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Dna Methylation-Based Epigenetic Biomarkers In Cell-Type Deconvolution And Tumor Tissue Of Origin Identification, Ze Zhang

Dartmouth College Ph.D Dissertations

DNA methylation is an epigenetic modification that regulates gene expression and is essential to establishing and preserving cellular identity. Genome-wide DNA methylation arrays provide a standardized and cost-effective approach to measuring DNA methylation. When combined with a cell-type reference library, DNA methylation measures allow the assessment of underlying cell-type proportions in heterogeneous mixtures. This approach, known as DNA methylation deconvolution or methylation cytometry, offers a standardized and cost-effective method for evaluating cell-type proportions. While this approach has succeeded in discerning cell types in various human tissues like blood, brain, tumors, skin, breast, and buccal swabs, the existing methods have major …

Probing And Enhancing The Reliance Of Transformer Models On Poetic Information, Almas Abdibayev

Dartmouth College Ph.D Dissertations

Transformer models have achieved remarkable success in the widest variety of domains, spanning not just a multitude of tasks within natural language processing, but also those in computer vision, speech, and reinforcement learning. The key to this success is largely attributed to the self-attention mechanism, particularly its ability to scale in performance as it grows in the number of parameters. Extensive effort has been underway to study the major linguistic properties learned by these models during the course of their pretraining. However, the role of certain finer linguistic phenomena present in language and their utilization by Transformers has not been …

Equilibrium And Quench-Dynamical Studies Of Ultracold Fermions In Ring-Shaped Optical Traps, Daniel Gordon Allman

Dartmouth College Ph.D Dissertations

The unique capability to precisely tune the few and many-body configurations of
ultracold Fermi gases provides a multi-dimensional platform for studying novel, ex-
otic aspects of quantum systems. These aspects include superfluid/superconducting
phenomena supported by potentially exotic pairing mechanisms, non-equilibrium and
critical dynamics, and proposed quantum sensing or computing applications based on
atomtronics.
Ring geometries provide natural arenas for probing transport properties of super-
fluids. Metastable states of quantized superfluid flow —persistent currents— exhibit
remarkable properties, and the manner in which they form is an incredibly rich sub-
ject. Studies of quenched superfluids demonstrate that persistent currents can form
from …

Tracing Evolution Of Gene Transfer Agents Using Comparative Genomics, Roman Kogay

Dartmouth College Ph.D Dissertations

The accumulating evidence suggest that viruses and their components can be domesticated by their hosts, equipping them with convenient molecular toolkits for various functions. One of such domesticated system is Gene Transfer Agents (GTAs) that are produced by some bacteria and archaea. GTAs morphologically resemble small phage-like particles and contain random fragments of their host genome. They are produced only by a small fraction of the microbial population and are released through a lysis of the host cell. Bioinformatic analyses suggest that GTAs are especially abundant in the taxonomic class of Alphaproteobacteria, where they are vertically inherited and evolve …

Rough Numbers And Variations On The Erdős--Kac Theorem, Kai Fan

Dartmouth College Ph.D Dissertations

The study of arithmetic functions, functions with domain N and codomain C, has been a central topic in number theory. This work is dedicated to the study of the distribution of arithmetic functions of great interest in analytic and probabilistic number theory.

In the first part, we study the distribution of positive integers free of prime factors less than or equal to any given real number y>=1. Denoting by Phi(x,y) the count of these numbers up to any given x>=y, we show, by a combination of analytic methods and sieves, that Phi(x,y)<0.6x/\log y holds uniformly for all 3<=y<=sqrt{x}, improving upon an earlier result of the author in the same range. We also prove numerically explicit estimates of the de Bruijn type for Phi(x,y) which are applicable in wide ranges.

In the second part, we turn …

Design And Synthesis Of Chiral, Conformationally Constrained Fatty Acid Mimetics, Lauren Elizabeth Markham Ph.D.

Dartmouth College Ph.D Dissertations

Fatty acids interact with a wide variety of proteins, as they are either directly or indirectly involved in essentially every physiological process. Mimetics of these fatty acids have the potential to address unique issues associated with these proteins, in ways that the native ligands cannot. The pharmacological panel of targets for fatty acid mimetics is very large and comprises nuclear hormone receptors, cell surface receptors, and enzymes. This thesis describes approaches to the design and synthesis of novel fatty acid mimetics. Specifically, techniques introducing chirality and conformational constraints are employed to produce potent and selective modulators of various receptors. Synthetically, …

Development Of Single-Crystalline And 3d-Printable Porous Organic Materials, Mingshi Zhang

Dartmouth College Ph.D Dissertations

Porous organic materials with designable structures, large surface areas, low densities, and unique electronic and optical properties have found widespread applications in adsorption, separation, energy storage, and catalysis. However, the majority of organic porous materials are synthesized as fluffy powders, which poses two fundamental challenges for them. Firstly, they lack a single-crystal structure at the microscopic scale, making it difficult to study the specific pore size, shape, and potential substrate binding sites at the atomic level and further establish the structure-property relationship. Secondly, they lack the general processing method and macroscopic shape design, making it difficult to manufacture suitable components …

Oligodendrocyte 2phatal Reveals Dynamics Of Myelin Degeneration And Repair, Timothy W. Chapman

Dartmouth College Ph.D Dissertations

Oligodendrocytes are responsible for producing myelin in the central nervous system. This lipid-rich coating along axons helps to increase action potential velocity, provide metabolic support to axons, and facilitate fine-tuning of neuronal circuitry. Demyelination and/or myelin dysfunction is widespread in neurodegenerative diseases and aging. Despite this, we know very little about how individual oligodendrocytes, or the myelin sheaths they produce, degenerate. Myelin repair, carried out by resident oligodendrocyte precursor cells (OPCs), is known to occur following myelin damage in certain contexts. We sought to investigate the cellular dynamics of oligodendrocyte degeneration and repair by developing a non-inflammatory demyelination model, combining …

A Framework And Approach For Leveraging Unsteady Response In Turbocompressor Flowfields, Eric M. Krivitzky

Dartmouth College Ph.D Dissertations

Turbomachinery is an essential technology in the transfer of mechanical work to or from a fluid stream. Forming a cornerstone component in nearly all electrical energy production and air transportation propulsion systems, turbomachinery also accounts for significant en- ergy transfer due to its omnipresence in fluid handling, including water pumping and pro- cess machinery. As system designers look towards optimized arrangements that enhance system flexibility to highly variable conditions, increase the density of energy transfer, and reduce the amount of lost work, the performance and operability demands on turbomachin- ery components continue to increase. For turbocompressors, a turbomachinery subtype that …

Self-Supervised Pretraining And Transfer Learning On Fmri Data With Transformers, Sean Paulsen

Dartmouth College Ph.D Dissertations

Transfer learning is a machine learning technique founded on the idea that knowledge acquired by a model during “pretraining” on a source task can be transferred to the learning of a target task. Successful transfer learning can result in improved performance, faster convergence, and reduced demand for data. This technique is particularly desirable for the task of brain decoding in the domain of functional magnetic resonance imaging (fMRI), wherein even the most modern machine learning methods can struggle to decode labelled features of brain images. This challenge is due to the highly complex underlying signal, physical and neurological differences between …

Genome-Scale Methylation Analysis In Blood And Tumor Identifies Immune Profile, Age Acceleration, And Dna Methylation Alterations Associated With Bladder Cancer Outcomes, Ji-Qing Chen

Dartmouth College Ph.D Dissertations

Bladder cancer patients receive frequent screening due to the high tumor recurrence rate (more than 60%). Nowadays, the conventional monitoring method relies on cystoscopy which is highly invasive and increases patient morbidity and burden to the health care system with frequent follow-up. As a result, it is urgent to explore novel markers related to the outcomes of bladder cancer. Immune profiles have been associated with cancer outcomes and may have the potential to be biomarkers for outcomes management. However, little work has been conducted to investigate the associations of immune cell profiles with bladder cancer outcomes. Here, I utilized the …

Design Of Asic Based Electrical Impedance Tomography Microendoscopic System For Prostate Cancer Surgical Marginal Assessment, Mohsen Shahghasemi

Dartmouth College Ph.D Dissertations

Prostate cancer is the second most common cancer in the United States. It is typically treated by surgically excising the cancerous section of the prostate. Because there is not always a visible distinction between the healthy and cancerous sections, surgery often leaves some cancerous tissue behind. This is referred to as a positive surgical margin and it requires adjuvant treatment with adverse side effects. Electrical impedance tomography (EIT) is a low-cost low-form-factor method that can be used to assess surgical marginal intraoperatively to ensure that no cancerous tissue is left behind. EIT-based surgical margin assessment works on the principle that …

Rhodium-Catalyzed Asymmetric Synthesis Of P-P And P-C Bonds, Sarah T. Chachula

Dartmouth College Ph.D Dissertations

Chapter 1: Synthesis, Structure, Dynamics, and Enantioface-Selective η3-Benzyl Coordination in the Chiral Rhodium Complexes Rh(diphos*)(η3-CH2Ph) Abstract: The rhodium benzyl complexes Rh(diphos*)(η3-CH2Ph) (1-14, diphos* = chiral bis(phosphine)) were prepared either by treatment of Rh(COD)(η3-CH2Ph) (15, COD = 1,5-cyclooctadiene) with diphos*, or from the reaction of [Rh(diphos*)(Cl)]2 (16- 20) with PhCH2MgCl. For C2-symmetric diphos*, observation of one set of NMR signals for complexes 1-12 suggested that the two diastereomers in which different 3-benzyl enantiofaces were coordinated to rhodium interconverted rapidly on the NMR time scale via suprafacial shifts; observation of five inequivalent aryl 1H NMR signals showed that antarafacial shifts were slow …

Proteomic Approaches To Identify Unique And Shared Substrates Among Kinase Family Members, Charles Lincoln Howarth

Dartmouth College Ph.D Dissertations

Protein phosphorylation is a reversible post-translational modification that is a critical component of almost all signaling pathways. Kinases regulate substrate proteins through phosphorylation, and nearly all proteins are phosphorylated to some extent. Crucially, breakdown in phosphorylation signaling is an underlying factor in many diseases, including cancer. Understanding how phosphorylation signaling mediates cellular pathways is crucial for understanding cell biology and human disease.

Targeted protein degradation (TPD) is a strategy to rapidly deplete a protein of interest (POI) and is applicable to any gene that is amenable to CRISPR-Cas9 editing. One TPD approach is the auxin-inducible degron (AID) system, which relies …

Design Of A Burst Mode Ultra High-Speed Low-Noise Cmos Image Sensor, Xin Yue

Dartmouth College Ph.D Dissertations

Ultra-high-speed (UHS) image sensors are of interest for studying fast scientific phenomena and may also be useful in medicine. Several published studies have recently achieved frame rates of up to millions of frames per second (Mfps) using advanced processes and/or customized processes.

This thesis presents a burst-mode (108 frames) UHS low-noise CMOS image sensor (CIS) based on charge-sweep transfer gates in an unmodified, standard 180 nm front-side-illuminated CIS process. By optimizing the photodiode geometry, the 52.8 μm pitch pixels with 20x20 μm^2 of active area, achieve a charge-transfer time of less than 10 ns. A proof-of-concept CIS was designed and …

System-Characterized Artificial Intelligence Approaches For Cardiac Cellular Systems And Molecular Signature Analysis, Ziqian Wu

Dartmouth College Ph.D Dissertations

The dissertation presents a significant advancement in the field of cardiac cellular systems and molecular signature systems by employing machine learning and generative artificial intelligence techniques. These methodologies are systematically characterized and applied to address critical challenges in these domains. A novel computational model is developed, which combines machine learning tools and multi-physics models. The main objective of this model is to accurately predict complex cellular dynamics, taking into account the intricate interactions within the cardiac cellular system. Furthermore, a comprehensive framework based on generative adversarial networks (GANs) is proposed. This framework is designed to generate synthetic data that faithfully …

Regulation Of The Wnt/Wingless Receptor Lrp6/Arrow By The Deubiquitylating Complex Usp46, Zachary T. Spencer

Dartmouth College Ph.D Dissertations

The evolutionarily conserved Wnt/Wingless signal transduction pathway is critical for the proper development of all animals and implicated in numerous diseases in adulthood. Upon binding of the Wnt/Wingless ligand, a cascade of events culminates in inactivation of the destruction complex, a negative regulator of the pathway, and the subsequent formation of singalosomes which mediate pathway activation. A critical component of signalosome formation is the Wnt/Wingless receptor LRP6/Arrow. Upon canonical pathway activation, LRP6/Arrow undergoes activation via phosphorylation by several kinases and complexes with another Wnt/Wingless receptor Frizzled, along with several cytoplasmic components. While many studies have investigated the regulatory mechanisms of …

Intraoperative Quantification Of Bone Perfusion In Lower Extremity Injury Surgery, Xinyue Han

Dartmouth College Ph.D Dissertations

Orthopaedic surgery is one of the most common surgical categories. In particular, lower extremity injuries sustained from trauma can be complex and life-threatening injuries that are addressed through orthopaedic trauma surgery. Timely evaluation and surgical debridement following lower extremity injury is essential, because devitalized bones and tissues will result in high surgical site infection rates. However, the current clinical judgment of what constitutes “devitalized tissue” is subjective and dependent on surgeon experience, so it is necessary to develop imaging techniques for guiding surgical debridement, in order to control infection rates and to improve patient outcome.

In this thesis work, computational …

Complement System In Multiple Sclerosis: Its Role In Disease Course And Potential As A Therapeutic Target, Michael R. Linzey

Dartmouth College Ph.D Dissertations

Multiple sclerosis (MS) is a clinically heterogeneous neurological condition characterized by neuroinflammation and neurodegeneration. Relapsing-remitting MS, defined by inflammatory attacks, is the most common initial form of MS and there are currently 23 FDA-approved treatments for these patients. These therapies work primarily by reducing inflammation in the CNS; they do not work well in progressive disease. Therefore, an unmet medical need exists for effective therapeutic options to treat progressive MS (PMS).

In MS, intrathecal immunoglobulins synthesis (IIgS) correlates with disease progression. My goals for this dissertation were to establish the pathological role of IIgS and identify new potential therapeutic …

Epistemic Mentalizing And Causal Cognition Across Agents And Objects, Bryan S. Gonzalez

Dartmouth College Ph.D Dissertations

This dissertation examines mentalizing abilities, causal reasoning, and the interactions thereof. Minds are so much more than false beliefs, yet much of the existing research on mentalizing has placed a disproportionately large emphasis on this one aspect of mental life. The first aim of this dissertation is to examine whether representing others’ knowledge states relies on more fundamentally basic cognitive processes than representations of their mere beliefs. Using a mixture of behavioral and brain measures across five experiments, I find evidence that we can represent others' knowledge quicker and using fewer neural resources than when representing others’ beliefs. To be …

Cosmological Vector Fields And Constraining The Neutrino Masses, Avery J. Tishue

Dartmouth College Ph.D Dissertations

In this thesis I explore two main topics: the role and consequences of cosmological vector fields, and new ideas for constraining fundamental physics with state-of-the-art experiments. These topics are disparate in content and technique but unified in their attempt to leverage novel approaches to better understand longstanding questions in cosmology. These questions, such as ``What is causing the universe to accelerate today?'' and ``What are the neutrino masses?'', underpin the modern cosmological paradigm. They play a key role in our understanding of cosmic history, the formation of structure, and the fate of our universe. Answers to or hints about these …

Lignocellulose Conversion Via Consolidated Bioprocessing: High Solid Loadings, Bioreactor Development, And Technoeconomic Analysis, Matthew R. Kubis

Dartmouth College Ph.D Dissertations

Efficient deconstruction and conversion of inedible plant biomass, i.e., lignocellulose, is critical to decarbonizing the energy system in order to meet climate stabilization objectives. However, lignocellulose biomass is recalcitrant to deconstruction, and is often augmented by energy and capital intensive thermochemical pretreatment. Alternatively, Clostridium thermocellum is a thermophilic anaerobe capable of both deconstruction and conversion of lignocellulose without pretreatment. This thesis seeks to inform the deployment of cellulosic ethanol production by furthering our understanding of C. thermocellum mediated deconstruction, especially at industrially relevant conditions, i.e., solid loadings exceeding 100 g/L. In batch fermentations, it was observed that fractional deconstruction declines …

Jones Polynomial Obstructions For Positivity Of Knots, Lizzie Buchanan

Dartmouth College Ph.D Dissertations

The fundamental problem in knot theory is distinguishing one knot from another. We accomplish this by looking at knot invariants. One such invariant is positivity. A knot is positive if it has a diagram in which all crossings are positive. A knot is almost-positive if it does not have a diagram where all crossings are positive, but it does have a diagram in which all but one crossings are positive. Given a knot with an almost-positive diagram, it is in general very hard to determine whether it might also have a positive diagram. This work provides positivity obstructions for three …

Effective Non-Hermiticity And Topology In Markovian Quadratic Bosonic Dynamics, Vincent Paul Flynn

Dartmouth College Ph.D Dissertations

Recently, there has been an explosion of interest in re-imagining many-body quantum phenomena beyond equilibrium. One such effort has extended the symmetry-protected topological (SPT) phase classification of non-interacting fermions to driven and dissipative settings, uncovering novel topological phenomena that are not known to exist in equilibrium which may have wide-ranging applications in quantum science. Similar physics in non-interacting bosonic systems has remained elusive. Even at equilibrium, an "effective non-Hermiticity" intrinsic to bosonic Hamiltonians poses theoretical challenges. While this non-Hermiticity has been acknowledged, its implications have not been explored in-depth. Beyond this dynamical peculiarity, major roadblocks have arisen in the search …

Enabling The Integration Of Sustainable Design Methodological Frameworks And Computational Life Cycle Assessment Tools Into Product Development Practice, Tejaswini Chatty

Dartmouth College Ph.D Dissertations

Environmental sustainability has gained critical importance in product development (PD) due to increased regulation, market competition, and consumer awareness, leading companies to set ambitious climate targets . To meet these goals, PD practitioners (engineers and designers) are often left to adapt their practices to reduce the impacts of the products they manufacture. Literature review and interviews with practitioners show that they highly valued using quantitative life cycle assessment (LCA) results to inform decision making.

LCA is a technique to measure the environmental impacts across various stages of a product life cycle. Existing LCA software tools, however, are designed for dedicated …

Piezoelectric And Conductive Polymer Based Flexible Devices Enabling Cardiovascular Health Sensing And Energy Harvesting, Andrew Closson

Dartmouth College Ph.D Dissertations

Piezoelectric materials show great promise for low-power wearable and implantable sensing, but their rigidity makes it challenging to integrate them with biological tissue. To address this, researchers have started exploring polymer-based functional materials that offer flexibility and are suitable for interfacing with the human body. However, these materials are still in their early stages, and a framework is necessary to illustrate how these materials, in conjunction with novel fabrication techniques and device designs, can enable the development of multi-functional sensing and energy harvesting devices.

This thesis utilizes highly scalable fabrication methods for functional polymers to build and test a flexible …

Causes And Consequences Of Lasr Mutant Selection In Pseudomonas Aeruginosa Populations, Dallas L. Mould

Dartmouth College Ph.D Dissertations

Change is the only constant in life, and these changes, though random in nature, can have consequences. Quorum sensing is heterogeneous in phenotype and prone to negative selection. In P. aeruginosa, the regulator LasR is frequently non-functional in phylogenetically diverse isolates. Through repeated experimental evolution and mathematical modeling, we show that differences in growth enable lasR mutant evolutionary success and this requires a system enabling metabolic choices, known as carbon catabolite repression (or catabolite repression). The differences in catabolite repression between wild type and lasR mutants enable altered metabolite preferences, and the resulting differences in metabolic states enable intraspecies …

Sensitive And Makeable Computational Materials For The Creation Of Smart Everyday Objects, Te-Yen Wu Mr

Dartmouth College Ph.D Dissertations

The vision of computational materials is to create smart everyday objects using the materi- als that have sensing and computational capabilities embedded into them. However, today’s development of computational materials is limited because its interfaces (i.e. sensors) are unable to support wide ranges of human interactions , and withstand the fabrication meth- ods of everyday objects (e.g. cutting and assembling). These barriers hinder citizens from creating smart every day objects using computational materials on a large scale.

To overcome the barriers, this dissertation presents the approaches to develop compu- tational materials to be 1) sensitive to a wide variety of …

Extending The Wavelength Response Of Photon-Counting Image Sensors, Kaitlin M. Anagnost

Dartmouth College Ph.D Dissertations

Non-visible imaging is used in a variety of applications, including medical imaging, security, astronomy, light detection and ranging (LiDAR), and more. Typical silicon- based detectors are primarily limited to the visible, ultraviolet, soft x-ray (<10 keV), and short-wave infrared (IR) spectral regimes. To improve the sensor’s quantum efficiency for x-rays, for example, a scintillating layer may be deposited at the cost of decreased spatial resolution. State-of-the-art IR detectors, on the other hand, use HgCdTe, InSb, InP, III-V superlattices, and other materials with metal hybrid or bump bonds in favor of silicon direct-deposit detectors, decreasing yield. Silicon-based detectors with photon conversion layers are presented in this thesis as possible approaches to extend the wavelength response into the x-ray and IR spectral regimes. A photon attenuation layer (PAL) is first described for better x-ray sensitivity to mitigate the quantum efficiency vs. spatial resolution trade-off in scintillators. Next, silicon’s IR response is improved by considering GeSn and various III-V materials for direct deposition on CMOS image sensors. The band structures and detector parameters for these materials on silicon are calculated and compared to find the most favorable IR absorber. The deposition process for the photon conversion layers can cause the pixel’s transfer gate to lose functionality. CMOS image sensors without transfer gates, called 3-T pixels, are used to prevent this problem, but are dominated by kTC noise each time the device is reset. To combat this issue, a reset noise reduction method utilizing a feedback amplifier is correspondingly discussed, with both theoretical and experimental results presented. A novel pixel using an IR absorbing layer for LiDAR applications is proposed next to bring the IR absorbing layer to market. Single photon avalanche diodes (SPADs) are the iii current state-of-the-art detectors for direct time-of-flight applications because of their high speed and superior timing resolution. Quanta Image Sensors (QIS) have smaller pixel pitch and lower power dissipation per event, however. A pixel design with the advantages of each detector is presented and the simulation results are analyzed. Associated readout circuitry using a time-gating approach is also discussed and theoretical proof-of-concept is demonstrated.

Brill--Noether Theory Via K3 Surfaces, Richard Haburcak

Dartmouth College Ph.D Dissertations

Brill--Noether theory studies the different projective embeddings that an algebraic curve admits. For a curve with a given projective embedding, we study the question of what other projective embeddings the curve can admit. Our techniques use curves on K3 surfaces. Lazarsfeld's proof of the Gieseker--Petri theorem solidified the role of K3 surfaces in the Brill--Noether theory of curves. In this thesis, we further the study of the Brill--Noether theory of curves on K3 surfaces.

We prove results concerning lifting line bundles from curves to K3 surfaces. Via an analysis of the stability of Lazarsfeld--Mukai bundles, we deduce a bounded version …