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The purpose of this phenomenological study was to interpret the lived experience of Black and Latinx students from Lakeside Township High School (LTHS); to gain an understanding of how they make sense of their decision not to engage with AP Science coursework. After reviewing relevant literature, interviews were carried out with six Black and Latinx students who opted not to engage with such coursework. Analysis of the semi-structured interview transcripts identified three group experiential themes. First, the participants described taking an AP Science course as being an unsafe decision. Second, they identified their decision as being influenced by their academic areas of interest, by their teacher, and by their assessment of each course's curriculum being relevant to their lives. Lastly, the participants described a generally negative perception of AP science courses, primarily informed by hearsay from peers and family, as well as a lack of science self-efficacy despite success in previous science courses. Within the context of literature and theoretical framework of science self-efficacy, these findings suggest several recommendations for practice: creating science spaces that offer an inclusive community in which all students, particularly Black and Latinx student, feel safe; placing more teachers of color in AP Science spaces; simplifying the dissemination of information about science courses; recognizing and capitalizing on the influence of early high school science teachers; amplifying honest, positive experiences in AP Science among Black and Latinx students, as a means of improving the hearsay about AP Science classes, and enabling students to build their science self-efficacy in their early high school science those classes. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

The primary objective of this thesis is to understand the behaviour of extreme events taking place in the foreign exchange (FX) and stock exchange (SX) markets around the Global Financial Crisis using parametric and non-parametric methods. Specifically, it models the evolution of the extreme values and Black Swans measures of daily stock returns and volatility proxies from a set of more than thirty SX and FX markets and compares their statistical properties in the pre- and post-crisis periods. My findings suggest that irrespective of the modelling approach followed, there are substantial differences in the tail-behaviour of the two periods that cannot be accounted for by the mainstream mean-variance model although the identification of latent Non-linearities in the underlying mean and/or variance dynamics does indeed lead to a significant reduction in tail asymmetry and kurtosis. Moreover, the mainstream parametric models prove insufficient in encompassing the volatility tails. Consequently, this study demonstrates that during times of extreme financial turbulence in financial markets the existing financial risk models are inadequate to provide guidance for the probability of extreme events taking place and subsequently underlines the need for additional research on parsimonious models and for the use of encyclopaedic exercise of judgment in the real-world risk management.

Nanomechanical resonators have extremely low masses (~ 10−15 kg) and frequencies from a few megahertz all the way up to the gigahertz range. These properties along with a small damping rate make them very useful or ultrasensitive detection applications, now pushing into the realm of zeptonewtons (10−21 N) and zeptograms (10−21 g). On a more fundamental level, nanomechanical resonators are expected to display quantum mechanical effects when cooled down to millikelvin temperatures. The understanding of dissipation in nanomechanical resonators is important for device applications and to study quantum mechanical effects in such systems. However, despite a range of experiments on semiconducting and metallic devices, dissipation in nanomechanical resonators at low temperatures is not yet well understood. Although mechanical resonators have traditionally been operated in the linear regime, exploiting their nonlinearities can prove advantageous for industrial applications as well as opening up new experimental windows into the fundamental study of the nonlinear dynamics of mesoscopic systems. In this thesis, we present results from low temperature dissipation studies on pure gold and on gold-coated high-stress silicon nitride nanomechanical resonators. A theory, which predicts the existence of tunnelling two-level systems (TLS) in bulk disordered solids at low temperatures, is used as a framework to describe the data. The nonlinear interactions between different flexural modes of a single silicon nitride device, are explored experimentally and theoretically. The resonators were fabricated as doubly-clamped beams using a combination of optical lithography, electron-beam lithography, dry and wet etching techniques. The motion of the resonators was actuated and detected using the magnetomotive scheme. At low temperatures, all the beams had resonant frequencies between 3 and 60 MHz and quality factors in the range 105 − 106. The strong variation observed in dissipation and resonant frequency at the lowest temperatures (below 1 K) indicates the presence of tunnelling TLS in nanomechanical resonators.

Activation of innate immune signalling during influenza A virus (IAV) infection is essential for the development of protective antiviral responses. However, uncontrolled release of proinflammatory cytokines is also associated with severe and fatal disease caused by highly pathogenic avian and pandemic IAV strains. IAV infections are primarily detected by the retinoic acid-inducible gene I (RIG-I), which recognises the partially double-stranded, 5'-triphosphorylated RNA structure that is formed by the protein-free 3' and 5' termini (viral promoter) of viral genomic segments as well as aberrant replication products. However, it remains unknown how RIG-I gains access to the viral promoter when it is bound by the viral polymerase, and if other viral RNA species could play a role in RIG-I activation. The viral RNA polymerase itself was shown to act as both an innate immune agonist by producing immunostimulatory RNA species, and as an antagonist by directly interacting with the components of the RIG-I signalling pathway. However, the mechanisms underlying these roles of the viral polymerase in the IAV infection cycle are not completely understood. In this thesis, I investigated the mechanisms behind the immunostimulatory activity of two mutations (D27N and T677A) in the polymerase basic 1 (PB1) subunit that were identified in a single-cell sequencing screen. Viruses containing the PB1 D27N and T677A mutations activated interferon (IFN) responses via the RIG-I signalling pathway. The immunostimulatory activity of the T677A mutation was also recapitulated in an *in vitro* ribonucleoprotein reconstitution assay. Surprisingly, IFN induction by the T677A polymerase was to a large extent driven by its transcriptional activity. Co-immunoprecipitation assays showed that RIG-I bound capped positive-sense RNA produced by the T677A polymerase. This finding suggests the existence of a novel mechanism by which defects in viral RNA synthesis activate innate immune signalling during viral infection. The D27N and T677A viruses were also severely attenuated in cell culture. Reduced fitness of the D27N virus was partly associated with the defects in segment 6 packaging, which led to low levels of neuraminidase expression and impaired haemagglutinin maturation. Adaptation of the T677A and D27N viruses during serial passaging suggested that changes in other viral proteins compensated for the fitness defects created by the PB1 mutations. These changes could be further explored to understand the interplay between the RNA polymerase and other viral proteins at different stages of the viral life cycle.

Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting seven to ten million people worldwide. Familial forms of PD account for 5-10% of all PD cases suggesting that other factors such as the environment have a role in the development of sporadic cases of PD. Epidemiological studies have indicated that exposure to pesticides increases the risk for PD. Ziram, a dithiocarbamate fungicide commonly used in California, increases the risk of PD for individuals living and working in areas where the pesticide is sprayed. Ziram has previously been found in vitro to cause selective dopaminergic cell toxicity, inhibition of the ubiquitin proteasome system (UPS), and increased α-synuclein (α-syn) levels in primary neuronal cultures. In this dissertation we utilize zebrafish embryos (ZF, Danio rerio) to study ziram in an in vivo system and to determine if ziram’s toxicity is mediated via synuclein.We found that ziram is toxic to ZF at nanomolar concentrations and caused selective loss of dopaminergic (DA) neurons and impaired swimming behavior in ZF. Since ziram increases α-syn concentrations in rat primary neuronal cultures, we investigated the effect of ziram on ZF γ-synuclein 1 (γ1). ZF express 3 synuclein isoforms and ZF γ1 appears to be a functional homologue of α-syn. We found that recombinant ZF γ1 formed fibrils in vitro and overexpression of ZF γ1 in ZF embryos led to the formation of neuronal aggregates and neurotoxicity similarly to α-syn. Importantly, knockdown of ZF γ1 with morpholinos or disruption of oligomers with the molecular tweezer CLR01 protected against ziram’s DA toxicity.Over the course of this dissertation we have demonstrated that ziram is selectively toxic to DA neurons in vivo and that its toxicity is synuclein-dependent. These findings provide potentially important mechanistic implications on how ziram and possibly other environmental toxins can contribute to the pathogenesis of neurodegenerative disorders such as PD.