VictorJuiz/thesis huggingface dataset:
Understanding gene regulation and genetic variation through the lens of three-dimensional genome architecture [electronic resource]
Keywords: Genetics.

The three-dimensional organization of the genome defines a complex network of physical and functional interactions between distal regulatory elements, non-coding genetic variants they harbor and their target genes. In this thesis, I present a combination of computational and experimental techniques to explore the role of 3D genome architecture in gene regulation and disease. Chromosome conformation capture techniques such as Hi-C have revolutionized our ability to obtain genome-wide maps of 3D chromatin contacts. However, robust estimation of data quality and systematic comparison of these contact maps is challenging due to the multi-scale organization of the genome and the resulting esoteric properties of experimental noise affecting Hi-C data. To address these issues, I introduce new statistical measures based on a graph diffusion framework for multi-scale comparisons of 3D contact maps. I use our framework for estimating Hi-C data quality by evaluating reproducibility across replicate experiments and for robustly identifying differential contacts between cell types. Next, I present one of the first efforts to understand how non-coding genetic variation can affect diverse molecular phenotypes through 3D chromatin contacts. In this study, we integrated chromatin profiling experiments for three regulatory histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific 3D chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). We found that distal hQTLs are enriched within insulated topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. hQTLs were also enriched for common variants associated with autoimmune diseases and enabled identification of regulatory elements and genes that are putative downstream targets of disease-associated variants from genome-wide association studies. I continue by presenting an ongoing project to understand the effects of perturbing 3D genome architecture on gene regulation by using different types (activation, inhibition and knockout) of CRISPR-Cas9 competitive growth screens targeting thousands of binding sites of the CTCF transcription factor at critical 3D chromatin loops. We found that 3%-5% of the tested sites exhibit a significant effect on cellular growth across the screen and investigate models that can explain the effects based on genomic, regulatory and 3D properties of the loci. We validated a subset of loci. Finally, I present a method I have been working on for creating ectopic chromatin contacts using the CRISPR system coupled to a synthetic dimerization system. Together, these studies expand our understanding of gene regulation and genetic variation through the lens of 3D genome architecture.
Understanding human disease through integrated molecular and clinical analyses
Keywords: Biomedical Informatics.

Traditional biomedical experiments are designed to study a single cohort for a single disease using a single technology. I show that studying disease with a narrow lens has lead researchers to make discoveries that are not reproducible because they are not representative of the real heterogeneity of disease. I developed and implemented methods for integrating datasets to identify robust disease signatures. By integrating data from over 40 studies and 7,000 patients, we establish a robust signature of systemic lupus erythematosus which correlates with disease activity and persists across blood, tissue, and sorted cell populations. We compare relationships of 104 diseases based on molecular and clinical manifestations from 41,000 gene expression samples and 2 million patient records. Finally, we contextualize single-cell RNA-seq data with bulk gene expression profiles to understand the relationships of novel cell subsets to known cell populations and human disease. By integrating biomedical datasets, my work has enabled an unbiased and multi-scale understanding of disease.
Understanding morphology evolution in printed organic solar cells
Keywords: Chemical Engineering.

Polymer-based organic photovoltaics (OPVs) have emerged as a promising renewable energy candidate suitable for inexpensive and scalable production, being lightweight, flexible, and amenable to low-energy solution processing. However, despite having surpassed 10% power conversion efficiency (PCE) - widely held as the threshold for commercial viability - OPVs are still mostly constrained to lab-scale devices fabricated by spin coating. Efforts to translate to scalable roll-to-roll printing trail significantly in efficiency, commonly by an order of magnitude, highlighting the need to better understand the processing-morphology-performance relationship in the context of linear printing methods. The work presented will focus on two aspects of OPV development: 1) process control to translate from spin coating to printing in order to achieve scalable high-performance devices, and 2) application of improved tools for nanoscale morphological characterization. To the former, a thermodynamic model of phase separation is presented for a model polymer:fullerene system. Next we investigate a high-performance system which has demonstrated > 10% PCE via spincoating but only exhibits 1% PCE when roll-to-roll printed due to differences in drying dynamics and phase separation. OPV bulk heterojunctions are characterized using synchrotron X-ray scattering techniques, elucidating the impact of a critical residual chemical additive on the phase-separated morphology. It is discovered that excessive additive residence time within the semi-dry film gives rise to a hierarchal morphology that severely degrades device performance. Using the understanding gained in this study, we are able to achieve a printed OPV with 5.33% PCE, which is among the highest performing roll-to-roll OPVs to date. To the latter, we address the fact that commonly used microscopy techniques suffer from significant shortcomings for imaging OPVs. We demonstrate the first application of a technique known as Photo-induced Force Microscopy (PiFM) for imaging OPVs with nanoscale chemical specificity. Results from image processing are corroborated with established synchrotron methods and photovoltaic device performance, revealing excellent quantitative agreement. Further, we demonstrate that images from atomic force microscopy (AFM) and PiFM show poor correlation, highlighting the need to move beyond standard AFM for morphology characterization of bulk heterojunctions. We emphasize that PiFM is high-throughput, lab-scale, ambient, and requires no special sample preparation, filling an important underserved role in imaging of OPVs.
Understanding particle migration, margination and adhesion in cellular suspensions
Keywords: Chemical Engineering.

In this thesis, we develop a theoretical framework for red blood cell migration, platelet margination and adhesion in pressure-driven channel flow based on the hydrodynamic principles of particles in Stokes flow and the kinetic information on platelet adhesion under arteriole flow conditions. We also perform simulation and experimental studies to verify our theoretical predictions. We identify deformability-induced lift force and shear-induced diffusion as governing mechanisms for the cross-flow transport of red blood cells. The absence of a lift force for rigid platelets is the key to their margination. We explore the steady state and non-equilibrium behaviors of particle migration and margination and consider the scenarios of rigidified red blood cells due to malaria infection and migration in small arterioles. We also investigate the effects of flow properties (e.g. shear rate) and platelet properties (e.g. receptor densities) on platelet adhesion. We elucidate the role of particle deformability in changing the microstructure of such suspensions in wall-bound channel flow. Therefore we emphasize the role of red blood cell volume fraction (hematocrit) on the rates of these three processes which ultimately lead to hemostasis and thrombosis.
Understanding provenance signatures in active margin settings : modern central California and the the magallanes-austral foreland basin, Southern Patagonia
Keywords: Geological and Environmental Sciences.

From plate tectonics that act over thousands of kilometers and millions of years to sedimentary processes that operate over sub meter and sub annual timescales, provenance data integrates many types of information. The research in this dissertation attempts to advance the understanding of tectonic and sedimentological controls on provenance analysis by examining one modern and one ancient example. The modern example, coastal central California provides the advantage of being a well-studied modern setting for which boundary conditions of source region geology and sediment dispersal patterns are constrained. In the ancient example, the Magallanes-Austral retroarc foreland basin in southern Patagonia, considerable initial work was required to constrain the stratigraphic framework of the basin before provenance patterns and sediment dispersal could be examined in detail. Chapter 1 explores sediment dispersal off the modern coast of central California in an attempt to determine how sediment pathway partitioning and sediment mixing control the expression of provenance signatures. This chapter demonstrates that sediment mixing in the marine realm is an important control on provenance signatures and that submarine canyons and coastal geometries dictate the way sediment dispersal systems are partitioned along narrow-shelf margins. Chapter 2 provides a stratigraphic framework for the Magallanes-Austral foreland basin through field mapping and detrital zircon maximum depositional age calculations. This framework provides the first radiometrically-age-controlled, unified, framework for the basin between 49.5⁰S and 52⁰S. The focus of the chapter is constraining the age of the Cerro Fortaleza Formation. This unit had previously been assigned ages ranging from Cenomanian to Maastrichtian. Using detrital zircon maximum depositional ages we constrain the age of the unit to Campanian to Maastrichtian. Refining the age of this unit allows the rest of the stratigraphic framework of the basin to be defined. Chapter 3 is a provenance analysis of the Magallanes-Austral retroarc foreland basin that incorporates previously published provenance data from the basin along with 28 new detrital zircon and 34 new sandstone petrography samples. This analysis is informed by the systematic incorporation of geologic background information with an attempt made to describe sediment dispersal patterns from the whole-basin scale down to individual sediment dispersal systems.
Understanding the functionality and dimensionality of vector embeddings : the distributional hypothesis, the pairwise inner product loss and its applications
Keywords: Electrical Engineering.

Vector embedding is a foundational building block of many deep learning models, especially in natural language processing. We present a theoretical framework for understanding the effect of dimensionality on vector embeddings. We observe that the distributional hypothesis, a governing principle of statistical semantics, requires a natural unitary-invariance for vector embeddings. Motivated by the unitary-invariance observation, we propose the Pairwise Inner Product (PIP) loss, a unitary-invariant metric on the similarity between two embeddings. We demonstrate that the PIP loss captures the difference in functionality between embeddings, and that the PIP loss is tightly connected with two basic properties of vector embeddings, namely similarity and compositionality. By formulating vector embedding algorithms as matrix factorizations under noise, we reveal a fundamental bias-variance trade-off in the dimensionality selection process, which, similar to many signal processing problems, is between the signal and noise power. This bias-variance trade-off sheds light on many empirical observations which have not been thoroughly explained, for example the existence of an optimal dimensionality. Moreover, we discover two new results about vector embeddings, namely their robustness against over-parametrization and their forward stability. The bias-variance trade-off of the PIP loss explicitly answers the fundamental open problem of dimensionality selection for vector embeddings. The combination of vector embedding and the PIP loss can be applied to quantify diachronic evolution and domain adaptation of language. We develop the Global Anchor Method (GAM), a method for comparing embeddings trained on two different corpora. Corpora dissimilarity determines model transferability, namely, whether a model trained on one corpus will work on another. We used GAM to analyze diachronic and domain effects in English corpora, using the Google Books and arXiv datasets as examples, where we reveal interesting sociological and academic factors that affect the usage of language.
Understanding the impact of conversational AI on supportive interactions : towards the CARE (Conversational AI and Response Effects) model
Keywords: Communication.

In supportive interactions, people reveal their negative emotions and struggles to another person, who listens and responds with the goal of relieving distress. The nature of the responses from the partner can determine how well the conversation reduces distress, with validating responses being beneficial and invalidating being harmful. Yet new dynamics may emerge, causing different effects, with a conversational AI partner, such as a chatbot, rather than another person. This dissertation has two main portions. The first is an empirical study that used an experimental design to test whether the type of response (validating vs. invalidating) and perceived identity of the partner (chatbot vs. human) changed the effects of supportive interactions. The results suggest that for one component -- proximate reactions -- only the type of response, but not the identity of the partner, mattered. The other two components -- disclosure behavior and future well-being - raised new dynamics and different outcomes depending on the partner's identity. The second part of the dissertation is the introduction of a model of partner effects (CAI vs. human) in supportive interactions based on these findings and on past work.
Understanding trigonometric relationships by grounding rules in a coherent conceptual structure
Keywords: Psychology.

Mathematical cognition relies on a variety of representations, from algebraic rules to diagrams that convey the meaningful relationships expressed in the algebraic rules. My dissertation shows how a diagram that captures the conceptual structure underlying the domain of trigonometry can make symbolic expressions into more meaningful rules that can be applied and generalized successfully. We presented students with trigonometric identity problems, and examined the representations they used. Students most often reported using the unit circle, a diagram that captures the meaning of trigonometric expressions in an integrated way. Those who reported using the unit circle also tended to have higher accuracy. Other students, who did not report using the unit circle or reported using it less often, were more likely to rely on heuristics and rules that had no connection to the meanings of the trigonometric constructs involved. We created a formal rule-based lesson and another lesson which instead grounded relationships in the unit circle, and we randomly assigned students to each lesson. Students in the grounded lesson condition showed improved accuracy both on problems taught in the lesson and on problems held out for transfer. While the unit circle could be used simply as a standalone procedure to solve problems, some students appeared to apply an understanding of the relationships and symmetries in the unit circle to extend and combine rules. Students reported relying slightly more on a rule or formula when solving taught problems than transfer problems. However, across all problem types, students often reported relying on both the unit circle and a rule or formula on a particular problem. As students gained experience solving problems after the grounded lesson, they tended to reduce their active use of the unit circle, as indicated by their self-reported strategies and by their interactions with an external unit circle tool. Across our studies, the unit circle revealed itself to be a strong, coherent conceptual structure, and it creates a fertile ground for learning and understanding trigonometry through the interplay of visuospatial and rule-based approaches. Students learn how to map parts of a symbolic expression onto meaningful properties of the unit circle, and this grounded understanding facilitates application and generalization of rules in order to solve problems successfully. Helping students from all backgrounds master these grounded rules remains a challenge for teachers and cognitive psychologists.
Unequal contexts, unequal opportunity [electronic resource] : racial differences in school achievement distributions and neighborhood socioeconomic status
Keywords: Education.

Racial school and residential segregation mean that black students in schools, and black families in neighborhoods generally face different school and neighborhood contexts, respectively, than their white counterparts. These patterns persist despite decades of declining residential segregation, and court-mandated school desegregation. Just how different school and neighborhood contexts are, however, is an open question. This dissertation utilizes a novel approach to measuring racial differences in school and neighborhood context to answer this question. The first paper uses an exposure measure to describe the student achievement distributions in the schools of different race students, conditional on achievement. A similar measure is used in the second paper, which describes differences in neighborhood socioeconomic status for families of the same income, but different races. Both papers find that, even conditional on achievement, in the case of schools, and family income, in the case of neighborhoods, black students and families face strikingly different contexts than white students and families. The final paper of the dissertation links a version of the neighborhood measures to young adult outcomes to explore how differences in neighborhood context area associated with income, college-going, and teen pregnancy. Results suggest that neighborhood context matters for college enrollment and teen birth rates, while the evidence for adult income is less conclusive.
Unforeseen geochemical and hydrological triggers of arsenic release during managed aquifer recharge
Keywords: Earth System Science.

Managed aquifer recharge (MAR) is an increasingly applied groundwater storage method to enhance freshwater security and increase resilience to climate extremes. MAR projects are commonly implemented via infiltration or injection of various types of source water into underlying groundwater aquifers. Benefits of MAR extend beyond enhancement of local groundwater supplies; they can provide seawater intrusion barriers, enhance ecosystem services, maintain aquifer capacity and minimize subsidence. Despite the numerous potential benefits, artificial recharge can also adversely impact groundwater quality by altering the native geochemistry and triggering the release of toxic contaminants indigenous to aquifer sediments. Desorption or dissolution, and subsequent mobilization, of contaminants poses a principal challenge to maintaining local groundwater quality, and thus also to ensuring the viability of MAR as a water enhancement strategy. Arsenic imposes the most widespread threat, degrading water quality around the world, where it has deleterious impacts on human and ecosystem health. My research uses a combination of experimental, spectroscopic and modeling approaches to study the geochemical and hydrological causal mechanisms of As mobilization during groundwater recharge.
Universal meshes for two-dimensional domains with piecewise C2-regular boundaries
Keywords: Mechanical Engineering.

We introduce a method to deform a mesh to conform to a domain with piecewise C2-regular boundary, by only moving a fraction of vertices of the given mesh. The method preserves all vertices and connectivities of the mesh, and only small regions near the boundary are deformed, which makes it computationally efficient. The most appealing application of the method is when it is needed to mesh a group of domains, such as the case of moving boundary problems. For such problems, a single mesh that does not require any conformity to the boundary can be generated, which is then used to obtain conforming meshes for a number of domains by simply deforming it. The challenge for such an application is the robustness of the method, which allows the method to be automated without any user intervention. We provide the method with conditions that guarantee its success, which can be either satisfied or checked a priori. The outline of the method is as follows. The boundary is first divided into a set of C2-regular curves, called segments. Some vertices near the endpoints of each segment are perturbed so that each endpoint has a vertex assigned to it. Then, a set of edges, called domain edges, are selected from the mesh, and the domain edges or their vertices are projected onto the boundary. Some vertices near the curve are perturbed to relax any distorted triangles. A crucial necessary condition for the method to render a conforming mesh with elements of good quality is that the projection of domain edges onto the boundary be a homeomorphism, which involves both choosing an appropriate set of domain edges and projection map. In our method, we choose the set of domain edges individually for each segment. This set is "roughly" the set of all edges joining the two vertices on a given side of the curve, of each triangle that has a third vertex on the other side. The domain edges are then projected to their corresponding segment via the closest point projection. The highlight of the strategy is the algorithm to assign an orientation to each segment, which determines the set of domain edges for the segment. The algorithm prevents domain edges of distinct segments from intersecting at point other than the endpoints of a segment. Certain conditions are also required on the mesh and the curve for the projection to be a homeomorphism. Some angles in the mesh are required to be acute, and triangles near the boundary should be sufficiently small with respect to its local radius of curvature of the curve. We analyze the method and present theorems that show the conditions that guarantee the homeomorphism of the projection. The conditions solely depend on the features of the given boundary, and can be computed in advance to generate the background mesh, if needed.