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The Novel Innate Immune-Antagonistic Effects Of The Ectromelia Virus C15 Protein
No full textThe success of poxviruses as pathogens depends upon their extensive antagonism of host immune responses by an arsenal of immunomodulatory proteins. The study of these virulence factors in their natural host reveals not only the mechanisms of subversion by which pathogens cause disease but also the complex structure of immune defenses that function to protect the host. The C15 protein of ectromelia virus (ECTV, the agent of mousepox) is the largest of the ECTV immunomodulatory proteins and is a member of a well-conserved poxviral family that contributes profoundly to virulence and has previously been studied as inhibitors of T cell activation. Here, I reveal that C15 also impacts early viral replication and spread in vivo at a time prior to T cell-mediated control of ECTV. I show that this early pro-viral effect of C15 is independent of , CD4 and CD8 T cells and dependent upon natural killer (NK) cells. I demonstrate that in vivo the NK cell response to ECTV infection is restricted by C15 and that the antagonism is selective to NK cell cytolytic function and not cytokine production. This function is recapitulated in vitro, but was not due to the inhibition of C15 on the transcription of any factors related to NK cell recruitment or activation. I conclude that in addition to its previously identified capacity to antagonize traditional T cell receptor-dependent CD4 T cell activation, C15 inhibits NK cell cytolytic function resulting in increased viral replication and dissemination. Unexpectedly, I also demonstrate that, while this does not contribute to control of replication at this early time, C15 appears to be capable of similarly impacting the antigen-independent bystander function of CD4 and CD8 T cells, namely inhibiting T cell cytolytic function but not cytokine production. Together, this work reveals the intricate interactions of a single viral protein with various lymphocytes throughout the course of infection and builds on a body of literature demonstrating the importance of NK cells in early restriction of virus within the draining lymph node
Testing By Dualization
Get PDFSoftware engineering requires rigorous testing to guarantee the product\u27s quality. Semantic testing of functional correctness is challenged by nondeterminism in behavior, which makes testers difficult to write and reason about.
This thesis presents a language-based technique for testing interactive systems. I propose a theory for specifying and validating nondeterministic behaviors, with guaranteed soundness and correctness. I then apply the theory to testing practices, and show how to derive specifications into interactive tester programs. I also introduce a language design for producing test inputs that can effectively detect and reproduce invalid behaviors.
I evaluate the methodology by specifying and testing real-world systems such as web servers and file synchronizers, demonstrating the derived testers\u27 ability to find disagreements between the specification and the implementation
Methods for Comparative Effectiveness Research with Real World Data
No full textElectronic health records (EHR) contain a wealth of information that can potentially be used for research. EHR is particularly valuable for accelerating comparative effectiveness research, which seeks to estimate the relative benefit of alternative treatments in real-world settings. However there are also many challenges and limitations to conducting research with EHR-derived data, including measurement error, systematic differences between EHR and trial populations, and differential quantity and quality of data available across patients. In this dissertation, we first investigate the performance of several methods for mitigating bias due to measurement error applied to propensity scores created from error-prone covariates and provide recommendations for which methods to use in certain scenarios. Next, we develop a method to augment a randomized clinical trial with EHR data in order to create a hybrid control arm. This new method, data-adaptive-weighting, has promising properties when compared to more standard methods as well as another more recent propensity score-based method. Finally, we investigate the scenario of informed presence bias in longitudinal data, which arises when some subjects have more information in the EHR than others based on their intensity of utilization. We extend current work and explore several scenarios in which adjusting for biomarker values obtained at both pre-scheduled and patient-initiated visits in order to determine when there is risk of bias. For each topic we applied alternative methods to real-world EHR-derived data to demonstrate practical implications of alternative approaches in realistic settings
Selection Bias in Lung Allocation: Influence on Lung Allocation Score and Physician Decision-Making
No full textIn the U.S., donor lungs are allocated to recipients based on a lung allocation score (LAS). While the statistical models used to construct the LAS control for patients’ demographic and clinical values, they do not account for selection bias, which arises because: (1) individuals are removed from the waitlist once they receive transplant (dependent censoring), and (2) in order to receive transplant, individuals must survive on the waitlist long enough for a suitable lung to become available (survivor bias). Failure to account for selection bias can lead to inaccurate predicted probabilities and suboptimal organ allocation. The goal of this dissertation is to improve the predictive accuracy of the LAS by mitigating selection bias so that lungs are allocated to the appropriate patients in the appropriate order. This goal was accomplished via three aims. First, we proposed a weighted estimation strategy to mitigate selection bias in the pre- and post-transplant LAS models, constructed a modified LAS score using these weights, and compared its performance to that of the existing LAS. Second, we examined the clinical impact of our modified LAS in both observed data and through simulations. Third, we conducted qualitative semi-structured interviews with lung transplant surgeons and pulmonologists throughout the U.S. to examine respondents’ understanding of selection bias and how it may affect the LAS and organ distribution. We found that our modified LAS exhibited better discrimination and calibration than the existing LAS and led to changes in patient prioritization. Diagnosis group, six-minute walk distance, continuous mechanical ventilation, functional status, and age exhibited the largest impact on prioritization changes. Simulations suggest that one-year waitlist survival may improve under the modified LAS, while one-year post-transplant and overall survival remain comparable to that under the existing LAS. Finally, our qualitative study demonstrates that selection bias can arise at several points along the transplantation pathway. To address such bias, transplant centers must consider both patient health and program health within constraints imposed by donor organ scarcity. We hope that this work can inform future revisions of the LAS and other prediction models in organ transplantation to ensure more equitable allocation of donor organs
A Materials Study of Topological Insulators and Two-Dimensional Ferromagnets
No full textTopological insulators and two-dimensional ferromagnetic materials are novel phases with wideranging applications including quantum computing, spintronics, and other advanced electronic devices with the potential for ultrathin and ultralow-power wearables. TEM, AFM, EDS, Raman spectroscopy, and low-temperature transport measurement are used to characterize an unusual superconducting alloy formed between palladium and bismuth selenide under low-temperature annealing. TEM, AFM, and EDS are used to perform a materials study of metallic nickel and niobium annealed with Bi2Se3 under similar conditions, with the conclusion that Ni reacts to form a diffuse layer within Bi2Se3 flakes that travels along edges and line defects, and Nb does not react at all. Detailed materials analysis of Bi2Se3 flakes nanosculpted with a gallium focused ion beam and with a TEM beam is also presented, with the result that FIB ablation causes the formation of a debris field alongside the edges of a cut region, but electron-beam ablation does not. Finally, a materials, defect, and degradation study of electrochemically exfoliated ultrathin vanadium selenide nanoflakes is presented, in which the VSe2 is characterized by Raman spectroscopy and a newly-invented MFM technique inforporating torsional resonance oscillation, as well as time studies of AFM, MFM, and low-temperature TEM to investigate the effects of both air and electrolyte exposure. It is found that propylene carbonate exposure causes the breakdown of VSe2 into its elemental constituents and that passivation with dilute perfluorodecane thiol confers a concentration-dependent protective effect. This research lays the groundwork for exciting future studies into the nature and properties of Group X alloys of Bi2Se3 and potentially novel spin textures and transport characteristics of VSe2 heterostructures
Will and Capability: Western Governments\u27 Response to Russian Disinformation Since 2013
No full textIn 2013, the Kremlin resourced and launched a multiyear global operation to subvert democracy. The operation’s main weapon was intentionally harmful information—disinformation—spread through networks of paid trolls, bot networks, and users around the world. The information was aimed at sowing division within democracies and between democracies, particularly in NATO and the European Union. Some governments chose stronger responses than others. What explains the variation in government responses? I argue that each democracy’s combination of will and capability determined its response and that states with similar endowments of will and capability chose similar policies. I conduct an in depth cross-national of thirteen Western democracies supported by two case studies of specific states: Finland and the United States. My findings show that Kremlin disinformation has repeatedly adapted to changing contexts over the last century, is likely to continue adapting, and that Kremlin tactics having shown effectiveness, have spread to more state governments and even domestic actors. Future attacks will likely follow similar themes and patterns, so the lessons learned in this dissertation can help inform future responses
Visual-Inertial State Estimation with Information Deficiency
No full textState estimation is an essential part of intelligent navigation and mapping systems where tracking the location of a smartphone, car, robot, or a human-worn device is required. For autonomous systems such as micro aerial vehicles and self-driving cars, it is a prerequisite for control and motion planning. For AR/VR applications, it is the first step to image rendering. Visual-inertial odometry (VIO) is the de-facto standard algorithm for embedded platforms because it lends itself to lightweight sensors and processors, and maturity in research and industrial development. Various approaches have been proposed to achieve accurate real-time tracking, and numerous open-source software and datasets are available. However, errors and outliers are common due to the complexity of visual measurement processes and environmental changes, and in practice, estimation drift is inevitable. In this thesis, we introduce the concept of information deficiency in state estimation and how to utilize this concept to develop and improve VIO systems. We look into the information deficiencies in visual-inertial state estimation, which are often present and ignored, causing system failures and drift. In particular, we investigate three critical cases of information deficiency in visual-inertial odometry: low texture environment with limited computation, monocular visual odometry, and inertial odometry. We consider these systems under three specific application settings: a lightweight quadrotor platform in autonomous flight, driving scenarios, and AR/VR headset for pedestrians. We address the challenges in each application setting and explore how the tight fusion of deep learning and model-based VIO can improve the state-of-the-art system performance and compensate for the lack of information in real-time. We identify deep learning as a key technology in tackling the information deficiencies in state estimation. We argue that developing hybrid frameworks that leverage its advantage and enable supervision for performance guarantee provides the most accurate and robust solution to state estimation
Reorienting Sonic Creativity Amid Ecological Disorientation
No full textThis dissertation offers ecological disorientation as an analytic for making sense of affective experiences of the climate crisis and the epistemological shifts that attend it. It focuses this analytic on a range of thinkers and makers whose reckonings with the climate crisis appeal to sonic creativity. It contributes to the difficult labor of reorienting music studies, the humanities, and higher education institutions to better contend with the climate crisis, for which there is no panacea. Chapter one analyzes the discourse of theorists, critics, scientists, and public officials who deploy sonic figures to make sense of ecological disorientation. The chapter opens this project’s overriding concern—namely, that sonic figures and practices of embodied sense-making can spur action and mobilize affects. Chapter two constellates and analyzes music studies practitioners’ reckonings with ecological disorientation to argue that such reckonings may perpetuate anthropocentric, identitarian epistemologies. Chapter three theorizes parahuman sonic creativity and compiles an archive of practitioners whose creative work in sound contends with, figures, or otherwise relates with the climate crisis and its disorienting effects; it argues that such works aestheticize the climatic, ecological conditions of possibility for their own existence. Chapter four offers a suite of the author’s creative and pedagogical models for reorientation: a breath-controlled instrument linking users’ breath to the real-time air quality of three user-defined cities around the world; a short film demonstrating the instrument; a film about the afterlives of industrial asbestos waste and environmental racism in Ambler, Pennsylvania; a video experiment in “pneumatography”; and two syllabi, available as supplementary files
Impacting Change in Student Retention: How Institutions Decide on and Execute Retention-Based Initiatives in Higher Education
No full textAs institutions face uncertainty in enrollment projections due to changing demographics, the impact of the COVID-19 global pandemic, and stagnant high school graduation rates, focusing on improving student retention is important. Enrollment management models provide opportunities to assess the effectiveness of enrollment strategies and make improvements to increase the number of students an institution enrolls and improve the support and outcomes of those students through degree completion. This dissertation provided much needed research on the decision-making and execution processes around student retention initiatives. Using qualitative methodology through case studies at two institutions, institutional perspectives were investigated on (a) the processes by which institutions decided to execute retention-based initiatives and organizational structures, (b) the key players, and (c) how they helped coordinate the execution of student retention initiatives to improve student retention and graduation rates. Given the focus on impacting change, organizational change management theory, specifically Kotter’s (1996) eight-stage process for creating major change, guided this study. Findings suggested four main themes. First, the sense of urgency an institution is facing plays an important role in creating change necessary for improvement. The greater the sense of urgency, the greater the awareness, providing an opportunity to impact change. Second, in the absence of urgency, setting institutional goals can also impact change. Building a sense of urgency from a real crisis, or artificially creating one through a lofty but achievable goal, can help motivate institutions to move forward and impact change. Third, perhaps more important than sense of urgency itself is having the right leadership via a champion to impact change. However, to sustain change, champions must develop additional leadership to help them execute new initiatives. Finally, turnover (or lack thereof) can play an important role in a change process, both as an opportunity and a threat. Each of these themes were important to the institutions observed in this study, but in each case, the themes manifested differently
Laboratories of Innovation? A Review of Trends and Case Studies of Specialization in Georgia Charter Schools from 1995 to 2015
No full textThis dissertation explores a type of innovation that occurs when charter schools specialize missions within the public education marketplace to offer a particular theme, educational approach, or target a specific student population. Focusing on the Georgia charter school sector from 1995-2015, I ask two questions: What is the pattern of innovation? How do founders view their roles as innovators? Quantitative methods model the pattern of innovation. Qualitative methods document five innovative cases from the perspective of the founders who created them. This study finds increasing innovation in specialist charter schools in the types of new missions offered and in how these missions diversified in the state. The results also show a countertrend in the rise of general missions in a type of district charter school made possible by state law. Finally, I document an innovative specialist that emerges as a new organizational form. This research applies to leaders interested in the charter method of reform as a vehicle for innovation and contributes to the debate in education on the ability of charter schools to serve as laboratories of innovation