VictorJuiz/thesis huggingface dataset:
Mechanism of smoothened regulation by the hedgehog receptor patched
Keywords: Developmental Biology.

The Hedgehog (Hh) signaling pathway plays a central role in controling cell growth, survival, fate, and patterning during embryogenesis. The primary receptor for the Hedgehog signal in mammals is the twelve-pass transmembrane protein Patched (PTCH1). In the absence of Hedgehog ligand, PTCH1 constitutively suppresses a downstream seven-pass transmembrane protein Smoothened (SMO), thereby maintaining the quiescence of the pathway. When Hedgehog binds to PTCH1, it blocks its activity, lifting its suppression of SMO and allowing SMO to activate downstream signaling events. Although the genetic relationship between Hh pathway components has been known for over two decades, the fundamental mechanism by which PTCH1 regulates SMO has remained a central question in the Hedgehog signaling field. Based on the observations that PTCH1 is homologous to the Resistance, Nodulation and Division (RND) family of chemiosmotically-driven bacterial transporters, which transport hydrophobic substrates, that SMO is modulated by a series of lipid- and sterol-like ligands, and that PTCH1 suppresses SMO sub-stoichiometrically and does not appear to form a stable complex with SMO, it has been proposed that PTCH1 may regulate SMO by acting as a chemiosmotically driven transmembrane transporter of a lipidic Smo modulator. In this thesis, I investigated the underlying mechanism by which PTCH1 regulates SMO through two parallel strands of research, enabled by novel structures of PTCH1 and SMO: (i) investigating the functional importance of transporter-like structural features of the PTCH1 protein, and (ii) determining how PTCH1-mediated changes in the level of cholesterol in the inner leafet lead to SMO activation
Mechanistic metabolic interactions between gut microbiota and host
Keywords: Microbiology and Immunology.

The trillions of bacteria inhabiting the mammalian gastrointestinal tract, known as the gut microbiota, comprise a diverse community and exert wide-ranging systemic effects on the host. Members of the microbiota harbor diverse metabolic capability, are able to consume substrates unavailable to the host, and produce molecules that are not encoded by the human genome. This biochemical cross-talk between microbes and host constitutes an important avenue for signaling between the microbiota and host and coevolution of the mutualistic relationship. As such, metabolism is a valuable lens through which to explore the host-microbe relationship. This work presents four mechanisms by which metabolic interactions shape the ways in which members of the gut microbiota and the host interact: 1) A new understanding for the ways in which the enteric pathogen Clostridium difficile leverages inflammation to alter its metabolic activity in the gut as well as 2) persist during homeostatic conditions. 3) A prebiotic that shapes the microbiota in ways beneficial to the host, and 4) a previously unidentified mechanism for host detoxification of microbially-produced metabolites
Media production behavior on smartphones : time, content, structure, and context
Keywords: Communication.

People are producing lots of media. Digital media technology makes it easy for users to produce all sorts of content conveniently, anytime and anywhere. Understanding media production behavior is more pertinent than ever as more people produce different media in ways not possible even ten years ago. Although production behavior is a critical concept of communication research that interests many media scholars, we surprisingly know little about its specifics—how much production behavior is there? And how should it be described? This study explored production on the quintessential digital media device, the smartphone. Four aspects of production behavior on smartphones were examined: (1) patterns of production behavior over time; (2) content characteristics of production behavior; (3) the structure of production behavior; and (4) the context of production behavior. Using a novel framework for measuring moment-by-moment changes in digital behavior, this study looked into production behavior in different time domains and employed computational methods to generate behavioral measures and media categories. This study employed an inductive research strategy to describe patterns of use that should be important across a range of theories about digital life. A wide array of statistical modeling and testing techniques were used to identify intra- and inter-individual patterns of media production behavior. The results of this study help theorizing about digital communication processes, about patterns and functions of digital media use, and about digital media interaction
Membrane proximal F-actin as a master regulator of cell polarity, signaling dynamics, and protrusion during migration
Keywords: Chemical and Systems Biology.

Balanced regulation of cell migration is critical for all stages of the human life cycle. Furthermore, aberrant or inhibited motility can cause dire consequences ranging from embryonic lethality to metastasis. Despite the diversity and plasticity of cell migration, almost all forms of motility depend on dynamic regulation of F-actin cytoskeleton. While there has been a lot of effort to understand the underlying signaling of prominent F-actin pools such as lamellipodia, filopodia, and stress fibers, much less is known about the role of membrane proximal actin (MPA) and membrane adhesion has on cell migration and polarization. We currently lack the tools to resolve MPA from other F-actin pools in the cell with high spatio temporal resolution. In this thesis we first develop a fluorescent biosensor to measure the density of membrane proximal F-actin, here termed MPAct. MPAct can be used to investigate the absolute differences between conditions using FRAP and lateral diffusion measurements, or as ratiometric reporters of relative MPA distribution within the same cell. Using the MPAct sensor we then made the unexpected observation that MPA was higher in the rear of cells migrating in 1D, 2D, and 3D, unlike global F-actin concentration under these same conditions. We further demonstrated this observed gradient was due to the underlying F-actin architecture and that MPA gradients strengthened existing polarity by biasing nascent protrusions to areas with low MPA. Finally, we found that increased Cofilin-mediated F-actin turnover at the front contributed to the observed gradients. These results provide a framework to understand directional persistence from a biomechanical point of view: cells will continue protruding from the existing cell front thereby creating directional "inertia." Based on the results from this study we further investigated if MPA gradients could create other types of signaling and biomechanical polarity during migrations. We found that EGFR dynamics, ERM localization, Focal adhesion turnover, and Cdc42 activity showed distinct behavior based on local MPA. These follow-up studies demonstrate how MPAct and MPA gradients can be used to clarify signaling dynamics at the plasma membrane. This work provides a new tool, the MPAct sensor, for probing the role of membrane adhesion in a variety of contexts. We further uncovered a novel role for MPA in unifying migration polarity signaling and a global and local level
Memory-efficient optimization over positive semidefinite matrices
Keywords: Electrical Engineering.

We present an extension of the conditional gradient method to problems whose feasible sets are convex cones which we call conic descent. We provide a convergence analysis for the method and for variants with non-convex objectives, and we extend the analysis to practical cases with effective line search strategies. For the specific case of the positive semidefinite cone, we present a memory-efficient version based on randomized matrix sketches and advocate a heuristic greedy step that greatly improves its practical performance. Numerical results on phase retrieval problems indicate that our method delivers results of a specified accuracy in approximately half as many iterations as required by the conditional gradient method. Building off this foundation, we next use the augmented Lagrangian technique to enable the incorporation of equality constraints. This immediately leads to applying the memory-efficient version of conic descent over the positive semidefinite cone to the solution of large scale semidefinite programs. Numerical results on solving graph maximum cut problems demonstrate its usefulness and advantages over traditional Burer-Monteiro approaches. In a sensor network localization (SNL) problem, we attempt to determine the two- or three-dimensional layout of a network of sensors from some of their pairwise distances. We present an efficient projected gradient method to approximately solve the SNL problem if a good initial guess of the sensor locations is available. When the sensors are not static, our method is an efficient way to update the estimate of their positions and so provides a way of tracking the sensors as they move. Along the way, we present an analysis of the projected gradient method for arbitrary feasible sets onto which we can project exactly, which is of independent interest. Numerical results demonstrate the practical efficacy and robustness of our method
Methodologies for uncovering hidden information at molecular and cellular scales
Keywords: Chemical and Systems Biology.

The reductionism of molecular biology has been incredibly fruitful and instrumental in scientific advancement. The advent of high-throughput technologies and improved measurement techniques has allowed systems biology and quantitative biology to further revolutionize biology in the last half-century. A quantitative, systems biology approach allows scientists to uncover unknown unknowns by performing large-scale experiments in an unbiased manner. For example, DNA/protein sequencing, growth curve measurements, and microscopy are information rich, and the latter two are highly tunable to interrogate the relationship between environment and physiology. However, to fully exploit these advances, it is important to optimize these precise, quantitative measurements and understand how to interpret the data. Furthermore, it has become increasing important and feasible to develop algorithms to exploit the large amount of data that is being generated. This dissertation describes two such methodological advances that involve new methods for disentangling signal from noise. Chapter 2 describes a novel framework for analyzing protein coevolution to gain functional understanding of a protein. Chapter 3 describes refined methods for optimizing the measurement of bacterial growth parameters by carefully considering cellular physiology and environmental conditions. Chapter 4 provides concluding thoughts on future directions for using these methods. Taken together, my PhD work showcases the importance of developing methods to link molecular and structural biology with the ongoing systems and quantitative biology revolution
Methods for measuring selection on coding regulatory elements and gene expression divergence between human and chimpanzee brain development in vitro
Keywords: Genetics.

In this dissertation, I explore the impact of gene expression changes on human evolution in two distinct contexts. In chapter 2, I describe a method of quantifying the relative contributions of coding and non-coding changes in driving selection at three regulatory loci in the human genome. In chapter 3, I describe a novel system for quantifying cis- regulatory gene expression divergence between the human and chimpanzee genomes during fetal brain development in vitro. Overall, this body of work highlights the importance of precise methodology for understanding the role of gene regulation in human evolution
Microfluidic devices for studies of single cell wound repair, regeneration, and other biological phenomena
Keywords: Mechanical Engineering.

Microfluidics has enabled a wide range of biological studies. The objective of my thesis dissertation is to apply microfluidics for studies of wound repair and regeneration, as well as to use droplet microfluidics to study stochastic biological phenomena. My thesis covers three parts: In Chapters 2 and 3, I develop the microfluidic guillotine for high-throughput studies of wound repair in Stentor coeruleus. We were able to bisect over 150 cells in 3 minutes, which is 200 times faster than current methods, while achieving approximately 95% cell survival. I also develop quantitative and qualitative assays to assess wound repair. With these tools, we measured the wound repair time in Stentor and discovered the occurrence of three mechanical modes of wound repair, as well as Ca2+ activated wound repair processes. In Chapters 4 and 5, I further develop the microfluidic guillotine to bisect multicellular structures and show that organoids bisected by the guillotine can also regenerate. Furthermore, I optimize cutting performance by developing a method using the Nanoscribe, a sub-micron resolution 3D printer, to fabricate the blade at an angle. My work on the microfluidic guillotine in Chapters 2 -- 5 has been patented and we are in the process of commercializing the technology. Finally, in Chapters 6 and 7, I used the uniquely high-throughput, low volume nature of droplet microfluidics to study stochastic biological phenomena. I developed theory to understand the impact of drop-to-drop variance in studies of single cell phenotypic heterogeneity. Using droplet microfluidics also lead to the discovery of hundreds of novel RNAs that can be replicated by T7 RNAP, whereas before only five were known. This lead to my collaborator discovering the origin and replication mechanism of these replicating RNAs. We have submitted a provisional patent on this technology
Microfluidics meet ionizing radiation : drop-based flow radiocytometry and liquid sheet jet-based for X-ray spectroscopy
Keywords: Mechanical Engineering.

This thesis is focused on the development of two microfluidic platforms for multiphase sample delivery in assays involving ionizing radiation. In the first part of the work, a water-in-oil droplet microfluidic platform was designed and built for single-cell radiopharmaceutical studies. Radiotracers are widely used to track molecular processes with high sensitivity and specificity. However, most radiotracer detection methods have spatial resolution inadequate for single-cell analysis and cannot probe cellular heterogeneity, one of the most important challenges in cancer therapeutics. Here we introduce a robust, high-throughput single-cell radiometry based on radiofluorogenesis and droplet optofluidics. As a proof-of-concept application, we quantified [18F]fluorodeoxyglucose radiotracer uptake in single human breast cancer cells to assess glucose metabolism at the single-cell level. The second multiphase sample delivery system is a microfluidic nozzle designed to create liquid jet in air for X-ray spectroscopy analysis. We created stable free-surface liquid sheet jets with a width and length on the order of millimeters and sheet thickness on the order of microns and even sub-micron. These large aspect ratios provide a large target for the X-ray beam while minimizing background signal associated with line-of-sight integration of the detection. We conducted an experimental and numerical study to understand how fluid properties, pressure, momentum fluxes, surface tension, and nozzle geometry all interact to determine flow structures. The work developed scaling theories that predict sheet jet thickness, width, and length strictly from nozzle geometry, flow rate, and thermophysical fluid parameters. Interestingly, given this scaling analysis, no computer-aided simulations are needed for accurate flow structure prediction. Together the device design and theories provide a clear path to the rapid and efficient design of liquid sheet jets
The microfoundations of identity politics in Pakistan's megacity
Keywords: Political Science.

How do we make multi-ethnic, conflict-prone cities "work"? Urbanization offers an enormous opportunity to revive stagnating economics and lift millions out of poverty. This potential, however, can only be realized if proper attention is paid to the question of how best to manage such growth. If the growth of cities depends necessarily on in-migration of new populations, the causes and consequences of such migration deserve considered attention. One consequence of rapid urbanization and demographic change is the development of ethnic political parties that promise to advocate for the rights of particular identity groups. What accounts for the success or failure of ethnic parties in mobilizing urban populations in diverse cities? And what are the governance consequences of this form of politics? The three papers that constitute this dissertation project aim to answer these questions by exploring in-depth the megacity of Karachi, Pakistan. A central concept linking all three papers is that of descriptive ethnic representation. Chapter 1 shows that the demand for descriptive representation can systematically differ between urban ethnic groups based on their reason for migration to the city. Chapter 2 shows that once ethnic parties successfully leverage a demand for descriptive representation, they are better able to avoid accountability for poor governance on material dimensions -- such as on the provision of basic public goods. Chapter 3 shows that the relationship between coethnicity and citizen expectations of police bias is moderated by the level of perceived descriptive representation in the police forces. Altogether, these papers illustrate the abundant and as yet underexplored within-urban variation in the workings of ethnic politics, thereby enriching our pool of knowledge on how ethnicity structures the political landscape of cities in the global south
Mindality
Keywords: Learning Design and Technology
LDT
Graduate School of Education
GSE
Thesis

For individuals with moderate to severe depression, it can be difficult to manage decisions in everyday life. Research shows that depression reduces quality of life through cognitive distortions––biased perspectives that are considered irrational about oneself and the external world, creating damaging thought patterns and false beliefs. Such disparaging distortions make it especially important to be connected to supportive friends and family. Mindality is a platform that helps learners generate explanations of their day-to-day struggles. The goal is to enhance an individual’s capacity to effectively understand their own needs and communicate them to loved ones or licensed professionals in order to get support––and these self-generated explanations can leverage a variety of media, such as audio, text, and visual. The multimodal availability of expressing common symptoms found in depression and suicidal ideation proposes that this practice can potentially support mental health understanding, communication, and literacy for those impacted by mental health, both directly and indirectly. This report provides the reader with some research perspectives on major depressive disorder and its relationship to the effectiveness that multimedia can leverage for expression, communication, and support.
Minds, groups, and populations : harnessing the latent structure of social information
Keywords: Psychology.

Choices are woven into the fabric of social life: We buy things that have received glowing reviews, watch shows recommended by our friends, and assess a potential date based on their taste in music. Observing others' choices provides valuable insights into both the world and into the person doing the choosing. How do observers extract so much information from everyday, seemingly arbitrary choices? In this dissertation, I propose that observers make rich inferences from others' choices by harnessing structured representations of the physical world, of the contents of others' minds (e.g., their knowledge and preferences), and of the social world (e.g., of relationships and similarities between individuals). Chapters 2--3 examine how adults harness representations of other minds to recover information about the value of unexplored choice options. These studies find that adults do not simply imitate or ignore others' choices, but rather actively infer the latent mental states—such as beliefs and strategy—that gave rise to them. Chapters 4--5 examine how children and adults harness representations of the social world to learn about new individuals. This work finds that preschool-aged children and adults use minimal statistical information about how choices are distributed across individuals to judge their potential compatibility with new individuals (Chapter 4) and make inductive inferences about them (Chapter 5)
Missile Motivations: Assessing Russian Noncompliance with the Intermediate-Range Nuclear Forces Treaty
Keywords:  Center for International Cooperation and Security
Center for International Security and Cooperation
INF Treaty
Nuclear Arms Control
Missiles
Russia
USSR
United States
NATO
China
Thesis

The Intermediate-Range Nuclear Forces (INF) Treaty was a landmark bilateral arms control agreement signed by the United States and the Soviet Union in 1987, lauded for its substantial contribution to disarmament efforts. The United States formally withdrew from the Treaty on August 2, 2019, citing years of Russian noncompliance via the 9M729 missile system. This thesis examines the underlying motivations behind Russia’s development of this ground-launched, intermediate-range missile. Four hypotheses are presented: perception of traditional military threats from NATO and the United States; perception of emerging military threats from China and neighboring regions; a desire to exert political and psychological power over Europe; and independent action by and/or influence of the Russian military-industrial complex. Two novel datasets were developed: (1) a robust timeline detailing missile development, mechanics of the violation, Russian public commentary, and U.S. response, and (2) a collection of interviews of high-level American officials and American and European academic subject experts.
Based on these analyses, I conclude that the perception of traditional threats, specifically NATO enlargement and preeminence and U.S. ballistic missile defense systems in Europe, was the most influential impetus for the development of the 9M729 missile system. Additionally, the 9M729 was seen by Russian military planners as an important response to the emerging threats from Russia’s neighbors, particularly China. The Russian military-industrial complex wanted the 9M729 in order to provide flexibility in response to an increasing number of legitimate military threats across Eurasia and believed it could develop the missile with plausible deniability. Ambitious missile modernization programs and changes in relevant political and security environments eventually prompted the Russian leadership to determine that the rewards of having the 9M729 outweighed the risks associated with violating the Treaty. Understanding the rationale behind the creation of a treaty-noncompliant weapons system is an opportunity to consider how existing and future arms control agreements can be better developed, implemented, and verified.