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Title: Compliance to prenatal supplement use in relation to low birth weight in Malawi
Creator: Chikakuda, Aaron Thokozani
Date: 2017
Collection: Electronic Theses & Dissertations
Description: "Background: Prenatal iron and folic acid (IFA) supplements are offered free to pregnant women in Malawi to reduce maternal anemia and improve birth outcomes. We investigated the association between self-reported compliance to IFA intake and risk of low birth weight (LBW). Methods: Pregnant women who attended Bwaila Maternity Wing of Lilongwe District Hospital for delivery were recruited (n=220). We used questionnaire to collect self-reported information on IFA use and maternal...
Show more"Background: Prenatal iron and folic acid (IFA) supplements are offered free to pregnant women in Malawi to reduce maternal anemia and improve birth outcomes. We investigated the association between self-reported compliance to IFA intake and risk of low birth weight (LBW). Methods: Pregnant women who attended Bwaila Maternity Wing of Lilongwe District Hospital for delivery were recruited (n=220). We used questionnaire to collect self-reported information on IFA use and maternal sociodemographic data. Before delivery blood samples for maternal hemoglobin (Hb) and folate status, and upon delivery, birth weight, and other newborn anthropometrics were measured. We used multivariate logistic regression to determine risk of LBW by prenatal IFA intake. Results: The self-reported number of IFA pills taken during pregnancy was positively associated with Hb, but not serum and RBC folate concentration: 90 pills taken corresponded with mean (SD) Hb 10.7 (1.6), 11.3 (1.8), and 11.7 (1.6) g/dl respectively (P= 0.006). The prevalence of LBW was 20.1%, 13.5% and 5.6% for those who reported taken IFA pills < 45 , 45 - 89, and 2265 90 pills, respectively (P = 0.027). Taking > 60 IFA pills reduced risk of LBW delivery (OR (95% CI)= 0.11 (0.02-0.056), P = 0.008) than taking 2264 30 pills. Conclusion: Self-reported compliance to IFA is valid for assessing prenatal supplement program in Malawi, especially Hb status, can improve adherence and reduce LBW."--Page ii.
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Title: Characterization of axenic immune deficiency in arabidopsis thaliana
Creator: Kremer, James Michael
Date: 2017
Collection: Electronic Theses & Dissertations
Description: Evolution of land plants began and has since occurred, in concert with complex communities of microorganisms, giving rise to a vast spectrum of plant-microbe relationships. Over the past decade, plant molecular biologists and microbial ecologists have worked together to identify drivers of microbiome composition that inspire hypotheses about microbiome functional potential, but many fall short of offering empirical evidence of microbiome-mediated influence on host phenotypes. Herein, I...
Show moreEvolution of land plants began and has since occurred, in concert with complex communities of microorganisms, giving rise to a vast spectrum of plant-microbe relationships. Over the past decade, plant molecular biologists and microbial ecologists have worked together to identify drivers of microbiome composition that inspire hypotheses about microbiome functional potential, but many fall short of offering empirical evidence of microbiome-mediated influence on host phenotypes. Herein, I introduce a new suite of tools to explore microbiome function and report that many facets of plant immunocompetence are microbiome-dependent.Chapter One summarizes the current understanding of plant innate immunity and notable progress of plant microbiome research, including: (1) detection and response to microbe-associated molecular patterns, (2) hormone signaling during biotic interactions, (3) technology for exploration of plant microbiome ecology, (4) factors that influence microbiome community structure, and (5) a review of relevant model systems and gnotobiotic growth platforms. Chapter Two describes the development of a novel “FlowPot” growth system: a peat-based platform conducive to axenic (microbe-free), gnotobiotic (defined microbiota), and holoxenic (undefined, complex microbiota) Arabidopsis thaliana growth. This system provides the ability to maintain control of abiotic parameters and exogenous microbiota, thus providing a valuable platform for discovery for plant microbiome research. The FlowPot system and offers a substantial improvement over alternative growth systems regarding plant health, tractability to greenhouse conditions, and maintenance of bacterial alpha diversity upon inoculation with soil-derived microbiota. An implementation of the growth system is detailed in Chapter Three, featuring a comparative analysis of the axenic vs. holoxenic Arabidopsis transcriptome, metabolome, and immunocompetence. Axenic Arabidopsis has a reduced level of defense- and immunity-associated gene expression and the defense hormone salicylic acid (SA). We report that axenic Arabidopsis is compromised in defense against the foliar pathogen Pseudomonas syringae pv. tomato DC3000 (Pst). Immune elicitation experiments revealed that axenic Arabidopsis is also compromised in the ability to recognize and/or mount normal defense responses to the microbe-associated molecular pattern flg22. Axenic susceptibility to Pst is partially explained by defective innate immunity. Finally, we report the identity of differentially abundant metabolites and transcripts in axenic and holoxenic Arabidopsis that may be involved in microbiome-influenced host phenotypes. Collectively, research described in this dissertation provides new tools and a discovery platform to empirically characterize the function of plant microbiota, as well as detailed characterization of axenic phenotypes and axenic immune deficiency.
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Title: The search for "self" : cultural identity through representations of parent-child relationships in "Instructions Not Included" (2013) and "Under the Same Moon" (2007)
Creator: Moulding, Charles
Date: 2017
Collection: Electronic Theses & Dissertations
Description: This thesis analyzes the films Instructions Not Included (2013), a fish-out-of-water comedy drama about a single father from Mexico raising his daughter in the United States, and Under the Same Moon (2007), a melodrama which shows the quest of a young boy trying to arrive in California from Mexico in less than a week so that he can be reunited with his mother. Focusing on the representations of the parent-child relationship in the context of immigration that are presented in these films, this...
Show moreThis thesis analyzes the films Instructions Not Included (2013), a fish-out-of-water comedy drama about a single father from Mexico raising his daughter in the United States, and Under the Same Moon (2007), a melodrama which shows the quest of a young boy trying to arrive in California from Mexico in less than a week so that he can be reunited with his mother. Focusing on the representations of the parent-child relationship in the context of immigration that are presented in these films, this thesis addresses the debate between globalization and nationalism. The thesis analyses the films' representations of globalization, using the theoretical framework of Arjun Appadurai's "scapes" which postulates that there are five flows which enable people, ideas, and finances to cross political and ideological boundaries. Specifically, this thesis analyzes the implications of these representations for transnational communities and the development of cultural identity. Accordingly, this thesis also demonstrates how the representations of the parent-child relationship are effectively used to illuminate several aspects of immigrant and diaspora cultural identity using the theory of cultural identity of Stuart Hall to support this perspective. Finally, this thesis concludes by applying this analysis to demonstrate what role nationalist ideologies and politics play in the fracture of families, and to demonstrate the ineffectiveness of institutional attempts to curb or control forces of globalization based on the representations in the films.
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Title: Freezing and thawing of frost-susceptible soils : (development of a reliable predictive model)
Creator: Rajaei, Pegah
Date: 2017
Collection: Electronic Theses & Dissertations
Description: Frost depth is an important factor that affects the design of various transportation infrastructures including pavements, retaining structures, bridge foundations, utility lines, and so forth. Soil freezing can lead to frost heave and heave pressure, which may cause serious stability issues. On the other hand, at the beginning of spring season, the ice starts to thaw from the top down and to a lesser extend from the bottom up. The melted water below the pavement surface is trapped (setting on...
Show moreFrost depth is an important factor that affects the design of various transportation infrastructures including pavements, retaining structures, bridge foundations, utility lines, and so forth. Soil freezing can lead to frost heave and heave pressure, which may cause serious stability issues. On the other hand, at the beginning of spring season, the ice starts to thaw from the top down and to a lesser extend from the bottom up. The melted water below the pavement surface is trapped (setting on impermeable frozen materials). It saturates the top part of the upper pavement layer. Consequently, the stiffness of the saturated layer decreases causing substantial decrease in its load bearing capacity and high deformations, which lead to premature and localized failure. To decrease the spring thaw damage, Spring Load Restrictions (SLR) signs are usually placed along the roads. The objectives of this study are to develop accurate and reliable frost and thaw depth and frost heave prediction models, estimate heave pressure and develop a reliable SLR policy. After extensive literature review, various existing frost depth models were identified and tested. These include the finite difference UNSAT-H, the Stefan, the Modified Berggren, and the Chisholm and Phang models. Unfortunately, some of these models require substantial input data that are not available and all models yielded inaccurate results. Therefore, statistical frost depth models were developed using frost depth and air temperature data collected by Michigan Department of Transportation (MDOT); one for clayey soils and one for sandy soil. The two models were then combined using the measured thermal conductivity of clayey and sandy soils. The combined statistical model was then verified using frost depth and air temperature data collected by Minnesota Department of Transportation (MnDOT). Additionally, The Gilpin's mechanistic-empirical model was employed to predict frost heave. The model produced inaccurate and counterintuitive results in some cases. Therefore, the model was modified and the empirical frost depth model developed in this study was incorporated into the model. The resulting model was then simplified to replace some of the required of input data that are not available. The modified model accuracy was assessed using the frost heave data measured at 5 sites in Oakland County, Michigan. Further, the relationship between frost heave and heave pressures were established for four soil types.Moreover, a new statistical model was developed for calculating the cumulative thaw degree-day (CTDD) using pavement surface temperature and air temperate data collected by MDOT. Then, the thaw depth data measured in the state of Michigan were used to assess Nixon and McRoberts thaw depth predictions model. Since the model did not produce accurate and acceptable results, statistical thaw depth models were developed using the calculated CTDD values and thaw depth data collected by MDOT and MnDOT; one for clayey soils and one for sandy soils. The models were then verified using the calculated CTDD values and thaw depth data collected by MnDOT. Finally, based on the results of thaw depth model a new SLR policy was proposed.
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Title: Mechanistic connections between the proton motive force and ATP homeostasis in higher plant photosynthesis under dynamic environmental conditions
Creator: Carrillo, Leticia Ruby
Date: 2017
Collection: Electronic Theses & Dissertations
Description: Through photosynthesis, plants can capture light energy from the sun for the conversion to a more stable high-energy form, ATP and NADPH. These products are then used to fuel an array of metabolic processes including the biosynthesis of sugars and complex carbohydrates. Yet, the abundant source of solar energy used in the process is highly varied and fluctuates throughout the day, directly impacting the photosynthetic apparatus and carbon assimilation. This dissertation focuses on several...
Show moreThrough photosynthesis, plants can capture light energy from the sun for the conversion to a more stable high-energy form, ATP and NADPH. These products are then used to fuel an array of metabolic processes including the biosynthesis of sugars and complex carbohydrates. Yet, the abundant source of solar energy used in the process is highly varied and fluctuates throughout the day, directly impacting the photosynthetic apparatus and carbon assimilation. This dissertation focuses on several mechanisms by which plants are able to respond to the dynamic environmental pressures through modulation of the proton motive force (pmf) and ATP homeostasis.ATP is the primary energy currency in cells and is synthesized in plastids by the chloroplast ATP synthase. However, unlike other stromal thiol-regulated enzymes that incrementally become redox-activated in response to light, chloroplast ATP synthase acts more like an on-off switch, only requiring minimal irradiance to become fully active. Previous work suggested that the rapid sensitivity to light could be explained by the relative redox potentials of the regulatory thiols on the γ-subunit of ATP synthase. This work uncovered a new, unexpected component, NADPH thioredoxin reductase C (NTRC) that controls thiol regulation specifically under low light intensities. Mutants lacking NTRC show strong photosynthetic phenotypes, e.g., increased nonphotochemical quenching and inhibition of linear electron flow, at low irradiances, consistent with an inability to activate ATP synthase resulting in a buildup of the thylakoid pmf. We predict both NTRC and the canonical ferredoxin-thioredoxin reductase system co-regulate the thiol state of ATP synthase at specific light intensities using different reducing potentials (NADPH versus ferredoxin) that allow for added flexibility.Photosynthesis copes with, and adapts to, fluctuating environments using a wide range of mechanisms. While most of the research has been devoted to the processes occurring inside the plastid, work described here on the nucleotide triphosphate transporter (NTT) illuminates an additional mechanism of augmenting and balancing ATP. Previous work suggested that the chloroplast transporter, NTT, acted primarily as an importer of ATP during the night cycle, presumably under non-photosynthesizing conditions. However, isolated intact chloroplasts from both spinach and Arabidopsis thaliana export ATP at rapid rates that can constitute a large fraction of that generated by the light reactions. Furthermore, these findings suggest that earlier results of minimal rates of ATP transport were based on suboptimal assay conditions and incorrect characterization of T-DNA knockout lines, rendering NTT essential for seed germination. Work on double NTT knock-down lines (NTTdKD) have decreased gene expression levels of ntt1 and ntt2 and show strong photosynthetic responses, particularly in the pH and energy-dependent quenching response (qE) with related accumulation of the pmf under fluctuating light and/or decreased CO2 levels. These results indicate a greater role for NTT in balancing ATP levels between the stromal and cytosolic pools than previously thought.
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Title: The experiences and decision making processes of couples with a child with a childhood genetic disorder
Creator: McKee, Kate Szubeczak
Date: 2017
Collection: Electronic Theses & Dissertations
Description: There is a disparity in the research between the individual's and the family as a whole's interactional processes in the collection and dissemination of genetic information. There is a gap in our understanding of how couples deal with genetic information, especially when a child is diagnosed with an inherited genetic condition. Also, there is a lack of understanding of the decision-making processes regarding genetic testing. Furthermore, medical professionals and family therapists are...
Show moreThere is a disparity in the research between the individual's and the family as a whole's interactional processes in the collection and dissemination of genetic information. There is a gap in our understanding of how couples deal with genetic information, especially when a child is diagnosed with an inherited genetic condition. Also, there is a lack of understanding of the decision-making processes regarding genetic testing. Furthermore, medical professionals and family therapists are becoming more aware of the effect these tests will have on family systems and on the health beliefs of the family. Once a diagnosis has been received, families now have the task of making sense of the diagnosis and deciding on how the family system needs to change or adapt in order to accommodate the genetic disorder. The purpose of this qualitative study was to understand the lived experiences of couples who have a child suffering from a genetic disorder (affected child) and to understand the couple's experiences of receiving the diagnosis of an inherited genetic disorder in a child, and how they as a couple, and by extension, their family, adapted to that diagnosis. Nine couples from the Midwestern United States were interviewed using a semi-structured, joint interview process. Using thematic analysis and the couples' own words, two studies emerged from the data. The focus of study 1 was on the decision-making processes about genetic testing and the decision to have future children of couples who have a child with an inherited genetic disorder. The focus of study 2 was on how the family adapted after receiving the diagnosis for their child. Implications and further considerations for family therapists are addressed.
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Title: Real Fantasies in Mathematics Education : numeracy, Quantitative Reasoners, and Transdisciplinary Wicked Problems
Creator: Craig, Jeffrey Carl
Date: 2017
Collection: Electronic Theses & Dissertations
Description: This dissertation has seven chapters. In chapter one, I discuss through why I am doing this dissertation, my positionality, and how I learned from and with all of my committee members.Chapter two is where I situate my dissertation study through developing a social theory of quantitative literacy by translating a social theory of literacy (Barton & Hamilton, 2000). I also describe my epistemological stance towards research as a creative act, my theoretical commitments to critical postmodernism...
Show moreThis dissertation has seven chapters. In chapter one, I discuss through why I am doing this dissertation, my positionality, and how I learned from and with all of my committee members.Chapter two is where I situate my dissertation study through developing a social theory of quantitative literacy by translating a social theory of literacy (Barton & Hamilton, 2000). I also describe my epistemological stance towards research as a creative act, my theoretical commitments to critical postmodernism, and summarize my methodologies and methods for each of the three articles. Chapter three is my first article. In this article, I historicize the numeracy discourse by writing a genealogy that traces how statements about numeracy emerge in scholarship, with a focus on the United States. Scholars’ statements about numeracy form a discourse that pressures mathematics education to reform. These pressures are sustained when scholars connect numeracy to historically powerful justifications for reform. I name these as three promises embedded in the discourse: (1) numeracy promises to reflect modern reality, (2) numeracy promises to empower, and (3) innumeracy promises to have social costs. I conclude with a discussion of the literacy myth and its implications for mathematics education. Chapter four is my second article. In this article, I take the quantitative reasoner to be a persona embodying the goals mathematics educators describe for who our students should become. The quantitative reasoner has both cognitive and affective dimensions; they know and feel particular things about mathematics and statistics. As a member of a curriculum design team, I invoked the value of students becoming quantitative reasoners to defend new courses existing. My students helped me see that the quantitative reasoner is an incomplete person who is a fantasy of mathematics educators, including myself. Together, we re-humanized the quantitative reasoner and each other. Chapter five is my third article. This article describes findings from a study on students’ projects during a mathematics course in quantitative literacy. The issues students chose to research turned out to be connected to a particular class of problems. Across places and disciplines, people are working on these wicked problems which are messy, global, connected, responsive, and unavoidable. Wicked problems are in contrast to curricula that may center tame problems. This apparent mismatch provided the impetus to consider education for wicked problems. After coding students’ projects using the Rittel & Weber’s (1973/1984) ten characteristics of wicked problems, I found three themes: complexity, transdisciplinarity, and openness. Chapter six is my conclusion. In the chapter I synthesize what I have done in my dissertation and revisit some of my theoretical work – most notably my social theory of quantitative literacy. I also use my dissertation to revisit mathematics education as a whole, including research, and try to make some new connections and trouble my conclusions. Chapter seven is my parting thoughts. In it, I return to my positionality by discussing an aesthetic choice I have engaged during this dissertation. That aesthetic is the metamodern aesthetic and it involves the juxtaposition of incredible seriousness with playful detachment. I think about the metamodern aesthetic and my millennial identity in order to reframe doing education research.
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Title: Deep sequencing driven protein engineering : new methods and applications in studying the constraints of functional enzyme evolution
Creator: Wrenbeck, Emily Elizabeth
Date: 2017
Collection: Electronic Theses & Dissertations
Description: "Chemical engineers have long sought enzymes as alternatives to traditional chemocatalytic routes as they are highly selective and have evolved to function under mild conditions (physiological temperature, neutral pH, and atmospheric pressure). Enzymes, the workhorses of biological chemistry, represent a vast catalogue of chemical transformations. This feature lends their use in a variety of industrial applications including food processing, biofuels, engineered biosynthetic pathways, and as...
Show more"Chemical engineers have long sought enzymes as alternatives to traditional chemocatalytic routes as they are highly selective and have evolved to function under mild conditions (physiological temperature, neutral pH, and atmospheric pressure). Enzymes, the workhorses of biological chemistry, represent a vast catalogue of chemical transformations. This feature lends their use in a variety of industrial applications including food processing, biofuels, engineered biosynthetic pathways, and as biocatalysts for preparing specialty chemicals (e.g. pharmaceutical building blocks). The totality of an enzymatic bioprocess is a function of its catalytic efficiency (specificity and turnover), product profile (i.e. regio- and enantio-selectivity), and thermodynamic and kinetic stability. For native enzymes, these parameters are seldom optimal. Importantly, they can be modified using protein engineering techniques, which generally involves introducing mutation(s) to a protein sequence and screening for beneficial effects. However, robust enzyme engineering and design based on first principles is extremely challenging, as mutations that improve one parameter often yield undesired tradeoffs with one or more other parameters. In this thesis, deep mutational scanning - the testing of all possible single-amino acid substitutions of a protein sequence using high-throughput screens/selections and DNA counting via deep sequencing - was used to address two fundamental constraints on functional enzyme evolution. First, how do enzymes encode substrate specificity? To address this question, deep mutational scanning of an amidase on multiple substrates was performed using growth-based selections. Comparison of the resulting datasets revealed that mutations benefiting function on a given substrate were globally distributed in both protein sequence and structure. Additionally, our massive datasets permitted the most rigorous testing to date of theoretical models of adaptive molecular evolution. These results have implications for both design of biocatalysts and in understanding how natural enzymes function and evolve. Another fundamental constraint of enzyme engineering is that mutations improving stability (folding probability) of an enzyme are often inactivating for catalytic function, and vice versa. Towards overcoming this activity-stability constraint, I sought to improve the heterologous expression and maintain the catalytic function of a Type III polyketide synthase from Atropa belladonna. This was accomplished using deep mutational scanning and high-throughput GFP-fusion stability screening, followed by novel filtering methods to only accept beneficial mutations with high probability for maintaining function. Lastly, deep mutational scanning relies on the construction of user-defined DNA libraries, however current available techniques are limited by accessibility or poor coverage. To address these limitations, I will present the development of Nicking Mutagenesis, a new method for the construction of comprehensive single-site saturation mutagenesis libraries that requires only double-stranded plasmid DNA as input substrate. This method has been validated on several gene targets and plasmids and is currently being used in academic, government, and industry laboratories worldwide."--Pages ii-iii.
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Title: Information seeking of scholars in the field of higher education
Creator: Fitzgerald, Sarah Rose
Date: 2017
Collection: Electronic Theses & Dissertations
Description: This study examines the information seeking of scholars in the field of Higher Education. I interviewed Higher Education scholars about their use of the web, library resources, and interpersonal networking for their research. I also spoke with them about how the faculty reward system shapes their information seeking habits. I drew on information behavior concepts to describe their behaviors. Because Higher Education is an interdisciplinary field, there is a broad swath of literature Higher...
Show moreThis study examines the information seeking of scholars in the field of Higher Education. I interviewed Higher Education scholars about their use of the web, library resources, and interpersonal networking for their research. I also spoke with them about how the faculty reward system shapes their information seeking habits. I drew on information behavior concepts to describe their behaviors. Because Higher Education is an interdisciplinary field, there is a broad swath of literature Higher Education scholars might draw from. This study examined how these scholars seek information in an information rich environment with limited time. The findings of this study describe how the career expectations for Higher Education scholars shapes their information seeking choices, how scholars change their information seeking over time, how emotional and interpersonal factors influence their choices, and how the tools available for information seeking influence their research. Many of the findings appear to apply to faculty engaged in research across disciplines, particularly other applied social sciences. Scholars publish work that advances their careers, but this doesn't include all the work that could enhance the body of knowledge about Higher Education. Events in society and changes in educational policy which have a great impact on Higher Education do not necessarily get addressed by scholarship in the field. Keeping up with the scholarly literature in Higher Education will not keep one abreast of all the developments in Higher Education. Scholars' professional confidence, passion, and relationships effect their ambition in searching for information, branching out to new topics, and sharing their expertise. Information seeking and sharing is influenced by the supportiveness of the community of scholars they work in. This includes senior scholars in the field, scholars outside the field, and librarians. An individual's disposition may determine how willing they are to seek information and help, which can determine how successful they will be as a scholar.The technologies for information seeking are constantly and rapidly changing. It's important to keep faculty up to date with new developments and changes to library resources so they do not develop a static view of tools that are constantly in flux. Scholars should be aware that tools change and they should be on alert for new developments.
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Title: Climate change and algal blooms
Creator: Lin, Shengpan
Date: 2017
Collection: Electronic Theses & Dissertations
Description: "Algal blooms are new emerging hazards that have had important social impacts in recent years. However, it was not very clear whether future climate change causing warming waters and stronger storm events would exacerbate the algal bloom problem. The goal of this dissertation was to evaluate the sensitivity of algal biomass to climate change in the continental United States. Long-term large-scale observations of algal biomass in inland lakes are challenging, but are necessary to relate...
Show more"Algal blooms are new emerging hazards that have had important social impacts in recent years. However, it was not very clear whether future climate change causing warming waters and stronger storm events would exacerbate the algal bloom problem. The goal of this dissertation was to evaluate the sensitivity of algal biomass to climate change in the continental United States. Long-term large-scale observations of algal biomass in inland lakes are challenging, but are necessary to relate climate change to algal blooms. To get observations at this scale, this dissertation applied machine-learning algorithms including boosted regression trees (BRT) in remote sensing of chlorophyll-a with Landsat TM/ETM+. The results show that the BRT algorithm improved model accuracy by 15%, compared to traditional linear regression. The remote sensing model explained 46% of the total variance of the ground-measured chlorophyll-a in the first National Lake Assessment conducted by the US Environmental Protection Agency. That accuracy was ecologically meaningful to study climate change impacts on algal blooms. Moreover, the BRT algorithm for chlorophyll-a would not have systematic bias that is introduced by sediments and colored dissolved organic matter, both of which might change concurrently with climate change and algal blooms. This dissertation shows that the existing atmospheric corrections for Landsat TM/ETM+ imagery might not be good enough to improve the remote sensing of chlorophyll-a in inland lakes. After deriving long-term algal biomass estimates from Landsat TM/ETM+, time series analysis was used to study the relations of climate change and algal biomass in four Missouri reservoirs. The results show that neither temperature nor precipitation was the only factor that controlled temporal variation of algal biomass. Different reservoirs, even different zones within the same reservoir, responded differently to temperature and precipitation changes. These findings were further tested in 1157 lakes across the continental United States. The results show that mean annual algal biomass generally increased with annual temperature. Greater increase was found in lakes with more nutrients. Mean annual algal biomass generally decreased with annual total precipitation. In both the "low" and the "high" greenhouse-gas emission scenarios, mean annual algal biomass in lakes generally increased with climate change, and greater increases are predicted from the high emission scenario."--Pages ii-iii.
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Title: Mentor teachers as teacher educators : a qualitative study of educative mentoring
Creator: Yates, Claire (Claire Fredrick)
Date: 2017
Collection: Electronic Theses & Dissertations
Description: There is increasing pressure on Education Preparation Providers to provide clinically rich opportunities for interns that are connected with and embedded in local schools. Providing these clinically rich opportunities has become the primary responsibility of the mentor teachers that oversee the development of the interns placed in their schools. If mentor teachers are to become teacher educators, they need greater support to develop educative mentoring practices. The purpose of this study was...
Show moreThere is increasing pressure on Education Preparation Providers to provide clinically rich opportunities for interns that are connected with and embedded in local schools. Providing these clinically rich opportunities has become the primary responsibility of the mentor teachers that oversee the development of the interns placed in their schools. If mentor teachers are to become teacher educators, they need greater support to develop educative mentoring practices. The purpose of this study was to learn more about the experiences of mentor teachers as they applied educative mentoring strategies and to discover how their professional learning could be supported by Education Preparation Providers. This qualitative study, based on the experiences of six secondary level mentor teachers that mentored interns in year-long placements, interviewed them about their personal histories and values, captured specific mentoring moments with their interns, and conducted reflective interviews about their current mentoring practices. The central research question was: How do mentors use their knowledge and/or vision of teaching to provide learning opportunities for their interns? Four additional supportive questions were asked to provide a more robust picture of the mentor teachers' practices: ¥ How do mentors determine the professional development needs of their interns?¥ How do mentor teachers explicitly or implicitly use their knowledge and values about teaching in their mentoring of interns? ¥ What strategies do mentor teachers use to promote reflection on the part of interns?¥ How can experienced mentors continue to learn about mentoring? The results of this study showed that mentor teachers utilized a variety of mentoring strategies to develop the interns' vision of teaching. These methods allowed them to move beyond the transmission model of mentoring to a more transformative stance grounded in the values of educative mentoring.
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Title: Analysis of wind turbine blade vibration and drivetrain loads
Creator: Ramakrishnan, Venkatanarayanan
Date: 2017
Collection: Electronic Theses & Dissertations
Description: The reliability of wind turbines is a major issue for the industry. Drivetrain and blade failures are common, costly and not fully understood. Designers must thus examine and understand the key parameters that influence reliability. As wind turbines increase in size, the blades are designed to be more lightweight and flexible, increasing the potential for large-displacement oscillations during operation. This necessitates the incorporation of nonlinearity in the formulation of the blade model...
Show moreThe reliability of wind turbines is a major issue for the industry. Drivetrain and blade failures are common, costly and not fully understood. Designers must thus examine and understand the key parameters that influence reliability. As wind turbines increase in size, the blades are designed to be more lightweight and flexible, increasing the potential for large-displacement oscillations during operation. This necessitates the incorporation of nonlinearity in the formulation of the blade model to better understand the dynamics and stability characteristics. Also, oscillations in the blade impart dynamic loading onto the gearbox. Understanding these dynamic loads is essential for the design of reliable gears and bearings, and hence economically viable wind turbines. Traditional studies of wind turbines have focused on the aerodynamic performance of the blades, the reliability of gearbox and its components, grid connectivity and improvements in power distribution. The aspect of blade vibration from a dynamics point of view has garnered interest but not been fully developed and understood. In this work, the partial and ordinary differential equations that govern the in-plane and out-of-plane motion of a wind turbine blade subject to gravitational and aerodynamic loading are developed using Hamilton's principle and Lagrange formulations respectively. These differential equations include nonlinear terms due to nonlinear curvature and nonlinear foreshortening, as well as parametric and direct excitation at the frequency of rotation. The equations are reduced using an assumed uniform cantilevered beam mode to produce single second-order ordinary differential equations (ODE) to approximate the blade model for the case of constant rotation rate. Embedded in the ODE's are terms of a forced Mathieu equation with cubic nonlinearity. Different variations of the forced Mathieu equation are analyzed for resonances by using the method of multiple scales. The forced Mathieu equation has instabilities and resonances at multiple superharmonic and subharmonic frequencies. Second-order expansions are used to unfold the expressions that govern the amplitude of response at these critical resonances. The equations of motion (EOM's) also have regions of instability and we employ perturbation analysis to identify the stability transition curves of the system. These calculations compare well with numerical simulations for simple systems under study. The formulation is then extended to wind turbine blades. The effect of various parameters on the amount of blade oscillation is demonstrated using the amplitude-frequency curve. Aerodynamic forces on the wind turbine blades are calculated using the Blade Element Momentum (BEM) theory and its extensions. Commercial software, such as FAST, have also been used to simulate responses for specific blades to understand influence of various blade parameters. For current production wind turbine blades, the parameters are such that the superharmonic resonances are not excited significantly. From parametric studies of the blade EOM we can understand the parameter values at which these resonances become dominant. It is shown that as wind turbine blades become larger they are prone to superharmonic resonances, whose existence may not be within the scope of current design strategies. The amplitude of response at all resonances tend to become amplified for much larger blades. Both in-plane and out-of-plane responses will increase the loading at the rotor hub and consequently, increase the loads and moments on the wind turbine drivetrain. To capture the effect of increased loading on the wind turbine drivetrain, we follow two approaches. First, using RomaxWind, we model the 750 kW gearbox used as a part of the Gearbox Reliability Collaborative (GRC) headed by National Renewable Energy Labs (NREL). For this, we partnered with Romax Technology Ltd. to analyze the sensitivities of the load on the elements of the gearbox to variations in the input loads. Using the Romax gearbox model, we suggest methods to optimize the gear geometry to improve reliability of the drivetrain by minimizing influence of manufacturing and assembly tolerances and misalignments. We also designed novel approaches to predict gearbox vibration using the models and suggested changes that are required to improve the overall design of the gearbox (these have been implemented while manufacturing newer generations of the NREL GRC gearbox). Second, for the case of in-plane blade vibration, we use a simple torsional model of the wind turbine gearbox to study the influence of a time varying load on the torsional response of the drivetrain. The effect of increased loading on larger wind turbine systems is shown by scaling values of blade and gearbox properties. The fundamental work formulated in this thesis can be extended to more complex models to understand other system level dynamics of interest (multi-mode interaction, multi-blade resonance, etc.). More detailed formulation of aerodynamic loads (for example by using ONERA semi-empirical approach) would also improve model fidelity for predicting the influence of aerodynamic loads on blade vibration.
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Title: Transmissibility and localization of tetrodotoxin in the rough-skinned newt, Taricha granulosa
Creator: Wegener, Sarah (Graduate of Michigan State University)
Date: 2017
Collection: Electronic Theses & Dissertations
Description: "Tetrodotoxin (TTX) is a powerful neurotoxin that prevents the propagation of action potentials, leading to paralysis and sometimes death in nearly all animals. However, a diverse group of marine and freshwater animals possess TTX, which they use for offense, defense, and communication. One of most studied TTX-mediated interactions is the predator-prey arms race between the rough-skinned newt (Taricha granulosa) and common garter snake (Thamnophis sirtalis). Variation in toxicity among...
Show more"Tetrodotoxin (TTX) is a powerful neurotoxin that prevents the propagation of action potentials, leading to paralysis and sometimes death in nearly all animals. However, a diverse group of marine and freshwater animals possess TTX, which they use for offense, defense, and communication. One of most studied TTX-mediated interactions is the predator-prey arms race between the rough-skinned newt (Taricha granulosa) and common garter snake (Thamnophis sirtalis). Variation in toxicity among populations of newts matched by TTX-resistance in predatory snakes has captured the focus of much research centered on the hypothesis that the arms race is the sole driver of variation. Nevertheless, recent studies suggest a more complex dynamic. Explanations of the dramatic variation in TTX among different populations of newts can only be constructed once fundamental questions about the origin, function, and transmission of TTX in newts have been more thoroughly explored. In this study, I took two approaches to address the origin, function, and transmission of TTX: 1) a cohabitation experiment in which I paired toxic and non-toxic newts to test whether toxicity can be acquired through contact, and 2) an experiment to determine the distribution and concentration of TTX in different tissues. The cohabitation experiment revealed no detectable change in the toxicity of non-toxic male newts, suggesting that a physical or physiological impediment prevents non-toxic newts from becoming toxic. The tissue toxicity experiment demonstrated that TTX is present throughout the body in structurally and functionally diverse tissues, which has many implications for the involvement of TTX in communication and reproduction in addition to defense."--Page ii.
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Title: Urban and cluster agglomeration economies's effects on rural households in Asia
Creator: Hu, Chaoran
Date: 2017
Collection: Electronic Theses & Dissertations
Description: "Agglomeration effects play important roles for rural households in participating in farm and nonfarm activities. With the rapid growth of cities of different sizes and the development of food value chain, how these agglomerations of urban effects, networks, and food value chain clusters will affect rural households' participation in nonfarm employment and farm behavior (technology adoption) are not yet well known. The dissertation consists of three chapters that aim to assess the impacts of...
Show more"Agglomeration effects play important roles for rural households in participating in farm and nonfarm activities. With the rapid growth of cities of different sizes and the development of food value chain, how these agglomerations of urban effects, networks, and food value chain clusters will affect rural households' participation in nonfarm employment and farm behavior (technology adoption) are not yet well known. The dissertation consists of three chapters that aim to assess the impacts of these urban and cluster agglomeration economies' on rural households in Asia."--Excerpted from abstract.
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Title: Cross-cultural comparative study of burial sites
Creator: Xu, Haoxuan
Date: 2017
Collection: Electronic Theses & Dissertations
Description: "Burial grounds, as one of the most important landscape that connect the living and the dead, can often represent culture, tradition and aesthetic evaluation of a local community; therefore, understand the similarities and differences among the burial sites can help people understand the culture and tradition of places behind the burial sites. This research studies the similarities and differences among different Western and Chinese burial sites, including Pere Lachaise in Paris, three...
Show more"Burial grounds, as one of the most important landscape that connect the living and the dead, can often represent culture, tradition and aesthetic evaluation of a local community; therefore, understand the similarities and differences among the burial sites can help people understand the culture and tradition of places behind the burial sites. This research studies the similarities and differences among different Western and Chinese burial sites, including Pere Lachaise in Paris, three municipal cemeteries in Michigan, USA, three public cemeteries in Shanghai, China, Two Chinese imperial tombs in Nanjing, China, and two rural ancestral burial grounds in Jiangsu, China." -- Abstract.
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Title: Field modeling, symplectic tracking, and spin decoherence for EDM and muon g-2 lattices
Creator: Valetov, Eremey Vladimirovich
Date: 2017
Collection: Electronic Theses & Dissertations
Description: "While the first particle accelerators were electrostatic machines, and several electrostatic storage rings were subsequently commissioned and operated, electrostatic storage rings pose a number of challenges. Unlike motion in the magnetic field, where particle energy remains constant, particle energy generally changes in electrostatic elements. Conservation of energy in an electrostatic element is, in practice, only approximate, and it requires careful and accurate design, manufacturing,...
Show more"While the first particle accelerators were electrostatic machines, and several electrostatic storage rings were subsequently commissioned and operated, electrostatic storage rings pose a number of challenges. Unlike motion in the magnetic field, where particle energy remains constant, particle energy generally changes in electrostatic elements. Conservation of energy in an electrostatic element is, in practice, only approximate, and it requires careful and accurate design, manufacturing, installation, and operational use. Electrostatic deflectors require relatively high electrostatic fields, tend to introduce nonlinear aberrations of all orders, and are more challenging to manufacture than homogeneous magnetic dipoles. Accordingly, magnetic storage rings are overwhelmingly prevalent. The search for electric dipole moments (EDMs) of fundamental particles is of key importance in the study of C and CP violations and their sources. C and CP violations are part of the Sakharov conditions that explain the matter-antimatter asymmetry in the universe. Determining the source of CP violations would provide valuable empirical insight for beyond-Standard-Model physics. EDMs of fundamental particles have not to this date been experimentally observed. The search for fundamental particle EDMs has narrowed the target search region; however, an EDM signal is yet to be discovered. In 2008, Brookhaven National Laboratory (BNL) had proposed the frozen spin (FS) concept for the search of a deuteron EDM. The FS concept envisions launching deuterons through a storage ring with combined electrostatic and magnetic fields. The electrostatic and magnetic fields are in a proportion that would, without an EDM, freeze the deuteron's spin along its momentum as the deuteron moves around the lattice. The radial electrostatic field would result in a torque on the spin vector, proportional to a deuteron EDM, rotating the spin vector out of the midplane. The principle of an anomalous magnetic dipole moment (MDM) measurement using a storage ring, shared by BNL's completed E821 Experiment and the ongoing E989 Experiment operated by Fermi National Accelerator Laboratory (FNAL), requires injecting muons into a magnetic ring at the so-called magic momentum. The magic momentum, as defined in this context, would freeze the muon's spin vector along its momentum if the anomalous MDM was zero. The spin precession in the horizontal plane relative to the momentum is proportional to the anomalous MDM. Storage rings for measurement of EDM and anomalous MDM present a new frontier in tracking code accuracy requirements. For accurate tracking of storage rings with electrostatic particle optical elements, it is necessary to model the fringe fields of such elements accurately, in particular, because not doing so provides a mechanism for energy conservation violation. However, the previous research on fringe fields tended to focus on magnetic rather than electrostatic particle optical elements. We will study and model the fringe fields of several electrostatic deflectors. Field falloffs of electrostatic deflectors are slower than exponential, and Enge functions are not suitable for accurate modeling of these falloffs. We will propose an alternative function to model field falloffs of electrostatic deflectors. We will use conformal mapping methods to obtain the main field of the Muon g-2 storage ring high voltage quadrupole, and we will calculate its fringe field and effective field boundary (EFB) using Fourier analysis. Furthermore, we will study tracking of storage rings with electrostatic elements using map methods. We will find that, for simultaneous symplecticity and energy conservation, it is only necessary to enforce symplecticity in COSY INFINITY. We will model and track several benchmark lattices - an electrostatic spherical deflector, a homogeneous magnetic dipole, and a proton EDM lattice - in COSY INFINITY and MSURK89, our in-house eighth order Runge-Kutta-Verner tracking code. Finally, we will investigate spin decoherence and systematic errors in FS and quasifrozen spin (QFS) lattices. Spin decoherence effects are similar in FS and QFS lattices, and spin decoherence in said lattices often remains in the same range over time, indicating the feasibility of EDM measurement using FS and QFS lattices."--Pages ii-iii.
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Title: Application of high-impact polystyrene (HIPS) as a graphene nanoparticle reinforced composite thermoplastic adhesive
Creator: Stitt, Erik
Date: 2017
Collection: Electronic Theses & Dissertations
Description: "Adhesive bonding is a more efficient joining method for composites than traditional mechanical fasteners and provides advantages in weight reduction, simplicity, and cost. In addition, the utilization of mechanical fasteners introduces stress concentrations and damage to the fiber-matrix interface. Adhesive bonding with thermoset polymers distributes mechanical loads but also makes disassembly for repair and recycling difficult. The ability to utilize thermoplastic polymers as adhesives...
Show more"Adhesive bonding is a more efficient joining method for composites than traditional mechanical fasteners and provides advantages in weight reduction, simplicity, and cost. In addition, the utilization of mechanical fasteners introduces stress concentrations and damage to the fiber-matrix interface. Adhesive bonding with thermoset polymers distributes mechanical loads but also makes disassembly for repair and recycling difficult. The ability to utilize thermoplastic polymers as adhesives offers an approach to address these limitations and can even produce a reversible adhesive joining technology through combining conductive nanoparticles with a thermoplastic polymer. The incorporation of the conductive nanoparticles allows for selective heating of the adhesive via exposure to electromagnetic (EM) radiation and simultaneously can augment the mechanical properties of the adhesive and the adhesive joint. This approach provides a versatile mechanism for efficiently creating and reversing structural adhesive joints across a wide range of materials. In this work, a high-impact polystyrene (HIPS) co-polymer containing butadiene as a toughness modifier is compounded with graphene nano-platelets (GnP) for investigation as a thermoplastic adhesive. The properties of the bulk composite adhesive are tailored by altering the morphology, dispersion, and concentration of GnP. The thermal response of the material to EM radiation in the microwave frequency spectrum was investigated and optimized. Surface treatments of the adhesive films were explored to enhance the viability of this nanoparticle thermoplastic polymer to function as a reversible adhesive. As a result, it has been shown that lap-shear strengths of multi-material joints produced from aforementioned thermoplastic adhesives were comparable to similar thermoset bonded joints."--Page ii.
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Title: Examining off-campus students' sense of belonging and behaviors in a town-gown context
Creator: Carter, Erin Hundley
Date: 2017
Collection: Electronic Theses & Dissertations
Description: The current study emerged from the need to address student behavior issues in town-gown communities and the practical need to know more about off-campus students as central actors in these behaviors. Off-campus students have long been labeled as commuter students because of limited recognition of the known diversity within the commuter population (Dugan, Garland, Jacoby, & Gasiorski, 2008) and an absence of town-gown scholarship focused on college student residents of the local community ...
Show moreThe current study emerged from the need to address student behavior issues in town-gown communities and the practical need to know more about off-campus students as central actors in these behaviors. Off-campus students have long been labeled as commuter students because of limited recognition of the known diversity within the commuter population (Dugan, Garland, Jacoby, & Gasiorski, 2008) and an absence of town-gown scholarship focused on college student residents of the local community (Kemp, 2013). The current study sought to remedy the little attention given to off-campus students through the exploration of their sense of belonging to the local community, and in turn, how sense of belonging influenced behavior in the town-gown context. An American college town was the town-gown context chosen for the current study because of its capacity to showcase the unique influence the university has on the character of the town (Gumprecht, 2008). Using a stratified random sampling, the sample (n = 645) was drawn from the population of undergraduate students living off campus in the City of East Lansing, Michigan. Strata were determined based on residential density levels due to an interest in assessing how residential environments of varying densities influenced sense of belonging in off-campus students. The current study utilized sense of belonging and town-gown literature to guide the selection of exogenous and intervening predictor variables relevant in the town-gown context. These predictor variables included demographic characteristics (e.g., age, sex, race, year in school) and density categorization along with intervening variables such as environmental perceptions, social interactions, and behavior participation. Criterion variables included sense of belonging and positive and negative behavior participation. Hierarchical regression analyses were used to determine the extent these demographic and community factors influenced sense of belonging, as well as how sense of belonging influenced participation in positive and negative behaviors in the town-gown context. The study concluded off-campus students were a unique cohort in the student population, warranting future attention from scholars and practitioners. Sense of belonging was not predicted by demographic and density characteristics, but was positively influenced by perceptions of community (e.g., reliability, friendliness) and positive behavior participation (e.g., attending community events, utilizing city services). Number of roommates, semesters lived off-campus, and residential density associated with houses were positive predictors of behavior participation, both positive and negative. Environmental and social relations constructs were positive predictors of both positive and negative behavior participation. Sense of belonging was a positive predictor of positive behavior participation, but was not a predictor of negative behaviors. The discussion offers insights and direction for town-gown administrators tasked with creating policy and practical interventions aimed at supporting off-campus students, while also addressing the unique challenges stemming from student behaviors in the local community.
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Title: Examining the results of an intervention to influence factors of group dynamics in video conferencing learning environments
Creator: Cain, William Christopher
Date: 2017
Collection: Electronic Theses & Dissertations
Description: "The following study was framed around a simple question: when a group of people is engaged in video conferencing, what sort of things can they do to improve their group dynamics? This is an important question for current and future educational practice because web-based video conferencing has increasingly become an important tool for use in online and distance education programs. Using computer-based audio and visual equipment, web-based video conferencing allows groups of students and...
Show more"The following study was framed around a simple question: when a group of people is engaged in video conferencing, what sort of things can they do to improve their group dynamics? This is an important question for current and future educational practice because web-based video conferencing has increasingly become an important tool for use in online and distance education programs. Using computer-based audio and visual equipment, web-based video conferencing allows groups of students and teachers to see and hear each other in real-time, providing a channel of communication that is often rich in information. Informal video chat, using applications like Skype, FaceTime, and Google Hangouts, has become a popular means of communication in much the same way as phone calls. Formal group video conferencing, however, is a different communication and interaction format from informal video chat, and many teachers and students often unfamiliar with rules and norms associated with it. For example, best practices literature on video conferencing stress that things like framing, lighting, proximity to the camera, and the composition of background can all affect the way a person is perceived by others. These factors can also affect the overall quality of the video conferencing session, making it easier or harder for people to hold sustained interactions with each other. In short, formal group video conferencing requires people to be mindful of certain things that they may not pay attention to when they are engaged in either face-to-face conversations or informal video chats. When people are not mindful, they can cause serious disruptions to overall group dynamics. Group dynamics play a role in any setting where people come together for a period of time. Forsyth defines a group as "two or more individuals who connected by and with social relationships" (Forsyth, 2009, p. 4). Dynamics are the interactions between and among factors in a context or system of elements. Group dynamics therefore refers to the qualities of interaction with one another in a group. Factors that influence group dynamics include morale, belongingness, tone, atmosphere, influence, participation, trust, leadership, conflict, competition, cooperation, etc. (Hanson, 2005). The goal of this study was to design an intervention based on a series of activities that instructors or facilitators could use with students in simulated high-stakes video conferencing learning environments. The results were illuminating but not in a way the author intended. The intervention at the heart of this study was not implemented as it was originally designed, which affected not only the results but the entire direction of analysis. This is not necessarily a bad thing. This study shows the importance of intervention design and the role that facilitators play in bringing the benefits of an intervention to those who need it. The different chapters in this dissertation discuss why the author felt this study was important and necessary, how he went about designing the central intervention, what the results suggest about intervention design and implementation, and his recommendations for future research in the area of group dynamics in video conferencing learning environments. It is the author's wish that readers gain a new appreciation for the complexity of research in this area, as well as a newfound or renewed interest in seeing this research continue."--Pages ii-iii.
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Title: Inhibitors of mycobacterium tuberculosis DosRST signaling and persistence
Creator: Zheng, Huiqing
Date: 2017
Collection: Electronic Theses & Dissertations
Description: Tuberculosis (TB) is one of the most deadly infectious diseases in human history and is caused by the bacterium Mycobacterium tuberculosis (Mtb). Current TB therapy requires 6-9 months of treatment with four different antibiotics, including isoniazid, rifampin, ethambutol and pyrazinamide. However, due to the long course of TB therapy and the evolution of drug-resistant Mtb strains, first-line anti-mycobacterial drugs are not sufficient to control the TB epidemic. Therefore, it is urgent to...
Show moreTuberculosis (TB) is one of the most deadly infectious diseases in human history and is caused by the bacterium Mycobacterium tuberculosis (Mtb). Current TB therapy requires 6-9 months of treatment with four different antibiotics, including isoniazid, rifampin, ethambutol and pyrazinamide. However, due to the long course of TB therapy and the evolution of drug-resistant Mtb strains, first-line anti-mycobacterial drugs are not sufficient to control the TB epidemic. Therefore, it is urgent to develop new drugs with novel targets to shorten the course of therapy, control the spread of drug-resistant TB and eradicate this deadly disease. In response to host immune cues, Mtb modulates its metabolism to establish a state of low metabolic activity called non-replicating persistence (NRP). During NRP, Mtb can remain viable in the host without causing disease symptoms, a state known as latent TB. DosRST is a two-component regulatory system that plays an essential role to establish and maintain NRP in Mtb. It is induced by host immune stimuli, such as hypoxia, carbon monoxide and nitric oxide, through the histidine kinase sensors DosS and DosT. The response regulator DosR regulates about 50 genes in the dormancy regulon. NRP bacilli are problematic for two reasons: 1) they are insensitive to several anti-mycobacterial agents and drive the long course of TB therapy; and, 2) they can resuscitate for growth once the immune system weakens, thereby serving as a source for reactivation of disease and infectious transmission of the Mtb. Therefore, inhibiting the DosRST pathway may help reduce the population of NRP bacteria during infection and thus function to reduce drug tolerance and shorten TB treatment. This dissertation presents a whole-cell phenotypic high-throughput screen of a ~540,000 compound small-molecule library. The screen employed a DosR-dependent, hypoxia-inducible fluorescent reporter strain, CDC1551(hspX::GFP), and successfully identified six distinct, novel chemical inhibitors of DosRST signaling, named HC101A-106A. Physiological and mechanistic studies were performed to characterize HC101-104 and HC106A. All five inhibitors are shown to inhibit genes of the DosRST regulon and persistence-associated physiologies, such as triacylglycerol accumulation. HC101A, HC102A, HC103A and HC106A also reduce Mtb survival when cultured under strongly hypoxic conditions. UV-visible spectroscopy studies show that HC101A (artemisinin) and HC106A target the heme group of sensor kinases DosS/T via distinct mechanisms. For example, artemisinin modulates the redox status of DosS/T and alkylates the heme to form artemisinin-heme adducts, whereas HC106A interacts with DosS heme in a similar manner to direct CO-heme or NO-heme interactions. In contrast, HC102A and HC103A do not target the heme group, but instead inhibit sensor kinase autophosphorylation activity. Electrophoretic mobility assays suggest that HC104A functions by directly inhibiting DosR DNA binding activity. Overall, this dissertation provides proof-of-concept that multiple components of the DosRST pathway can be targeted by small molecules to inhibit Mtb persistence and antibiotic tolerance. Additionally, this dissertation presents the discovery of a new chemical inhibitor, HC2091, that kills Mtb by targeting the mycolic acid transporter MmpL3. MmpL3 is an essential protein that functions to transport trehalose monomycolate across mycomembranes for trehalose dimycolate biosynthesis. HC2091 is bactericidal against Mtb in a dose- and time- dependent manner in vitro. It also has activity against Mtb inside of macrophages. Whole genome sequencing spontaneous mutants resistant to HC2091 identified five single nucleotide variants primarily located in the C-terminus of MmpL3, and HC2091-treated Mtb exhibits decreased mycolic acid synthesis, thus supporting that MmpL3 is the target of HC2091.
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