VictorJuiz/thesis huggingface dataset:
Factors Affecting the Fracture Strength and Fatigue Resistance of Molar Crowns Produced Using a Zirconia-based System
Keywords: Ceramic
Crown
zirconium oxide
Fracture
Fatigue

Zirconium-oxide ceramic was introduced as a potential restorative material for posterior teeth due to its superior mechanical properties. However, zirconia is opaque and needs to be masked with an esthetic veneer. Short-term clinical studies showed a high rate of veneer chipping/delamination for zirconia-based posterior crowns. This may be attributed to either inferior strength of the veneering porcelain or weakness in the zirconia-veneer bond. The aims of this in-vitro project were to analyze some of the factors that can influence the performance of zirconia-based molar crowns and to characterize the zirconia-veneer interface. The project consisted of four parts. The first part aimed to evaluate the effect of total thickness, core thickness and veneering technique on fracture mode and strength of zirconia-porcelain specimens of simple geometry. Results indicated that all three variables significantly affected mean fracture load, while only two (total thickness and core thickness) affected fracture mode. The second part aimed to assess the effect of core design and thickness on fatigue resistance, fracture strength and fracture mode/extent of zirconia-based molar crowns. Results indicated that core thickness, but not core design, had a significant effect on fracture strength. The anatomically-shaped core design reduced the size of the veneering porcelain fracture. In the third part, the effect of core design and two different CAD-CAM-produced veneering materials on fatigue resistance, fracture load and fracture mode of zirconia-based molar crowns was examined. Results indicated that the veneering material, but not core design, had a significant effect on fracture load and mode. The fourth part aimed to characterize the zirconia-porcelain interface using modern surface analysis techniques (Time of Flight Secondary Ion Mass Spectrometry (ToF-SIMS) and X-ray Photoelectron Spectroscopy (XPS)). Results indicated chemical changes of zirconium along the interface. In conclusion, improving the strength of the veneering layer by using pressed veneering porcelain can enhance performance of posterior zirconia-based crowns in comparison to manual build-up technique. Furthermore, fusing a CAD-CAM-produced veneering layer to the underlying zirconia core is a promising technique that can augment veneering porcelain strength and enhance zirconia-porcelain bond. Modifying core design, crown thickness and core thickness can improve performance of zirconia-based molar crowns.
Genetic Factors Contributing to Body Weight in Anorexia Nervosa and Bulimia Nervosa
Keywords: anorexia nervosa
bulimia nervosa
eating disorders
genetics
candidate gene
body weight

Anorexia nervosa (AN) is an eating disorder (ED) with substantial morbidity and the highest mortality among psychiatric disorders. Low body mass index (BMI) is the sine qua non of AN, and behaviours associated with reaching it are the primary reason for AN's high morbidity and mortality. Low BMI is also the main criterion diagnostically separating AN from bulimia nervosa (BN). The aim of this dissertation was to determine the role of genes regulating weight and appetite in BMI in AN and BN. Study 1 utilized carefully selected DNA samples to explore the role of markers in the leptin, melanocortin, and neurotrophin system genes with known or putative function in AN, BN, and controls, as well as in lifetime BMIs in EDs. Study 2 investigated dopamine pathway genes and FTO in weight regulation in a large sample of AN cases. The results revealed that an MC4R variant linked to antipsychotic-induced weight gain was underrepresented in AN, and AGRP and NTRK2 genetic variants were linked to minimum BMI in AN and maximum BMI in BN, respectively. In Study 2, a significant association between FTO and BMI at recruitment was observed. To our knowledge, this is the first study to utilize two distinct but complementary genetic approaches in the study of weight in EDs. These genetic findings may serve as an important first step toward gaining a better understanding of weight regulation in AN and BN, as well as having the potential for developing more effective treatment options and providing a highly specific target for novel medications. Alongside this work, other ED genetic studies utilizing different clinical phenotypes were also carried out during my PhD, and the papers published are inserted as appendices for reasons of thematic unity.
Investigating the Cerebral Cavernous Malformation 3 (CCM3) Pathway in a Zebrafish Model of CCM Disease
Keywords: Vascular Malformations
Zebrafish
Angiogenesis
CCM3

Cerebral cavernous malformations (CCMs) are vascular anomalies of the central nervous system characterized by enlarged, thin vascular channels that can result in hemorrhage, stroke, and death. 40% of CCMs are familial and arise due to mutations in genes encoding three unrelated proteins: CCM1 (KRIT1), CCM2 (Malcavernin/OSM) and CCM3 (PDCD10). Biochemical and mutant studies suggest that CCM1 and CCM2 act as part of a physical complex to regulate vascular morphogenesis and integrity, while mouse Ccm3 mutant and cell culture data suggest an independent role for CCM3. There is currently no pharmacological treatment available to reverse lesion formation due to an incomplete understanding of the molecular pathways that lead to familial or sporadic CCMs. Here, I examine the role of ccm3 in cranial vessel development using the zebrafish model system. I establish a new vertebrate model of CCM disease, where inhibition of ccm3 leads to dilation and mispatterning of cranial vessels, resembling the human disease pathology. I show that zebrafish ccm3 plays a role distinct from ccm1/2 in cranial vascular development and acts via Stk25b, a GCKIII kinase previously shown to interact with CCM3. Further, I provide the first characterization of the zebrafish striatin proteins, which are members of the large STRIPAK complex along with CCM3 and STK25. I demonstrate an important role for striatin1 in cranial vascular integrity, which suggests it may be an effector of CCM pathogenesis. My investigation of the cellular mechanisms responsible for observed cranial vasculature defects indicates aberrant vesicular trafficking in ccm3 and striatin1 morphants. Resulting defective localization of factors important for vascular integrity, such as RhoGTPase Cdc42, may be responsible for the observed ccm3 and striatin1 phenotypes. Together, this research demonstrates important functional relationships between three members of STRIPAK complex CCM3, GCKIII, and striatin, and therefore suggests a role for STRIPAK in vascular integrity.
NLF-1 delivers a sodium leak channel to regulate neuronal excitability and modulate rhythmic locomotion
Keywords: leak channel
neuronal excitability
channel trafficking
rhythmic locomotion

Neuronal excitability is determined by complex interactions between a repertoire of ion conductance across the membrane. The sodium and potassium leak conductance primarily establish the resting membrane potential (RMP) and excitability of the neuron. However, the molecular identity of the ion channel carrying the sodium leak remains a mystery until recently. A conserved cation channel, NALCN in mouse and NCA in Caenorhabditis elegans, in association with auxiliary subunits UNC-79 and UNC-80, contribute to the sodium leak, and affect the RMP and excitability of neurons. In my study, I first describe the identification and characterization of a novel, functionally conserved and dedicated endoplasmic reticulum (ER) protein NLF-1 (NCA Localization Factor-1) that regulates neuronal excitability by promoting the axon localization of the NCA channel. The loss of either NLF-1 or NCA leads to a reduced sodium leak current, a hyperpolarized RPM, and decreased activity in premotor interneurons. Next, I describe the functional conservation of NLF-1. The mouse NLF-1 is localized to ER when expressed in C.elegans neurons and mammalian cell lines. In C. elegans, it functionally substitutes for NLF-1. In primary mouse cortical neuron cultures, shRNA-mediated knockdown of mNLF-1 leads to reduced sodium leak and hyperpolarized RMP. mNLF-1 physically interacts with NALCN in vitro. Lastly, I show that restoring NLF-1 in C. elegans premotor interneuron circuits alone significantly restores the animal’s rhythmic locomotion, defining a critical role of the premotor interneuron network in the initiation or maintenance of rhythmic locomotion. Collectively, a sodium leak channel, delivered to axon membranes by a dedicated ER protein, constitutes a conserved molecular mechanism that underlies the excitability of a neuronal network critical for the initiation and maintenance of rhythmic locomotion.
The State of T Cell Immunity against Influenza Virus in Humans and Exploration of Potential Strategies to Enhance Cell-Mediated Protection from Influenza Infection
Keywords: influenza
CD8 T cells
immune memory
vaccination
immune aging
human immunology

There is great interest in developing a broadly efficacious influenza vaccine, as current antibody-eliciting formulations require annual re-immunization and are not effective in those most susceptible to influenza-related mortality. In contrast to antibody responses, influenza-specific CD8 T cells are broadly cross-reactive between strains, and previous reports have indicated that cellular immunity is a better correlate of protection than neutralizing antibody titers. However, little is known about the state of influenza-specific cellular immunity in humans. To address this, we examined the CD8 T cell responses of humans of different age, vaccination, and infection history to determine whether any of these factors alter the functionality of cell-mediated immune memory. We identified distinct phenotypic changes in influenza-specific T cells from older subjects, which were predictive of their antibody responses upon influenza vaccination. However, the inactivated vaccine itself had no discernible immediate or persisting effects on influenza-specific CD8 T cell responses of young or old humans. Furthermore, adults (mean age 44) who acquired natural influenza infections of the 2009 pandemic strain also had similar influenza-specific CD8 T cell responses 8-10 months after infection compared to controls. From these results, we concluded that influenza infection and vaccination do not result in significant long-term boosting of pre-existing influenza-specific CD8 T cell responses and that a lifetime of acute influenza infections can result in a senescent phenotype similar to chronically stimulated dysfunctional cells. These data suggested that boosting functional influenza-specific CD8 T cells in middle age that endure into old age could enhance protection in the elderly. To test this, we evaluated a murine prime/boost model using the 4-1BB costimulatory pathway to induce persisting CD8 T cell responses. 4-1BBL signals during boost immunization resulted in superior numbers and function of persisting influenza-specific CD8 T cells. Since TRAF1, an adaptor molecule for 4-1BB signaling, is polymorphic in humans, a preliminary investigation was undertaken to assess the effect of TRAF1 polymorphisms on T cell responses. Although a range of TRAF1 expression was detected, all donors exhibited enhanced T cell activation with anti-4-1BB, suggesting that targeting this pathway has therapeutic potential in a human T cell-stimulating influenza vaccine.
Multiscale Modeling of Nano-Reinforced Aerospace Adhesives
Keywords: Nanocomposites
multiscale modeling
carbon nanotubes
atomistic based continuum
aerospace
adhesives
micromechanics

In this work, the mechanical properties of carbon nanotube reinforced structural adhesives are investigated both theoretically and experimentally. The theoretical investigations employ a novel multiscale modeling technique that integrates the governing atomistic constitutive laws in a continuum framework. This technique takes into account the discrete nature of the atomic interactions at the nanometer length scale and the interfacial characteristics of the nanotube and the surrounding polymer matrix. Fundamental to the proposed concept is the notion that atomic bonds between two atoms act like load-bearing continuum elements, whereas individual atoms can be represented by nodes of the related structure. Molecular dynamic interatomic potentials were used to derive the constitutive behavior of the finite elements thereby reducing the computational complexity of the problem while maintaining the accuracy of the model. The governing formulations were developed to allow for the atomistic-based continuum modelling of nano-reinforced structural adhesive bonds on the basis of a nanoscale representative volume element that accounts for the nonlinear behaviour of its constituents; namely, the reinforcing carbon nanotube, the surrounding adhesive and their interface. This model was used to evaluate the constitutive response of carbon nanotubes with varied chiral indices, the load transfer and the strengthening mechanisms between the nanotube and the surrounding adhesive as well as their interfacial properties. The newly developed representative volume element was then used in analytical (Mori-Tanaka) and computational (finite element) micromechanical modeling techniques to investigate the homogeneous dispersion of the reinforcing element into the adhesive considered upon its mechanical properties. In this way, the model allowed for the prediction of the full constitutive response of the bulk composite. The work is further extended experimentally to establish the relative merits of using carbon nanotubes as mechanical reinforcements in structural adhesive bonds. In this part of the research, we identified an appropriate dispersion methodology to achieve a uniform distribution of the nanotubes in the epoxy matrix and evaluated its mechanical properties. Scanning electron and transmission electron microscopy techniques were routinely used to characterize the quality of the dispersion, the geometrical properties of the nanotubes, and the fracture surfaces of the test specimens.
The role of Diencephalon/Mesencephalon Homeobox 1 (Dmbx1) in Zebrafish Visual System Development
Keywords: zebrafish visual system
cell cycle
dmbx1

Visual system development is highly conserved across all vertebrates. The retina receives visual inputs and transfers the sensory information to the brain for processing. In zebrafish, the largest synaptic target of the retinal projections is the optic tectum, which acts as a relay center that organizes visuomotor activities. My research has revealed that the transcriptional regulator Diencephalon/mesencephalon homeobox 1 (dmbx1), of which there are two paralogs represented in the zebrafish genome, plays a pivotal role in coordinating neurogenesis in these functionally integrated regions. During the course of my doctoral research, I have characterized the functions of dmbx1 paralogs in zebrafish retinal and tectal development and showed that they are required for sustaining growth in the retina and the optic tectum. Functional deficiency of the dmbx1 genes caused a severe cell cycle defect in progenitor cells, resulting in reduced tissue growth and delayed differentiation within those structures. Further analysis revealed that progenitor cells require dmbx1 to reduce the level of cyclinD1 expression, in order to promote cell cycle exit. In addition, I discovered that misexpression of both dmbx1 genes could duplicate wnt3a expression and lead to enhanced proliferation at the tectal midline. This suggested that the two transcription factors could regulate different cellular mechanisms with the presence of canonical Wnt signaling. Overall, this research demonstrates that dmbx1 is involved in the timing of retinal and tectal neurogenesis, and provides novel insight into the transcriptional regulation of visual system development in vertebrates.
The Atomic Capital of the World: Technoscience, Suburbanization, and the Remaking of Pittsburgh during the Cold War
Keywords: Technoscience
Suburbs
Pittsburgh
Cold War
Nuclear industry
Urban renewal
Scientists and engineers

Using metropolitan Pittsburgh as an example, this dissertation traces the relationship between suburbanization, the remaking of urban space, technoscience, and the Cold War. It argues that producing spaces for technoscience was a central part of the remaking and suburbanization of metropolitan Pittsburgh. An elite regional alliance enrolled scientists and engineers in their efforts to transform the region from a center of manufacturing to a place focused on rationalizing, administering, and financing production that took place elsewhere. In doing so they created a technological landscape that cast the region’s transformation as part of an inevitable search for progress and as a widely deployable symbol of capitalist rebirth. To enroll scientists and engineers in their efforts they created spaces – research centers, residential suburbs, and urban renewal projects among others – that helped reproduce scientists and engineers’ privilege and authority. Metropolitan Pittsburgh became a key site where technoscience took place, but it was also remade through technoscience. This points to the need for a broader understanding of the processes that reproduce scientists and engineers and their authority and the spaces where technoscience takes place.
Securitizing the Coast of Somalia: Political Geographies of Piracy
Keywords: Security
Development
Gender
Political Economy
Somalia
Piracy
United Nations
Containment
Political Geography
Geopolitics

This dissertation is an organizational ethnography about the process of securitizing piracy off the coast of Somalia. Rather than assume an apolitical shift towards a security-development counter piracy framework, this research explores the relationship between the actors, motives, and contexts underlying efforts to securitize Somali piracy. It seeks to draw out commonly held assumptions about the causal link between security, development and piracy in Somalia. In an effort to disrupt these assumptions, it offers an alternative understanding that highlights the political geographies and economic motivations for securitizing piracy. Through an exploration of the discourse and practices of a United Nations’ messaging campaign it demonstrates the centrality of manufactured narratives, identity constructions, and gendered practices in efforts to securitize piracy. It also explores how securitizing piracy became institutionalized within participating sectors and enabled securitizing actors to rework the spatial and temporal geographies of combating piracy to gain institutional advantage. This dissertation argues that the process of securitizing piracy is a geopolitical project that reflects a wider, emerging trend of employing security-development technologies as disciplinary strategies for the prevention and containment of particular actions and bodies. It reveals that securitizing actors, including the development sector, are complicit in (re)working territorial sovereignties and producing markets of security and development. As these markets are produced in Somalia, it demonstrates the specific local manifestations of broader global patterns of racialized incarceration and criminalization in contemporary millennial capitalist crisis/expansion at work in numerous other locations around the world.
A Public Health Ethics Analysis of Consent as a Least Restrictive Alternative for Newborn Screening in Ontario
Keywords: public health ethics
newborn screening
qualitative research
case study

Background: Public health ethics (PHE) is a theoretical lens used to analyze public health initiatives. PHE strives to find a balance between achieving population health goals and promoting individual liberty. To reach this balance PHE scholars encourage the use of least restrictive alternatives. However, least restrictive approaches are often taken for granted as presumed goods and their ability to protect individual liberty and the common good is often assumed. I examine this presumption through an examination of informed consent – implied and express – for newborn screening (NBS) in Ontario. Methods: I conducted an exploratory qualitative case study to understand how 57 individuals involved in the lobbying, development, and implementation of expanded NBS in Ontario perceive consent policy for NBS. Semi-structured interviews were audio-recorded and transcribed. Data transformation was descriptive, analytic, interpretive, and applied. Findings: Participants described their attitudes towards informed consent for NBS. PHE principles of least restrictive alternatives, effectiveness, autonomy, and social justice were key themes within implied consent data. Participants appreciated implied consent’s capacity to achieve high screening uptake, yet doubted its ability to generate informed decisions. Regarding express consent, participants introduced a host of concerns – interpreted as harm-causing – perceived to threaten NBS’s public health goals and individual autonomy. I applied the practice of consent to a PHE framework as a mechanism through which to consider consent policy for NBS in a way that moves towards achieving a balance between fulfilling public health goals and respecting individual rights and freedoms. Conclusion: What participants in advisory capacities (and those to whom they turn for input) think about consent for NBS arguably influences their recommendations to the government. Challenging informed consent as a presumed good and submitting the practice of consent to the same ethical scrutiny as the NBS program itself legitimates the concerns of those wary of consent, illuminates the perceived benefits and risks of consent, and creates an opportunity to mitigate risks before implementing or adjusting consent policy. Treating the practice of consent as an intervention in theory could work to ensure that the ideals reflected in the concept of consent are realized in NBS practice.
Verifiable Fictions: Didactic Narrative in the Antirealist American Novel
Keywords: American Literature
Antirealist Fiction
Didactic Literature
Literary Cognitivism

This study examines the revival of didactic narrative in exemplary antirealist American novels of the last forty years. In chapters on Don DeLillo, William H. Gass, William Gaddis, and Richard Powers, I trace the ways in which these writers deploy antirealist literary practices of ontological destabilization, metafictional digression, and deliberate textual difficulty as ways of revisiting the proposition, rejected by many among their cohort, that fiction may have pedagogical value. These novelists attempt to reconcile their commitment to formal innovation with the belief that fiction offers cognitive gains, beholden though it is to humanistic values of the sort that avant-garde principles ostensibly repudiate. As such, these novelists grapple with an ambivalent conception of the novel as both a self-enclosed aesthetic object and a culturally promiscuous text that samples from--and speaks back to--a range of nonfictional discourses. In reading these works, I consider the epistemological potency of literature within a tradition of antirealist experimentation that has typically disavowed any affiliations with the didactic, and in particular its pejorative connotations with rigid, authoritarian moralizing. Drawing upon Jacques Rancière's model of the ignorant schoolmaster, I argue that these novelists reject the mantle of encyclopedic mastery, deploying instead a "pedagogy of failure" that encourages an autodidactic mode of verification among readers. In exploring scenes of failed instruction, these novels reconfigure postmodern authorship in terms of a reluctant teacher addressing an audience of recalcitrant students. These works thus acclimatize readers to a mode of attention that encourages a continual revision of one's beliefs and attitudes in the wake of failure and misunderstanding. In so doing, these authors attempt--with varying success--to avoid the self-imposed cultural marginalization that comes with adhering to antirealism's more ludic, oppositional strictures.