VictorJuiz/thesis huggingface dataset:
Sparsification, online optimization, and an almost-linear time algorithm for maximum flow

This thesis designs efficient algorithms for combinatorial and continuous optimization problems. By combining new techniques developed in this thesis pertaining to iterative methods, dynamic algorithms, and high-dimensional geometry, we give an almost-linear-time algorithm that computes an exact maximum flow and minimum cost flows in directed graphs. Our insights lead to algorithms for broader classes of combinatorial and continuous optimization problems including online discrepancy minimization, regression, and dynamic maxflow. In the first part of the thesis we study iterative methods, which are procedures which solve an optimization problem through a sequence of simpler subproblems. By understanding the geometry of the underlying optimization problem, we give iterative methods with improved convergence rates and runtimes for the problems of $\ell_p$ regression, maximum flow, and mincost flow. In the second part of the thesis we study dynamic algorithms and online optimization which naturally arise from studying iterative methods. In particular, we give the improved algorithms that maintain an approximate maximum flow in dynamic graphs undergoing edge insertions, and also nearly-optimal algorithms for minimizing the discrepancy of vectors arriving online. In the third part of the thesis, we study sparsification problems motivated by high-dimensional geometry. The goal of sparsification is to reduce the size of an objective while approximately maintaining the desired properties, such as the value on all inputs. We give improved and nearly-optimal size bounds for sparsification of several objectives including spectral hypergraph energies and sums of symmetric submodular functions. Finally, we give nearly-linear size bounds for sparsification of generalized linear models satisfying natural bounds on their growth, which imply nearly-optimal algorithms for solving $\ell_p$-regression for \in (1, 2]$. This thesis contains material from the papers \cite{KLS20, ALS20, LSS21, CKLPPS22, JLS22, JLS23, BLS23, JLLS23, JLLS23b}

Keywords: Humanities and Sciences.
Mathematics.
Advisor: Sidford Aaron
Vondrak Ján (Mathematician)
Charikar Moses
Spatial and molecular analysis of growth patterns in the lung adenocarcinoma microenvironment

Non-small cell lung cancer adenocarcinoma tumors are composed of heterogeneous cell populations that contribute to the development and dissemination of malignancies. Lung adenocarcinoma tumors have been observed to progress through a well-defined series of histologic growth patterns, including lepidic, acinar, papillary, and solid designations. These patterns are routinely utilized clinically and have been shown to correlate with clinical prognosis. Fibroblast cells are among the most prevalent within this microenvironment, but their relationship to growth patterns in lung adenocarcinoma is understudied. Despite the close association of lung adenocarcinoma growth patterns with prognosis and growing interest in the roles of pathological fibroblasts, the predominant fibroblast subtypes and their interactions within the context of each lung adenocarcinoma growth pattern are poorly defined. To understand the many cell types present in the lung adenocarcinoma tumor microenvironment, with a focus on resident lung fibroblasts, I generated an imaging dataset comprising whole-slide images of 8 lung adenocarcinoma tumors and analyzed spatially bound growth pattern regions annotated by an expert pathologist. I initialized a novel multiplexed immunofluorescence microfluidics instrument, developed a tumor marker panel for use in said instrument, and collected an in-house lung tumor tissue sample bank. I utilized this pipeline and methods to investigate specific biological hypotheses in lung adenocarcinoma fibroblast subtype localization with other cell types in varying histological growth patterns. In particular, I observed that colocalization of fibroblasts expressing the surface marker CD90 with CD3+ T cells are more associated with invasive acinar than noninvasive lepidic growth patterns. I utilized an independent lung tumor microarray dataset to perform concurrent analyses and found that this spatial cell association signature is correlated with prognosis and survival. I also leveraged multiple sources of imaging in these samples, revealing the potential of extracellular matrix features in predicting nodal status of individual samples. I observed differential changes in the localization of specific cell types and calculated extracellular matrix features in lung adenocarcinoma samples depending on nodal involvement. By defining pathological lung fibroblast subtypes through their shared markers, interactions with other cells, and functions, I shed light on these crucial components of the tumor microenvironment and ultimately define fibroblast- and microenvironment-based treatment targets for lung adenocarcinoma. These studies contribute to the field's understanding of spatial fibroblast interactions with the lung adenocarcinoma microenvironment and offer a conceptual framework for future investigations into the tumor microenvironment

Keywords: Medicine.
Advisor: Plevritis Sylvia
Gentles Andrew J.
Graves Edward (Edward Elliot)
Mallick Parag
Spatially-resolved multiomic characterization of the maternal-fetal interface

This thesis explores the intricate dynamics of pregnancy, focusing on the dynamics of trophoblast invasion and the remodeling of uterine spiral arteries. Through a cutting-edge multiomic approach employing spatial proteomics and transcriptomics, we construct a comprehensive spatio-temporal atlas of the maternal-fetal interface in early pregnancy and expand this to examine pertubations in preeclampsia. Our findings shed light on cellular interactions between fetal and maternal cells, the evolution of this process with gestational age and spiral artery remodeling, and the mechanisms behind EVT invasion. Our work offers new insights into the regulation of maternal-fetal tolerance in healthy and pathological pregnancy and providse a framework for elucidating etiological perturbations in pregnancy complications. Our research can also serve as a model for comprehending the abnormal recruitment and combination of immune tolerance, tissue remodeling, and angiogenesis during the advancement of tumors.

Keywords: Medicine.
Microbiology and Immunology.
Advisor: Angelo Michael
Aghaeepour Nima
Bendall Sean
Winn Virginia
Spatial-omics approaches to dissect host-disease interaction

The spatial interaction between different biological agents and the host immune system plays a critical role in maintaining tissue homeostasis and influencing disease outcomes. These interactions can be characterized by their complexity and diversity, encompassing various scenarios: Harmonized Interaction, for example, the mutualistic relationship between the microbiota and the immune system is vital for maintaining tissue integrity and immune homeostasis. Hostile Interaction, for example when a viral infection occurs, it triggers a local immune response aimed at eliminating the pathogen. This immune response can result in systemic retaliation, leading to inflammation and other systemic effects. Dynamic Interaction, for example within the tumor microenvironment, there exists a dynamic interplay between tumor cells and immune cells. This complex interaction influences the efficacy of immunotherapy and can determine the outcome of the disease. However, studying these interactions requires methodologies that go beyond traditional single-domain approaches. To comprehensively understand these complex phenomena, we need methods that can capture and preserve spatio-temporal information, identify cross-domain feature responses in a high-plex format, and harmonize biological knowledge across different modalities and biological entities. This thesis work attempts to bridge this gap. Chapter 1 provides a background on tissue biology and the methodologies developed so far, and the unmet need in this field. Chapter 2 introduces MicroCart, an experimental assay for studying host-microbiome interactions, highlighting its design, validation process, and compatibility with different modalities. Chapter 3 presents Redsea, a computational method addressing lateral signal contamination in imaging, emphasizing its significance in improving imaging quality. Chapter 4 discusses Mario, a data integration algorithm enabling the matching and integration of data from different single-cell proteomic and multi-modal methods. Chapter 5 focuses on MaxFuse, a data integration algorithm designed for 'weakly-linked' modalities, facilitating the creation of a spatial-trimodality dataset, showcasing its benefits and applications

Keywords: Medicine.
Microbiology and Immunology.
Advisor: Nolan Garry P.
D'Angelo Robert
Gaudilliere Brice
Huang Kerwyn Casey
Spatiotemporal dynamics of plant-soil-microbe interactions

Understanding how communities assemble across space and time remains a fundamental ecological question. In this dissertation, I investigate how plants, soil, and microbes interact to shape the outcome of aboveground and belowground communities. To understand temporal dimensions of microbially mediated plant-soil feedback, I quantified how the strength of conspecific and heterospecific feedback changes over time in greenhouse experiments. Using molecular sequencing, I show that plant-associated microbial communities changes within a plant generation, depending on the initial microbial source. I then show that microbial community turnover between generations affects the coexistence outcomes of plant communities driven by natural gaps in growing seasons and litter decomposition. In the spatial dimension, I use spatially-explicit field data to show how plant and microbial community distribution varies in relation to soil nutrients. Using observations from forest dynamics plots, I show that mycorrhizal association drives the aggregation patterns of trees across a gradient of soil fertility, interacting with the dispersal mode of different species and age structure within each species. All together, my dissertation explores various temporal and spatial structures of plant--soil--microbe interactions and their role in shaping species diversity above- and belowground.

Keywords: Humanities and Sciences.
Biology.
Advisor: Daily Gretchen
Fukami Tadashi
Dirzo Rodolfo
Spatiotemporal gene expression mapping of brain aging in mice

In aging individuals, the brain is a vulnerable organ and at higher risk of neurodegenerative disease, yet mechanisms underlying the aging process in the brain are not fully understood. Previous studies have shown that the impact of aging on the brain involves a multitude of biological processes which differ between brain regions, however a comprehensive understanding of age-related gene expression dynamics in many brain regions across multiple ages remains to exist. This research aims to characterize spatiotemporal gene expression patterns associated with aging across several brain regions in mice. 10X Visium spatial transcriptomes of healthy mice aged 6, 18, and 21 months are analyzed to investigate region-specific expression changes over time. An interactive web application is available to enable access to the spatial transcriptomic dataset. The findings suggest that aging across the brain occurs in a heterogenous fashion, affecting different brain regions at different magnitudes and through a variety of gene pathways. Due to their accelerated rates of aging, white matter tracts, areas in the brain made up of myelinated axons, may be of interest as “hotspots” of aging.

Keywords:  Department of Biology
Hahn, Oliver
Aging
Brain regions
Spatial transcriptomics
Gene expression
Text
Thesis
Specific extrusion of Enterovirus-A71-infected cells from human colonoids and consequences for viral spread

Enterovirus-A71 (EV-A71) is a causative agent of Hand Foot and Mouth Disease and occasionally progresses to life-threatening encephalitis and viral meningitis; it is currently endemic in East Asia. There are no antiviral treatment options and no FDA-approved vaccine. EV-A71 is transmitted via fecal-oral routes and thus first enters the body through the GI tract. The Kirkegaard laboratory has cultured colonic epithelial organoids (colonoids) so as to present their apical surface to the medium, mimicking the lumen of the intestine, to study EV-A71. We have found, after eight hours of infection, infected cells are extruded from the epithelium via mechanosensitive pathways. Given that this both liberates virus-infected cells from the epithelium and is likely to preserve epithelial integrity, we hypothesize that the specific extrusion of infected cells benefits both the virus and the host.
To test this hypothesis, I have employed colonoids to investigate the fate of extruded cells and the virus within, as well as how extrusion affects overall viral burden. Extruded cells initially sequester virus, but significantly release virus by sixteen hours post infection. Additionally, viral Stability was equivalent in cell-associated and free virus, indicating that infected extruded cells can propagate infection. Cell-associated virus displayed decreased levels of secondary infection as compared to equivalent titers of cell free virus; clusters of secondarily-infected cells were observed in RD monolayers when intact extruded cells were used to propagate infection, indicating that extruded cells could propagate infection en bloc. When extrusion was blocked by inhibiting force-sensitive ion channels with GsMTx4, virus was still released as free-virus, which ultimately increased viral burden. Thus, blocking extrusion led to more severe infection. Overall extrusion establishes a limited and persistent infection, which benefits both the host and the virus.
Extrusion of infected cells has shown to be a host response to a growing number of pathogens, including poliovirus, measles, Salmonella enterica serovar Typhimurium, and Listeria. Understanding extrusion and its role in the EV-A71 infectious cycle can illuminate the factors that promote or prevent severe disease and elucidate targets for antiviral treatments.

Keywords:  Department of Biology
Biology
Microbiology
Virology
Enteroviruses
Organoid
Extrusion
Text
Thesis
Advisor: Kirkegaard Karla
Cyert Martha
Spectroscopic modeling and ultraviolet laser absorption spectroscopy measurements for the development of nonequilibrium thermometry and speciation diagnostics of for O2, NO and CN

Accurate spectroscopic modeling, when coupled with state-of-the-art laser diagnostics, enables quantitative measurements of the often poorly characterized nonequilibrium chemistry distinctive of hypersonic flows. The validation and improvement of existing chemical and fluid mechanical models that attempt to capture the complex molecular dynamics in such high-speed flows rely heavily on the temperature and concentration measurements delivered by laser-based sensors. The nonequilibrium thermochemistry that diatoms such as oxygen (O2), nitric oxide (NO), and the cyano-radical (CN) undergo requires high-fidelity experimental quantification, as these molecules and their internal energy distributions, rotational and vibrational, significantly impact the heat loads experienced by hypersonic vehicles. This dissertation will leverage the strong ultraviolet absorption spectra of the three aforementioned molecules, O2, NO, and CN, to develop a combination of laser diagnostics to probe the rotational and vibrational temperatures and species concentrations, both total and in specific vibrational quantum states. Low uncertainty, time-resolved measurements of such quantities provide invaluable data for the various modeling efforts to compare calculations against and improve model specific parameters. In this work, four sets of studies were undertaken to develop a spectroscopic model, use the model to inform temperature diagnostic wavelengths, perform an experimental spectroscopic validation, and finally demonstrate the accuracy of the diagnostic. Three major spectroscopic systems were modeled for the purposes of these works, the Schumann-Runge system, which give rise to the strong ultraviolet absorption spectrum of O2, the NO γ-bands, one of the strongest ultraviolet systems of NO, and the CN Violet system, one of the strongest molecular absorption systems in the ultraviolet. The developed models informed wavelengths that probed specific quantum states of the aforementioned diatoms and could be used in a two-color thermometry scheme to infer state-specific temperature and number density time histories in a shock tube environment. The experimental validation of the spectroscopic models at novel conditions and wavelengths improved the modeling capabilities and provides a framework for future spectroscopic studies that seek to further quantify the absorption spectra of air diatoms. Upon validating the spectroscopy, the laser diagnostics could be deployed to study the nonequilibrium chemistry of these diatoms behind strong shock waves and yielded quantitative temperature and concentration data critical to modeling heat loads experienced by hypersonic vehicles and the design of the thermal protection systems to withstand such loads.

Keywords: Engineering.
Mechanical Engineering.
Advisor: Hanson Ronald
Cappelli Mark A. (Mark Antony)
Cruden Brett
Spin and surface textures in nanophotonics

Light carries information on its multiple degrees of freedom, underlying a variety of optical imaging and characterization methods. To benefit from such methods, it is essential to achieve precise control over light waves based on the intrinsic properties of light. Although this has been typically obtained by using bulky conventional optics, it has recently been recognized that optical resonances in high-index nanostructures can be harnessed to manipulate light waves in a controlled fashion. This novel approach, called flat optics, offers new opportunities for the integration of the ability to control light waves into optoelectronic devices. In this thesis, we illustrate our approaches with thin nanopatterned semiconductor films to achieve improved control over optical degrees of freedom in optoelectronic devices, especially focusing on optical spin and surface textures.

Keywords: Engineering.
Materials Science and Engineering.
Advisor: Brongersma Mark
Fan Shanhui
Miller David
Stability and dynamics at non-aqueous fluid-fluid interfaces

Fluid-fluid interfaces are common in nature and in various industrial processes and products, including personal care, lubricating oils, wildfire fighting, and food science. Understanding the stability of these interfaces is crucial to their morphology and dynamics, and can enable engineering of interfaces towards an end application. Aqueous liquids are ubiquitous and their interfacial behavior has been reasonably well studied. There is much less known about interfaces involving non-aqueous liquids. In this thesis, we are concerned with two classes of phenomena that are constructed of fluid-fluid interfaces with a non-aqueous liquid component: non-aqueous foams and emulsions. Non-aqueous foams are dispersions of air in liquid, and therefore comprised of many air - non-aqueous liquid interfaces. We explore various mechanisms by which the interfaces are stabilized and destabilized, subsequently influencing the resulting foams. These mechanisms can also be engineered to intentionally control stability of foams, stabilizing beneficial and destabilizing disadvantageous foams. Here, we primarily examine systems where foaming is detrimental, with the aim to destabilize the foam by destabilizing the component interfaces. Diesel fuels are one such system, with unique characteristics that make antifoaming additives challenging. Using custom single bubble interferometry, we show experimental validation of conventional antifoams in diesel and, importantly, demonstrate that a globally viable ash-free alternative is effective. Additionally, we present experimental evidence illustrating the likely physical mechanisms behind each antifoam. Widely used antifoam additives are insoluble and present challenges in implementation and robust function over time. Inspired by evaporation-induced stabilization observed in multi-component mixtures such as diesel and lubricant oils, we introduce a novel miscible antifoam mechanism. By strategically inverting the surface tension gradient and thus the direction of induced flows, this mechanism leverages solutocapillary Marangoni flows to destabilize a foam. Emulsions are dispersions of aqueous liquid in non-aqueous liquid or vice versa, and are built of non-aqueous - aqueous interfaces. We focus on double emulsions (DEs) (water-in-oil-in-water 2-interface emulsions), generated via microfluidics. We conduct a systematic characterization of DE size and shell thickness across a wide range of flow rates, fluid composition and properties, and stability and instability. Understanding interface stability in double emulsions allows better control of DE size, uniformity, and robustness, essential for applications in biomedical research. This dissertation corroborates that fluid-fluid interfaces are key to understanding factors influencing the stability and dynamics of numerous foams and emulsions and their applications, illuminating areas of great potential.

Keywords: Engineering.
Chemical Engineering.
Advisor: Fuller Gerald
Fordyce Polly
Mai Danielle
The stairway to heaven : EMP2 links cell cycle arrest, lipid metabolism, and ferroptosis sensitivity

Ferroptosis is a non-apoptotic form of cell death that can be triggered by inhibiting the system xc- cystine/glutamate antiporter or the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). Here, we show that cells arrested in the cell cycle by stabilization of wild type p53 or by inhibition of cyclin-dependent kinase activity have increased sensitivity to GPX4 inhibitors but not system xc- inhibitors. Cell cycle arrest alters the lipidome to increase the abundance of oxidizable polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), which drives sensitivity to GPX4 inhibitors. Changes in PUFA-PL abundance upon cell cycle arrest are linked to reduced expression of membrane bound O-acyltransferase domain containing 1 (MBOAT1) and epithelial membrane protein 2 (EMP2). A candidate orally bioavailable GPX4 inhibitor increased ferroptotic lipid peroxidation and shrunk tumor volumes when combined with a CDK4/6 inhibitor. Thus, cell cycle arrest may make certain cancer cells more susceptible to ferroptosis in vivo.

Keywords: Medicine.
Advisor: Dixon Scott James
Long Jonathan Z.
Sage Julien
Skotheim Jan