the climatology, a novel spectral decomposition of wave disturbances into standing and travelling components is developed. Unlike previous methods, it explicitly accounts for the covariance between the two components. The decomposition is applied to planetary waves in the Northern Hemisphere winter. It is shown that standing waves explain the majority of the variance of the linear part of the upward wave activity flux. Furthermore, the connection between upward wave activity flux in the troposphere and the strength of the stratospheric polar vortex is shown to be primarily driven by standing waves amplifying and attenuating the climatological wave. The relationship between the linear and nonlinear parts of the upward wave activity flux is investigated. It is shown that there is a roughly quadratic relationship between the two when considering individual wavenumbers, and that this can act as an explanation for the positive skewness of the wavenumber-1 upward wave activity flux distribution. A statistical model is constructed which demonstrates that a westward tilted climatological wave is the key ingredient in having a positively skewed wave activity flux distribution. Last, the analysis is extended to consider the dynamics of tropospheric variability and weather extremes. The standing-travelling wave decomposition is applied to tropospheric weather variability in order to separate the slow and fast drivers of cold winter weather over eastern North America. It is found that standing waves driven from the tropics largely control the large-scale ridge-trough structure over North America, but that eastward travelling synoptic waves can strongly modify it on shorter timescales.
Data Envelopment Analysis Models for a Mixture of Non-ratio and Ratio Variables
Keywords: Data Envelopment Analysis
Non-oriented Models
Performance measurement
Ratio Analysis
Ratio variables
Relative Efficicency

Performance comparison is a delicate business, even among organizations of the same kind. The simplest of all is usually the ratio of a single output to a single input. The problem lies in the fact that one aspect of the business could hardly represent the whole picture and the landscape the business is operating in. Businesses have complex structures and oer variety of products so it is only fair to take all into consideration to judge their performance against others in an industry. Data Envelopment Analysis (DEA) is one method suitable when there are multiple inputs and outputs to be considered. It is a non-parametric method conceptualized by Farrell in 1957. However, it was not untill 20 years later, that Charnes, Cooper and Rhodes brought this concept into practice by finding a way to realize this idea and make it work. The breakthrough came from the fact that under certain assumptions Farrell's idea could be formulated as a linear mathematical program (LP) which could be solved using the simplex and similar methods. One limitation of the existing DEA models is their inability to work with ratio variables because the linear combination of DMUs do not generally translate to linear combination of inputs and outputs in the ratio form. In this work, our contribution to the field includes extending Farrell's idea to include ratio inputs and outputs and operationalizing four models under variable returns to scale assumption. Three non-oriented models are formulated and linearized and one non-linear model is solved using a heuristic.
Advancing Astronomical Instrumentation: an Adaptive Optics Kinematic Study of z~1 Star-Forming Galaxies
Keywords: adaptive optics
astronomical instrumentation
galaxy dynamics
galaxy evolution
galaxy formation
integral field spectrograph

This thesis has a dual focus on improving ground-based astronomical instruments and an observational study of distant star-forming galaxies to study galaxy formation and evolution. Of fundamental importance to this work are adaptive optics (AO) technology and integral field spectrographs (IFSs), both of which offer powerful means of studying high redshift galaxies. First, I describe the design and development of an instrument to characterize the vertical atmospheric turbulence using the SLODAR (SLOpe Detection and Ranging) method. This instrument was used in a campaign at Ellesmere island (∼ 80◦N) and determined that the site has half of the total turbulence residing in the ground layer (
CEACAM3: Specific Innate Immunity
Keywords: CEACAM
Neisseria
Neutrophil

The bacterial species Neisseria gonorrhoeae remains one of the most prevalent bacterial causes of sexually transmitted infections. Gonorrhea is typically characterized by a painful purulent discharge and inflammation, the outcome of overzealous recruitment of neutrophils, phagocytic immune cells highly specialized in the detection and elimination of microbial pathogens. Although molecular mechanisms of gonococcal pathogenesis have been studied in great detail, the causes for the excessive inflammation and immunopathology that follow infection are still not clear. The human neutrophil-restricted innate immune receptor CEACAM3 has been previously shown to promote opsonin-independent uptake and killing of N. gonorrhoeae by neutrophils. In the course of my thesis work, I have established that the role of CEACAM3 is not restricted to the neutrophils’ direct engulfment and killing of gonococci, since it also drives a vigorous inflammatory response that typifies gonorrhea. By carrying the potential to mobilize increasing numbers of neutrophils, CEACAM3 represents a tipping point between the protective and pathogenic outcomes of N. gonorrhoeae infection. My biochemical profiling of gonococcal-infected, genetically modified neutrophils revealed that CEACAM3 engagement triggers a Syk-, PKCδ-, Bcl10-MALT1-, and Tak1-dependent signaling cascade that leads to the activation of an NF-κB-dependent transcriptional response, with consequent production of pro-inflammatory cytokines. I also showed that CEACAM cross-linking on neutrophils signals in synergy with TLR4, significantly amplifying the response to LPS, suggesting that CEACAM3 acts as an integral part of a complex innate immune detection network. Finally, I co-led a study that characterized Opa protein variant expression among a collection of clinical specimen-derived N. gonorrhoeae, and then assessed their CEACAM binding profile. This study suggested that mucosal infection in humans selects for binding to epithelial-expressed CEACAMs but against CEACAM3 binding in vivo. Together, my studies implicate a role for CEACAM3 as a host-adaptive innate receptor that promotes gonococcal detection and elimination in the context of natural infection, but also reveal potential pathogenic consequences of CEACAM3 activation.
Chasing the Promise of Performance: A Case Study Exploring the Implementation of a Standards-Based Accountability Policy Intervention in the Ontario Public Health System
Keywords: accountability
implementation
performance management
public health policy
quality improvement

OBJECTIVE: This research project examines the development and implementation of Ontario’s system of public health accountability and performance management through two cross-cutting themes: control and results. This research project represents one of the first attempts to bridge the fields of public administration and new public management, policy implementation, and quality improvement in an examination of accountability and performance improvement in the public health sector. METHODS: This study involved semi-structured, in-depth interviews with informants in three public health units (n=20) and with representatives from the Ministry of Health and Long-Term Care (MOHLTC) (n=4). A web-survey of public health managers (n=53) was also carried out. Document review supplemented these two main data sources. Qualitative data were coded and analyzed using Atlas.ti 6.2 and quantitative data were exported to SPSS for descriptive and bivariate analysis. FINDINGS: Control, emphasizing compliance-based accountability, top-down implementation, and performance measurement for quality assurance had a dominant presence in policy development and implementation that negatively affected the pursuit of results (i.e. emphasis on performance, bottom-up implementation, and measurement for quality improvement). Pre-existing accountability structures challenged efforts to establish performance improvement as a key consideration. Despite evidence of consultation with the field, the MOHLTC’s exercise of final decision rights in policy development reinforced limitations on managerial discretion. Top-down implementation featured considerable conflict over the means of policy achievement (i.e. measurement components, resources, timelines, and some service protocols). Conflict was often met with concern amongst local public health informants over the prospective utility of performance information for improving population health outcomes. The province’s adoption of continuous quality improvement, presenting both barriers and facilitators, also confounded the prospect of substantial systemic improvement. CONCLUSION: This empirical examination of a nascent and evolving system of public health accountability and performance management strongly emphasized a control orientation with some elements supporting results. The bridging of these three fields and the application of these two cross-cutting themes provided a useful basis on which to understand public health accountability and performance improvement in Ontario. This approach merits use in future examinations of this or similar systems, particularly where performance output and outcome information is available.
Navigating Bodies, Borders and the Global Game: An Ethnography of Youth, Football and the (Productive) Politics of Privation in Ghana, West Africa
Keywords: Agency
Ethnography
Football
Mobility
Poverty
Youth Masculinities

This dissertation explores the precarity and politics of youth as it intersects with the game of football in postcolonial Ghana. Departing from scholarly assertions of a ‘crisis’ of youth in its masculine guise, the study is predicated on the lived experiences of a male youth citizenry excluded from the prosperous narrative of Ghana’s neoliberal state, and unable to procure the basic means to work, wage and wedlock. Drawing on multi-sited ethnographic fieldwork in southern Ghana, I ask of how this generation of peripheral male youth construct the game of football vis-à-vis the precarious nature of their societal ‘becoming’, and their broader quest to live productively through the fractured, crisis-ridden exigencies of these neoliberal times. Drawing on the metaphor-concept of the borderland, I proceed to argue that the game of football – both as a mediated form of global popular culture and a hegemonic masculine practice – has come to represent an alternative source of mobility and a most millenarian resolution to the ‘crisis’ of youth in its masculine and West African guise. I contend that the game now serves as a primary vehicle for utopian imaginaries of future amongst male youth in Ghana, where migration and the quest to ‘go outside’ have become fundamental features of a youth culture edging ever-further away from its former anchoring in Pan-African narratives. Ultimately, this project is an ethnography of the non-linear journeys that are enacted by male youth in their quest to become mobile out of Africa, and through their corporeal investment in the ‘global’ game. Stretching from the impoverished hinterlands of Accra to the insulated rural confines of one of West Africa’s premier football academies, it is an ethnography which speaks to the virile forging of personal biography amidst postcolonial history – its foremost contribution being to illuminate the productive politics of youth, agency and mobility as they manifest on the margins of the modern world.
Physiognomy as a Strategy of Persuasion in Early Christian Discourse
Keywords: Early Christianity
Physiognomy

Abstract Ancient physiognomic thought held that the body and soul were intrinsically related, and that observation of a subject's physical appearance provided insight into his or her character. Beyond being a diagnostic tool, however, physiognomy was also used as a strategy of persuasion to bolster or malign an individual's character to an author or speaker's audience, and appears in a host of different ancient genres. However, with a few notable exceptions, the important role that physiognomic thought played in early Christian texts and discourse has not received the scholarly attention it warrants. The following addresses some of the different ways in which physiognomy was employed as a form of rhetoric by early Christians. It was utilized as a means of undermining or discrediting theological opponents or "heretics" on the one hand, but as a strategy for positive self-representation among their own detractors on the other. Some early Christians also used physiognomy to reinforce their understanding of Paul as a philosopher: the description of Paul's physical appearance in the Acts of Paul and Thecla is best understood as designed to evoke the image of the prototypical ancient philosopher in general, and Socrates in particular. Here the importance placed on "looking the part" of a given type of person in antiquity underlies this presentation. Related to this, this dissertation also addresses the phenomenon that arises when the opposite is the case, namely the conception of Jesus as being physically unattractive based on a literal interpretation of the suffering servant imagery in Isaiah. This dissertation demonstrates that physiognomic thought held important persuasive traction for early Christian authors negotiating boundaries and ideologies of group self-identity.
The Mechanisms of Genome Entry in Bacteriophage HK97
Keywords: bacteriophage
FkpA
genome entry
PtsG
superinfection exclusion
tape measure protein

The process of entry of the bacteriophage genome into host cells is poorly understood. In this thesis, I used bacteriophage HK97 as a model to investigate the mechanisms of entry. Phage genome entry begins with adsorption of HK97 to the outer membrane receptor, LamB. Next, the phage DNA passes from the phage capsid through the barrier of the cell envelope to reach the cytoplasm where it can be replicated. The mechanism behind the transfer of the DNA is unknown, though it involves interactions between host and phage components. Using host gene knockout mutants, I searched for proteins involved in entry of bacteriophage HK97 and identified required proteins found within the host cell envelope, FkpA and PtsG. These proteins are not required by all phages including some with a high degree of sequence identity compared to phage HK97. I also found a phage HK97 protein, gp15, whose expression was able to block entry of the same phages that required both PtsG and FkpA. Changes in the requirement of a phage for either FkpA and PtsG for entry and the sensitivity of a phage to gp15 correlated with sequence divergence in one particular phage protein, the tape measure protein (TMP). I illustrated that TMP sequence is responsible for dictating the requirements for FkpA and PtsG as well as the sensitivity to gp15 by exchanging TMPs between phages. The requirement for PtsG and the sensitivity to gp15 were mapped to residues between 452-600 within the HK97 TMP. PtsG mediates entry of the HK97 genome through a direct interaction with these residues within the TMP, and gp15 blocks entry by trapping the PtsG TMP complexes to prevent the formation of the structure that mediates entry.
Applications Of The Signed Distance Function To Surface Geometry
Keywords: 30C15
53A05
53B20
Differential Geometry
Surfaces in Euclidean Space

In studying the geometry of a submanifold, it is often convenient to represent the submanifold as the zero set of an appropriately chosen defining function. For a hypersurface, a natural function to consider is its signed distance function. In this thesis we study the differential geometry of surfaces embedded in Euclidean 3-space by expressing the curvatures and principal directions of a surface in terms of the derivatives of its signed distance function. This allows us to derive many established and new results using simple multivariable calculus. After first defining the signed distance function to a surface and demonstrating its basic properties, we prove several integral formulas involving the surface's principal curvatures, including a generalization of the divergence theorem. We then derive a complex linear differential equation in the principal radii and directions of the surface that is based on the Mainardi-Codazzi equations, and establish a connection between the function in this equation and the surface's support function. These are used to obtain a characterization of the principal directions around an umbilical point on a surface, and to reduce the Loewner index conjecture for real analytic surfaces to a problem about the location of the roots of a specific class of polynomials. Finally, we extend our generalized divergence theorem to submanifolds of arbitrary co-dimension equipped with a Riemannian metric.
Elucidation of the Plasmacytoid Dendritic Cell Response to HIV-1
Keywords: HIV
Interferon
Plasmacytoid Dendritic Cell
Tim-3

Plasmacytoid dendritic cells (pDCs) are a specialized type I interferon (TI-IFN) producing cell of the innate immune system; they are critical in the control of HIV-1 infection. pDCs isolated from the blood during HIV-1 infection demonstrate profound dysfunction in their ability to produce the prototypic TI-IFN, IFN-α. In this thesis, I explore the factors that lead to pDC dysfunction during HIV-1 infection. Tim-3 (CD366), typically associated with activated T cells and of current interest as a target for immunotherapy, was identified on pDCs and shown to be upregulated during HIV-1 infection. Tim-3 expression in HIV-1 infection correlated with pDC dysfunction. Similarly, in healthy donors, Tim-3 expression was PI3K-dependent and induced in response to both TLR activation and in response to IFN-directly. Strong toll-like receptor (TLR) agonists, such as CpG, imiquimod and Sendai virus were potent inducers of Tim-3, leading to subsequent dysfunction. The mechanism of action of Tim-3 was also explored. Anti-Tim-3 antibodies did not affect pDC function. However, surface Tim-3 associated with submembrane disruption of TLR after activation. Tim-3 staining intensity inversely correlated with decreased IRF7 staining and intracellular Tim-3 co-localized with p85 and IRF7 within LAMP1+ lysosomes. Most surprisingly, we found that HIV-1 itself was a poor inducer of Tim-3 expression. Thus, we investigated the agonistic capacity of HIV-1 on pDCs. When the amount of TLR7 triggering viral RNA was taken into consideration, influenza virus was a vastly superior pDC agonist. Efficient uptake of HIV-1 was observed, but failed to initiate a response, however, if a second agonist was added to the culture, HIV-1 augmented that response in a TLR7 dependent manner. Thus, we investigated the possibility of HIV-1 structural proteins in the evasion of the pDC response. We found that chemical agents that target the zinc-finger nuclease region of the nucleocapsid increased IFN-α production in response to HIV-1 stimulation. Thus, I propose a putative model of pDC dysfunction during HIV-1 infection where HIV-1 is endocytosed and remains dormant within the pDC endosome with the capacity to augment the response to secondary pathogens leading to disproportionate responses and Tim-3 upregulation.
Addressing Uncertainties in Health Utilities
Keywords: Empirical Bayes
Health Utilities
Mapping Algorithms
Multiple Imputation
Shrikage Estimator
Uncertainties

Uncertainties in health utilities have received little attention in the literature. Health utility is a preference-based quality of life measure. It is commonly used to calculate quality-adjusted life years and to conduct cost-utility analysis. Under-estimation of the uncertainty of health utilities will lead to under-estimation of the uncertainty of the results of any economic evaluation that requires the use of health utilities. This thesis focuses on addressing uncertainty in health utilities in three areas: (1) the underestimation of uncertainties of health utilities derived from mapping algorithms and the derivation of methods to address it, (2) the challenge with prediction error in multi-attribute utility instrument valuation studies with small sample size and an emphasis of the use of shrinkage estimators as a potential solution, and (3) the underestimation of uncertainties of health utilities derived from multi-attribute utility instruments with an emphasis of the use of multiple imputation as a potential solution. For each issue, theoretical statistical explanations are provided and then followed by the proposed methods to address those issues. Simulation methods are also used to explore the usefulness of the proposed methods.