Dissecting cancer using computational pathway-analysis

MacNeil, Shelley M The University of Utah ProQuest Dissertations & Th 2017 해외박사(DDOD)

Cancer is extremely challenging to treat as every patient responds differently to treatments, depending on the specific molecular aberrations and deregulated signaling pathways driving their tumors. To address this heterogeneity and improve patient outcomes, therapies targeting specific pathways have been developed. The use of computational pathway analysis tools and genomic data can help guide the use of targeted therapies by assessing which pathways are deregulated in patient subpopulations and individual tumors. However, most pathway analysis tools do not account for complex interactions inherent to signaling pathways, and are not capable of integrating different types of genomic data (multiomic data). To address these limitations, this dissertation focuses on developing user-friendly multiomic gene set analysis tools, and utilizing bioinformatics tools to measure pathway activation for multiple pathways simultaneously in cancer. Chapter 2 first describes the need for genomics and pathway-based analyses in cancer using the commonly aberrant RAS pathway as an example. Chapter 3 utilizes pathway-based gene expression signatures and the pathway analysis toolkit ASSIGN to interrogate pathways from the growth factor receptor network (GFRN) in breast cancer. Two discrete phenotypes, which correlated with mechanisms of apoptosis and drug response, were characterized from GFRN activity. These phenotypes have the potential to pinpoint more effective breast cancer treatments. Chapter 4 describes the development of Gene Set Omic Analysis (GSOA), a novel gene set analysis tool which uses machine learning to identify pathway differences between two given biologicalconditions from multiomic data. GSOA demonstrated its capacity to identify pathways known to play a role in various cancers, and improves upon other methods because of its ability to decipher complex multigene and multiomic patterns. Chapter 5 describes GSOA-shiny, a novel web application for GSOA, which provides biologists with lack of bioinformatics experience access to multiomic gene set analysis from an easy-to-use interface. Overall, this dissertation presents novel breast cancer phenotypes with clinical implications, provides the research community with gene expression signatures for GFRN components, and presents an innovative method and web application for gene set analysis--all contributing to furthering the field of personalized oncology.

A conceptual leadership framework for systemic reform in a rural educational setting

MacNeill, Patricia F East Carolina University 2006 해외박사(DDOD)

This study describes a district-wide school renewal process that attempts to develop consistency and continuity of organization and communication across four rural schools. This renewal process resulted in the implementation and refinement of leadership structures designed to facilitate the development of learning communities within schools and across the district. The study used case study methodology and includes records of meetings, survey results, interviews, and school records. The data and conclusions for this study have been drawn and organized around the theoretical framework of rural school renewal and communication structures and are based on the following propositions: (1) School renewal/reform efforts should be implemented with an awareness of the context of the school district. Renewal efforts in a rural setting should address the unique characteristics of rural schools. (2) The role of the district curriculum director is to provide guidelines for school renewal efforts that reflect a shared vision across the district while maintaining each school's flexibility in adapting those guidelines to the needs of its student population. (3) Effective leadership includes building leadership capacity at all levels of the organization. (4) Effective and clear communication processes are essential to the process of school/district renewal. (5) Identifying and maintaining a district-wide focus for all renewal efforts helps to maintain consistency and continuity of programming across the district. (6) An effective structure of leadership and communication contributes to the growth of a school and district learning community. Based on an analysis of the data in relation to the propositions, the leadership/communication model is effective in providing the structures necessary for meaningful and sustained school reform across the school district. Thus, the six original propositions were supported by the data, and other school districts engaged in renewal efforts could benefit from the use of this framework within their educational context.

Measurement of top quark-antiquark pair production in association with a Z boson with a trilepton final state in pp collisions at 8 TeV center of mass energy

MacNeill, Ian Christopher University of California, San Diego 2015 해외박사(DDOD)

A search for Z boson production with associated top-antitop pairs is performed with a final state which contains trileptons and b-tagged jets. The measurement is performed on the complete dataset of pp collisions at a center-of-mass energy of 8 TeV collected at the CMS detector, for a total instantaneous luminosity of 19.5 fb-1. A cross section is calculated for this final state and compared to the standard model prediction. The cross section for ttZ production is measured to be sigma=194 _{-89}. {+105} fb. The measured cross section to theoreticalcross section ratio is 0.94 _{-0.43}. {+0.51}. The process is measured witha significance of 2.33. This measurement is then combined with an outside 4 lepton channel measurement for an equivalent cross section measurement of sigma = 200 _{-76}. {+90} fb and a significance of 3.1.

Youth-adult collaborative leadership: Strategies for fostering ability and authority

MacNeil, Carole A University of Colorado at Boulder 2000 해외박사(DDOD)

Collaborative leadership, in which diverse constituents come together to address issues and make decisions, has the potential to respond effectively to current and future issues facing U.S. society (Chrislip and Larson, 1994; Kretzmann and McKnight, 1993; Nemerowicz and Rosi, 1997). Most of the research on collaborative leadership, however, focuses solely on contexts of adults. This study addressed this gap by examining a youth leadership program that creates opportunities for youth-adult collaborative leadership. Leadership can be conceptualized as the combination of ability (skills, talents, knowledge, and self-concept) and authority (decision-making power, influence, and “voice”). The youth leadership literature deals more often with the former: how or why to develop young people's skills and self-concept (Gardner, 1990; Smith, 1997; Woyach and Cox, 1996). Yet, without a concurrent examination of authority issues (that is, how young people come to have voice and to practice decision-making), one could argue that young people are simply learning <italic>about</italic> leadership, rather than learning leadership. This study found that a concern for both ability and authority was integrated into many of the organizational structures, programmatic activities, and interactions of the program and organization. Certain strategies, like “leadership volleyball” (a practice of deflecting authority or responsibility onto the youth participants) were practiced by adult staff members, and served to reinforce the authority facets of leadership. The study also found that task and morale functions of leadership were tightly intertwined for the youth participants and that they invested a great deal of energy and attention toward the establishment, maintenance, and repair of their relationships with other participants. The data also showed that each of the organizational levels addressed in the research questions (that is, organizational structures, programmatic activities, and interactions) had a significant impact on the degree of success and/or satisfaction that both youth and adults experienced with their youth-adult partnerships. This suggests that other organizations, looking to establish or improve their youth-adult partnerships, will need to address more than simply the programmatic aspects of their work, but also the broader picture of organizational philosophy, policies and practices, and their individual interactions with youth.

Stoichiometry as a Driver of Elemental Cycling in Tropical and Temperate Montane Streams

MacNeill, Keeley Lynn ProQuest Dissertations & Theses Cornell University 2019 해외박사(DDOD)

Elemental cycling is fundamental to life and can be an indicator of ecosystem condition and function. We have long known that the cycles of elements, both nutrients and toxins, are intimately linked, but there are still many aspects of linked elemental cycles we do not understand and new links we have not explored. For example, classic stoichiometry studies typically focus on carbon (C), nitrogen (N), and phosphorus (P) while much less literature is devoted to other elements. Expanding the framework to incorporate new interactions and new elements is an important next step for ecological stoichiometry given that ~25+ elements are required to build organisms and given the potential for toxic elements to interact with essential elements. Throughout my PhD, I have used ecological stoichiometry as a unifying theme. Ecological stoichiometry describes how the balance of energy and elements affects and is affected by organisms and their interactions in ecosystems. My thesis research examines drivers of nutrient and toxic element cycles in tropical and temperate streams.First, I compare three common methods for estimating nutrient uptake in streams. I found that while the relative ranking was preserved across uptake methods, the absolute values varied. Also, in streams with high nutrient uptake, longer residence times underestimate uptake. Next, I tested the importance of climate regime and a suite of other biogeographical factors in driving nutrient uptake in streams along a temperature gradient. I compared streams in the tropical, Ecuadorian Andes with streams in the temperate, Colorado Rockies. I found that temperature has a larger influence on nutrient uptake in tropical streams. I then explore if the stoichiometric linkages between N and P extend to As. Through a series of field and lab experiments, I found that microbial As uptake is driven by relative N:P, not absolute P concentration alone. Finally, I expanded the finding that N:P drives microbial As cycling to whole-stream As retention by food webs. I quantified As, N, and P in basal resources, in higher trophic levels (invertebrates) and in invertebrate excretion. I found that some food web pathways retain more As as a result of N:P. I conclude that the utility of ecological stoichiometry is multi-faceted and in its infancy in terms of application to broader scales and systems. Understanding of biogeochemical processes will be strengthened by incorporating additional elements and considering stoichiometric interactions.

A framework for the checking and refactoring of crosscutting concepts

Shonle, Macneil Charles University of California, San Diego 2009 해외박사(DDOD)

Modularity is a fundamental technique used for the composition of large software systems. Under modularity, design decisions that are likely to change are encapsulated within individual modules. However, programmers also employ crosscutting concepts, such as design patterns and programming idioms, which cannot be effectively modularized. Consequently, implementations of these crosscutting concepts can be expensive to change, even when the code is well-structured. In this dissertation, I describe an extension to the refactoring paradigm that provides for the modular maintenance of crosscutting concepts, supporting both substitutability of implementations and the checking of essential constraints. This extension was realized through the Arcum framework, a plug-in for Eclipse that allows programmers to describe the use of their crosscutting programming concepts with a declarative language. I present the conceptual underpinnings of the Arcum approach, and show how Arcum can be used to address several classical software engineering problems. I also present evidence from a user study of three pairs of programmers showing that Arcum can be easy to learn and use.