Doctoral Dissertations (before 2014 -- partial holdings)

Permanent URI for this collection

The Office of Graduate & Professional Education deposits all master's theses from a given semester after the official graduation date.

For the time being, this particular UDSpace collection of doctoral dissertations from before 2014 is of limited scope. However, doctoral dissertations from 1948 to present are also available online at ProQuest/UMI through Dissertations & Theses @ University of Delaware. Check DELCAT Discovery to locate print or microform copies of dissertations that are not available online.

More information is available at Dissertations & Theses.


Recent Submissions

Now showing 1 - 15 of 15
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    Pathogenomic approaches to characterizing the avian host innate immune response to microbial infection
    (University of Delaware, 2012) Maughan, Michele Nancy
    The avian innate immune response is activated within hours of infection. While it is difficult to prevent infection by a pathogen, clinical signs of disease can be ameliorated once the host-pathogen interactions are elucidated. Host-pathogen interaction research has predominantly focused on the adaptive immune response and cell signaling events later in infection; recently however, the innate immune response and early signaling events have garnered increased attention as another area worthy of investigation and intervention. Cells of innate immunity serve as the first-responders to infection, their signaling and antigen presentation is critical to the development of a protective adaptive immune response, and the cellular products of their activity (cytokines, reactive oxygen species, complement, etc.) are responsible for many of the clinical signs associated with disease. ☐ Avian immunology research is expanding quickly due to the growing knowledge base of the chicken cytokines, Toll-Like Receptors (TLRs) and their immune signaling pathways. Our aim was characterize the avian innate immune response to microbial infection by utilizing a pathogenomics approach. By performing microarray experiments using our Avian Innate Immune Microarray (AIIM), we were able to measure the transcriptional host immune response to several important avian pathogens. Furthermore, by performing immunotherapeutic interventions using TLR agonists prior to challenge with highly pathogenic avian influenza virus, we were able to extend survival time of treated birds by 14% (p<0.01). This project has led to the characterization of the avian innate immune in different avian species, to different pathogens, at early time points throughout infection, and with and without the aid of a pre-treatment.
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    Metabolic flux analysis of mammalian cell metabolism using multiple isotopic tracers and mass spectrometry
    (University of Delaware, 2012) Ahn, Woo Suk
    Metabolic flux analysis (MFA) is a powerful technology to characterize intracellular metabolism in living cells using isotopic tracers and mass spectrometry. Therefore, in the past two decades, MFA techniques have been developed to study biological systems. However, the applications of MFA for mammalian cells have been limited due to the complexity of cellular metabolism even though mammalian cells are key platforms for biopharmaceutical production and biomedical research. Here, we present two applications for glycolysis and gluconeogenesis systems. First, we describe the analysis of metabolic fluxes in CHO metabolism at fed-batch mode. We established two metabolic models of CHO cells for non-stationary and stationary 13C-MFA. It was found that cellular metabolism in CHO cells were significantly rewired from exponential growth to stationary phases during culture. The results provide a solid foundation for applications such as cell line development and medium optimization. Second, we describe gluconeogenesis metabolism of Fao rat hepatoma cells perturbed by transcription factors. Using multiple isotopic tracers and combined 13C-MFA, we observed the regulations of metabolic fluxes by transcriptional activators and inhibitors for gluconeogenesis metabolism. The discovery and the applied MFA techniques can allow us to evaluate the pharmaceutical drug for metabolic disease, e.g. Type II diabetes. And finally, we provide the comprehensible procedures to be considered for 13C-MFA technique: isotopic and metabolic stationarity, isotopic tracer design, key measurements, multiple isotopic tracers and model validation.
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    Monstrous creators: the female artist in nineteenth-century women's gothic
    (University of Delaware, 2012) Miller, Kathleen A.
    Using archival research, as well as literary, cultural, and media criticism and the theoretical frameworks of women's studies and disability studies, this dissertation creates a new understanding of the "Female Gothic," as it demonstrates that the presence of the artistic heroine is the genre's true defining feature and that the issue of women's art is its much-contested focus. The work analyzes distinctions among nineteenth, twentieth, and twenty-first-century figurations of the female artist in Gothic texts by women across a variety of media, from Jane Austen's novel Northanger Abbey through Sandra Goldbacher's Neo-Victorian film, The Governess. It illuminates how and why anxieties regarding women's economic and social independence, gender norms, sexuality, ethnic and racial difference, physical disability, and questions of representation have been and continued to be filtered through a Gothic lens.
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    Tuning material properties via peptide design and photopolymerization of self-assembled peptide based hydrogels
    (University of Delaware, 2009) Rughani, Ronak
    Self-assembly of de novo designed peptides is a promising approach towards fabrication of functional materials. Hydrogels are one such class of materials, which are highly hydrated and mechanically rigid, and show potential as scaffolds for tissue engineering and drug delivery applications. Schneider and Pochan labs have developed a strategy to fabricate three-dimensional scaffolds for biomedical applications employing self-assembling beta-hairpin peptides. These 20 amino acid peptides can be triggered to fold and self-assemble in response to environmental cues such as pH and ionic strength, which then leads to formation of a physically crosslinked mechanically rigid hydrogel. A hallmark of these hydrogels is that they can be syringe delivered to a target site with spatial and temporal resolution. This property has been investigated towards development of injectable hydrogels for therapeutic and cellular delivery. ☐ An important criterion for development of scaffolds for tissue engineering applications is that the mechanical properties of the engineered scaffold should be similar to the mechanical properties of the native tissue to restore normal function. A limitation of many physically crosslinked hydrogels is that they are mechanically weak. A potential approach to enhancing the mechanical properties of these hydrogels includes formation of covalent crosslinks through chemical modification of the peptide sequence. This thesis specifically focuses on molecular level design of stimuli responsive self-assembling peptides to fabricate hydrogels with enhanced mechanical properties. In particular, two avenues were investigated to construct mechanically rigid hydrogels. First, the beta-hairpin peptides were covalently modified with photopolymerizable groups at specific positions to allow covalent crosslinking of the hydrogel network. In addition, peptide-polymer hydrogel constructs were prepared using self-assembling peptides and bifunctional polymers to create interpenetrating network hydrogels with enhanced mechanical properties. The material rigidity of the interpenetrating networks could be modulated depending upon the method of its preparation. Second, self-assembling, three-stranded antiparallel beta-sheets were designed. These peptides exhibited faster kinetics of self-assembly and formed mechanically more rigid hydrogels than their beta-hairpin counterpart. The mechanical properties of the gels formed by the three-stranded peptides were further modulated by varying the hydrophobicity of the turn region residues. ☐ The results described in this thesis demonstrate that peptide-based hydrogel scaffolds with tailored mechanical properties can be constructed through molecular level design. These hydrogel materials show potential for use as load bearing substitutes for tissue engineering applications.
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    Streamlining internationalization strategies for the Department of Education at a Mid-Atlantic State University: context and recommendations
    (University of Delaware, 2002) Tigan, Anna
    This Educational Leadership Portfolio (ELP) provides recommendations on internationalization strategies for the Department of Education (DoE) at a Mid-Atlantic State University (MASU). These recommendations are based on the premises that most U.S. institutions of higher education are responding to global challenges and pressures to internationalize their programs, curricula, and degree offerings. Findings of this portfolio demonstrate that a given DoE has the capacity to build on internationalization practices parallel to university-wide strategies while adhering to its own specific goals. ☐ Artifacts illustrate the efforts I made to develop these recommendations. Efforts began with conducting literature and policy reviews on the topic. I also conducted an organizational review of a sponsoring agency as an illustrative example of how international partners might differ from U.S. higher education institutions in their approach of considering what constitutes a reliable institution for international students. Understanding these nuances will save U.S. higher education institutions time and money because principles of customer service and stakeholder engagement are a priori present in the U.S. higher education system (Lapovsky, 2019). Similarly, when U.S. higher education institutions engage with international sponsors, they need to understand that successful partnerships are a result of accepting and understanding the norms and principles of operation as seen by the sponsors. Sometimes (as discussed in Appendix D) international institutional partners have different management mechanisms than U.S. counterparts. ☐ Next, I developed a program evaluation plan for an international professional development program currently administered by MASU. Although conducting a longitudinal study for programs like this will be a challenge, recommendations provided in the artifact can be considered in the context of similar customized programs that the Department of Education can initiate with other global partners. I then conducted a comparative analysis of written strategic institutional plans of MASU’s comparator institutions or Schools/ Departments of Education to analyze how internationalization is articulated in those plans and what specific initiatives serve as a sign of success for those institutions. Finally, through conducting a faculty survey I was able to identify the perceptions of the DoE faculty towards different aspects of internationalization and identify the areas of interest for further internationalization. ☐ As a result, I developed four recommendations that the Department of Education at MASU can consider to potentially streamline efforts in internationalization. These recommendations include forming a faculty task force; expanding on communication and interaction with institutional partners and volunteer ambassadors to expand on domestic internship opportunities in international education; conducting educational seminars for faculty and staff to explain the benefits of internationalization; and capitalizing on the Department’s domestic and international reputation by promoting its programs to international students and scholars. These recommendations, if implemented in whole or in part, can serve as a solid ground for continuous internationalization of the Department of Education at MASU. The University already demonstrated strong commitment to internationalization by incorporating internationalization strategies and initiatives in the Strategic Plan and participation in the American Council on Education (ACE) Internationalization Laboratory for the 2019-2020 cycle. Because ACE Internationalization Lab focuses on strategies developed for institutions rather than individual departments, recommendations of this ELP focus on the DoE’s capacity and articulated interest in internationalization and how those fit with institutional mandate for internationalization.
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    Incorporating groups, collective behavior, and information visualization in agent-based models of evacuation
    (University of Delaware, 2013) Best, Eric
    This dissertation is intended to advance research in building evacuation modeling through the introduction of detailed social groups, collective behavior, and improvements in information visualization. The model built as a part of this dissertation makes significant original contributions to both input and output of building evacuation models. ☐ Regarding inputs, this work prototypes new ways to catalog social groups, leadership, and the concept of supra force - a combination of high density, contraflows of crowds, and environment. The central difference between this model and previous efforts is the role of group affiliations. The effort resulting from this dissertation, SocEvac, creates a three-layer decision tree for most agents, who have to balance individual and group responsibilities while attempting to avoid supra force. This interaction of individually optimal exit paths and social responsibilities creates significantly more contraflow situations as agents attempt to locate and evacuate with their loved ones. These contraflows impede efficient evacuation, helping to explain scenarios such as the Station nightclub evacuation; where there were significantly more fatalities then would have been expected based on population and number of exits. ☐ On the output side, this work creates new methods to examine simulation models in real-time, and suggests new methods of measurement to determine what makes an accurate model. The real-time visualization methods allow for researchers to quickly understand what is happening while a model is running. These visualizations allow for users of a simulation to control what features they want to highlight in a model in real-time. The new methods of output measurement center around tracking agents as individuals, cataloging outcomes of agents each modeling a real-world counterpart complete with demographics and relationships. By transitioning away from aggregate population tracking and focusing on individuals, it is now possible to compare models to an entire evacuation narrative instead of only attempting to recreate end results. ☐ These improved inputs and outputs result in the most descriptive model to date of population movements during the Station nightclub fire in 2003. More than ten years after the fire, I believe the SocEvac model can finally begin to explain the complex events that led to the high fatalities and unconventional exit paths of the evacuation. ☐ While this dissertation focuses on one scenario, the underlying program can be used to model almost any building evacuation. This platform is designed to inspire other model builders to consider adding group social behaviors to models.
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    Understanding the flavoenzyme human augmenter of liver regeneration: biochemical and structural perspectives
    (University of Delaware, 2013) Ramadan, Stephanie Aron
    Augmenter of liver regeneration (ALR) is a multifaceted protein with biological roles including, but not limited to, disulfide bond formation, mitochondrial fission and fusion, spermatogenesis and activation of the MAP kinase pathway. This dissertation explores kinetic, thermodynamic and structural aspects of this protein. The first three Chapters provide background information on disulfide bond formation, the ERV/ALR family of proteins and biological roles of ALR, respectively. In Chapter 4, we determine the rate-limiting step of this flavin-dependent enzyme during the oxidation of the model substrate dithiothreitol by molecular oxygen. We also determined the redox potential of the redox-active disulfide proximal to the FAD cofactor and gained new insight into the formation and stabilization of the charge-transfer intermediate. Chapters 5 and 6 investigate the structural and functional consequence of replacing sulfur with selenium in both a random (Chapter 5) and specific (Chapter 6) manner. The final Chapter briefly describes the structure of two active site mutants of ALR, C142S and C142A. The C142S mutation crystallized with the charge-transfer interaction intact while the C142A construct was susceptible to oxidation that resulted in a cysteine sulfinic acid at position 145.
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    A bail of two cities: Atlanta vs. Philadelphia, the first criminal court phase
    (University of Delaware, 2012) Starks, Brian Chad
    This study examines bail operational procedures in Atlanta and Philadelphia. These two urban cities were chosen to provide a comparative analysis of bail systems based on geographical location (northeast and south). The comparison with an agency in the South is being done to examine the thesis in the criminal justice literature that the South has different criminal justice practices than most other locations. Specifically, race/ethnic disparities in arrest rates, trial outcomes and sentencing practices provide support for this thesis. Conducting an organizational analysis of the bail system will help structure the methodology for the project. The objective is to investigate the individuals‟ roles, the group process and the structure of the organization of bail in order to provide clarity on how the system(s) actually work. The social organization of both locales offers more insight to how the administration of bail produces disparate outcomes. This dissertation offered a more holistic view of operational bail procedures.
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    Lord Byron and the cosmopolitan imagination, 1795-1824
    (University of Delaware, 2011) Steier, Michael P.
    Following George Gordon, Lord Byron across Britain, Europe, and the Eastern Mediterranean, "Lord Byron and the Cosmopolitan Imagination, 1795-1824" traces Byron's cosmopolitanism to its foundations in Greek Cynical philosophy and to its founder, Diogenes, Byron's self-confessed mentor. The Cynics are commonly regarded as the first cosmopolitans; yet the cosmopolitanism they practiced is quite different from the cosmopolitanism we value today. Instead of stressing a need for social progress and global interconnectedness, the Cynics chose to live outside of society, challenging its conventions and declaring themselves to be citizens of the cosmos. I argue that Byron followed Cynical ideas closely and, as a Cynical cosmopolitan, rejected the theories of cultural unity and social progress that had become popular during the Enlightenment. My first two chapters, which focus on Byron and Anglo-Scottish relations, chart the development of Byron's internationalism in English Bards and Scotch Reviewers and Hints from Horace, two early neoclassical satires rarely studied as cosmopolitan texts. The next two chapters, which focus on Byron's travels in Europe and the Eastern Mediterranean, explore the limits of universal cosmopolitanism in Childe Harold's Pilgrimage, Byron's first poem explicitly to adopt a Cynical philosophy. My last chapter focuses on Byron's later years when he internalized the principles of Cynical philosophy in Don Juan and The Age of Bronze. The conclusion brings the full scope of Byron's cosmopolitan into focus by examining the urbane rhetoric of the prose writings he prepared in defense of Alexander Pope in 1820 and 1821.
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    "I've lost my city": law, community, and immigration under colorblind neoliberalism
    (University of Delaware, 2011) Longazel, Jamie G.
    This research is centered around Hazleton, Pennsylvania's Illegal Immigration Relief Act (IIRA). Passed in 2006 and subsequently ruled unconstitutional (i.e., Lozano et al. v. Hazleton), the IIRA sought to punish landlords and sanction businesses who rented to or hired undocumented immigrants and to make English the official language of the city. Taking a constitutive approach to the study of law and society and using a variety of ethnographic and qualitative methods (e.g., archival analysis, in-depth interviews, focus groups, participant observation, and media analysis), this research explores how and to what effect white working class residents, politicians, and activists have made sense of social, demographic, and economic change in Hazleton. Set in the context of the neoliberal political economic climate and a post-Civil Rights era characterized by colorblind racial discourse, this dissertation argues that we can understand the IIRA as a reassertion of local collective identity made in the face of change and constructed along racial rather than class lines. I proceed in two parts. First, I explore how Hazleton residents came to misinterpret their city's economic struggles as an undocumented immigrant "invasion." In this regard I explore how local elites (e.g., developers, politicians) injected hegemonic "pro-growth" and "tough on crime" narratives with sentiments that appealed to residents' nostalgia and sense of community solidarity. Second, I explore the activism that followed the passage of the IIRA. Here I describe how a vision of rights emerged that coincided with community imaginings, leaving Hazleton's newcomers and their advocates in a tenuous position despite the legal victory in Lozano. Taken together, this dissertation illuminates how social upheaval mobilizes discourses of `community' and `rights.' Ultimately, however, neither community nor rights are realized on the ground. In contrast, local hierarchies are strengthened and attention is diverted away from core economic troubles to the detriment of white working class residents and Latino/a immigrants alike.
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    Characterization of surface plasmon resonance (SPR) active nanohole array sensing platforms: development and application of novel instrumentation and methodology
    (University of Delaware, 2013) Kegel, Laurel L.
    Surface plasmon resonance (SPR) active nanohole array substrates offer a diverse biosensing platform with high sensitivity and unique characteristics. This dissertation investigates the sensitivity and fundamental SP features of various nanohole array substrates and demonstrates higher sensitivity than conventional continuous gold platforms, tunability to specific analytes, and great enhancement of the local field intensity. Novel instrumentation and analytical techniques are developed and utilized to assess the nanohole array SPR sensing substrates in the near infrared as well as with interaction of other nanostructures. The nanohole array substrates are evaluated throughout the near-infrared (NIR) region by novel SPR instrumentation and methodology that extends the working SPR wavelength range and measurement reliability. Development of a robust NIR-SPR instrument allows access to higher wavelength ranges where sensitivity is improved and novel SP modes and plasmonic materials may be investigated. Different aspects of the NIR-SPR instrument, including temporal stability, mechanical resilience and sensitivity, are evaluated and presented. Furthermore, a method is developed for improving precision and accuracy of empirically determined SP penetration depth, a merit of SPR spectroscopy sensitivity. The technique incorporates an adsorbate-metal bonding effect which improves the consistency in the penetration depth value calculated at different adsorbate thicknesses from 41-1089% relative deviation (without bonding effect) to 2-11% relative deviation (with bonding effect). It also improves the experimental agreement with theory, increases the accuracy of assessing novel plasmonic materials and nanostructures, and increases the precision in adsorbate parameters calculated from the penetration depth value, such as thickness, binding affinity, and surface coverage. Utilizing this NIR-SPR instrument and improved technique for calculation of penetration depth, the sensitivity and various SP modes of the nanohole arrays throughout the NIR range are evaluated, and an improvement in sensitivity compared to conventional continuous gold is observed. Both the Bragg SPs arising from diffraction by the periodic holes and the traditional propagating SPs are characterized with emphasis on sensing capability of the propagating SPs. There are numerous studies on the transmission spectroscopy of nanohole arrays; however this dissertation presents one of the few studies in Kretschmann mode, and the first in the near infrared, where greater surface sensitivity is observed. The sensitivity profile of various nanohole array parameters (periodicity, diameter, excitation wavelength) and SP modes is also presented. Further control and enhancement of the SP field is pursued by interaction between nanohole array substrate and nanoparticles to exploit field intensification between plasmonic structures, i.e. gap mode enhancement. Under specific conditions, the SPs couple together and the electric field between the structures is amplified and localized, which may be exploited for sensing purposes and surface enhanced techniques, including tip enhanced Raman spectroscopy (TERS) or surface enhanced Raman spectroscopy (SERS). A technique for observing nanohole array-nanoparticle distance dependent SP interaction is developed and utilized to demonstrate SP interaction. Scanning probe microscopy controls the position of a single nanoparticle (SNP) affixed to an atomic force microscope probe, and the location specific interaction of the SNP-nanohole array surface plasmons is measured by darkfield surface plasmon resonance spectroscopy. Coupling of the nanoparticle to the nanohole array exhibits a maximum when the SNP resides within a nanohole, which resulted in a maximum SPR wavelength shift of 17 nm and an increase in scatter intensity. This dissertation presents the first empirical observations of SPM controlled gap mode enhancement of more complex nanostructures and allows for optimization of positioning prior to use in sensing.
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    Acoustic characterization of ultrasound contrast microbubbles and echogenic liposomes: applications to imaging and drug-delivery
    (University of Delaware, 2013) Paul, Shirshendu
    Micron- to nanometer - sized ultrasound agents, like encapsulated microbubbles and echogenic liposomes, are being actively developed for possible clinical implementations in diagnostic imaging and ultrasound mediated drug/gene delivery. Contrast microbubbles (1-10 micron in diameter) contain a low solubility gaseous core stabilized by an encapsulation made of lipids/proteins/polymers/surfactants. Echogenic liposomes (ELIPs), which combine the advantages of liposomes such as biocompatibility and ability to encapsulate both hydrophobic and hydrophilic drugs with a strong reflection of ultrasound, are also excellent candidates for concurrent ultrasound imaging and drug delivery applications. The primary objective of this thesis is to characterize the acoustic behavior and the ultrasound-mediated content release of these contrast agents for developing multi-functional ultrasound contrast agents. The first part of this thesis reports the investigation of encapsulated microbubbles utilized as ultrasound contrast agents, whereas the second part reports the experimental characterizations of echogenic liposomes (ELIPs) and echogenic polymersomes. Contrast microbubbles are nonlinear systems capable of generating a subharmonic response i.e., response at half the excitation frequency, which can improve image quality by providing a higher signal to noise ratio. However, design and development of contrast microbubbles with favorable subharmonic behavior requires accurate mathematical models capable of predicting their nonlinear dynamics. To this goal, ‘strainsoftening’ viscoelastic interfacial models of the encapsulation were developed and subsequently utilized to formulate a modified form of the Rayleigh-Plesset equation to model the nonlinear dynamics of these encapsulated microbubbles. A hierarchical twopronged approach of modeling — a model is applied to one set of experimental data to obtain the model parameters (material characterization), and then the model isvalidated against a second independent experiment — is demonstrated in this thesis for two lipid coated (Sonazoid™ and Definity®) and a few polymer (polylactide) encapsulated microbubbles. We performed in vitro acoustic characterization with these contrast microbubbles, i.e., determined the material properties of their encapsulations and compared model predictions with experimental observations. The nonlinear elastic models developed were successful in predicting several experimentally observed behaviors e.g., low subharmonic thresholds and “compression-only” radial oscillations. Results indicate that neglecting the polydisperse size distribution of contrast agent suspensions, a common practice in the literature, can lead to inaccurate predictions and unsatisfactory results. Recent numerical investigations of the nonlinear dynamics of encapsulated microbubbles from our group contradicted previously published experimental results on the dependence of subharmonic behaviors on ambient pressure. We wanted to investigate this issue through new in vitro acoustic experiments by designing a modified experimental setup. Preliminary results indicate that the previously published conclusion that subharmonic response from contrast microbubbles linearly decreases with increasing ambient pressure might not be correct under all excitation conditions; it may both increase or decrease under appropriate excitations in conformity with the results of numerical investigations. Experimental characterization of the ELIPs and polymersomes was performed with the goal of demonstrating their potential as ultrasound agents with simultaneous imaging and drug/gene delivery applications — ‘dual-purpose’ contrast agents. Carefully performed experiments conclusively demonstrate the ultrasound reflectivity (echogenicity) of the liposomes prepared using an established protocol. Although, no subharmonic response from these ELIPs was observed, altering the constituents of the lipid bilayer and polymerizing it generated a subharmonic response indicating that the echogenic properties of ELIPs can be controlled by altering the preparation protocol. Our results indicate that the freeze-thaw cycle and lyophilization in presence of mannitol followed by reconstitution in a buffer was critical for generating echogenic response from these liposomes. A finite amount of mannitol (above 100 mM) proved critical for echogenicity, but increasing the mannitol concentration above that amount did not change the echogenicity. Lyophilized powders create a polydisperse suspension of liposomes upon reconstitution, which in turn results in a response without a distinct resonance peak. We believe that the echogenicity of the liposomes results from the larger diameter liposomes present in this polydisperse suspension. In spite of the conclusive experimental evidence of echogenicity, the underlying mechanisms are not completely understood primarily due to the uncertainty regarding the exact location of the gas pockets. An accurate knowledge of the locations and dimensions of the gas pockets is critical for developing improved mathematical models of their acoustic behaviors. For the experimental validation of the concept of ‘dual-purpose’ contrast agents, four novel formulations were investigated—a lipopeptide conjugated ELIP formulation that can be triggered by the extracellular enzyme matrix metalloproteinase-9 (MMP- 9), a polymer coated redox triggered ELIP formulation for cytosolic drug delivery, pH sensitive liposomes with tunable echogenicity capable of drug-release in mildly acidic micro-environment and redox sensitive echogenic polymersomes. Both in vitro acoustic studies and ultrasound imaging (the latter performed in NDSU by our collaborators) demonstrated the echogenicity of each of these formulations. Although, ultrasound excitation (< 5 MHz) alone was incapable of causing optimal release of contents, a dualtriggering strategy proved successful. Application of ultrasound in conjunction of other triggers (e.g., enzyme, pH, redox) showed significant enhancements (10-20%), which resulted in a total release of up to 80-90%. Considering these experimental results, it can be concluded that these novel formulations have the potentials for simultaneous imaging and therapeutic applications. These contrast agents hold the potential of providing powerful treatment strategies for many diseases, including cardiovascular ones and various cancers.
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    Solid-state NMR studies of structure and dynamics of HIV-1 capsid (CA) protein assemblies
    (University of Delaware, 2013) Han, Yun
    There are around 34 million people in the world living with HIV-1, which is a causative agent of acquired immunodeficiency syndrome (AIDS). AIDS has become the ninth leading cause for death of people ages 25-34 in the US. Even though highly active antiretroviral therapy (HAART) showed effectiveness in suppressing the virus replication and significantly prolonged the patients lives, AIDS still remains an uncured disease. To develop new therapies, atomic-level understanding of the mechanism of HIV-1 lifecycle, including the structures of the various protein assemblies, is needed. The Gag polyprotein and its component capsid (CA) protein are essential constituents of the HIV-1 life cycle, and have recently attracted attention as targets for drug development. However, the atomic resolution structure and the dynamics of Gag and CA protein assemblies and their complexes with small-molecule inhibitors are not available because these assemblies are not amenable for characterization by traditional structural biology methods, X-ray diffraction and solution NMR spectroscopy. Solid-state NMR spectroscopy has the unique capability of providing atomic-level structural and dynamics information in large protein assemblies. The focus of this dissertation is establishing solid-state NMR spectroscopy as an atomic-level probe of structure and dynamics in HIV-1 protein assemblies. This effort required first establishing sample conditions for formation of HIV-1 protein assemblies that give rise to high-resolution solid-state NMR spectra for subsequent structural studies. In my Ph.D. work, I have optimized protocols to prepare homogeneous HIV-1 CA protein assemblies in vitro, developed confocal imaging method to characterize the morphologies of the resulting assemblies. With the suitable samples in hand, I have acquired solid-state NMR spectra on assemblies of CA protein and the maturation intermediate, CA-SP1, for structural analysis. Using these solid-state NMR data, I and my colleagues have obtained novel insights into the following aspects of HIV-1 structural biology: i) conformation of CA protein in conical assemblies; ii) the role of conformational dynamics of the hinge region in the structural polymorphism of CA in conical assemblies; iii) conformation of spacer peptide SP1 in tubular CA-SP1 assemblies; iv) conformation and dynamics of CA in tubular assemblies. In this thesis, I will first discuss the preparation and characterization of HIV-1 CA and CA-SP1 protein assemblies (Chapter 2 and 3). I will then describe the resonance assignments and secondary structure analysis of conical assemblies of HIV-1 CA protein (Chapter 4). Next, in Chapter 5, I will present the dynamics studies of conical assemblies of HIV-1 CA protein assemblies. In Chapter 6, I will discuss the resonance assignments and conformational analysis of tubular assemblies of HIV-1 CA and CA-SP1 proteins. The long-term goal of this research is developing comprehensive understanding of the mechanism of capsid assembly and disassembly, HIV-1 maturation, through the structural and dynamics analysis of the CA and Gag assemblies. The work discussed here represents the first step toward this goal and lays out the methodological and intellectual foundations enabling the solid-state NMR analysis of HIV-1 protein assemblies.
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    Stewards of tomorrow: the Student Conservation Association, youth service, and postwar American environmentalism, 1953-1975
    (University of Delaware, 2011) Jones, Megan Anne
    The early history of the Student Conservation Association (SCA), a youth conservation work-service program founded in 1957, provides a fruitful new perspective on postwar American environmentalism. Even as new environmental concerns and constituencies arose in the 1960s and 1970s, an older concern with conserving natural resources gained new currency with the SCA's arrival. Using newly available SCA archival materials, government documents and reports, contemporary newspaper accounts, oral histories, and internal surveys, this dissertation argues that the search for "stewards of tomorrow" marshaled the power of traditionally privileged groups to protect the nation's public lands, a mission which simultaneously limited and expanded opportunities for youth. The SCA's early history demonstrates that this small organization embodied the complexity of many contemporary social dynamics and intellectual trends. Successive chapters analyze the SCA's emergence in the mid-1950s, its administrative and financial history, recruitment of volunteers and volunteers' experiences in national parks, contrasting philosophies of service formulated by the SCA and the national Youth Conservation Corps, and the impact of conservation work on youthful volunteers. Indelibly tied to the life of its founder, the organization carried on the traditions of women's voluntary service and ideas about the restorative power of nature while devising original programming that enabled young volunteers, especially young women, to acquire important occupational and educational experiences. In the 1950s and 1960s, the SCA's directors and supporters challenged generally accepted understandings of women's work, pushing for greater gender equity by obtaining opportunities for talented, ambitious young women interested in conservation and natural science. Working with the Garden Club of America, the SCA created a program that combined conservation education, experiential learning, and occupational exploration. The role of clubwomen, students, and philanthropists in the rise of modern environmentalism has often been overlooked, and the actions of these individuals complicate the historical narrative by demonstrating that tradition and innovation often went hand in hand. Many 1950s conservationists wished to preserve natural resources, and sought to enlist volunteers who would not only help relieve the burdens placed on the nation's resources, but who would also replace them as the next generation of conservation leaders. This dissertation finds that the SCA, an organization rooted in the traditions of an elite women's club and the assumptions of the privileged classes that supported it, subscribed to an interpretation of "service" that valued unpaid volunteer labor over paid conservation work. This interpretation, which assumed that any monetary value placed on work automatically corrupted such service, stemmed from the voluntary tradition on which the SCA was built. Voluntary service served as a way for the SCA to distinguish itself from other similar programs, such as the Youth Conservation Corps, but it also highlighted the inherently exclusive ideas about who could participate and what constituted service to the nation. Despite such an emphasis on the importance of volunteer work, SCA participants themselves did not find that characteristic particularly important for their overall experience, focusing instead on their heightened awareness about the environment and conservation issues.
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    Insights into structure, dynamics of thioredoxin reassembly and dynein light chain 8 and ionization states of thiamin cofactor by MAS NMR spectroscopy
    (University of Delaware, 2011) Paramasivam, Sivakumar
    Magic angle spinning (MAS) NMR spectroscopy has found applications as a versatile technique in chemistry and biochemistry to probe structure and dynamics of materials and biological systems. In recent years, MAS NMR spectroscopy has been rapidly developing as a method for atomic-resolution structural characterization of proteins and protein assemblies that are insoluble and difficult to crystallize. A number of laboratories including ours are working on developments of MAS technologies that would enable analysis of complex biological systems. In this dissertation, the applications of MAS NMR approaches to two types of problems in structural biology and biochemistry are demonstrated. First, structural and dynamics studies of two proteins, E. coli thioredoxin reassembly and dynein light chain 8 (DLC8) in the solid state are carried out yielding atomic-level details, as discussed in Chapters 2, 3, and 4. Second, ionization and tautomeric states of thiamin diphosphate cofactor (ThDP) in large protein, ThDP-dependent family of enzymes are probed using MAS NMR spectroscopy, described in Chapters 5 and 6.