Hormonal factors and insulin-like growth factor-1 in North American postmenopausal women

Background: Mechanisms underlying the effect of estrogen exposure on breast cancer risk remain unclear. Insulin-like growth factor-1 (IGF-1) levels have been positively associated with breast cancer and are a potential mechanism. Objectives: The objectives of this thesis are: 1) to explore whether the reproductive risk factors and the lifetime cumulative number of menstrual cycles (LCMC), as measures for long-term estrogen exposure, are associated with IGF-1 levels, and 2) to examine the effect of an aromatase inhibitor (AI) on IGF-1 levels, and the potential interaction with BMI. Methods: A cross sectional study and a randomized controlled trial nested with the MAP.3 chemoprevention trial were used to address objective 1 and 2, respectively. 567 postmenopausal women were selected. Anthropometric measurements, lifestyle factors, reproductive characteristics and serum IGF-1 concentrations were collected at baseline and one year. Objective 1. The LCMC was computed as a composite measure of the reproductive characteristics. Multivariable linear regression models were used to assess the association between IGF-1 levels and LCMC and the hormonal risk factors, while adjusting for potential covariates. Objective 2. Changes in IGF-1 were compared between the exemestane and placebo, and effect modification by BMI was tested with an interaction term. Results: Objective 1. Women aged 55 years or older at menopause had 16.26 ng/mL (95% CI: 1.76, 30.75) higher IGF-1 compared to women aged less than 50 years at menopause. Women in the highest category of menstrual cycles (≥500 cycles) had an average 19.00 ng/mL (95%CI: 5.86, 32.14) higher concentration of IGF-1 compared to women in the lowest category (<350). Exogenous hormones had no effect on postmenopausal IGF-1 levels. Objective 2. Exemestane significantly increased IGF-1 levels by 18% (95% CI: 14%-22%); while, placebo had no effect on IGF-1. The changes in IGF-1 were significantly different between the treatment arms (P<0.0001) and no significant interaction was observed between treatment and BMI on IGF-1 changes (P=0.1327). Conclusion: Objective 1. Larger number of menstrual cycles and a later age at menopause are positively associated with IGF-1. IGF-1 may be one mechanism by which prolonged estrogen exposure increases cancer risk. Objective 2. We conclude that the reduced cancer risk observed with AI therapy likely occurs in an IGF-1 independent mechanism. Further studies exploring the clinical consequences of increased IGF-1 on AI therapy are needed.

β-Arrestin-mediated Regulation of the Human Ether-a-go-go-Related Gene (hERG) Potassium Channel

The human ether-a-go-go-related gene (hERG) encodes the voltage-gated K+ channel, hERG (Kv11.1). This channel passes the rapidly-activating delayed rectifier K+ current (IKr), which is important for cardiac repolarization. A reduction in IKr due to loss-of-function mutations or drug interactions causes long QT syndrome (LQTS), which can lead to cardiac arrhythmias and sudden cardiac death. The density of hERG channels in the plasma membrane is a key determinant of normal physiological function, and is balanced by trafficking to and from the cell surface. Many LQTS-associated hERG mutations result in a trafficking deficiency of otherwise functional channels. Thus, elucidating mechanisms of hERG regulation at the plasma membrane is useful for the prevention and treatment of LQTS. We previously demonstrated that M3 muscarinic receptor activation increases mature hERG expression through a Gq protein-dependent protein kinase C (PKC) pathway. In addition to conventional Gq protein-coupling, M3 receptors recruit β-arrestins upon agonist binding. Traditionally known for their role in receptor desensitization and internalization, β-arrestins also act as adaptor proteins to facilitate G protein-independent signaling. In the present work, I investigated the exclusive effect of β-arrestin signaling on hERG expression by utilizing an arrestin-biased M3 designer receptor (M3D-arr) exclusively activated by clozapine-N-oxide (CNO). By expressing M3D-arr in hERG-HEK cells and treating with CNO under various conditions, I found that M3D-arr activation increased mature hERG expression and current. Within this paradigm, M3D-arr recruited β-arrestin to the plasma membrane, and promoted the PI3K-dependent activation of Akt. I further found that the activated Akt acted through phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) and Rab11 to facilitate endosomal recycling of hERG channels to the plasma membrane.

Knot/Knotting Practice in Craft and Space

Knot/knotting Practice in Craft and Space is a three part research-creation project that used a study of knotting techniques to locate craft in an expanded field of spatial practice. The first part consisted of practical, studio based exercises in which I worked with various natural and synthetic fibres to learn common knotting techniques. The second part was an art historical study that combined craft and architecture history with critical theory related to the social production of space. The third part was an exhibition of drawing and knotted objects titled Opening Closures. This document unifies the lines inquiry that define my project. The first chapter presents the art historical justification for knotting to be understood as a spatial practice. Nineteenth-century German architect and theorist Gottfried Semper’s idea that architectural form is derived from four basic material practices allies craft and architecture in my project and is the point of departure from which I make my argument. In the second chapter, to consider the methodological concerns of research-creation as a form of knowledge production and dissemination, I adopt the format of an instruction manual to conduct an analysis of knot types and to provide instructions for the production of several common knots. In the third chapter, I address the formal and conceptual underpinnings of each artwork presented in my exhibition. I conclude with a proposal for an expanded field of spatial practice by adapting art critic and theorist Rosalind Krauss’s well-known framework for assessing sculpture in 1960s.

An investigation of lower limb joint powers as a predictive measure of countermovement vertical jump height.

Measuring and tracking athletic performance is crucial to an athlete’s development and the countermovement vertical jump is often used to measure athletic performance, particularly lower limb power. The linear power developed in the lower limb is estimated through jump height. However, the relationship between angular power, produced by the joints of the lower limb, and jump height is not well understood. This study examined the contributions of the kinetic value of angular power, and its kinematic component, angular velocity, of the lower limb joints to jump height in the countermovement vertical jump. Kinematic and kinetic data were gathered from twenty varsity-level basketball and volleyball athletes as they performed six maximal effort jumps in four arm swing conditions: no-arm involvement, single-non-dominant arm swing, single-dominant arm swing, and two-arm swing. The displacement of the whole body centre of mass, peak joint powers, peak angular velocity, and locations of the peaks as a percentage of the jump’s takeoff period, were computed. Linear regressions assessed the relationship of the variables to jump height. Results demonstrated that knee peak power (p = 0.001, ß = 0.363, r = 0.363), its location within takeoff period (p = 0.023, ß = -0.256, r = 0.256), and peak knee peak angular velocity (p = 0.005, ß = 0.310, r = 0.310) were moderately linked to increased jump height. Additionally, the location, within the takeoff period, of the peak angular velocities of the hip (p = 0.003, ß = -0.318, r = 0.419) and ankle (p = 0.011, ß = 0.270, r = 0.419) were positively linked to jump height. These results highlight the importance of training the velocity and timing of joint motion beyond traditional power training protocols as well as the importance of further investigation into appropriate testing protocol that is sensitive to the contributions by individual joints in maximal effort jumping.

The Evolution of the Los Negritos Porphyry Copper Deposit, Coquimbo, Chile: Geological, Geochronological, Mineralogical and Geochemical Evidence

The Los Negritos porphyry copper deposit is located ~ 4 km to the northeast of Carmen de Andacollo Mine in the Chilean Cretaceous metallogenic belt. The mineralization is hosted in andesite of the Quebrada Marquesa Formation and a series of at least four early to intramineral porphyry intrusive rock types: plagioclase quartz biotite porphyry (P1b and P1a dated at 109.60± 0.75 Ma and 107.22± 0.40 Ma); plagioclase biotite porphyry (P2: 106.30 ± 0.47 Ma); and quartz plagioclase biotite porphyry (P3: 106.19 ± 0.42 Ma). These units are cut by late‐ to post‐mineral plagioclase‐hornblende porphyritic rocks (P4b: 106.20 ± 0.69 Ma and P4a: 106.50 ± 0.68 Ma). The earliest intrusive units (P1) were affected by an initial stage of K‐feldspar‐biotite alteration, with chalcopyrite, molybdenite (date at 108.5 ± 0.5 Ma) and gold (up to 0.11 ppm), and the surrounding volcanic host rock was overprinted by chlorite‐epidote dominated (propylitic) alteration. Subsequent to the P2 and P3 intrusion, these rocks were affected by albite and then a second stage of potassic alteration. The Ti and Ba contents in hydrothermal biotite are notably lower (typically Ti = 0.100‐0.144 a.p.f.u. and Ba = 0.001‐0.005 a.p.f.u) than in magmatic ones (generally Ti = 0.186‐0.222 a.p.f.u. and Ba = 0.014‐0.023 a.p.f.u.), and constitute an excellent discriminant of the nature of biotite. These early stages of alteration were overprinted by copper‐molybdenum bearing chlorite‐sericite alteration at 106.60 ± 0.5 Ma (Re‐Os age in molybdenite) and by quartz‐sericite‐pyrite veins (phyllic), respectively in the southwest and northeast areas. The average temperature associated with these two alteration facies is estimated around 305 °C. Weak albite‐calcite alteration, spatially associated with sulfosalts and distributed along the margins of P3, overprinted the phyllic facies. The intrusive rock units at the Los Negritos and Carmen de Andacollo deposits are geochemically classified as diorite to granodiorite with a calc‐alkaline magmatic affinity, and formed in a volcanic arc setting from partial melting of a metasomatized mantle wedge. They are interpreted to be cogenetic, and related to a common long‐lived magma chamber that emplaced during a period of tectonic inversion known as the Subhercynian, Peruvian or Pacific event.

The Relationship Between Self-Awareness and Psychotic-Like Experiences

The psychosis phenotype is thought to exist on a continuum, such that the same symptoms experienced by individuals diagnosed with psychotic disorders can also manifest in the general population to a less severe degree. The subclinical psychotic-like experiences reported by healthy individuals share a number of risk factors with psychotic disorders and confer greater risk of developing a psychotic disorder. Thus, healthy individuals with psychotic-like experiences comprise a valid population in which to study the underlying mechanisms of clinically significant psychotic symptoms. In this thesis, we aimed to further our understanding of psychotic-like experiences and the individuals who report them. We explored the relationships between tasks measuring different aspects of self-awareness and self-reported psychotic-like experiences using data obtained from 30 university students. We found that greater sensitivity to the difference between one’s own voice and another person’s voice predicted fewer symptoms of persecutory ideation. Additionally, we found that greater tendency to misattribute one’s own voice to an external source predicted greater symptoms of persecutory ideation.

Modeling the impact of large-scale solid mass transfers on the gravity field

The focus of this thesis is to explore and quantify the response of large-scale solid mass transfer events on satellite-based gravity observations. The gravity signature of large-scale solid mass transfers has not been deeply explored yet; mainly due to the lack of significant events during dedicated satellite gravity missions‘ lifespans. In light of the next generation of gravity missions, the feasibility of employing satellite gravity observations to detect submarine and surface mass transfers is of importance for geoscience (improves the understanding of geodynamic processes) and for geodesy (improves the understanding of the dynamic gravity field). The aim of this thesis is twofold and focuses on assessing the feasibility of using satellite gravity observations for detecting large-scale solid mass transfers and on modeling the impact on the gravity field caused by these events. A methodology that employs 3D forward modeling simulations and 2D wavelet multiresolution analysis is suggested to estimate the impact of solid mass transfers on satellite gravity observations. The gravity signature of various submarine and subaerial events that occurred in the past was estimated. Case studies were conducted to assess the sensitivity and resolvability required in order to observe gravity differences caused by solid mass transfers. Simulation studies were also employed in order to assess the expected contribution of the Next Generation of Gravity Missions for this application.

Bipartite Assertion: A New Account of Assertion, Defined in Terms of Responsibility and Explicit Presentation

Assertion is a speech act that stands at the intersection of the philosophy of language and social epistemology. It is a phenomenon that bears on such wide-ranging topics as testimony, truth, meaning, knowledge and trust. It is thus no surprise that analytic philosophers have devoted innumerable pages to assertion, trying to give the norms that govern it, its role in the transmission of knowledge, and most importantly, what assertion is, or how assertion is to be defined. In this thesis I attempt to show that all previous answers to the question “What is assertion?” are flawed. There are four major traditions in the literature: constitutive norm theories of assertion, accounts that treat assertion as the expression of speaker attitudes, accounts that treat assertion as a proposal to add some proposition to the common ground, and accounts that treat assertion as the taking of responsibility for some claim. Each tradition is explored here, the leading theories within the tradition developed, and then placed under scrutiny to demonstrate flaws within the positions surveyed. I follow the work of G.E. Moore and William P. Alston, whilst drawing on the work of Robert Brandom in order to give a new bipartite theory of assertion. I argue that assertion consists in the explicit presentation of a proposition, along with a taking of responsibility for that proposition. Taking Alston's explicit presentation condition and repairing it in order to deal with problems it faces, whilst combining it with Brandom's responsibility condition, provides, I believe, the best account of assertion.

Bridging the link between trauma, brain development and depression: epigenetic mechanisms

Despite its large impact on the individual and society, we currently have only a rudimentary understanding of the biological basis of Major Depressive Disorder, even less so in adolescent populations. This thesis focuses on two research questions. First, how do adolescents with depression differ from adolescents who have never been depressed on (1a) brain morphology and (1b) DNA methylation? We studied differences in the fronto-limbic system (a collection of areas responsible for emotion regulation) and methylation at the serotonin transporter (SLC6A4) and FK506 binding protein gene (FKBP5) genes (two genes strongly linked to stress regulation and depression). Second, how does childhood trauma, which is known to increase risk for depression, affect (2a) brain development and (2b) SLC6A4 and FKBP5 methylation? Further, (2c) how might DNA methylation explain how trauma affects brain development in depression? We studied these questions in 24 adolescent depressed patients and 21 controls. We found that (1a) depressed adolescents had decreased left precuneus volume and greater volume of the left precentral gyrus compared to controls; however, no differences in fronto-limbic morphology were identified. Moreover, (1b) individuals with depression had lower levels of FKBP5 methylation than controls. In line with our second hypothesis (2a) greater levels of trauma were associated with decreased volume of a number of fronto-limbic regions. Further, we found that (2b) greater trauma was associated with decreased SLC6A4, but not FKBP5, methylation. Finally, (2c) greater FKBP5, but not SLC6A4, methylation was associated with decreased volume of a number of fronto-limbic regions. The results of this study suggest an association among trauma, DNA methylation and brain development in youth, but the direction of these relationships appears to be inconsistent. Future studies using a longitudinal design will be necessary to clarify these results and help us understand how the brain and epigenome change over time in depressed youth.

Digging Deeper than Platinum: South Africa's Participation in an Emergent Fuel Cell Industry

South’s Africa’s position as global platinum supplier provides a unique opportunity for an emergent fuel cell industry. The innovative technology’s reliance on platinum has sparked interest in the mining sector, promoting the clean energy-producing devices in their own operations. This research focuses upon contemporary structures of racial oppression within the industry, to analyse how these dynamics influence the development and implementation of innovative technology. It also challenges the sustainability discourse associated with fuel cell technology in South Africa. The study follows a qualitative research approach, incorporating a political ecology focus to highlight the politicized nature of these interactions. The methodology incorporates a literature review, key informant interviews, fieldwork observations and document analysis. Findings indicate that the implementation of fuel cell technology in South Africa’s platinum mines will disproportionately burden historically disadvantaged South Africans, with the lack in technical knowledge-base considered a major challenge. Additionally, it was found that sustainability claims surrounding fuel cell technology are largely based on environmental characteristics. This has resulted in an oversimplification and a depoliticised account of the impacts of the technology. This study looked critically at the convergence of history and innovation, placing emphasis on context, power relations and knowledge to provide a more holistic account of the research problem. Opportunities exist for making a meaningful and viable contribution towards development and sustainability by means of investing in a South African fuel cell industry. The challenge will be in deliberately seeking pathways which address the more complex components of sustainability, benefitting all stakeholders and paying particular attention to the historical, political and social contexts from which the technology emerges. It is this particular context which allows for a questioning and perhaps even a re-evaluation of the sustainability narratives broadly applied to fuel cell technology.

Speed and Accuracy of People's Trustworthiness Judgment across Cultures

Previous research on person perception has shown that people form first impressions with remarkable speed and accuracy, but relatively little is known about the speed and accuracy of trustworthiness judgments across cultures. The present research examined these by asking Chinese and Canadians to infer trustworthiness from faces of criminals and non-criminals from different cultural backgrounds across two domains (i.e., financial crime in Study 1 and violent crime in Study 2). Across both studies, we found that when participants were given time and opportunity, Chinese tended to take a longer time than Canadians to make trustworthiness judgments (although this difference did not reach statistical significance in Study 2). In Study 1, we found that perceivers from both cultures were accurate at judging European North Americans (ENA) corporate criminals as less trustworthy than ENA non-criminal executives, although they did not differentiate Asian corporate criminals from Asian non-criminal executives. In Study 2, we found that perceivers from both cultures were accurate at judging both Asian and ENA violent criminals as less trustworthy than Asian and ENA non-criminals. Chinese were also accurate at rating Middle Eastern violent criminals as less trustworthy than Middle Eastern non-criminals, but Canadians did not differentiate them in terms of their trustworthiness ratings. In terms of their crime likelihood ratings, however, both Chinese and Canadians accurately rated all the criminals as more likely to commit violent crimes than the non-criminals, regardless of the targets’ ethnicities. Finally, we discussed some of the practical implications of our findings on detection of deception, as well as how providing a context for trustworthiness judgments might have played an important role in people’s judgmental accuracy.

Irreducibility of Random Hilbert Schemes

We prove that a random Hilbert scheme that parametrizes the closed subschemes with a fixed Hilbert polynomial in some projective space is irreducible and nonsingular with probability greater than $0.5$. To consider the set of nonempty Hilbert schemes as a probability space, we transform this set into a disjoint union of infinite binary trees, reinterpreting Macaulay's classification of admissible Hilbert polynomials. Choosing discrete probability distributions with infinite support on the trees establishes our notion of random Hilbert schemes. To bound the probability that random Hilbert schemes are irreducible and nonsingular, we show that at least half of the vertices in the binary trees correspond to Hilbert schemes with unique Borel-fixed points.

Time-dependency of Rocks and Implications Associated with Tunnelling

The formulation of a geotechnical model and the associated prediction of the mechanical behaviour is a challenge engineers need to overcome in order to optimize tunnel design and meet project requirements. Special challenges arise in cases where rocks and rockmasses are susceptible to time-effects and time-dependent processes govern. Progressive rockmass deformation and instability, time-dependent overloading of support and delayed failures are commonly the result of time-dependent phenomena. The research work presented in this thesis serves as an attempt to provide more insight into the time-dependent behaviour of rocks. Emphasis is given on investigating and analyzing creep deformation and time-dependent stress relaxation phenomenon at the laboratory scale and in-depth analyses are presented. This thesis further develops the understanding of these phenomena and practical yet scientific tools for estimating and predicting the long-term strength and the maximum stress relaxation of rock materials are proposed. The identification of the existence of three distinct behavioural stages during stress relaxation is presented and discussed. The main observations associated with time-dependent behaviour are employed in numerical analyses and applied at the tunnel scale. A new approach for simulating and capturing the time-dependent behaviour coupled with the tunnel advancement effect is also developed and analyzed. Guidance is provided to increase the understanding of the support-rockmass interaction and the main implications and significance of time-dependent behaviour associated with rock tunnelling are discussed. The work presented in this thesis advances the scientific understanding of time-dependent rock and rockmass behaviour, increases the awareness of how such phenomena are captured numerically, and lays out a framework for dealing with such deformations when predicting tunnel deformations. Practical aspects of this thesis are also presented, which will increase their usage in the associated industries and close the gap between the scientific and industry communities.

An Ergonomic Evaluation of a Wrist Brace for Canadian Tree Planters

Tree planting is one of the most physically demanding occupations in Canada and as a result, tree planters are at an elevated risk of injury, specifically at the wrist. Wrist injuries develop on account of the highly repetitive nature of the job, as well as other musculoskeletal risk factors including non-neutral wrist postures and high impact forces sustained at the wrist during shovel-ground impact. As a result, wrist brace use has become common among planters, in an effort to limit deviated wrist postures while also providing enhanced stability at the wrist. The external stability provided by a wrist brace is thought to reduce the muscular effort required to provide stiffness at the wrist during shovel-ground impact. Since these prospective benefits have not been formally investigated, the purpose of this study was to determine the effect of a wrist brace on wrist posture, muscle activity, and joint rotational stiffness about the wrist joint (for two degrees of freedom: flexion/extension and ulnar/radial deviation). We hypothesized that the brace would promote more neutrally aligned wrist angles, and that muscle activity and joint rotational stiffness would also decrease when participants wore the brace. Fourteen tree planters with at least one season of experience were recruited to complete two planting conditions in a laboratory setting: one condition while wearing the brace (with brace, WB) and one condition without the brace (no brace, NB). The results from this study showed that at shovel-ground impact muscle activity trended towards increasing in three muscles when participants wore the brace. Additionally, wrist angles improved about the flexion/extension axis of rotation while increasing in deviation about the ulnar/radial axis of rotation when participants wore the brace. Joint rotational stiffness increased when participants wore the wrist brace. Participants from this study indicated difficulty gripping the shovel due to the bulk of the wrist brace, and this feature is discussed with possible suggestions for future iterations of design. In addition to grip diameter this analysis also prompts the suggestion that hand length and experience should also be considered in the design of tree planting tools, specifically an ergonomic aid such as a wrist brace.

Polymer Process Partitioning: Extruding Plastic Pipe

When plastic pipe is solidified, it proceeds through a long cooling chamber. Inside this chamber, inside the hollow extrudate, the plastic is molten, and this inner surface solidifies last. Sag, the flow due to the self-weight of the molten plastic, then happens in this cooling chamber, and sometimes, thickened regions (called knuckles) arise in the lower quadrants, especially of large diameter thickwalled pipes. To compensate for sag, engineers normally shift the die centerpiece downward. This thesis focuses on the consequences of this decentering. Specifically, when the molten polymer is viscoelastic, as is normally the case, a downward lateral force is exerted on the mandrel. Die eccentricity also affects the downstream axial force on the mandrel. These forces govern how rigidly the mandrel must be attached (normally, on a spider die). We attack this flow problem in eccentric cylindrical coordinates, using the Oldroyd 8-constant constitutive model framework. Specifically, we revise the method of Jones (1964), called polymer process partitioning. We estimate both axial and lateral forces. We develop a corresponding map to help plastics engineers predict the extrudate shape, including extrudate knuckles. From the mass balance over the postdie region, we then predict the shape of the extrudate entering the cooling chamber. We further include expressions for the stresses in the extruded polymer melt. We include detailed dimensional worked examples to show process engineers how to use our results to design pipe dies, and especially to suppress extrudate knuckling.