VictorJuiz/thesis huggingface dataset:
Matador and the Regulation of cyclin E1 in Normal Human Placental Development and Placental Pathology

Preeclampsia and molar pregnancy are two devastating placental pathologies characterized by an immature proliferative trophoblast phenotype accompanied by excessive cell death. It is therefore of paramount importance to study the regulation of cell fate in the placenta, to gain a further understanding of the mechanisms that contribute to these diseases. In this dissertation we report that during normal placental development and in preeclampsia, Matador (Mtd), a pro-apoptotic member of the Bcl-2 family, has a dual function in regulating trophoblast cell proliferation and death. Importantly, we reveal a novel role of Mtd-L in promoting cyclin E1 expression and cell cycle progression. Of clinical importance, we also identify that both cyclin E1 and the CDK inhibitor p27, are increased in severe early onset preeclampsia. However, the inhibitory function of p27 in this pathology may be hampered due to its increased phosphorylation at Ser10, resulting in its nuclear export. Of equal importance, data presented demonstrate that placentae from severe early onset preeclampsia display a molecular profile distinct from late onset preeclampsia or intrauterine growth restricted pregnancies. In the final data chapter we demonstrate that Mtd is highly expressed in molar tissue, where it localizes to both apoptotic and proliferative cells. Our data suggests that an abundance of Mtd and cyclin E1 in conjunction with the low level of p27 may contribute to the hyperproliferative nature of the disorder. The body of work in this dissertation uncovers novel insights into the regulation of trophoblast cell fate. Importantly, the impact of Mtd on cyclin E1 to promote G1-S transition is a novel mechanism found to regulate trophoblast cell proliferation in normal and pathological placentation. Equally important is our identification of molecular differences between placental pathologies that may help to differentiate early and late onset preeclampsia, IUGR and molar pregnancy.

Keywords: Preeclampsia
Molar pregnancy
Bcl-2 family members
Matador
Human Placenta
Trophoblast
cell cycle
cyclin E1
Advisor: Caniggia, Isabella
Jurisicova, Andrea
Gold Nanoparticles for Efficient Tumour Targeting: Materials, Biology & Application

As of 2010, cancer remains the leading cause of death in Canada, and second in the United States of America. This is despite decades of research into development of chemotherapeutics and diagnostics. A number of major challenges have prevented new discoveries from translating into a reduction in mortality rates. One challenge is the poor efficiency with which anti-cancer agents (diagnostic contrast agents and therapeutics) reach deregulated cells in the body. Therefore, development of new methods and technologies for improving efficiency of delivery has been a focus of research. Nanoparticles are leading candidates for improving the efficiency of delivery because they can act as payload vehicles for anti-cancer agents, because it is possible to mediate their interaction with biological systems and thus their pharmaockinetics, and because they can exploit inherent vulnerabilities of tumours. This thesis describes the results from a series of research projects designed to progress our understanding of how nanoparticles behave in vivo, and how their design can be optimized to improve tumour targeting.

Keywords: Nanotechnology
Cancer
Tumour
Nanoparticle
Advisor: Chan, Warren C. W.
Health Expenditures, Time to Death, and Age: A Study of Individual-level, Longitudinal Data to Identify the Combined Role of Age and Mortality in Determining Health Utilization of the Elderly

While there is great concern about the potential impact of aging populations on health care systems in the developed world, evidence from recent decades has shown at best a weak relationship between population aging and health expenditures at the aggregate level. This thesis explores the literature that frames the relationship between age and health care utilization in the context of reduced mortality and shorter periods of morbidity at the end of life. We add to this literature with an empirical study of individual health expenditures of the British Columbia senior population in the years 1991-2001 in the categories of hospital services, continuing care, doctor billings, and pharmaceutical prescriptions. Expenditures for decedent and survivors of the same age are compared and are fitted to a model using age and time-to-death as explanatory factors. The partial derivative of the model with respect to age is analyzed for empirical estimates of the effect of age after controlling for time-to-death. Results show that decedent costs rose over the study period while costs for survivors fell, particularly in continuing care, so that the relative cost of dying increased. The effect of age, after controlling for time to death, was muted or negative for hospitals, doctors, and drugs, but strongly positive for continuing care and, as a result, for all services combined. Overall, these results suggest that age is not a ‘red herring’, as some researchers have suggested, with respect to forecasting future demands on health systems. While future reductions in mortality and morbidity could mitigate pressures on hospitals, aging populations will put increased pressure on long-term residential care and other forms of social care.

Keywords: Health expenditures
Demographics
Economics
Cost of dying
Advisor: Coyte, Peter C.
The Principals' Role in Facilitating Inclusive School Environments for Students Considered to be Experiencing Behavioural Problems in Intermediate Level Schools

This research examines the understandings and practices of inclusive minded principals toward facilitating the development of inclusive school environments for intermediate level (Grade 7 and 8) students who are experiencing behavioural problems in their schools. Qualitative interviews with 16 principals across 4 school districts were conducted to explore how these inclusive minded principals conceptualize and understand the needs of this particular group of students, and what they consider to be their roles and responsibilities as principals in meeting these needs. The data suggest that despite the number of barriers that serve to hamper principals’ efforts to develop the ideal inclusive school, there are a great many strategies principals intentionally use to facilitate change toward more inclusive school cultures and pedagogy. These strategies emanate from, and are reflective of, an inclusive philosophy that is common among participants. Principals’ individual philosophies and ideologies serve as a compass in guiding decision-making and actions that affect staff, students, and the wider school community. In an inclusive school, these ideologies are reflective of the principles of inclusion, such as the need to create a culture of care wherein all students feel valued, supported, and experience a sense of belonging and individual self worth. The implications of this research toward improving the schooling experiences of students with behavioural problems as well as other marginalized groups of learners are discussed in the context of the call for a re-culturing of schools toward more inclusive environments.

Keywords: behavioural students
inclusion
inclusive leadership
facilitating change
re-culturing of schools
principals’ strategies
culture of care
at risk
Advisor: Ryan, James
Microfluidic Development of Bubble-templated Microstructured Materials

This thesis presented a microfluidic preparation of bubbles-templated micro-size materials. In particular, this thesis focused on the microfluidic formation and dissolution of CO2 bubbles. First, this thesis described pH-regulated behaviours of CO2 bubbles in the microfluidic channel. This method opened a new way to generate small (<10 µm in diameter) with a narrow size distribution (CV<5%). Second, the microfluidic dissolution of CO2 bubbles possessed the important feature: the local change of pH on the bubble surface. This allowed us to encapsulate the bubbles with various colloidal particles. The bubbles coated with particles showed a high stability against coalescences and Ostwald ripening. The dimensions and shapes of bubbles with a shell of colloidal particle were manipulated by the hydrodynamic and chemical means, respectively. Third, we proposed a microfluidic method for the generation of small and stable bubbles coated with a lysozyme-alginate shell. The local pH decrease at the periphery of CO2 bubbles led to the electrostatic attraction between lysozyme on the bubble surface and alginate in the continuous phase. This produced the bubbles with a shell of biopolymers, which gave a long-term stability (up to a month, at least) against the dissolution and coalescence. Fourth, we presented a single-step method to functionalize bubbles with a variety of nanoparticles. The bubbles showed the corresponding properties of nanoparticles on their surface. Further, we explored the potential applications of these bubbles as contrast agents in ultrasound and magnetic resonance imaging.

Keywords: microfluidics
microbubbles
carbon dioxide
colloids
pickering emulsion
ultrasound imaging
magnetic resonance imaging
nanoparticles
Advisor: Kumacheva, Eugenia
Dynamics of Carriers and Photoinjected Currents in Carbon Nanotubes and Graphene

This thesis reports results from the investigation of optically-induced carrier dynamics in graphite and graphitic carbon nanostructures. In this first set of experiments, the dynamics of photo-excited carriers in exfoliated graphene and thin graphitic films are studied by optical pump-probe spectroscopy. Samples ranging in thickness from 1 to 260 carbon layers are deposited onto an oxidized silicon substrate. Time-resolved reflectivity and transmissivity are measured at 1300 nm, following excitation by 150 fs, 800 nm pump pulses at room temperature. Two time scales are identified over which the extracted transient dielectric function returns to its quiescent value. A fast decay time of ~200 fs in graphene is associated with hot phonon emission and increases to ~300 fs for thicknesses greater than only a few carbon layers. The slow decay time, associated with hot phonon interaction and/or carrier recombination, increases more gradually, from ~2.5 to 5 ps over ~30 layers. A simple model suggests the thickness dependence of the slow decay time is likely a result of thermal diffusion into the substrate. In the second set of experiments, coherently-controlled two-colour injection photocurrents are generated via quantum interference of single- and two-photon absorption in bulk graphite and a variety of single-walled carbon nanotube samples, such as a CVD-grown aligned forest of nanotubes (tube diameter dt = 2.5 ± 1.5 nm), and both arc discharge (dt = 1.44 ± 0.15 nm) and HiPco (dt = 0.96 ± 0.14 nm) nanotube films separated by electronic type (metallic vs. semiconducting). At pump wavelengths of 1500 and 750 nm, the emitted terahertz radiation is used to estimate a peak current density of ~12 kA/cm² in graphite and a peak current of ~8 nA per nanotube. From the dependence of the injected current on pump polarization, the relative values of the current injection tensor elements are measured, and information is gained on the alignment and birefringence of the nanotube samples. The dependence of the injected current on pump wavelength implies that the currents are likely based on band-band electronic transitions and not on excitonic effects, which govern most linear optical processes.

Keywords: graphene
carbon nanotubes
coherent control
pump-probe
carrier dynamics
quantum interference
Advisor: Driel, Henry M. van
The Dynamics of Shoaling in Zebrafish

A wide array of species, from ants to humans, live or forage in groups. Shoaling – the formation of groups by fish – confers protection from predation and enhances foraging. However, little is known about the detailed characteristics or the dynamics of shoaling. Shoaling is a complex social interaction and a better understanding of its mechanisms and limitations would permit the study of natural and induced changes on social behavior generally in fish. Here, I present data on the shoaling characteristics of zebrafish (Danio rerio). Novel tracking techniques are used to extract detailed trajectories of all members of a free-swimming shoal of zebrafish. Multiple measures of shoaling – such as distributions of nearest neighbor distances, shoal polarizations, and speeds – are calculated, to better describe the subtleties of the behavior including, for the first time, the high resolution spatio-temporal dynamics of shoaling. In addition, a novel criterion is introduced to determine when and how individual fish or sub-groups leave the shoal. Comparisons are presented between the shoaling characteristics of three populations of zebrafish (LFWT, SFWT, AB) and between days and hours of repeated exposure to the same testing environment, demonstrating the gradual effects of habituation on shoaling. In addition, the effects of manipulating the number of fish in the shoal, hunger levels, and predation threat are also examined, lending empirical support to ecological theories on the adaptive functions of the behavior. Finally, the data are compared to two leading theoretical models of shoaling and a novel simulation approach is suggested. The data strongly suggest that various aspects of shoaling in zebrafish are constantly changing, complex, and flexible, representing a dynamic form of social cognition. The study of these characteristics sheds much-needed light on complex social interactions in this popular genetic model organism, which may eventually lead to a better understanding of social behaviors in other species, including our own.

Keywords: Zebrafish
Shoaling
Advisor: Gerlai, Robert
Motivational Factors and Frameworks for Counsellors and Psychotherapists

The purpose of this study was to examine the lived experience of the day-to-day and continuing work motivation of professional counsellors and psychotherapists. A life history methodology was employed to distill discrete motivational factors and to construct broader motivational frameworks. Nine professional mid-career counsellors/psychotherapists (6 women, 3 men, 3 psychologists, 3 social workers, 2 counselling psychologists and 1 privately trained PhD) drawn from private practice (3) and institutional workplaces (6) were given in-depth interviews to delve into the motivational experience occasioned by their work. Employing a series of guided questions each of the research participants were interviewed about the overall experience of the gratifications, satisfactions, and motivations occasioned by their work and discrete motivational experiences in session, in-the moment. Other questions delved into the experience of dissatisfaction and de-motivation, the factors that allowed them to persist in adverse circumstances, changes in their work motivation from the time they first entered the profession, and the effects of their work on their feelings of self-esteem and well-being. Through a grounded theory analysis of the interview transcripts and informed by work motivation theory, the research participants’ observations on their motivational experience were used to construct three models. The first model demonstrated that the overall work motivation of the research participants was generated by the opportunity to simultaneously meet the three universal needs postulated by self-determination theory – autonomy, competence, and relatedness. The second model was based on the phenomenon of privilege experienced by the research participants. In essence, the research participants were motivated to return the gift of intimacy, honour, and trust accorded to them by vulnerable clients in the establishment of the therapeutic bond and alliance, which allowed them to meet their own needs for relatedness and competence and generated feelings of responsibility and obligation to safeguard trust and protect vulnerability. The third model was generated from the research participants’ experience of the process of counselling and psychotherapy, incorporating goal-setting with clients, privilege, in-the-moment experiences of efficacy, and effectance feedback to the realization of proximal goals within the process, which reinforced the motivation to work towards the distal goals of positive outcome. The three models were incorporated into an integrated framework, describing the factors and processes underlying the work motivation, work satisfaction, self-esteem, and well-being of the research participants. The research may be useful for professional counsellors and psychotherapists and the institutions which employ them.

Keywords: Work Motivation of Counsellors and Psychotherapists
Self-determination theory
therapeutic alliance, process factors in counselling and psychotherapy, effectance feedback, self-esteem of counsellors and psychotherapists
Advisor: Piran, Niva
Place Differentiation: Redeveloping the Distillery District, Toronto

What role does place differentiation play in contemporary urban redevelopment processes, and how is it constructed, practiced, and governed? Under heightened forms of interurban competition fueled by processes of globalization, there is a desire by place-makers to construct and market a unique sense of place. While there is consensus that place promotion plays a role in reconstructing landscapes, how place differentiation operates – and can be operationalized – in processes of urban redevelopment is under-theorized in the literature. In this thesis, I produce a typology of four strategies of differentiation – negation, coherence, residue, multiplicity – which reside within capital transformations and which require activation by a set of social actors. I situate these ideas via an examination of the redevelopment of the Gooderham and Worts distillery, renamed the Distillery District, which opened to the public in 2003. Under the direction of the private sector, the site was transformed from a space of alcohol production to a space of cultural consumption. The developers used a two pronged approach for the site’s redevelopment: historic preservation and arts-led regeneration. Using a mixed method approach including textual analysis, in-depth interviews, visual analysis, and site observation, I examine the strategies used to market the Distillery as a distinct place, and the effects of this marketing strategy on the valuation of art, history, and space. Two central arguments direct the thesis: first, in an attempt to construct place differentiation, what emerges is a sense of sameness which limits the potential of the district and produces a disconnect between the space and its users; second, it is only by understanding how differentiation operates in discourse and practice that alternative formations of place-making can emerge and socio-spatial disconnectedness can be rethought.

Keywords: cultural geography
urban geography
place differentiation
place identity
urban redevelopment
art
heritage
distillery district
space
Advisor: Leslie, Deborah
Lewis, Robert
Host-pathogen Interactions: Roles for the Modulation of Lipids and Actin

Elements that are foreign to the human body, such as bacteria, viruses and fungi, are recognised by cells of the innate immune system. Through a process termed phagocytosis, microorganisms are bound, internalised and destroyed. In this thesis, we focus upon how host cells respond to IgG-opsonised targets, studying both the initial stages of Fc-receptor (FcR) ligation and the later stages of phagocytic cup formation. We provide evidence that after clustering of the receptors, the mobility of diacylated probes such as those found in Src-family of kinases, was reduced. This immobilisation was found to be insensitive to cholesterol depletion, arguing against a role for conventional ‘lipid rafts’ in the initiation of receptor signalling. Furthermore, decreased mobility was only partially dependent upon the presence of actin which could provide a physical restriction. Importantly, inhibiting Src-family kinase activity, completely abrogated immobilisation. These results are highly suggestive of a previously unrecognised mechanism for the initation of FcR signalling. At later stages, receptor-derived signalling leads to the formation of an actin-rich phagocytic ‘cup’. We found that even before a large particle was fully internalised, actin cleared from the base of the phagocytic cup. This clearance was necessary for the internalisation of large particles, as chemically stabilising actin prior to clearance, abrogated internalisation. Actin clearance was shown to be the indirect result of the localised disappearance of phosphatidylinositol 4,5-bisphosphate and the dephosphorylation of tyrosine-phosphorylated proteins. Strikingly, phosphatidylinositol 3-kinase activity was required for both the protein dephosphorylation and for the phosphatidylinositol 4,5-bisphosphate hydrolysis that was responsible for actin disassembly. We propose that actin disassembly is required to recycle actin to the advancing pseudopods, in order to complete phagocytosis. For many microorganisms, internalisation through phagocytosis means certain death. Obligate intracellular bacteria, such as Salmonella enterica serovar Typhimurium however, can readily survive inside host cells. This is achieved through modulation of the host-cell signalling pathways that normally lead to microbial destruction. In S. Typhimurium, a needle-like complex, delivers small protein effectors that aid in the survival of the bacterium. We studied one such effector: SigD, that had been suggested to have phosphatidylinositol phosphatase activity. Indeed, we showed that when the cDNA for SigD was exogenously expressed in mammalian cells, phosphatidylinositol 4,5-bisphosphate was depleted and phosphatidylinositol 5-phosphate was formed. We characterised the physiological effects of this 4-phosphatase activity and furthermore, describe the use of SigD as a research tool for modulating host cell phospholipids.

Keywords: cell biology
actin
lipids
microbiology
macrophage
immunology
Advisor: Grinstein, Sergio
Development of the Design of Eccentrically Braced Frames with Replaceable Shear Links

In current design of steel eccentrically braced frames (EBFs), the yielding link is coupled with the floor beam. This often results in oversized link elements, which leads to over-designed structures and foundations. In addition, the beams are expected to sustain significant damage through repeated inelastic deformations under design level earthquakes, and thus the structure may require extensive repair or need to be replaced. These drawbacks can be mitigated by designing EBFs with replaceable shear links. Two different replaceable link types with alternate section profiles, connection configurations, welding details and intermediate stiffener spacing were tested. A total of 13 cyclic quasi-static full-scale cyclic tests were performed, which included tests on eccentrically braced frames with the replaceable shear links, to study their inelastic seismic performance. The links exhibited a very good ductile behaviour, developing stable and repeatable yielding. Additional inelastic rotation capacity can be achieved with bolted replaceable links when allowing bolt bearing deformations to occur. The on-site replaceability of the link sections is confirmed even in the presence of residual deformations of 0.5% drift.

Keywords: eccentrically braced steel frames
shear link
replaceable link
seismic fuse
bolted connection
inelastic rotations
residual drifts
aftershock
bolt bearing
seismic design
cyclic full scale testing
Advisor: Christopoulos, Constantin