Catalyst and substrate effects in enantioselective C–H insertion reactions of α-diazosulfones

This thesis describes a systematic investigation of the mechanistic and synthetic aspects of intramolecular reactions of a series of α-diazo-β-oxo sulfone derivatives using copper and, to a lesser extent, rhodium catalysts. The key reaction pathways explored were C–H insertion and cyclopropanation, with hydride transfer competing in certain instances. Significantly, up to 98% ee has been achieved in the C–H insertion processes using copper-NaBARF-bisoxazoline catalysts, with the presence of the additive NaBARF critical to the efficiency of the transformations. This novel synthetic methodology provides access to a diverse range of enantioenriched heterocyclic compounds including thiopyrans, sulfolanes, β- and γ-lactams, in addition to carbocycles such as fused cyclopropanes. The synthesis of the α-diazosulfones required for subsequent investigations is initially described. Of the twenty seven diazo sulfones described, nineteen are novel and are fully characterised in this work. The discussion is subsequently focused on a study of the copper and rhodium catalysed reactions of the α-diazosulfones with Chapter Four concentrated on highly enantioselective C–H insertion to form thiopyrans and sufolanes, Chapter Five focused on C–H insertion to form fused sulfolanes, Chapter Six focused on C–H insertion in sulfonyl α-diazoamides where both lactam formation and / or thiopyran / sulfolane formation can result from competing C–H insertion pathways, while Chapter Seven focuses on cyclopropanation to yield fused cyclopropane derviatives. One of the key outcomes of this work is an insight into the steric and / or electronic factors on both the substrate and the catalyst which control regio-, diastereo- and enantioselectivity patterns in these synthetically powerful transformations. Full experimental details for the synthesis and spectral characterisation of the compounds are included at the end of each Chapter, with details of chiral stationary phase HPLC analysis and assignment of absolute stereochemistry included in the appendix.

The morphology of ordered block copolymer patterns as probed by high resolution imaging

The microphase separation of block copolymer (BCP) thin films can afford a simple and cost-effective means to studying nanopattern surfaces, and especially the fabrication of nanocircuitry. However, because of complex interface effects and other complications, their 3D morphology, which is often critical for application, can be more complex than first thought. Here, we describe how emerging microscopic methods may be used to study complex BCP patterns and reveal their rich detail. These methods include helium ion microscopy (HIM) and high resolution x-section transmission electron microscopy (XTEM), and complement conventional secondary electron and atomic force microscopies (SEM and TEM). These techniques reveal that these structures are quite different to what might be expected. We illustrate the advances in the understanding of BCP thin film morphology in several systems, which result from this characterization. The systems described include symmetric, lamellar forming polystyrene-b-polymethylmethacrylate (PS-b-PMMA), cylinder forming polystyrene-b-polydimethylsiloxane (PS-b-PDMS), as well as lamellar and cylinder forming patterns of polystyrene-b-polyethylene oxide (PS-b-PEO) and polystyrene-b-poly-4-vinylpyridine (PS-b-P4VP). Each of these systems exhibits more complex arrangements than might be first thought. Finding and developing techniques whereby complex morphologies, particularly at very small dimensions, can be determined is critical to the practical use of these materials in many applications. The importance of quantifying these complex morphologies has implications for their use in integrated circuit manufacture, where they are being explored as alternative pattern forming methods to conventional UV lithography.

Occurrence and Function of Hoogsteen Base Pairs in Nucleic Acids

Nucleic acids (DNA and RNA) play essential roles in the central dogma of biology for the storage and transfer of genetic information. The unique chemical and conformational structures of nucleic acids – the double helix composed of complementary Watson-Crick base pairs, provide the structural basis to carry out their biological functions. DNA double helix can dynamically accommodate Watson-Crick and Hoogsteen base-pairing, in which the purine base is flipped by ~180° degrees to adopt syn rather than anti conformation as in Watson-Crick base pairs. There is growing evidence that Hoogsteen base pairs play important roles in DNA replication, recognition, damage or mispair accommodation and repair. Here, we constructed a database for existing Hoogsteen base pairs in DNA duplexes by a structure-based survey from the Protein Data Bank, and structural analyses based on the resulted Hoogsteen structures revealed that Hoogsteen base pairs occur in a wide variety of biological contexts and can induce DNA kinking towards the major groove. As there were documented difficulties in modeling Hoogsteen or Watson-Crick by crystallography, we collaborated with the Richardsons’ lab and identified potential Hoogsteen base pairs that were mis-modeled as Watson-Crick base pairs which suggested that Hoogsteen can be more prevalent than it was thought to be. We developed solution NMR method combined with the site-specific isotope labeling to characterize the formation of, or conformational exchange with Hoogsteen base pairs in large DNA-protein complexes under solution conditions, in the absence of the crystal packing force. We showed that there are enhanced chemical exchange, potentially between Watson-Crick and Hoogsteen, at a sharp kink site in the complex formed by DNA and the Integration Host Factor protein. In stark contrast to B-form DNA, we found that Hoogsteen base pairs are strongly disfavored in A-form RNA duplex. Chemical modifications N1-methyl adenosine and N1-methyl guanosine that block Watson-Crick base-pairing, can be absorbed as Hoogsteen base pairs in DNA, but rather potently destabilized A-form RNA and caused helix melting. The intrinsic instability of Hoogsteen base pairs in A-form RNA endows the N1-methylation as a functioning post-transcriptional modification that was known to facilitate RNA folding, translation and potentially play roles in the epitranscriptome. On the other hand, the dynamic property of DNA that can accommodate Hoogsteen base pairs could be critical to maintaining the genome stability.

A Model of Lung Tumor Angiogenesis in a Biomimetic Poly(ethylene glycol)-based Hydrogel System

Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. A major outstanding challenge associated with studying tumor angiogenesis is that existing preclinical models are limited in their recapitulation of in vivo cellular organization in 3D. This disparity highlights the need for better approaches to study the dynamic interplay of relevant cells and signaling molecules as they are organized in the tumor microenvironment. In this thesis, we combined 3D culture of lung adenocarcinoma cells with adjacent 3D microvascular cell culture in 2-layer cell-adhesive, proteolytically-degradable poly(ethylene glycol) (PEG)-based hydrogels to study tumor angiogenesis and the impacts of neovascularization on tumor cell behavior.

In initial studies, 344SQ cells, a highly metastatic, murine lung adenocarcinoma cell line, were characterized alone in 3D in PEG hydrogels. 344SQ cells formed spheroids in 3D culture and secreted proangiogenic growth factors into the conditioned media that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells alone in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, the engineered 2-layer tumor angiogenesis model with 344SQ and vascular cell layers was employed. Large, invasive 344SQ clusters developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed 344SQ cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration.

Two other lung adenocarcinoma cell lines were also explored in the tumor angiogenesis model: primary tumor-derived metastasis-incompetent, murine 393P cells and primary tumor-derived metastasis-capable human A549 cells. These lung cancer cells also formed spheroids in 3D culture and secreted proangiogenic growth factors into the conditioned media. Epithelial morphogenesis varied for the primary tumor-derived cell lines compared to 344SQ cells, with far less epithelial organization present in A549 spheroids. Additionally, 344SQ cells secreted the highest concentration of two of the three angiogenic growth factors assessed. This finding correlated to 344SQ exhibiting the most pronounced morphological response in the tumor angiogenesis model compared to the 393P and A549 cell lines.

Overall, this dissertation demonstrates the development of a novel 3D tumor angiogenesis model that was used to study vascular cell-cancer cell interactions in lung adenocarcinoma cell lines with varying metastatic capacities. Findings in this thesis have helped to elucidate the role of vascular cells in tumor progression and have identified differences in cancer cell behavior in vitro that correlate to metastatic capacity, thus highlighting the usefulness of this model platform for future discovery of novel tumor angiogenesis and tumor progression-promoting targets.

Non-equilibrium induction of tin in germanium: towards direct bandgap Ge1-xSnx nanowires

The development of non-equilibrium group IV nanoscale alloys is critical to achieving new functionalities, such as the formation of a direct bandgap in a conventional indirect bandgap elemental semiconductor. Here, we describe the fabrication of uniform diameter, direct bandgap Ge1-xSnx alloy nanowires, with a Sn incorporation up to 9.2[thinsp]at.%, far in excess of the equilibrium solubility of Sn in bulk Ge, through a conventional catalytic bottom-up growth paradigm using noble metal and metal alloy catalysts. Metal alloy catalysts permitted a greater inclusion of Sn in Ge nanowires compared with conventional Au catalysts, when used during vapour-liquid-solid growth. The addition of an annealing step close to the Ge-Sn eutectic temperature (230[thinsp][deg]C) during cool-down, further facilitated the excessive dissolution of Sn in the nanowires. Sn was distributed throughout the Ge nanowire lattice with no metallic Sn segregation or precipitation at the surface or within the bulk of the nanowires. The non-equilibrium incorporation of Sn into the Ge nanowires can be understood in terms of a kinetic trapping model for impurity incorporation at the triple-phase boundary during growth.

Dynamique de la variation génétique et épigénétique chez un vertébré kleptogène

La variation phénotypique est essentielle à la persistance des organismes dans le temps ainsi qu’à la colonisation de nouveaux habitats. Les principales sources de variation phénotypique sont la génétique et l'épigénétique. L'épigénétique a été proposé comme un atout important pour les organismes asexués pour compenser le manque de diversité génétique. L'objectif de cette étude est d'évaluer si l’absence de variation génétique est compensée par l'épigénétique en comparant les profils de méthylation d’individus gynogènes et kleptogènes des hybrides de salamandre à points bleus. Les individus échantillonnés s’organisent en cinq groupes génétiquement différenciés, provenant du même haplome paternel A. jeffersonianum. Deux des cinq groupes sont exclusivement gynogènes, pour des raisons écologiques ou génomiques. Les trois autres groupes sont formés d’individus parfois kleptogènes, car ils présentent une variation génétique plus élevée au sein d’un site qu’entre les sites, en plus de porter des allèles très divergents par rapport à la distribution globale des allèles hybrides, trouvés en haute fréquence dans les populations sympatriques de A. laterale. Les patrons épigénétiques sont variables et distincts entre les cinq groupes génétiques. Les groupes gynogènes sont les seuls à présenter un effet environnemental significatif sur leurs patrons épigénétiques, suggérant que ces individus clonaux doivent être en mesure de maximiser leur potentiel de variation épigénétique pour faire face à des variations environnementales.

Hearing the Child's Voice: Their Lived Experience in the Pediatric Intensive Care Unit

Background: More than 200,000 children are admitted annually to Pediatric Intensive Care Units (PICUs) in the US. Research has shown young children can provide insight into their hospitalization experiences; child reports rather than parental reports are critical to understanding the child’s experience. Information relating to children’s perceptions while still in the PICU is scarce. Aims: The purpose of this qualitative study was to investigate school age children’s and adolescents’ perceptions of PICU while in the PICU; changes in perceptions after transfer to the General Care Unit (GCU); differences in perceptions of school age children/adolescents and those with more invasive procedures. Methods: Interviews were conducted in PICU within 24-48 hours of admission and 24-48 hours after transfer to GCU. Data on demographics, clinical care and number/types of procedures were obtained. Results: Participants were 7 school age children, 13 adolescents; 10 Hispanic; 13 males. Five overarching themes: Coping Strategies, Environmental Factors, Stressors, Procedures/Medications, and Information. Children emphasized the importance of peer support and visitation; adolescents relied strongly on social media and texting. Parent visits sometimes were more stressful than peer visits. Video games, TV, visitors, and eating were diversional activities. In the PICU, they wanted windows to see outside and interesting things to see on the ceiling above them. Children expressed anticipatory fear of shots and procedures, frustration with lab work, and overwhelming PICU equipment. Number of child responses was higher in PICU (927) than GCU (593); the largest difference was in Environmental Factors. Variations between school age children and adolescents were primarily in Coping Strategies, especially in social support. Number of GCU procedures were the same (8 children) or greater (2 children) than PICU procedures. Discussion: Admission to PICU is a very stressful event. Perceptions from children while still in PICU found information not previously found in the literature. Longitudinal studies to identify children’s perceptions regarding PICU hospitalization and post-discharge outcomes are needed.

Integrity-Based Kernel Malware Detection

Kernel-level malware is one of the most dangerous threats to the security of users on the Internet, so there is an urgent need for its detection. The most popular detection approach is misuse-based detection. However, it cannot catch up with today's advanced malware that increasingly apply polymorphism and obfuscation. In this thesis, we present our integrity-based detection for kernel-level malware, which does not rely on the specific features of malware. We have developed an integrity analysis system that can derive and monitor integrity properties for commodity operating systems kernels. In our system, we focus on two classes of integrity properties: data invariants and integrity of Kernel Queue (KQ) requests. We adopt static analysis for data invariant detection and overcome several technical challenges: field-sensitivity, array-sensitivity, and pointer analysis. We identify data invariants that are critical to system runtime integrity from Linux kernel 2.4.32 and Windows Research Kernel (WRK) with very low false positive rate and very low false negative rate. We then develop an Invariant Monitor to guard these data invariants against real-world malware. In our experiment, we are able to use Invariant Monitor to detect ten real-world Linux rootkits and nine real-world Windows malware and one synthetic Windows malware. We leverage static and dynamic analysis of kernel and device drivers to learn the legitimate KQ requests. Based on the learned KQ requests, we build KQguard to protect KQs. At runtime, KQguard rejects all the unknown KQ requests that cannot be validated. We apply KQguard on WRK and Linux kernel, and extensive experimental evaluation shows that KQguard is efficient (up to 5.6% overhead) and effective (capable of achieving zero false positives against representative benign workloads after appropriate training and very low false negatives against 125 real-world malware and nine synthetic attacks). In our system, Invariant Monitor and KQguard cooperate together to protect data invariants and KQs in the target kernel. By monitoring these integrity properties, we can detect malware by its violation of these integrity properties during execution.

Toward an Understanding of Faculty Perceptions about Factors that Influence Student Success in Online Education

This paper explores factors that faculty perceive as significant in influencing student success in online education. Technological support, degree of comfort with technology and a student’s personal characteristics were deemed by faculty as critical to success. Understanding these key factors could help to improve student success in online education.

Mg/Ca ratio of Globorotalia tumida and subsurface temperature reconstruction for ODP Site 130-806

The tropical Pacific thermocline strength, depth, and tilt are critical to tropical mean state and variability. During the early Pliocene (~3.5 to 4.5 Ma), the Eastern Equatorial Pacific (EEP) thermocline was deeper and the cold tongue was warmer than today, which resulted in an mean state with a reduced zonal sea surface temperature gradient, or El Padre. However, it is unclear whether the deep thermocline was a local feature of the EEP or a basin-wide condition with global implications. Our measurements of Mg/Ca of Globorotalia tumida in a western equatorial Pacific site indicate Pliocene subsurface temperatures warmer than today; thus, El Padre included a basin-wide thermocline that was relatively warm, deep, and weakly tilted. At ~4 Ma, thermocline steepening was coupled to cooling of the cold tongue. Since ~4 Ma, the basin-wide thermocline cooled/shoaled gradually, with implications for thermocline feedbacks in tropical dynamics and the interpretation of TEX86-derived temperatures.

Disruptive Threads and Renegade Yarns: Domestic Textile Making in Selected Women's Writing 1811-1925

Images of domestic textiles (items made at home for consumption within the household) and textile making form an important subtext to women’s writing, both during and after industrialization. Through a close reading of five novels from the period 1811-1925, this thesis will assert that a detailed understanding of textile work and its place in women’s daily lives is critical to a deeper understanding of social, sexual and political issues from a woman’s perspective. The first chapter will explore the history of the relationship between women and domestic textile making, and the changes wrought to the latter by the Industrial Revolution. The second chapter will examine the role of embroidery in the construction of “appropriate” feminine gentility in Jane Austen’s Mansfield Park (1814). The third chapter, on Elizabeth Gaskell’s Cranford (1853), will explore how the older female body became a repository for anxieties about class mobility and female power at the beginning of the Victorian era. The fourth chapter will compare Sara Jeannette Duncan’s A Social Departure (1890) and Kate Chopin’s The Awakening (1899) to consider how later Victorian women both internalized and refuted public narratives of domestic textile making in a quest for “self-ownership.” The last chapter, on Martha Ostenso’s Wild Geese (1925), examines the corrosive, yet ultimately redemptive, relationships of a family of women trapped by abuse and degradation. For all five authors, images of textiles and textile making allow them to speak to issues that were usually only discussed within a community of women: sexuality, desire, aging, marriage, and motherhood. In all five works, textile making “talks back” to the power structures that marginalize women, and lends insight into the material and emotional circumstances of women’s lives.

The political economy of industrial policy in Peru and Ecuador: 1980-2010

This dissertation focuses on industrial policy in two developing countries: Peru and Ecuador. Informed by comparative historical analysis, it explains how the Import-Substitution Industrialization policies promoted during the 1970s by military administration unravelled in the following 30 years under the guidance of Washington Consensus policies. Positioning political economy in time, the research objectives were two-fold: understanding long-term policy reform patterns, including the variables that conditioned cyclical versus path-dependent dynamics of change and; secondly, investigating the direction and leverage of state institutions supporting the manufacturing sector at the dawn, peak and consolidation of neoliberal discourse in both countries. Three interconnected causal mechanisms explain the divergence of trajectories: institutional legacies, coordination among actors and economic distribution of power. Peru’s long tradition of a minimal state contrasts with the embedded character of Ecuador long tradition of legal protectionism dating back to the Liberal Revolution. Peru’s close policy coordination among stakeholders –state technocrats and business elites- differs from Ecuador’s “winners-take-all” approach for policy-making. Peru’s economic dynamism concentrated in Lima sharply departs from Ecuador’s competitive regional economic leaderships. This dissertation paid particular attention to methodology to understand the intersection between structure and agency in policy change. Tracing primary and secondary sources, as well as key pieces of legislation, became critical to understand key turning points and long-term patterns of change. Open-ended interviews (N=58) with two stakeholder groups (business elites and bureaucrats) compounded the effort to knit motives, discourses, and interests behind this long transition. In order to understand this amount of data, this research build an index of policy intervention as a methodological contribution to assess long patterns of policy change. These findings contribute to the current literature on State-market relations and varieties of capitalism, institutional change, and policy reform.

The Debate on First Nations Education Funding: Mind the Gap (Working Paper 49)

It is at long last becoming part of the public discourse that improving living conditions and opportunities for First Nations communities in Canada is a national imperative. It is also widely recognized that the education is critical to fostering a better future for First Nations people. Yet, for many First Nations youth, particularly those on reserve, completing even high school is well beyond reach. The graduation rate of First Nations people living on reserve was 35.3 per cent as recently as 2011 compared with 78 per cent for the population as a whole. At the same time, the First Nations population is young and growing fast - in First Nations communities 49 per cent of the population is under 24 years of age compared to 30 per cent of the general population. Despite some incremental improvements in education success rates for First Nations students in recent years, the education gap between First Nations and the rest of the country is increasing. The concerns expressed in the 2011 Auditor General report continue to hold weight: "In 2004, we noted that at existing rates, it would take 28 years for First Nations communities to reach the national average. More recent trends suggest that the time needed may still be longer.

Proving My Competency One Test at a Time: Internationally Educated Nurses and the Canadian English Language Benchmark Assessment for Nurses

Abstract Professional language assessment is a new concept that has great potential to benefit Internationally Educated Professionals and the communities they serve. This thesis reports on a qualitative study that examined the responses of 16 Canadian English Language Benchmark Assessment for Nurses (CELBAN) test-takers on the topic of their perceptions of the CELBAN test-taking experience in Ontario in the winter of 2015. An Ontario organization involved in registering participants distributed an e-mail through their listserv. Thematic analyses of focus group and interview transcripts identified 7 themes from the data. These themes were used to inform conclusions to the following questions: (1) How do IENs characterize their assessment experience? (2) How do IENs describe the testing constructs measured by the CELBAN? (3) What, if any, potential sources of construct irrelevant variance (CIV) do the test-takers describe based on their assessment experience? (4) Do IENs feel that the CELBAN tasks provide a good reflection of the types of communicative tasks required of a nurse? Overall, participants reported positive experiences with the CELBAN as an assessment of their language skills, and noted some instances in which they felt some factors external to the assessment impacted their demonstration of their knowledge and skill. Lastly, some test-takers noted the challenge of completing the CELBAN where the types of communicative nursing tasks included in the assessment differed from nursing tasks typical of an IENs country or origin. The findings are discussed in relation to literature on high-stakes large-scale assessment and IEPs, and a set of recommendations are offered to future CELBAN administration. These recommendations include (1) the provision of a webpage listing all licensure requirements (2) monitoring of CELBAN location and dates in relation to the wider certification timeline for applicants (3) The provision of additional CELBAN preparatory materials (4) Minor changes to the CELBAN administrative protocols. Given that the CELBAN is a relatively new assessment format and its widespread use for high-stakes decisions (a component of nursing certification and licensure), research validating IEN-test-taker responses to construct representation and construct irrelevant variance is critical to our understanding of the role of competency testing for IENs.

Clipped wings: corporate social and environmental responsibility in the airline industry

Within the developed world, airlines have responded to the advice of advocates for corporate social and environmental responsibility (CSER) to use the intertwined CSER dimensions of economics, society and environment to guide their business activities. However, disingenuously, the advocates and regulators frequently pay insufficient attention to the economics which are critical to airlines’ sustainability and profits. This omission pushes airlines into the unprofitable domain of CSERplus. The author identifies alleged market inefficiencies and failures, examines CSERplus impacts on international competition and assesses the unintended consequences of the regulations. She also provides innovative ideas for future-proofing airlines.　 Clipped Wings is a treatise for business professionals featuring academic research as well as industry anecdotes. It is written for airlines (including their owners, employees, passengers and suppliers), airports, trade associations, policy makers, educators, students, consultants, CSERplus specialists and anyone who is concerned about the future of competitive airlines.