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Developing Immunomodulatory Nanocarriers for the treatment of Myocardial Infarction
No full textPh.D.Myocardial infarction is the leading cause of death worldwide. Although reperfusion therapy restores blood flow to the ischemic myocardium and limits infarct size, it can cause additional damage to the ischemic heart, which is also known as reperfusion injury. Angiotensin-converting-enzyme inhibitors (ACEI) and beta-blockers play a key role in reducing the mortality rate of MI, however, there is no evidence that they can improve heart function. Due to the high economic and societal burden of MI, new therapies are urgently needed. Inflammation has been implicated in playing a central role in heart remodeling post MI. The inflammation response is mediated by a dynamic and sequential infiltration of inflammatory cells after MI. Although inflammation is integral to cardiac healing after MI, accumulating evidence suggests that dysregulated inflammation leads to deteriorative remodeling and subsequently heart failure. Modulating the immune response by targeting inflammatory cells and cytokines provides a promising platform for the treatment of cardiovascular diseases. To decrease toxic side effects of drugs, enhance specific targeting, and obtain controlled drug release, researchers have been developing nanotechnology-based drug delivery systems for the treatment of cardiovascular diseases. Both synthetic nanoparticles (NPs) and natural biocarriers have been reported to successfully deliver molecules with specific biological activity to the ischemic heart.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Evaluating Concordance among Physiological and Cognitive Dimensions of Music Performance Anxiety over Time
No full textPh.D.Past research on music performance anxiety has focused on how trait anxiety moderates concordance between physiological and cognitive components in musicians without much attention to how these components might change over time, both during the course of a performing event and as a function of one's past performing experience. The current study examined how trait anxiety and past solo singing experience related to electrodermal activity (EDA) and changing self-reported state anxiety before, during, and after a socio-evaluative singing task in individuals who were not music students or professionals. A self-organizing map (SOM) trained on participants' data indicated that higher trait anxiety was not systematically associated with higher average EDA and state anxiety. Only those with the highest trait anxiety score exhibited the greatest change in EDA between phases. For state anxiety, those falling in the middle range of trait anxiety scores had not only the highest state anxiety ratings just before singing, but also exhibited the greatest and least change in state anxiety going from one phase of the performance to the next. Individuals who had the most singing experience showed two distinct sub-groups of response profiles characterized by differences in reported state anxiety across phases and an inverse relationship between trait anxiety and average baseline EDA. Results of the study provide early evidence of greater heterogeneity in patterns of anxiety-related responses among individuals during evaluated performance settings.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Pharmacokinetic Strategies to Enhance the Efficacy of Anti-Cancer Antibodies in Solid Tumors
No full textPh.D.Although the development and regulatory approval of therapeutic monoclonal antibodies (mAb) have shown dramatic growth over the past two decades, the application of mAb for the treatment of solid tumors has yielded only modest benefit. Many physiologic abnormalities are present within solid tumors that limit the uptake and intra-tumoral distribution of mAb, contributing to observations of sub-optimal efficacy. In this dissertation, new strategies are introduced and experimentally evaluated to improve the entry and distribution of antibodies within tumors, and to improve the prediction of tumor exposure following systemic mAb administration. In the first portion of this dissertation, we introduce the use of anti-idiotypic distribution enhancers (AIDEs) that allow transient competitive inhibition of mAb-antigen binding to enable mAb to bypass the binding site barrier (BSB), which limits antibody distribution in solid tumors. Mathematical modeling and simulation were employed to explore desirable characteristics for AIDEs, leading to the prediction that AIDEs with dissociation half-lives between 1-36 hours would provide dramatic enhancements in the within-tumor distribution of mAb. 1HE, a previously reported anti-idiotypic single-domain antibody (sdAb) against trastuzumab, was characterized using in-vitro binding assays and was selected as a lead inhibitor, with a trastuzumab binding half-life of ~17 hours. 1HE co-administration did not alter the plasma pharmacokinetics of trastuzumab or ado-trastuzumab emtansine (T-DM1). An image analysis algorithm was developed to evaluate trastuzumab distribution in whole tumor sections following cryosectioning and immunofluorescent staining. 1HE co-administration increased the mean penetration distance of trastuzumab from tumor vasculature by >50% (p<0.001). To evaluate the impact of competitive inhibition on T-DM1 efficacy, 1HE was administered with T-DM1 at a 1.8 mg/kg dose to Nu/J mice bearing NCI-N87 xenografts. 1HE significantly improved T-DM1 efficacy, extending the median survival time, in-comparison to T-DM1 alone, from 29 to 42 days. New 1HE mutants, with trastuzumab binding half-lives between 4-482 hours, were isolated following error-prone PCR and phage display. These mutants may be used to translate the competitive inhibition strategy beyond pre-clinical animal models or extend the strategy to additional trastuzumab-based therapies. The second approach developed in this dissertation explored the application of tumor-targeted matrix modulating enzymes (TTMME) as a means of enhancing mAb distribution in tumors. Clostridial collagenase H (ColH) was used as a model enzyme, and 2Rs15d was used as a model anti-tumor sdAb. Genetic conjugates of ColH with 2Rs15d and the albumin-binding domain 035 (ABD) were expressed recombinantly in the E. coli strain SHuffle. The 2Rs15d-ColH-ABD construct bound HER2 with an equilibrium dissociation constant (KD) of 2.5 nM, bound mouse serum albumin with a KD of 1.5 nM, and retained ColH catalytic activity with ~500 collagenase units/mg of purified protein. Co-administration of 2Rs15d-ColH-ABD with trastuzumab increased trastuzumab uptake into NCI-N87 xenografts, 24 hours after administration, by 2.9-fold. 2Rs15d-ColH-ABD co-administered with T-DM1 significantly decreased the observed tumor growth rate, up to 14 days after administration, in comparison to T-DM1 administered alone, from 0.044 to 0.002 day-1 (p=0.0007). In the final section of this dissertation, a mathematical model-based approach was developed to improve predictions of mAb exposure in tumors, following systemic administration. The strategy, which utilized dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to inform predictions made via physiologically-based pharmacokinetic PBPK modeling, may have utility in increasing the efficacy of mAb therapy by tailoring antibody doses to individual patients. Incorporation of DCE-MRI parameter relationships into a PBPK model substantially improved a priori predictions of cetuximab distribution, for a range of tumor xenograft models. The new approach decreased the mean prediction error of antibody exposure in tumors, in individual mice, from 223 to 69%. The studies outlined in this dissertation have led to the evaluation of three, previously unreported, pharmacokinetic methods to improve the efficacy of anti-cancer antibodies in solid tumors. Our mathematical modeling and preclinical data support the utility of anti-idiotypic distribution enhancers (AIDEs) for improving the penetration and efficacy of mAb therapies. Protein engineering and recombinant expression resulted in the development of a tumor-targeted matrix modulating enzyme (TTMME), 2Rs15d-ColH-ABD, that was shown to increase the tumor distribution and efficacy of anti-tumor antibody-based therapy. Lastly, we showed that tumor-specific DCE-MRI kinetic parameters may be used as covariates to improve the accuracy of PBPK model predictions of mAb exposure in tumors; this modeling paradigm may hold clinical utility in individualizing mAb dosing protocols and stratifying patients for mAb therapy**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Automated Procedure Reconfiguration Framework for Augmented Reality-Guided Maintenance Applications
No full textM.S.The application of Augmented Reality (AR) to maintenance issues has resulted in significant improvements in reducing the time operators spend finding and comprehending manual maintenance procedures. One area that requires innovation is reducing the rigidity of procedures within AR-guided maintenance applications. Current strategies are limited in that they can only be completed off-site, or they can be completed on-site but rely on operator knowledge or expert intervention to perform reconfiguration. In this work, a novel framework is presented to allow for automatic reconfiguring of procedures within AR-guided maintenance applications. Once triggered, the presented framework is able to work autonomously. The framework relies on subassemblies of the machine being maintained and analyzes the effect a defective part has within its subassembly. This information is used to create a modified procedure using automatic procedure creation methods. An implementation of the framework is presented using a simple example and innovative combination of methods such as adjacency analysis, subassembly detection, disassembly sequence planning, and defective part analysis. Application examples outlined in the paper demonstrate the applicability of the developed framework.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Application of Supercontinuum Laser Absorption Spectroscopy to Combustion Environments
No full textPh.D.This thesis was motivated by the need to develop advanced diagnostic tools for combustion environments. In particular, it was desirable to build upon the benefits of in-situ laser diagnostic techniques which can perform measurements of temperature, pressure, and species concentration without disturbing the flow field of interest. Supercontinuum laser absorption spectroscopy (SCLAS) is a novel diagnostic technique with the potential to overcome existing challenges to spectroscopic measurements in combustion environments. The two goals for this thesis are to demonstrate the accuracy of SCLAS in well understood conditions, and to perform measurements of combustion flow fields using this technique. Experiments for the first topic utilized traditional optical gas cells to prepare precise mixtures of hydrocarbon gasses at known temperatures and pressures. SCLAS measurements were performed both using an optical spectrum analyzer (OSA) as well as a novel detection technique using a dispersion compensating module (DCM) that enabled measurement speeds up to 10kHz. SCLAS results were compared to both theory and previously published measurements with good agreement. Minimum detection limits and measurement uncertainty were calculated using data from these experiments. Experiments for the second topic required the development of a unique annular gas cell that encircles a flame inside of it, while also increasing measurement pathlength. Simulations with ray-tracing software were used in the design stages of this gas cell in order to determine a proper geometry. Additional modifications were also required to enable the gas cell to withstand the elevated temperatures caused by the flame inside. Once designed, this cell was used to perform temperature measurements in the preheat region of premixed methane-air flames, with excellent agreement between measured results and thermocouple verification. To conclude this thesis, new applications and future improvements to the multipass optical cell are discussed. These modifications and new research areas can expand the application of this gas cell to other fuel sources and more complicated environments.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Jim Crow in Blue: Policing While Black in Postwar New York City
No full textPh.D.Jim Crow in Blue is an interdisciplinary exploration of the lives of African American police officers in postwar New York City. Grounded in my eight years of fellowship with retired and on-duty NYPD officers, the project draws from personal interviews and archival materials public and private to examine postwar African American NYPD life and labor. As hiring African American officers became a national priority in the 1960s, black NYPD officers faced anti-black racism that structured their careers and everyday lives—a "Jim Crow in blue." In response, African American officers often blurred the lines between official duties and the broader struggle for racial justice. All the while, black officers crafted and maintained anti-racist commitments on and off the clock, ultimately providing a sense of purpose and hope within the Jim Crow North’s largest police force. Weaving together critical race theory, popular culture analysis, black freedom studies historiography, memoir, film, TV, oral history, and archival research, the first three chapters peel back the layers of "policing while black" in postwar New York City. The final two chapters focus on individual officer experiences, particularly those who worked on the NYPD's Preventative Enforcement Patrol Squad and served as members of the NYPD Guardians Association. This dissertation contributes to the field of black freedom studies in three ways. First, by telling African American police history from the bottom-up and recognizing black officers as political actors, Jim Crow in Blue makes a place for African American law enforcement at the black freedom studies table—a growing literature that continues to expand civil rights movement narratives. Second, by understanding black officers as workers and activists, this dissertation argues that the promise and limitations of policing while black continue to be both products of and strategic tools for the broader work of freedom. Third, this project adds to understandings of African American law enforcement as "dilemmas," namely the challenges that black police face in the African American community as both saviors and race traitors. While acknowledging such dilemmas, the project explores how black cops manage the entirety of their professional and personal lives, as workers in majority white and often hostile workplaces, as members of experimental units of color, and as activists in the long civil rights movement.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Role of Candida albicans DFG5 and DCW1 in Regulation of Chitin Synthesis under Cell Wall and Morphogenetic Stress
No full textM.S.Objective: Dfg5 and Dcw1 are cell wall proteins in Candida albicans which play important roles in maintaining cell wall integrity. Past studies in our laboratory have shown that mutants of DFG5 and DCW1 are affected in basal Hog1 MAPK levels to regulate chitin synthesis in C. albicans. Parallel studies in our laboratory have indicated that Dfg5 and Dcw1 regulate chitin synthesis by transcriptional regulation of chitin synthases. The aim of this study is to compare the cell morphology of DFG5/DCW1 mutants and HOG1 mutants and to determine the changes in gene expression of chitin synthases under cell wall and morphogenetic stress conditions. Methods: Morphologic analysis of DFG5/DCW1 mutants and HOG1 mutants was performed under conditions of cell wall stress and hyphal induction. Scanning electron microscopy (SEM) analysis was performed to determine cell shape and morphology. Gene expression analysis of chitin synthase genes CHS1, CHS2, CHS3 and CHS8 was performed under cell wall stress and hyphal induction conditions. Results: The DFG5 and DCW1 mutants showed defective hyphal growth as compared to controls. There was change in cell shape and cell size in DFG5 and DCW1 mutants as compared to WT. The expression of chitin synthase genes CHS1, CHS2, CHS3 and CHS8 was increased in DFG5 and DCW1 mutants as well as HOG1 mutant in response to cell wall stress using calcofluor white (CFW). Calcium Chloride (CaCl2) was able to suppress and reverse this increased expression of chitin synthases that occurred in response to cell wall stress. Induction of hyphal growth completely suppressed the increased expression of chitin synthases. Conclusions: The data confirms that DFG5 and DCW1 are required for hyphae formation. Also, DFG5 and DCW1 mutants showed defects in cell polarity suggesting that DFG5 and DCW1 are important for maintaining cell shape. Several signaling pathways (PKC, HOG1 and Calcineurin) may function in coordination to control the expression of chitin synthase**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
The Effects of Training on Change Deafness Task Performance
No full textPh.D.Training with feedback has previously been shown to improve performance on auditory change detection tasks. The present study assessed whether training-related improvements are stimuli specific, generalize across changes in the locations of objects, generalize across tasks, and are dependent on the type of training. Participants were trained with feedback on a "flicker" change detection task where the pre- and post-change scenes were alternated until a response was made. In Experiment 1, participants were trained on a location-change-detection task or completed an unrelated visual task on Day 1. Trained participants heard one set of stimuli in the auditory scenes. On Day 2, all participants were tested on the flicker task during which EEGs were recorded. Participants heard sounds from Day 1 or "novel" sounds they had not heard before. Participants who were trained on the change-detection task performed better than control participants. Trained participants did not perform better when hearing sounds they were trained with, but they did perform better on the generalization test than the control participants. There were no ERP differences between control and trained participants; all participants showed higher P1, N1, and P2 and lower P3a and P3b amplitudes for correct change trials. In Experiment 2, participants were divided into three groups: Space-trained, ID-trained, and Space/ID-trained. Each group received training on a flicker task with only one type of change in scene composition on Day 1. On Day 2, all participants were tested on a one-shot task with no change, ID-change, and Space-change trials. Results showed that training type did not impact performance in the one-shot task or ERP component amplitudes for the different types of change trials during testing. However, differences were present in ERP amplitudes during Scene 1 depending on the types of errors participants made. P3b amplitudes during Scene 2 were higher for wrong change trials than change-deaf trials for all participants. Overall, improvements from training were not specific to sound, generalizing to novel sounds. The different training regimens did not produce prominent ERP differences for the different types of trials and trained subjects did not show different ERP patterns from controls. Training improves performance in an auditory change detection task, but the changes are not specific to familiar sounds, and do not generalize from one type of task to another.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Mission Area Encoding and Monitoring Methods for Swarm Robotic Applications
No full textM.S.This thesis presents work done in the area of swarm robotics, with the goal of advancing the practicality, feasibility, and applicability of swarm robots to solve complex problems. Two major algorithmic tools are developed for improving the performance of swarm robotics systems. The first is a dynamic area monitoring algorithm, which uses clustering and auctioning of cells in a discretized space to balance the load between agents, based on their initial states. This algorithm accounts for discontinuities in a specified area, and provides an optimized ordered list of way-points per agent using a discrete, computationally efficient, nearest neighbor path planning algorithm. The second tool is an automated topological encoder of geographical maps, which feeds into a unique topological graph generator. This algorithm provides as many map samples from which to train swarm learning models, drastically expanding the data set available, allowing more generalization of learned behaviors. These two algorithms can further help to strengthen the effectiveness and reliability of swarm systems for current and future applications.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Development of Photoacoustic and Related Optical – Acoustic Techniques for Bio-sensing and Biometrics
No full textPh.D.The primary focus of this dissertation was to explore the use of optical, ultrasound, and photoacoustic (PA) technologies in the field of bio-sensing and biometrics. Optical and ultrasound imaging probably represent the two oldest kinds of imaging technologies. However, recent advances in powerful light sources, highly sensitive ultrasound electronics, and portable detectors have enabled new applications using light and sound. Their combination has also been achieved through photoacoustic imaging, which offers the benefits of both light and ultrasound imaging. In this dissertation, we developed and explored various sensing technologies for different biometric and bio-sensing applications. As for bio-sensing, we developed a noninvasive glucose estimation system based on near-infrared spectroscopy and pulse-echo ultrasound. Diabetes mellitus has become a worldwide issue, affecting patients of wide age ranges. The invasive blood glucose monitoring method is uncomfortable for patients and inconvenient for long-term usage. To address this problem, we combined two technologies: namely the Pulse-Echo Ultrasound (PEU) and the Near-Infrared Spectroscopy (NIRS) to measure blood glucose levels noninvasively. The technique was tested through in-vitro and in-vivo experiments, and two modeling techniques were developed to estimate glucose levels. The results of this study are presented in Chapter 1. As food sweetness also plays an important role in glucose control, we developed a portable ultrasound system for detecting food sweetness based on chewing dynamics. The detector was placed under the chin to quantify tongue movement, whose correlation with food sweetness was investigated through different data processing techniques. Our results indicate that there is a positive correlation between food sweetness and tongue movement. This study is presented in Chapter 2. The last biosensing study focuses on cancer imaging. Using MnO2 as the contrast agent, we established a switchable photoacoustic imaging technique for dynamic imaging of glutathione (GSH), which plays a crucial role in cancer progression. Our imaging approach was tested both in vitro and in vivo, and the experimental results are presented in Chapter 3. Biometric investigations mainly utilized photoacoustic technology. In these studies, we optimized light delivery and acoustic detection schemes for high-quality imaging of vascular structures, which can be used for personnel identification and liveness detection. To give an overview of various linear-array-based photoacoustic imaging techniques, in Chapter 4, we reviewed current developments in the field and highlighted our co-planar light illumination and acoustic detection approach. In Chapter 5, we developed a system for 3D finger vessel imaging and biometric identification. The system contains both the hardware for data acquisition and software for feature extraction and matching. Results from 36 subjects clearly demonstrated the potential of our imaging approach. Chapter 6 concludes this dissertation with an overview of future directions. Given the promising results from our investigations, we believe that optical, ultrasound, and photoacoustic technologies have enormous potential in the field of bio-sensing and biometrics.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*