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Modulation of Self-Perpetuating Protein Aggregation by Sequence and External Factors
No full textThe National Aeronautics and Space Administration (NASA) and the European Space Agency (ESA) are studying how to improve the safety of future planetary science sample return missions that would bring back materials to Earth. Backward planetary protection requirements have been identified as a critical technology development focus in order to reduce the possibility of harm to Earth’s biosphere from returned materials. To address these challenges, NASA has identified the need for an appropriate suite of biological indicators (BIs) that would be used to develop, test, and ultimately validate sample return mission sterilization systems. BIs traditionally used at NASA have been selected based on past mission requirements and mainly focused on bacterial spores. However, spore-based BIs are insufficient as the only analog for a nominal case in sample return missions. Thus, it is important to develop a mitigation strategy that addresses various known forms of biology, from complex organisms to biomolecular assemblies (including self-perpetuating non-nucleic acid containing structures). The current effort seeks to establish a BI that would address a stable biomolecule capable of replication. Yeast aggregating proteins (yeast prions) exhibit behavior similar to mammalian prion protein and have been successfully employed by researchers to understand fundamental prion properties such as aggregation and self-propagation. Despite also being termed “prions,” yeast prions are not hazardous to humans and can be used as a cost-effective and safer alternative BI to mammalian prions, which is addressed in the first two chapters of this thesis. In the final data chapter, we characterize a deletion derivative of Sup35NM missing the N-terminal region, and therefore only have a C-terminal PrD, in comparison to the wildtype Sup35NM and derivatives containing deletions of the N-terminal region of the PrD in order to describe the various amyloidogenic regions within the Sup35NM PrD. We also investigate a Sup35NM derivative where the N-terminal region of the PrD has been replaced by a human amyloid-forming protein, Aβ42. Our data shows that, while the Sup35NM derivative with an N-terminal deletion has a similar lag time to wildtype Sup35NM, the amyloid core of the deletion derivative must be quite different based on seeding dynamics. This work fundamentally advances our understanding of the effect of the environment on yeast amyloid-forming amino acid sequences and amyloid structure via our attempts to perturb it with extreme sterilization modalities, and how sequence factors influence amyloid variant emergence. Furthermore, this work will be directly utilized by NASA and the European Space Agency (ESA) for upcoming mission planning purposes.Ph.D.Biolog
Modeling and Characterization of Structural, Thermophysical, and Dynamical Evolutions of Small Bodies in the Solar System
No full textExplorations of small bodies in the solar system––such as asteroids and comets––offer unique opportunities to study the remnants of the early solar system. These small bodies often challenge our expectations, revealing surprising findings that raise questions about planetary formation, evolution, and even the origins of life. The field of planetary science seeks to address these questions through interdisciplinary approaches, combining insights from astronomy, geology, chemistry, physics, and engineering to better understand the story of our solar system.
This dissertation concerns the evolution of near-Earth asteroids, focusing on their structural, thermophysical, and dynamical evolutions to provide a more comprehensive view of their life cycle. Asteroids exhibit a remarkable diversity of shapes, reflecting their complex evolutionary pathways. This dissertation begins by exploring their structural condition through the development of a semi-analytical model based on granular physics, offering rapid yet accurate insights into asteroid reshaping and mass-loss processes. Second, a 3-dimensional thermophysical model is developed to better characterize the thermal conditions of asteroids, a key factor giving rise to non-gravitational perturbations on their dynamics. Finally, the work extends to binary asteroid systems, coupling detailed shape models with full two-body gravitational dynamics and thermal torque modeling to quantify the effects of both impact-induced reshaping and the binary-YORP effect. Collectively, these studies provide a more integrated understanding of the physical processes governing small body evolution, with direct applications to planetary defense mission such as NASA’s DART and ESA’s Hera.Ph.D.Aerospace Engineerin
Lymphatic Impairment Following Heart Transplantation
No full textLymphatics play a role in every vascularized organ yet are often overlooked in research as a potential therapeutic target. Their ability to modulate tissue homeostasis and immune cell trafficking holds promise in influencing a variety of disease states. Heart transplantation (HTx) is particularly intriguing as the lymphatic network is severed upon donor heart excision and not surgically reconstructed. The consequence resulting from severed lymphatic vessels in transplanted hearts is unknown. This thesis aimed to address gaps in cardiac lymphatic research from both a clinical and basic science perspective. Our clinical study investigated lymphatic variations in transplant patients with and without late graft dysfunction to assess the impact of lymphatics on metrics of transplant rejection and survival. These data correlated lower lymphatic areas to higher mortality in this patient population. Our findings validate lymphatics as a promising biomarker to evaluate mortality risks or even organs prior to procurement. We believe our work will not only stimulate new avenues of research in this field, but also inspire reflection on current surgical techniques, immune suppression, and organ procurement processes. The outcomes of our clinical study motivated us to do more detailed investigations through animal modeling. We established a heterotopic abdominal heart transplant model (HAHT) to assess longitudinal changes in lymphatic vasculature after HTx and its effect on graft function and survival. These data demonstrated significant increases in lymphatic number and luminal area for extended periods of time post-HAHT and some degree of functional lymphatic drainage at day 14. The period between day 14 and 28 was identified as a critical turning point in pathologic cardiac remodeling with vast therapeutic implications. These findings improve our understanding on lymphatic adaptations after HAHT but more importantly provide a characterized platform to study induced lymphangiogenic responses intended to rescue transplant function. Understanding pathologic conditions associated with lymphatic dysfunction in HTx will provide novel therapeutic targets that enhance the longevity of donor grafts and reduce mortality among the transplant community.Ph.D.Biomedical Engineerin
Development of a Bottom-Up Contacting Method for Use in Nanoelectronic Devices
No full textBottom-up methods enable 3D bulk synthesis and enhance production scalability, yet nanoelectronic devices like diodes and transistors are still contacted using top-down techniques like photolithography, which restrict processing to planar surfaces. This thesis introduces a dopant-selective atomic layer deposition (ds-ALD) process for the bottom-up fabrication of Pt contacts on Si. The ds-ALD method involves the blanket attachment of a blocking mask, followed by its selective removal with an etchant that targets specific doping concentrations to pattern metal thin films. To develop this method, we first study the attachment and selective removal of a blocking layer on Si and Ge surfaces, demonstrating selective removal using an aqueous etchant. We then explore the ds-ALD method using undecylenic acid and KOH for selective Pt deposition on heavily doped Si, observing blanket attachment of undecylenic acid regardless of doping type or concentration, and then selective removal on heavily doped Si using KOH. Finally, we characterize Pt contacts formed using ds-ALD. These contacts exhibit ohmic behavior, current flow through bulk Si and an improvement in the contact resistivity.Ph.D.Chemical and Biomolecular Engineerin
Linking Climate and Air Quality: Insights from Machine Learning, Chemical Transport Modeling, and Field Measurements
No full textClimate change and air pollution are two of the most significant global challenges of the industrial era, both exerting adverse impacts on human health. Their complex interactions make this an urgent area of research. Climate and air quality are interconnected through multiple pathways: many anthropogenic sources emit both air pollutants and greenhouse gases, while climate change affects air quality by altering meteorological conditions that govern the emissions, formation, transport, and removal of air pollutants. In turn, air pollutants influence climate directly through interactions with solar radiation and indirectly by modifying cloud properties. To improve future air quality and climate projections and support effective policymaking, it is of vital importance to understand underlying processes linking climate and air pollution and to accurately represent the relationships in regional and global models.
This dissertation investigates the impact of rising temperature on surface PM2.5 (particulate matter with aerodynamic diameters less than 2.5 μm) and ozone (O3) levels across the contiguous United States (CONUS), reproduces and explains these observed sensitivities using a state-of-the-art chemical transport model, and characterizes the mixing state and optical properties of light absorbing particles—black carbon (BC) —in different environments in the Southeast US. The research integrates high resolution datasets derived from machine learning models, nationwide observational networks, chemical transport modeling, and in situ field measurements to address key gaps in our understanding of the temperature dependence of air pollution and the climate implications of aerosol mixing state.
Chapter 2 examines the sensitivity of surface-level PM2.5 and O3 to summer temperature using long-term, high-resolution datasets generated by ensemble machine learning models. Across the eastern US, stringent emission control strategies over the past two decades have significantly reduced the positive temperature responses of PM2.5 and O3, thereby lowering the population exposure to air pollution during heat events. In contrast, the western US has experienced an increase in PM2.5–temperature sensitivity, probably driven by the growing temperature-sensitivity of wildfires. These findings underscore the effectiveness of emission reductions in mitigating climate-induced air quality deterioration in some regions, while highlighting new challenges in areas facing intensified climate-driven pollution sources such as wildfire.
Chapter 3 improves the representation of temperature-dependent PM2.5 responses in the GEOS-Chem chemical transport model through targeted updates to emission inventories and secondary organic aerosol (SOA) formation from biogenic emissions. Simulations for 2000–2022 reveal that chemical production processes—particularly isoprene-derived SOA and sulfate formation—dominate PM2.5 sensitivity in the eastern US, with a declining trend driven by reductions in anthropogenic SO2 emissions. In the western US, primary emissions from wildfires, increasingly drive the observed sensitivity. Transport processes are major contributors to interannual variations nationwide. For the first time, this work quantitatively attributes PM2.5–temperature sensitivity to individual processes, demonstrating how the interplay between chemistry, emissions, and meteorology determines regional air quality responses to warming.
Chapter 4 presents field measurements of the mixing state of refractory BC (rBC)-containing particles from two campaigns conducted at an urban site in Atlanta, GA (ATL) and a rural high-elevation site in Boone, NC (APP). At ATL site, rBC core size increases linearly with particle diameter, indicating more uniform internal mixing. In contrast, APP site exhibits a bimodal distribution of rBC core sizes in larger particles, suggesting the influence of local and long-range transported aerosols with distinct aging histories. The absorption enhancement factor (Eabs), calculated based on realistic mixing states, deviates significantly from estimates assuming fully internal mixing—particularly at the APP site, where mixing state heterogeneity leads to overestimation of Eabs by over 40%. These findings emphasize the importance of accurately resolving aerosol mixing states in optical properties simulations, especially in regions influenced by both local emissions and long-range transport.
In summary, this dissertation: (1) quantifies the temperature dependence of PM2.5 and O3, and demonstrates the effectiveness of emission control policies in mitigating climate-induced air quality degradation across the CONUS; (2) improves the performance of GEOS-Chem in simulating PM2.5–temperature relationships and identifies the dominant temperature-sensitive processes that drive regional and temporal variability; and (3) characterizes the mixing state of black carbon in contrasting environments and demonstrates the impact of mixing state heterogeneity on modeled optical properties. These findings have several implications: (1) stringent emission control strategies can effectively reduce air pollution sensitivity to warming and thereby lowering associated public health risks; (2) wildfire in the western US is becoming increasingly temperature sensitive, underscoring the need for urgent attention and regulation action; and (3) resolving the mixing state of light-absorbing aerosols is critical for reliable estimation of aerosol radiative effects, especially in regions with more heterogeneously mixed aerosol population. Together, these studies enhance our understanding of key aspects of interactions between climate and air pollution and support the development of science-based strategies for air quality and climate management.Ph.D.Earth and Atmospheric Science
Characterizing Microarchitectural Side-channel Threats on the Security of Web Browsers
No full textImproving the performance of modern processors faces challenges in frequency, power consumption, and relatively slower memory subsystems. In response, architects have devised complex caching, speculation, and prefetching mechanisms for cutting-edge processors to sidestep such limitations. The resulting products have paved the way for an ecosystem of high-performance web applications, leading to users 'living in the browser' for several hours each day. In turn, these habits have led to web browsers becoming a central store for users' secrets, such as passwords and payment information.
This thesis explores the effect of recent hardware optimizations in processors on the security of web applications rendered by browser engines. Building on the knowledge that some hardware optimizations may backfire for isolation across security domains in the form of microarchitectural side-channels, this thesis discovers optimizations that were previously unseen in production, and demonstrates that both old and new optimizations carry consequences that permeate through the layers of computing abstraction -- all the way to high-stakes application software on top.
The multifaceted attacks that cause the disclosure of users' secrets in this thesis propound that the current landscape of retroactive and incremental side-channel mitigations in web browsers are insufficient to defend against future threats, especially by demonstrating how to undermine several such countermeasures with novel hardware and software primitives. By characterizing the adversarial capabilities of web-based microarchitectural threat actors, this thesis intends to serve as an initial step towards principled defenses for hardening future web browsers
A Methodology for Forecasting and Mitigating Risk in Cislunar Mission Planning Using Real Options
No full textSpace mission planning is made extremely difficult by the nature of space itself: it is a hostile environment for human exploration, requiring large budgets and advanced technologies. Space exploration is also a dangerous endeavor; crewed missions have consistently exceeded the risk guidelines set by NASA, and the most stringent safety requirements are set on the launch and landing phases, which are also the phases where an accident is statistically most likely to occur. The focus of future exploration is on creating a foundation on the Moon for the eventual launch of crewed Mars missions, so the operating environment is becoming even more challenging. Additionally, mission budgets are tied to public perception and assumed risk, so there is an increased need for methodology improvements to reduce programmatic and personal risk.
There are several approaches for decision-making under deep uncertainty that were investigated for possible application to space mission planning. Real options and analysis through decision trees presents serious potential for improving decision-making methods, and was selected from the other alternatives as the primary focus of this thesis research. Real options is an analysis strategy that borrows principles from economics and financial markets to model how the value of a project changes over time, where the project exists in an uncertain future.
Applying a real options-based methodology addresses many of the existing gaps in forecasting project value in a deeply uncertain future. A major advantage of real options is the built-in flexibility: there are opportunities at decision nodes to abandon a project, increase investment, or change the structure. It was hypothesized that applying real options to space mission planning would enable methodology improvements and meet these stated needs
There are limitations in the application of real options that have prevented its widespread use for this type of problem in the past, and that need to be addressed in order to see the benefit of this updated approach; these limitations include that the decision trees that need to be developed for this kind of approach include too many nodes for a decision-maker to fully consider all of their options, many of these mission planning methods create silos around individual metrics of success which lead to the need for iterative designs and repeated sequential analysis, there are an intractable number of possible failures so there is a need to determine the areas that are most critical for analysis and mitigation, and traditional planning methods are driven by Subject Matter Expert (SME) expertise but do not contain the necessary structure to overlay subjective information from the stakeholder and scenario definition. These limitations define the experimental gaps that are addressed through the hypotheses and results.
The demonstration of real options applied to space mission planning problems used the decision tree from NASA’s Human Exploration of Mars Design Reference Architecture (DRA) 5.0 document. By looking at the resultant architectures for the performance and schedule emphasis scenarios, it was found that the impact of stakeholder priorities is consistent across simulation cases in spite of the stochasticity and other complicating factors.
The overarching research hypothesis aims to develop a methodology that uses real options to locate satisficing architectures more efficiently and include input from decision-makers. The use of decision trees accelerates architecture selection because the results of the analysis display the possible outcomes for a variety of architectures and include uncertainty information about each individual architecture as well as the entire scenario in general. This analysis can be run in minutes, as opposed to some of the current modeling of mission outcomes which takes months to fully complete, and does not include the same level of flexibility as this methodology. The primary inclusion of user input comes through the section of the methodology involving the interactions with a parametric decision-making environment. The explicit purpose of this tool, based on principles from military wargaming, is to include this input through allowing the selection of the relevant architectures and allowing the user to modify the scenario and requirements and see how that impacts the preferred mission architectures in real time.Ph.D.Aerospace Engineerin
An investigation into the mechanics of parallelogram-based origami
No full textOrigami sheets, particularly those with parallelogram faces, are archetypal examples of flexible mechanical metamaterials, which possess well-defined uniform deformation modes, but exhibit spatially complex response patterns under generic loads that are relatively less explored. Thus, I explore which nonuniform, low-energy deformations are accessible to one such broad but special class of origami, four--parallelogram origami, and report on three approaches I take with collaborators to address this question. The first approach centers on a reciprocal-space compatibility matrix that uncovers a topological invariant, the sign of the Pfaffian, previously only identified in quantum mechanical systems, which governs the existence of linear, nonuniform modes of deformation of four--parallelogram origami. The second approach applies differential geometric methods to nonlinear, nonuniform deformations of the Morph, a broad subclass within the four--parallelogram class of origami that includes the Miura and eggbox patterns, which results in a numerically validated prediction that the volume in configuration space swept out by the origami sheet adheres closely to a "hyperribbon" with a large extent resulting from the four--parallelogram's planar mode and small extents resulting from its bend and twist modes. The third approach is another nonlinear, continuum theoretical approach, but one which begins from enforcing compatibility and utilizing symmetry of the microscopic structure of the sheet. The main result of this approach is an edge gradient compatibility equation which enforces the compatibility of each vertex in the unit cell, and which we expand in the long-wavelength limit to derive a continuum model for the system. We find strong statistical agreement between theory and simulation for our edge gradient compatibility equation over a wide range of geometries and applied loads over decades of amplitudes of the applied loads, as well as for the linear part of our continuum theory, which works over the same wide range of geometries and applied loads for small amplitudes of deformation as well as for nonlinear activations of the Miura-ori's rigid, planar mechanism, and discuss ongoing work to allow the continuum theory to capture nonlinear departures from uniform configurations of the four--parallelogram.Ph.D.Physic
Auxetic iPSC-Cardiomyocyte Patches for Heart Repair After Myocardial Infarction
No full textMyocardial infarction is one of the largest contributors to cardiovascular disease and reduces the ability of the heart to pump blood. One promising therapeutic approach to address the diminished function is the use of cardiac patches, including new designs such auxetic geometries that can expand in multiple directions when stretched longitudinally, can have high energy absorption, and can be modified to suit the mechanics of the infarct and surrounding cardiac tissue. This project developed an auxetic composite polycaprolactone and fibrin cardiac patch that can support induced cardiomyocyte (iCM) function. Aim 1 focuses on designing an auxetic cardiac patch capable of supporting iCM function, highlighting that a 3D printed polycaprolactone missing rib auxetic pattern can support basic cell viability, contractility, and electrical propagation after 14 days of culture. Aim 2 examines maturation potential of iCMs encapsulated within the auxetic cardiac patch under cyclic loading conditions. We showed how continuous unidirectional 10% mechanical strain of the auxetic patch upregulated key maturation markers of iCMs, created syncytium electrical propagation across the whole patch, and led to more organized ultrastructure and increased mitochondrial presence. Finally, aim 3 evaluated therapeutic cardiac function in vivo after patch delivery following a chronic myocardial infarction model and showed increased global functional outcomes and increased regenerative potential of the iCM auxetics. Taken together these aims demonstrate the validity of using auxetics for long-term cardiomyocyte culture and maturation, as well as broadening the impact of auxetics in tissue engineering approaches to treating cardiac disease.Ph.D.Biomedical Engineerin
