VictorJuiz/thesis huggingface dataset:
Molecular mechanisms governing the identity and clinical functionality of type 1 regulatory t cells

Type 1 regulatory T cells (Tr1) are a peripherally derived regulatory T cell subset that confer antigen-specific tolerance in vivo. While Tr1 cells possess potent regulatory capabilities, they represent a rare T cell population. Therefore, the successful implementation of Tr1 based cell therapies will require simultaneous efforts to develop efficient in vitro induced Tr1 (iTr1) methods while uncovering basic Tr1 biology. One iTr1 method is the enforced expression of the IL-10 gene in CD4+ T cells, referred to here as LV-10 cells. LV-10 cells can dampen harmful immune responses while exhibiting myeloid-specific cytotoxicity, thus bringing forth a unique opportunity to concurrently reduce graft vs host disease after allogeneic hematopoietic stem cell transplantation for myeloid cancers and promote graft versus leukemia. Two major areas that are explored in this thesis are the identification of 1) transcription factors (TF) that control Tr1 identity and 2) protein interactions between leukemic blasts and LV-10 cells that impact cytotoxicity. The master TFs driving human Tr1 development are still unknown. We conducted the first transcriptome analysis on de novo human Tr1 by RNA sequencing. Utilizing a variety of tools such as gene knockout, gene overexpression, and in vitro differentiation, we have characterized the role of BHLHE40 in both primary human CD4+ T cells and naïve CD4+ T cells. Ultimately, identifying Tr1-specific TFs will improve our ability to detect, isolate, and manipulate endogenous Tr1, and design efficient protocols to generate iTr1 for cell therapy. LV-10 cells are an attractive iTr1 cell product because they allow for the efficient conversion of Tr1-like cells that secret high IL-10 while exhibiting myeloid cytotoxicity. We investigated the extent of their anti-leukemic effect on primary pediatric acute myeloid leukemia (pAML). We tested 23 pAML and found that pAML exhibited a range of sensitivities to LV-10 killing: sensitive, intermediate-resistant, and resistant. After comparing the immune phenotypes of pAML via flow cytometry and the transcriptome via RNA-sequencing, we determined that sensitive and resistant pAML are molecularly distinct. We specifically identified that resistant pAML express high levels of CD200 and after co-culturing CD200 overexpressing sensitive cell lines with LV-10 cells, we observed a reduction in LV-10 degranulation. Altogether, LV-10 cells represent a promising clinical use for pAML, though further characterization is needed to optimize their potential clinical usefulness

Keywords: Stem Cell Biology and Regenerative Medicine.
Advisor: Roncarolo Maria-Grazia
Cleary Michael L.
Nakauchi Hiromitsu
Shizuru Judith Anne
Molecular origins of heterogeneity in cancer cell death

Anti-cancer drugs and other lethal agents can induce heterogeneous cell death responses in a population of cancer cells, a phenomenon referred to as fractional killing (FK). FK arises from a wide variety of molecular mechanisms, the study of which has been limited by inadequate tools for quantifying and studying cell death. We have developed and validated methods to quantify FK in a high-throughput manner. Here, I use this approach to investigate FK induced by inhibitors of mitogen activated protein kinase kinase (MEK) 1/2. I show that Bcl-2 family members play a critical role in executing cell death upon MEK inhibition, and that among pro-survival Bcl-2 family members, MCL1 (and not BCL-xL) is an important determinant of FK. I show that JNK activity modulates MEK inhibitor-induced death via effects on MCL1. These effects are consistent across some, but not all cell lines, suggesting that generalizable molecular models of FK are rare. These studies lay the foundation for quantitative high-throughput analyses of FK

Advisor: Dixon Scott James
Bassik Michael 
Morrison Ashby J.
Molecular tools to understand blood-brain barrier function in health, aging, and disease

Aging is the single greatest risk factor for neurodegenerative disease. Yet amidst an aging global population, there still do not exist effective therapies for such diseases. Recent clinical trials of therapies targeting disease-associated pathology, such as beta-amyloid accumulation in Alzheimer's disease, have found little benefit. Thus, new approaches capable of modifying the underlying process of brain aging are likely needed. Intriguingly, exposure to young blood plasma has been consistently found sufficient to rejuvenate the aging brain. Yet, since the first tracer experiments in 1900, the brain has been believed largely isolated from circulatory proteins via a structure termed the blood-brain barrier (BBB). Here I describe my initial efforts to address this paradox, and in the process, reveal major aspects of BBB function in health and with age. I developed new enzymes for labeling and tracking secreted proteins, and separately, applied single cell transcriptomics to discover the BBB's surprising responsiveness to circulatory proteins. Combining these approaches, I tagged and tracked the blood plasma proteome as a discovery tool to reveal widespread endogenous transport of proteins into the healthy brain and the pharmacologically modifiable mechanisms by which this process becomes impaired with age. These findings suggest the BBB may promote optimal brain function not by its impermeability but by its continuous and organized uptake of plasma proteins, with implications for the pathogenesis of neurodegeneration and the delivery of drugs to treat it

Keywords: Bioengineering.
Advisor: Wyss-Coray Anton 
Bertozzi Carolyn R.
Cochran Jennifer R.
Monitoring and modeling the elastic and transport properties of organic-rich marl during maturation through pyrolysis experiments

Organic-rich marl is an important type of shale reservoir because its stiff matrix leads to relatively high permeability and frackability compared to clay-rich shale. However, how the stiff matrix affects the changes in the elastic and transport properties of organic-rich marl during maturation remains poorly understood, obstructing the remote characterization of this reservoir type across different maturity levels. One major cause of the poor understanding is the lack of rock physics a dataset tracking the changes in these properties as a function of maturity. To overcome this obstacle, I induced ex-situ maturation of core plugs from Eagle Ford marl by conducting confined pyrolysis experiments in fine-steps across all maturity windows from the immature through the early-peak oil, late oil, wet gas, and finally the dry gas window. The confined pyrolysis provides a confining pressure during maturation, imitating lithostatic pressure in the subsurface condition. This is a key improvement over previous unconfined pyrolysis experiments in which unrealistically large aperture fractures developed during pyrolysis. After each of my pyrolysis runs, I monitored the changes in microstructure, porosity, velocity, permeability, and geochemical properties. The results show systematically decreasing kerogen volume, increasing porosity, decreasing velocity, and increasing permeability as maturation progresses. These results reveal that secondary porosity from the loss of kerogen volume is the predominant microstructural alteration and the primary driver for decreasing velocity and increasing permeability. Based on these findings, I developed an elastic model for organic-rich marl that incorporates the maturation process. I used the pyrolysis dataset from this study along with previous petrographic and nanoindentation studies to calibrate a few ill-defined parameters in the model—such as kerogen porosity and the moduli of kerogen—as a function of maturity. These parameters cannot be directly measured and their estimated values in the literature are too sparse to be used in the calibration alone. Lastly, I employed the calibrated elastic model to build a rock physics template for characterizing organic-rich marl based on their elastic properties. I tested the applicability of the template against a rock physics dataset from natural (in-situ) maturation. The dataset comprises Bakken, Eagle Ford, and Niobrara core plugs and 11 Eagle Ford well logs across different maturity levels. The test results show that the template is able to map the scatter in the elastic properties of the naturally matured dataset to the variations in maturity, kerogen content, lithology, and fluid saturation. Therefore, this thesis provides a coherent pyrolysis dataset, a rock physics model, and a rock physic template for characterizing the properties of organic-rich marl across different maturity levels

Keywords: Geophysics.
Advisor: Vanorio Tiziana 
Graham S. A. (Stephan Alan)
Mavko Gary
Morphisms and cohomological comparison for Henselian schemes

The global analogue of a Henselian local ring is a Henselian pair - i.e., a ring R and an ideal I which satisfy a condition resembling Hensel's lemma regarding lifting coprime factorizations of polynomials over R/I to factorizations over R. The geometric counterpart is the notion of Henselian schemes, which can serve as an "algebraic" substitute for formal schemes in applications such as deformation theory. In this thesis we discuss Henselian schemes and quasi-coherence in detail, including the correction of an error in the existing literature concerning quasi-coherent sheaves on affine Henselian schemes. We also develop the theory of smooth and etale morphisms of Henselian schemes and prove that quasi-coherent sheaves on Henselian schemes are sheaves for the Henselian-etale topology. Finally, we prove a GAGA-style cohomology comparison result for Henselian schemes in in positive characteristic, and discuss algebraizability of coherent sheaves on the Henselization of a proper scheme

Keywords: Mathematics.
Advisor: Conrad Brian
Bump Daniel
Vakil Ravi
Motion artifact mitigation in magnetic resonance angiography

Magnetic Resonance Imaging (MRI) is a safe, effective, and non-invasive method for examining the human body with excellent soft-tissue contrast. However, because of prolonged scan times, MRI is particularly sensitive to motion. Motion can arise from any number of sources, including respiration, pumping action of the four cardiac chambers, and even sudden involuntary patient movement. This dissertation describes several novel strategies to reduce motion artifacts in cardiovascular magnetic resonance angiography (MRA), which encompasses a class of techniques to image blood vessels with high contrast

Keywords: Electrical Engineering.
Advisor: Nishimura Dwight George
Pauly John (John M.)
Vasanawala Shreyas
Multi-fidelity wing optimization utilizing 2D-to-3D mapping in transonic conditions

Due to time and resource constraints, the conceptual design process for new aircraft is typically limited to the use of inexpensive low-fidelity methods. Unfortunately, these methods generally only provide the fidelity necessary to confidently go forward with a new design when they have been calibrated to previous aircraft of similar type and the design space does not include significant non-linearities. This substantially limits the application of new technology early in the design cycle, and means that only high-level information can be obtained, potentially limiting the available design space. To remedy this, new methods must be developed that can produce higher-fidelity results without a significant increase in cost. Here, a method is proposed for higher-fidelity aerodynamic analysis that incorporates 2D and 3D pressure distribution mapping into a multi-fidelity framework. This expands on previous work in the area by providing a multi-fidelity approach that allows for the prediction of the shape of the pressure distribution in addition to the level of aerodynamic performance. The novel methods presented are a procedure for smooth identification of transonic feature points, and an extension of shape-preserving response functions to include derivative information. To demonstrate their application, results are presented for a wing that has been optimized using the 3D solver FLO107 exclusively, as well as a combination of the 2D solver FLO103 and FLO107. The differences in required evaluations and the final results are documented, showing the potential for significant computational savings in both direct optimization and inverse design

Keywords: Aeronautics and Astronautics.
Advisor: Alonso Juan José
Kochenderfer Mykel J.
Kroo Ilan
Multi-modal integration in number sense acquisition

Mathematical concepts usually have multiple representations. Even the simplest mathematical concepts, such as natural numbers, can be grounded in various ways. Different representations of natural numbers are supported by diverse sensorimotor modalities. How do children learn to integrate representations of numbers from different modalities like visual, verbal, motion and gestures? In fact, this flexible mapping between different representations of natural numbers is an important component in numeric knowledge development, such as counting number of objects in a set (mapping cardinality to number word), naming an Arabic numeral (mapping written number symbols to verbal number words), number line estimation (mapping number words to positions on a number line), etc. In this PhD work, we systematically answer this question by building neural network models that simulate the learning procedure underlying diverse numeric processing tasks and thus account for multi-modal integration in number sense acquisition. It explains why symbolic numbers demonstrate similar properties as non-symbolic numbers, why training children on non-symbolic number arithmetic results in improvement on symbolic arithmetic and how they learn to selectively attend to different aspects of a number and processing numbers according to different instructions. Furthermore, we apply our model to a situated learning scenario, the number board game (e.g., Siegler and Ramani (2008)). We use our model to explain why playing the number board game leads to improvement in various basic number-related tasks, including numeral identification, magnitude comparison, counting, number line estimation, etc., and how such cross-task transfer happens. Our model provides a unified framework that simulates a diverse set of numeric processing tasks. Overall, it offers computational accounts for various empirical findings in the number cognition literature and deepens our understanding of the underlying mechanism in number sense acquisition

Keywords: Psychology.
Multipath detection and mitigation in urban environments

The Global Navigation Satellite System (GNSS) has become more and more widely used in commercial applications such as smart phones, cars, and drones. GNSS is one of the core technologies used for automotive navigation. For consumer automotive applications, it is typically the only navigation system that provides precise absolute positioning and timing. As transportation technology moves towards greater autonomy, the need for and the reliance on precise GNSS with integrity becomes increasingly urgent. For terrestrial applications, multipath becomes the biggest challenge having GNSS with high accuracy and high integrity. This work explored and examined several approaches to detect and mitigate multipath using newly available resources and technologies. A multipath detection method using three- dimensional (3D) building model with statistical ray tracing was developed that provides better resilience toward initial user position error than deterministic ray tracing and does not rely on redundancy in received GNSS measurements. A multipath mitigation method using multi-frequency signals was also developed that leverages the new civil signals and the correlation in multipath characteristics between different frequency signals from the same satellite to estimate and remove multipath effect on correlation function. Finally, a mapping methodology to infer obstacles in the environment using obscured and unobscured rays was proposed and algorithms were developed to generate 3D maps using GNSS measurements

Keywords: Aeronautics and Astronautics.
Advisor: Walter Todd
A multi-physics corrosion induced deterioration framework for durability performance management of reinforced concrete structures

Reinforced structures are continuously at risk from corrosion, fatigue, and other deterioration processes over a decades-long lifetime. During the last decades, various numerical models have been developed that capture the corrosion-induced deterioration of reinforced concrete structures over time. While these models are useful, the practice of numerical deterioration modeling remains largely foreign to engineers, building owners, and managers. This thesis establishes a framework to enable durability performance management of reinforced concrete structures subjected to corrosion-induced deterioration using multi-physics models that are based on fundamental material characteristics and environmental exposures. This framework first develops a method to build multi-physics deterioration models rapidly and efficiently with limited human intervention, and a method to interpret and present the simulation results in a straightforward manner for decision makers. This framework also addresses the need for a realistic model of initiation of chloride-induced corrosion by developing a method to assign critical chloride content more appropriately in numerical models by explicitly considering both spatial variation and time-dependency. A three-dimensional modeling framework of carbonation-induced deterioration of reinforced concrete that covers both the initiation and propagation phases of corrosion is also developed in this thesis and integrated with chloride-induced corrosion to more realistically model reinforced concrete elements with multiple longitudinal rebars and stirrups. Finally, using neural network model as surrogates for multi-physics deterioration models of reinforced concrete service life is developed and evaluated in this thesis to enable faster computational simulations of reinforced concrete service life that are statistically equivalent to simulations based on highly complex multi-physics deterioration models

Advisor: Lepech Michael 
Fischer Martin
Geiker Mette
Multipolar order and fluctuations in TmAg2 and YbRu2Ge2

In this thesis we will show thermodynamic and transport properties of two 4f intermetallic materials, YbRu2Ge2 and TmAg2. Both of these materials have been proposed to undergo ferroquadrupolar phase transitions in the B1g symmetry channel, at 10.2K and 5K respectively. The B1g elastoresistivity and low-temperature X-ray measurements of YbRu2Ge2, and the strain-tuning of the phase transition for TmAg2 as inferred from the elastocaloric technique, that are presented here establish that this is indeed the case for both of these materials. We investigate in detail how both of these ferroquadrupolar phase transitions can be/are suppressed towards a quantum phase transition at 0K, through the application of a magnetic field applied along the c-axis at 21.3T and 3.1T for YbRu2Ge2 and TmAg2 respectively. The quadrupole-strain susceptibilities of these materials are investigated throughout their respective H-T phase diagrams (using two different complimentary probes), revealing higher-order octupolar couplings in YbRu2Ge2, and a transverse-field mean field Ising susceptibility for the quadrupole-strain susceptibility of TmAg2. Resistivity measurements indicate potential signatures of quantum criticality in the proximity of the field-suppressed ferroquadrupolar phase transition for YbRu2Ge2

Keywords: Applied Physics.
Advisor: Fisher Ian H.
Kapitulnik Aharon
Kivelson Steven
Multiscale approaches to study the biophysics of parasites and plankton

Multi-scale interactions of motile microorganisms with their environment are crucial in understanding disease transmission, as well as the ecology and biophysics of our oceans. This theme underlies the two problems I tackle in this thesis. The first part of the thesis is focused on the schistosomiasis parasite which currently infects 200 million people world-wide, with 700 million more at risk. Infection occurs when the free-living, motile stage of the parasite known as cercariae swim through fresh-water and infect human hosts by penetrating the skin. The swimming motility of cercariae is therefore crucial to disease transmission but is not well understood emphasizing an urgent need for research efforts. Towards this I combined biological experiments, with robotics and mathematical models to uncover how cercariae use their unique forked-tail to generate a robust and efficient "T-swimmer" swimming gait. Further I discuss results from our model and experiments which point to specific degrees-of-freedom that cercariae create that are crucial for their swimming efficiency, suggesting novel drug-targets for disrupting host-seeking. Studying schistomiasis cercariae in their native, ecological setting of ponds, rivers and lakes in Madagascar revealed an unsolved experimental challenge in studying such multiscale problems in the lab. Significantly, this challenge is also present in studying microscale biophysical processes in the ocean: how to measure single cells and organisms, at microscale resolution, while allowing them to freely move over ecological-scales (hundreds of meters) along the axis of gravity? To address this, I invented "Scale-free Vertical Tracking Microscopy", based on a "hydrodynamic-treadmill for single cells" with no bounds for motion along the axis of gravity. Using this method to bridge spatial-scales, I assembled the first multi-scale behavioral dataset of freely-swimming planktonic cells and organisms. Using this tool, I also demonstrate a "virtual-reality system for single cells",  wherein cell behavior directly controls its ambient environmental parameters and vice versa, enabling novel quantitative behavioral assays. The microscopy platform is built using open-source hardware and software components and has further been deployed in field settings such as marine stations in Puerto Rico, Monterey as well as oceanic research-vessels. This ability to bring the lab to the ocean has resulted in new discoveries such as rapid buoyancy modulation over millisecond timescales in planktonic diatoms as well as discovering gravity-oriented swimming behaviors among 8 phyla across the tree-of-life. This microscope and the results presented, exemplify a new paradigm of multi-scale measurement wherein one can observe macroscale, ecologically relevant phenomena at microscale resolution

Keywords: Mechanical Engineering.
Advisor: Lele Sanjiva K. (Sanjiva Keshava)
Prakash Manu 
Wang Bo (Researcher in bioengineering)