VictorJuiz/thesis huggingface dataset:
Lipid - protein interactions : from signal transduction to drug delivery

Based on the hydrophobic tendencies exhibited by certain groups of molecules, the primary focus of this dissertation has been to create environments enriched in lipids and amphipathic molecules to explore the effect on their biological behavior. To this effect, ternary complexes of phospholipid, an apolipoprotein scaffold and a hydrophobic bioactive MDM2 inhibitor, nutlin-3a were used to form nanoassemblies of nutlin-3a nanodisks (ND). Nutlin-3a, as a part of ND was conferred with aqueous solubility, formed a homogeneous population of ND particles and associated reversibly with the ND. Biological activity of nutlin-3a ND was examined in three distinct glioblastoma cell lines, U87MG, SF763 and SF767. An overall robust decrease in cell viability, increase in apoptosis, increase in protein levels of p53 and MDM2 was observed in U87MG cells in response to nutlin-3a ND incubation while the other two cell lines remained mostly unresponsive. The nanoscale size of the formulation particles, their facile assembly and nutlin-3a solubilization capability suggest ND represent a potentially useful vehicle for in vivo administration of this anti-tumor agent./n“Wnt” family of signaling molecules regulates cell fate and proliferation in tissues of many multicellular organisms. Structure function studies of Wnts have been impeded due to the high propensity of isolated Wnts to self-associate. Stably transfected Drosophila S2 cells were used to improve recovery of recombinant murine Wnt3a. As a part of Wnt3a characterization, modulators of Wnt3a signaling were evaluated. Based on the central role played by low density lipoprotein receptor related protein 5 or 6 (LRP5/6) in Wnt3a signaling and apolipoprotein (apo)E3 lipoprotein metabolism, the ability of apoE3 to modulate Wnt signaling was evaluated. Wnt3a canonical signaling was down regulated in the presence of lipid-free apoE3 N-terminus however, this interaction appeared to be mediated through apoE3 binding with Wnt3a rather than LRP5/6. Additionally, while dissecting the supporting scaffolds of Wnt3a using thrombin mediated limited proteolysis, a site-specific cleavage within the N-terminal domain of Wnt3a was identified. Within the N-terminal (NT) domain there exists a motif that is superimposable upon saposin-like protein (SAPLIP) family members. SAPLIPs possess lipid surface seeking activity. Further inspection into the Wnt3a saposin-like sub-domain (SLD) revealed that neighboring structural elements within full-length Wnt3a affect SLD conformational stability. Overall, SLD function(s) in Wnt proteins appear to have evolved away from those commonly attributed to SAPLIP family members.

Advisor: Ryan, Robert O
Energy-Efficient System Design Through Adaptive Voltage Scaling

Improving the energy efficiency of processor systems-on-chip (SoCs) is key to improving the performance and utility of thermally-limited servers, battery-constrained mobile devices, and energy-harvesting Internet-of-Things nodes. Adaptive voltage scaling adjusts voltage levels at runtime in response to changes in workload, reducing voltage when additional performance is not required. The granularity of this voltage scaling greatly impacts its effectiveness. Fine-grained adaptive voltage scaling (FG-AVS) in time reduces wasted energy by tracking microsecond-scale changes in workload; FG-AVS in space independently adjusts voltage levels in many different portions of an SoC, saving additional energy. FG-AVS has the potential to save considerable energy, but it has not yet seen adoption in commercial systems due to several challenges that complicate its implementation. Integrated voltage regulators are required to supply the many voltages required and switch quickly between modes, but efficient implementations impose high area overhead. Clocking, synchronization, and power management have their own requirements and difficulties./nThis work presents key components of fully-featured SoCs that enable demonstration of FG-AVS. Integrated simultaneous-switching switched capacitor voltage regulators are presented that achieve high conversion efficiency when coupled with an adaptive clock generator. Power management is accomplished with programs run on a dedicated power management unit (PMU), and a pausible bisynchronous FIFO circuit that can achieve low-latency communication between asynchronous voltage domains is described. These components are integrated into systems that demonstrate the potential energy savings of FG-AVS. The Raven-3 testchip demonstrates efficient voltage regulation supplying a complicated digital load; the system achieves 26.2 GFLOPS/W while operating its processor under the generated supply voltage and adaptive clock. The Raven-4 testchip includes integrated power management circuits that allow fully integrated feedback for FG-AVS. The programmable PMU can run a wide variety of power management algorithms, including an AVS algorithm that saves 39.6% energy in a synthetic microbenchmark with minimal performance penalty. The Hurricane-1 testchip implements multiple independent voltage domains and hardware counters that can be used for power management. The Hurricane-2 testchip features finer spatial partitioning and more effective instrumentation for power management; simulation results show up to 13.3% energy savings for an algorithm exercising FG-AVS in time and 46.0% energy savings for an algorithm using FG-AVS in space. Together, these testchip implementations show the potential of FG-AVS to save energy in production SoCs.

Advisor: Nikolic, Borivoje
Asanovic, Krste
Mechanisms of Ras Signaling and Activation on Reconstituted Membrane Surfaces

The membrane is a crucial component of the cell that modulates protein spatial organization and enzyme-substrate reactions, which, in turn, mediates cellular signal transmission. One key membrane protein is the small GTPase Ras, which acts as a signaling node that determines cellular outcome. Though Ras is an attractive target for anticancer therapies, effective treatments against its oncogenic mutants remain elusive due to the incomplete understanding of its signaling potential in the membrane environment. Here, we seek to elucidate some of the key biophysical properties and regulations of Ras on membranes in reconstituted systems./nLateral organization, especially dimerization, of Ras on cellular membranes has long been a subject of great interest. We find that Ras dimers can form on membranes by photosensitization reactions, in which molecular oxygen mediates protein radicalization under typical fluorescence experimental conditions. Inter-protein dityrosine crosslinking is one of the dimerization motifs, and the specific surface tyrosine distribution on Ras renders the protein especially sensitive to this reaction. Photosensitization reactions are reflective of physiological oxidative stress induced by reactive oxygen species, suggesting such processes may occur naturally in cells./nRas activation is a critical step for receptor tyrosine kinase signal transduction. One key activator of Ras is the enzyme Son of Sevenless (SOS), which catalyzes Ras nucleotide exchange. The complex domain architecture of SOS ensures efficient Ras turnover only when all activation inputs are met, including stable membrane recruitment. Notably, a single molecule of SOS can processively turnover thousands of Ras molecules upon allosteric Ras engagement, and generation of Ras.GTP creates positive feedback by enhancing SOS recruitment. We developed a real-time Ras activation assay to detect the activity of purified, full-length SOS (SOSFL) molecules exposed to inactive Ras on membranes. Despite the collective autoinhibition from the N- and C-terminal domains of the enzyme, SOSFL is nonetheless capable of inducing rapid Ras activation by single proteins. Our measurements further reveal a new mechanism of Ras.GTP-mediated SOS activation through enhancement in probability of single SOS to transition to the hyperactive state. Processively active single SOS molecules are thus consequential in Ras signaling and additional measures are necessary to suppress spurious Ras activation.

Advisor: Groves, Jay T
Integrated molecular diagnostic platform

Infectious and non-communicable diseases impose a global burden of health on both developing and developed countries despite technological advancements in medicine and healthcare. In this perspective, point-of-care testing (POCT) has been paid attention as an area with enormous potential to solve this problem. Point-of-care molecular diagnostic enables to provide diagnoses from clinical samples to clinicians without wasting time such as sample transporting or sample preprocessing. However, most of nucleic acid diagnostics still are performed in central health facilities because they need top-notch equipment and well-trained personnel. To overcome these difficulties, the emergence of microfluidics has been attracted because of its inherent features including consuming small volume of sample and reagent, precise controllability of laminar flow, short processing time for analysis, and miniaturization of devices. This dissertation is a part of effort to develop an integrated molecular diagnostic platform for improving global health care and the quality of life. Firstly, we developed a microfluidic device for sample preparation. The purpose of sample preparation is to enrich target cells, remove unnecessary cells, and lyse target cells for nucleic acid detection. The preconcentration and selective capture of cells are demonstrated in the microfluidic device by using porous materials and antibody without any external bulky equipment such as a centrifuge. Then, photonic PCR is presented as a new technology of thermal cycling. When light comes to gold (Au), Au can absorb light efficiently due to its plasmonic-assisted high optical absorption (~ 65% at 450 nm) and quickly release the light energy as a thermal energy. Using this simple principle, we demonstrate the target DNA amplification within 5 minutes on 30 cycles. In addition, a comprehensive heat transfer simulation of the photonic PCR is carried out to improve the performance of the photonic PCR. Simulation of heat transfer model demonstrates the importance of optical absorption of Au and thermal diffusivity of materials on heating and cooling ramping rates. Finally, the development of a new integrated molecular diagnostics is demonstrated for bacterial detection in urine samples.

Advisor: Lee, Luke P.
Seeing the Forest from the Trees: Scientific Forestry and the Rise of Modern Chinese Environmentalism, 1864 - 1937

This dissertation narrates the rise of Chinese scientific forestry during the late nineteenth and early twentieth centuries. Focusing primarily on central officials in Beijing and local officials in Jilin Province, it argues that forestry served as the lens through which Chinese officials first engaged with the ecological, cultural, and economic dimensions of international environmentalism. This meant that they saw forest cover as indicative of the quality of a nation’s culture, as well as the health of its land and economy. For the first time, Chinese officials sought to manage timber as a national resource. In so doing, they revealed the importance of environmental perceptions and realities to shaping global modernity./nChina gained international notoriety for its deforested landscapes around the turn of the twentieth century. The Taiping Rebellion and other wars of the nineteenth century had resulted in a dramatic loss in China’s forest cover. Nevertheless, foreign observers and Chinese literati uniformly blamed China’s deforestation on its inferior culture. Under the leadership of Yuan Shikai and the Ministry of Agriculture and Commerce, Republican officials sought to solve the forest problem with the help of American-trained foresters such as Ling Daoyang and Han An. This meant that central officials became newly responsible for managing the entire nation’s timber resources. Forestry’s proponents argued this would salvage China’s international reputation. Just as importantly, they argued that efficient forest management would foster the nation’s ecological health and economic self-sufficiency. In other words, they developed a style of Chinese environmental nationalism tied to forestry./nThe Ministry of Agriculture and Commerce imported the American tradition of Arbor Day in order to transmit this new ideology to the Chinese public. Henceforth, all local and provincial governments throughout the Chinese nation would conduct reforestation projects as part of the Arbor Day celebration. This was to be done regardless of the suitability of local climates, soils, and social conditions to planting trees. For some officials, reforestation necessitated a struggle to tame the land to support trees. For others, it meant guarding trees against banditry, warfare, animals, or even small children. For some, reforestation meant reinvigorating traditionally forested areas, such as sacred mountains, temples, and riverbeds. For others, it meant establishing economic tree farms and modern parks. Those who succeeded in growing and maintaining China’s forest cover displayed a commitment to creating a China that was as ecologically modern as they imagined the landscapes throughout the world to be. Forestry thus served as the lens through which Chinese officials from Beijing to rural Jilin engaged with the cultural and economic dimensions of global environmentalism.

Advisor: Yeh, Wen-hsin
Publicly Funded Renewable-Energy Innovation and Appropriate Methods of Analysis

In this dissertation, I will conduct a critical analysis of several methods typically used for modeling patent data, and then use insights gleaned from that analysis to explore four instances of public financing of innovation in the form of renewable-energy technology./nChapter 1 introduces my overall research objectives, frames the research in terms of its policy relevance, and provides a brief preview of the major results. Chapter 2 provides background on innovation, causes and results thereof, with a particular focus on patent data, and thereby a framework for understanding the relevance of chapters 3 and 4./nThe first main essay (chapter 3) addresses statistical regression techniques frequently used with patent-count time-series data, namely negative binomial regressions and log-log regressions. It reveals high rates of spurious correlation (false positives, also known as Type I errors) when using these techniques on patent data, investigates possible ways of addressing this problem, and creates a method for detecting it when using those and other regression techniques on similar data types./nUsing lessons learned from the first essay, the second essay (chapter 4) examines public research and development (R&D) funding of four renewable-energy technologies – wind turbines, solar photovoltaics, solar thermal electric, and solar water heating. It employs several novel patent analysis techniques that allow patents to more closely represent the date of inventive activity. It finds that, contrary to popular narratives of public R&D funding driving increased invention (patenting), a diverse set of relationships exist in the renewable energy sector. These relationships range from changes in funding being correlated with future changes in invention rates, to changes in invention rates preceding changes in funding, to changes in funding and invention rates having no discernible relationship./nTaken together, these essays demonstrate the interdependent relationship between appropriate analytic techniques and accurate analysis when examining the sometimes subtle effects of complex policies.

Advisor: O'Hare, Michael
Bridging the Gap: Understanding Eye Movements and Attentional Mechanisms is Key to Improving Amblyopia Treatment

Amblyopia is a developmental visual disorder resulting in sensory, motor and attentional deficits, including delays in both saccadic and manual reaction time. It is unclear whether this delay is due to differences in sensory processing of the stimulus, or the processes required to dis-engage/shift/re-engage attention when moving the eye from fixation to a saccadic target. In the first experiment we compare asymptotic saccadic and manual reaction times between the two eyes, using equivalent stimulus strength to account for differences in sensory processing. In a follow-up study, we modulate RT by removing the fixation dot, which is thought to release spatial attention at the fovea, and reduces reaction time in normal observers. Finally, we discuss the implications for these findings on future amblyopic treatment, specifically dichoptic video game playing. Playing videogames may help engage the attentional network, leading to greater improvements than traditional treatment of patching the non- amblyopic eye. Further, when treatment involves both eyes, fixation stability may be improved during the therapeutic intervention, yielding a better outcome than just playing a video game with a patch over the non-amblyopic eye.

Advisor: Levi, Dennis M
Causes and Consequences of Convergence

In speech convergence, people's speech becomes more like the speech they hear. Such convergence behavior has been observed along many domains of linguistic structure and in many different situational contexts. Convergence has been argued to be socially motivated (Communication Accommodation Theory — Giles et al. 1991), and also to be an unconscious, resource-free process (Interactive Alignment Theory — Pickering & Garrod 2004). This dissertation presents an alternative approach in which convergence is not a discrete process in itself; rather, convergence behavior is the consequence of episodic storage and recall, moderated by attention./nThe first chapter of this dissertation consists of an elaboration of this approach, called the categorization schema account. In this approach, episodic storage is constrained by the categorization schemata that are currently active, and categories are only active when attention is paid to those categories' defining features. Convergence across disparate domains of linguistic structure is then an empirical pattern that falls out naturally from the assumption that multiple representations of the same input are stored separately and recalled independently. In consequence, speakers may converge to different domains of linguistic structure at different rates, depending on which domains have their attention./nThe two subsequent chapters report the results of a pair of studies designed to examine predictions made by the categorization schema account. A Mechanical Turk experiment, discussed in Chapter 2, failed to find a significant difference between convergence to words and convergence to pseudowords. In a dyadic game task experiment comparing convergence rates across levels of linguistic structure, discussed in Chapter 3, participants exhibited different patterns of convergence to phonetic features on the one hand, and to lexical and syntactic features on the other hand. Additionally, participants who self-reported a greater degree of personal autonomy in this experiment exhibited less convergence behavior across domains./nChapter 4 discusses the ramifications of these findings for theories of sound change, and reports the results of an experiment illustrating that accommodation can directly result in the appearance of new variants within an interaction, providing a possible pathway for the actuation of sound change.

Advisor: Johnson, Keith
Approaches to Plans in Public Health Emergency Preparedness and Response

In public health emergency preparedness and response (PHEP), plans are a central matter of concern. Understanding plans' role in establishing, facilitating, or securing preparedness and response objectives is of enduring practical and theoretical warrant. Drawing from practice-based perspectives and treating plans as sociotechnical objects, this project aims to describe ways in which theoretical approaches to plans shape their use, meaning, and value in actual practice. Employing empirically-grounded and interpretative methods, it investigates divergent accounts of plans' role for the purpose of identifying assumptions about the mechanisms by which plans' achieve their practical effects. The consequences of these assumptions on how plans are written and used are explored in separate case studies. The first focuses on the modalities for coordinating functional response activities within local health departments' preparedness and response plans in the U.S. The second focuses on the modalities for coordinating information globally within the International Health Regulations (2005). Both cases demonstrate that the capacities of plans to realize functional or operational objectives i.e., the mechanisms of how plans work, depend on the dominant theoretical approaches in the relevant setting.

Advisor: Keller, Ann
Scalable, Gravure-Printed Transparent Electronics: Materials and Process Design for Metal Oxide Thin-Film Transistors

Transparent metal oxides are one of the most promising material systems for thin film flexible electronics due to their unique balance of optical transparency and high electron mobility. Rapid progress in the field of solution-processed metal oxides in the last decade has established them as the leading material system for thin film transistors. Fully-integrating metal oxide materials with printing technologies could enable a wide range of applications such as flexible displays, imaging systems, resorbable bioelectronics, and low-power sensors that remain uneconomical or unmanufacturable with incumbent technologies. This thesis contributes materials and methods that can advance the scalable fabrication of transparent thin film transistors by high-speed gravure printing. Through these studies, an understanding of the interactions between ink chemistry, fluid parameters, printed feature formation, and electronic properties is presented./nIn the past, gravure-printed electronics has been limited to printing organic inks and metal nanoparticles. Here we couple an understanding of the physics of gravure printing on glass with strategies for inorganic sol-gel ink design to extend the scope of high-speed printing to new high-performance inorganic materials including transparent conductive oxides (TCOs). We explore the impact that ink design has on material properties such as crystallinity, conductivity, transparency, and performance under mechanical bending stress, leading to effective co-optimization of patterning and TCO performance. Furthermore, these ink design principles are applied to silver nanowire hybrid sol-gel inks which allow gravure printing of high figure of merit mechanically robust, transparent conducting films using low processing temperatures./nAdditionally, this thesis will discuss the design and construction of a custom gravure printer for high-speed patterning and accurate registration of printed layers. The novel design allows the decoupling of the individual subprocesses of gravure to allow mechanistic studies of major printing artifacts and improved areal uniformity. A new understanding of the role of gravure contact mechanics in ink transfer and doctoring is presented./nThis work also develops high-performance materials for scaling down the process temperatures of printed metal oxide devices. Aqueous ink formulations are explored for inkjet printing transparent electrodes and channel materials in transparent thin film transistors. The unique printing physics, electrical contact properties to aqueous semiconductors, and low-temperature processability of these inks are studied to achieve high-resolution printed TCOs at plastic compatible temperatures below 220 °C. Additionally, low-temperature, UV-annealed high-k dielectrics are presented for processing printed metal oxide transistors. High-performance printed transistors are achieved with high operational stability and connections between bias-stress stability and low-temperature processing are studied.

Advisor: Subramanian, Vivek