Digital Commons Network^™

Peripheral Immune Signatures Of Fibrotic Lung Diseases, Amy Zhao

Yale Graduate School of Arts and Sciences Dissertations

Fibrotic lung diseases constitute a heterogeneous group of disorders that cause scarring of the lung parenchyma, making breathing difficult for patients, and affect an estimated 300,000 people in the United States alone. These diseases may have either “intrinsic” or “extrinsic” immune etiologies. A subset of these fibrotic lung diseases, like Idiopathic Pulmonary Fibrosis (IPF; intrinsic) and Fibrotic Hypersensitivity Pneumonitis (FHP; extrinsic), can often be difficult to distinguish due to their similar symptoms, pulmonary function tests, and radiographic and histologic findings. However, their immune drivers, prognoses, and treatments are distinct; thus, accurate diagnosis of the fibrotic lung disease subtype is essential …

The Maladaptive And Adaptive Effects Of Trust And Distrust On Externalizing Behavior, Shou-An Ariel Chang

Yale Graduate School of Arts and Sciences Dissertations

A wide range of behaviors, from hostility and defiance to more severe forms ofnorm violations, such as theft and violence, comprise the spectrum of externalizing behaviors. The psychological, physical, and social consequences associated with externalizing behaviors place a significant burden on the individual, their families, and society. Research has made substantial advances in identifying environmental-level and individual-level risk factors for externalizing behavior. However, despite work indicating that both externalizing behaviors themselves and several risk factors associated with externalizing behaviors are related to disruptions in trust and distrust, limited work has considered interactions between environmental- and individual-level risk factors and levels …

Manipulating And Measuring States Of A Superfluid Optomechanical Resonator In The Quantum Regime, Yiqi Wang

Yale Graduate School of Arts and Sciences Dissertations

Quantum optomechanics describes utilizing optics to precisely manipulate and read out the motional degrees of freedom of a mechanical oscillator. If the mechanical oscillator is very weakly coupled to its environment, then the optomechanical interaction can be used to control the state of the mechanical oscillator in a quantum way. Applying these systems to advanced sensing techniques has inaugurated experiments on dark matter searches, gravitational wave detection, quantum gravitational phenomena tests, and sensing beyond the standard quantum limit. I am motivated by asking: “What is the largest and most tangible object to reveal purely quantum phenomena?” In addition, I seek …

Investigating Stem Cell Chromatin Organization And Oncogenic Tissue Morphogenic Change Through Intravital Microscopy, Sangwon Yun

Yale Graduate School of Arts and Sciences Dissertations

Tissue architecture is predicated on actively maintained cellular equilibrium. Loss of homeostatic tissue organization is a hallmark of epithelial derived malignancy. In the following studies, we attempt to understand the principles governing cell behavior in a regenerative tissue, the skin epidermis, under homeostatic conditions and during oncogenic expression. Epidermal cells undergo continual proliferation and differentiation, navigating drastic changes in gene expression and chromatin architecture during identity transition from stem to differentiated. However, when and where genome reorganization occurs continues to be an arena of active investigation. We developed a high-throughput, quantitative pipeline that enabled us to longitudinally measure chromatin compaction …

Consequences Of Childhood Maltreatment And Exposure To Community Violence: A Single-Moment And Longitudinal Trajectory Examination, Suzanne Charlotte Estrada

Yale Graduate School of Arts and Sciences Dissertations

Childhood adversity is one of the strongest predictors of long-term psychological,social, and physical negative life outcomes. Two subtypes of adversity, one perpetrated by someone in the home environment (i.e., childhood maltreatment, parental harshness) and the other perpetrated by someone in the community (i.e., exposure to community violence), are especially salient predictors of poor mental health and increased antisocial behavior. Research aimed at describing the occurrence of adversity often examines these subtypes separately. As a result, our understanding of the ways individuals experience adversity in the home and community and the long-term impact of co-occurring adversity is limited. Additionally, perhaps following …

Investigating The Synaptic Plasticity Mechanisms Underlying A Learned Behavioral Preference In C. Elegans, Joon Ha Lee

Yale Graduate School of Arts and Sciences Dissertations

A fundamental goal in neuroscience is to elucidate the cellular and molecular mechanisms that regulate learned behavioral preferences, or memories. While modulation of synaptic connections has been well-established as a component of memory formation, there remains a critical lack in understanding of how specific molecular changes that alter synaptic physiology result in learned behaviors. In this thesis, I utilize the paradigm of learned thermal preferences and the connection between a sensory neuron (AFD) and its postsynaptic partner (AIY) in Caenorhabditis elegans to bridge this gap at the single-synapse level. I first characterize the neurotransmission requirements of this synapse and find …

Learning Data-Driven Representations For Biomolecular Analysis, Optimization, And Design, Egbert Castro

Yale Graduate School of Arts and Sciences Dissertations

Recently, the study of biomolecules has undergone a shift toward high-throughput experimentation, leveraging advancements across various fields to produce datasets of unprecedented scale. Within these datasets, there are undiscovered truths that carry major implications for our understanding of biology and our ability to treat disease. However, innovative approaches are needed to distill signals from noise and enable the next generation of discoveries. Deep learning methods have excelled in their ability to learn from complex and large datasets in many domains, but their potential for biomolecular data has yet to be fully realized. To do so requires the ability to integrate …

Tenascin-C: A Regulator Of Venous Remodeling Following Aortocaval Fistula Creation, Luis Gonzalez

Yale Graduate School of Arts and Sciences Dissertations

End-stage kidney disease (ESKD) represents a growing medical problem globally with a high burden to patients. In the United States alone more than 740,000 individuals have ESKD and are primarily dependent on hemodialysis for treatment. For patients who require hemodialysis, arteriovenous fistulae (AVF) are the preferred mode of vascular access due to their superior patency rates and reduced infection rates when compared to grafts or catheters. However, the lifespan of an AVF is limited by several complications, which includes neointimal hyperplasia (NIH) and thrombosis. Loss of AVF patency at 1-year ranges ~40-50%. Successful AVF maturation is characterized by venous wall …

Functionalized Dna Nanostructures For Membrane Engineering, Qiancheng Xiong

Yale Graduate School of Arts and Sciences Dissertations

DNA nanotechnology is a powerful tool for constructing precisely designed nanostructures with applications in diverse fields, including synthetic biology, nanomedicine, and biomolecular engineering. This dissertation explores the use of DNA nanotechnology in membrane engineering, focusing on developing DNA endoskeleton-supported membranes and large functionalized DNA-toxin nanopores. The first approach encountered challenges while constructing interlocked DNA nanostructures for endoskeleton-supported membranes. The negative results highlighted the need to optimize the interlocked DNA endoskeleton cage design further to ensure its practical application in templating fully exposed, continuous membranes. The second approach incorporated pneumolysins into DNA-origami channels to create large, functionalized DNA-toxin nanopores. These hybrid …

Copper Complexes For Water Oxidation Electrocatalysis And Strong Bond Activation, Claire C. Cody

Yale Graduate School of Arts and Sciences Dissertations

In order to meet rising global energy and material demands while mitigating negative effects on our climate, renewable energy sources must offer a competitive alternative to fossil fuels. Understanding chemical activation of small molecules such as water can provide a basis for leveraging electrocatalytic reactions using electricity from photovoltaics paired with catalysts for chemical transformations. For an efficient and widely applicable system, catalysts should be robust and use cheap, earth-abundant elements. This thesis investigates Cu-based complexes for electrocatalytic transformations, structural studies, and bond activation. First, we investigate the influence of ligand structure on water oxidation electrocatalysis. In comparison to the …

Optimization And Sequential Decision Making: Implicit Loss Functions And Variance-Aware Reinforcement Learning, Ruitu Xu

Yale Graduate School of Arts and Sciences Dissertations

Machine learning, as a transformative tool, has demonstrated remarkable efficacy across diverse applications. This dissertation delves into a selection of learning algorithms, analyzing their learning dynamics and providing theoretical guarantees on their performance. First, we scrutinize a novel neural network learning paradigm, leveraging a set of random weights that represent more biologically plausible neural connections during the back-propagation training process. Our research establishes a theoretical framework, illustrating both the convergence of the training loss and the mechanism of alignment between the forward-propagated network weights and the randomized backward-propagated weights. Subsequently, we venture into the realm of model-agnostic meta-learning, examining an …

Antiviral Hiv-1 Serinc Restriction Factors Disrupt Virus Membrane Asymmetry, Ziwei Yang

Yale Graduate School of Arts and Sciences Dissertations

The human immunodeficiency virus 1 (HIV-1), which is the causative agent responsible for Acquired Immunodeficiency Syndrome (AIDS), is a retrovirus that primarily infects CD4+ T lymphocytes. When left untreated, HIV replication results in progressive CD4+ T cell loss and leads to a myriad of immunological abnormalities in the host, escalating the risk of infections as well as oncological complications. To combat the progression of HIV-1, host cells have evolved to produce proteins known as restriction factors, which are crucial elements of the innate immune system, to inhibit the HIV-1 infection by disrupting various stages of viral replication. Such factors include …

Statistical Methods In High-Throughput Biomedical Data With Application To Precision Medicine, Yunqing Liu

Yale Graduate School of Arts and Sciences Dissertations

Precision medicine has emerged as a critical approach in healthcare due to its potential to revolutionize patient care. Traditional medical practices often adopt a one-size-fits-all approach, treating patients based on generalized guidelines. However, individuals exhibit significant variations in their genetic makeup, lifestyle factors, and environmental exposures. Precision medicine recognizes and leverages these differences to deliver personalized treatment plans tailored to each patient's unique characteristics. Recent technological advancements have facilitated the generation of high-throughput data, such as single-cell RNA sequencing (scRNA-seq) data, spatial transcriptomics (ST) data, locomotor activity assays measuring behavior, which offers the potential to the development of precision medicine. …

Bacterial Cell Surface Characterization By Phage Display Coupled To High-Throughput Sequencing, Casey Grun

Yale Graduate School of Arts and Sciences Dissertations

Antimicrobial resistance is a looming threat that reflects the remarkable capacity of bacteria to adapt and change in response to selective pressures. The versatile pathogen P. aeruginosa is a model case---already intrinsically resistant to many antibiotics, it can establish decades-long chronic infections, during which it evolves to survive antimicrobial treatment and evade host defenses. Many changes occur on its cell surface, a key location for both virulence and antibiotic resistance, but our technologies for studying these adaptive phenotypes are limited. Here we combined phage display with high-throughput DNA sequencing to create a high throughput, highly multiplexed technology for surveying bacterial …

Chromatin Expansion Microscopy Reveals Nanoscale Organization Of Transcription And Chromatin, Mark Pownall

Yale Graduate School of Arts and Sciences Dissertations

Nanoscale chromatin organization regulates gene expression. While chromatin is dramatically reprogrammed during zygotic genome activation (ZGA), the organization of chromatin regulatory factors during this universal process remains unclear. Here, we developed chromatin expansion microscopy (ChromExM) to visualize chromatin, transcription, and transcription factors in vivo. ChromExM of embryos during ZGA revealed how the pioneer factor Nanog interacts with nucleosomes and RNA Polymerase II (Pol II), providing direct visualization of transcriptional elongation as string-like nanostructures. Blocking elongation led to more Pol II particles clustered around Nanog, with Pol II stalled at promoters and Nanog-bound enhancers. This led to a new model termed …

Nutrient Acquisition And Plant-Microbe Interactions In Savanna Trees, Arielle Biro

Yale Graduate School of Arts and Sciences Dissertations

Ecosystem productivity is often constrained by the availability of essential macronutrients. Ecosystem processes that are vital to nutrient acquisition like nutrient cycling and microbial activity are expected to change under global warming, but prediction accuracy in the face of global change is challenging, as prediction requires a thorough mechanistic understanding of how plants acquire nutrients from their environments. These strategies include exploration by roots for resources like nutrients or water, releasing enzymes that decompose organic matter into plant available forms, or forming symbioses with soil bacteria or mycorrhizal fungi, which can have downstream impacts on ecosystem nutrient budgets, nutrient cycling, …

Methods And Complexity In Phage-Bacteria Ecology And Evolution, Michael Blazanin

Yale Graduate School of Arts and Sciences Dissertations

Chapter I:Characterization of microbial growth is of both fundamental and applied interest. Modern platforms can automate collection of high-throughput microbial growth curves, necessitating the development of computational tools to handle and analyze these data to produce insights. However, existing tools are limited. Many use parametric analyses that require mathematical assumptions about the microbial growth characteristics. Those that use non-parametric or model-free analyses often can only quantify a few traits of interest, and none are capable of importing and reshaping all known growth curve data formats. To address this gap, here I present a newly-developed R package: gcplyr. gcplyr can flexibly …

The Role Of Dietary Fats In Driving Atherosclerosis, Zenan Wang

Yale Graduate School of Arts and Sciences Dissertations

Cardiovascular diseases (CVDs) are the number one killer of people worldwide, of which coronary heart disease, which is mainly due to atherosclerosis, is the main contributor to death. Nonetheless, the etiology of atherosclerosis remains poorly understood. It is universally accepted that dietary fat influences atherosclerosis, however, the role of specific fats is not well-understood. Despite the widely-held perception that saturated fats drive atherosclerotic CVDs while monounsaturated fats are protective, there have been numerous studies from human and mice that do not fit with this prevailing narrative. Thus, despite the importance of dietary fats in CVDs, the exact effects remain controversial …

Modifying The Surface Topography Of Pegylated Nanoparticles Based On Bottlebrush Block Copolymer For Drug Delivery Applications, Julian Grundler

Yale Graduate School of Arts and Sciences Dissertations

The clinical translation of nanomedicines has been closely tied to the development ofnovel drug delivery techniques. In particular, nanoparticle formulations promise to improve the pharmacokinetics, selective accumulation at the target site, and intracellular delivery of therapeutics. Extensive research efforts have identified structure-function relationships between nanoparticle physicochemical properties (e.g. size, charge, surface functionalization) and biological fate. However, studying the biological impact of nanoparticle surface topography still remains a challenge due to the limited spatial control of conventional nanoparticle surface coatings based on hydrophilic linear polymers including poly(ethylene glycol) (PEG). In this dissertation, we investigated a novel method to precisely control the …

Computational Study Of The Mechanism Of Attention In Cortical Information Coding, Xiang Wang

Yale Graduate School of Arts and Sciences Dissertations

The animals’ visual perception of natural scenes is influenced by both the external condi-tions of the environment and the internal states. External conditions include the contrast of the stimulus, the crowding of distractors and the complexity of visual features. Internal states include the level of arousal, the deployment of attention, and the goal of behavior. An important and extensively studied internal state is selective attention, which is thought to be critical in solving visual perception problems by increasing the saliency of the attended ob-jects against the background. Electrophysiological studies have indicated attentional modu-lation of single neurons along the hierarchy of …

Multi-Scale Gene Regulation Analysis With Chip-Seq And Beyond, Jiahao Gao

Yale Graduate School of Arts and Sciences Dissertations

Regulation of gene expression is one of the most important and fundamental aspects of biological systems. The intricate regulation could be observed in different aspects, including the variations in individual genes, dynamic interactions between multiple genes, and complicated regulatory relationships between expression and other properties such as methylation level. Therefore, studying gene regulation at all these multiple scales is crucial. Transcription factors (TFs) are a special group of proteins that recognize specific DNA sequences and control gene expression by DNA binding. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) had been developed to identify genome-wide protein–DNA interactions. It has become the standard …

Probing Diverse Biological Systems And Their Hydration Shells By Modeling Chiral Sum Frequency Generation Spectroscopy, Daniel Konstantinovsky

Yale Graduate School of Arts and Sciences Dissertations

All biological processes occur in aqueous solution. Water dictates biomolecular structure, is responsible for a large portion of the free energy of ligand binding, and participates structurally in protein-protein interactions. However, few experimental techniques can probe the biomolecular hydration shell and its diverse environments. Chirality-sensitive vibrational sum frequency generation spectroscopy (chiral SFG) is a powerful technique that probes hydration shell water. The work presented here clarifies the conditions required for a chiral SFG signal to emerge, identifies the water immediately neighboring a biomolecule as the source of the aqueous chiral SFG signal, and investigates the interaction between biomolecules and their …

Outbreak Dynamics Of Emerging Sars-Cov-2 Variants In Human And Animal Populations, Rebecca Lynn Earnest

Yale Graduate School of Arts and Sciences Dissertations

The COVID-19 pandemic is characterized by cycles of SARS-CoV-2 viral variant emergence followed by surges of infections and deaths. In the United States, the most notable variants to date are Alpha (B.1.1.7), Delta (B.1.617.2 and AY.x sub-lineages), and Omicron (BA.1, BA.2, BA.4, BA.5, and various sub-lineages). Pandemic response evolved along with the virus, raising three overarching research questions with each new variant that correspond to the chapters of this dissertation. When a new variant emerges, how is it different from the previously dominant variant(s) in circulation? The set of mutations that define a SARS-CoV-2 variant can affect viral properties such …

Exploiting Dna Repair Deficiencies In Cancer To Develop And Characterize Novel Therapeutics, Sateja Paradkar

Yale Graduate School of Arts and Sciences Dissertations

Genomic instability is one of the hallmarks of cancer, which underlies cancer development and progression. This DNA repair vulnerability presents cancer researchers with a therapeutic opportunity. Targeted therapies designed to overwhelm DNA repair pathways in cancer have proven largely effective as anti-cancer treatments. However, there are currently three major issues with their widespread use in cancer. Firstly, for cancers such as glioblastomas (GBMs), there have been no targeted therapies approved for decades. Secondly, for most targeted therapies there is an incomplete understanding of their precise mechanism of action, which limits their clinical utility. Thirdly, cancers develop resistance to most targeted …

Mechanisms That Control Lipid Synthesis At The Endoplasmic Reticulum And Nuclear Envelope, Jake Williams Carrasquillo Rodriguez

Yale Graduate School of Arts and Sciences Dissertations

The endoplasmic reticulum (ER) is the largest membrane bound organelle in most cells. The ER is made up of distinct structural and functional domains, which include the nuclear envelope (NE) and peripheral ER sheets and tubules. The nuclear envelope surrounds and protects the genome, while the peripheral ER is essential for protein and de novo lipid synthesis. Lipids synthesized at the ER are either retained or shuttled to other membrane bound organelles through membrane contact sites or vesicular trafficking. As such, regulation of ER lipid synthesis is a tightly controlled process carried out by a subset of enzymes that are …

Yale Medicine Magazine Autumn 2023, Issue 171, Yale University. School Of Medicine

Yale Medicine Magazine - alumni bulletin and magazine

This is the Autumn 2023 issue of Yale Medicine Magazine, issue 171. Prepared in cooperation with the alumni and development offices at the School of Medicine. Earlier volumes are called Yale School of Medicine alumni bulletins, dating from v.1 (1953) through v.13 (1965) and Yale Medicine: alumni bulletin of the School of Medicine, v.1 (1965) through v. 52, no.1. (Autumn 2017).

Decision Making In Patients With Initial Positive Deep Margins On Diagnostic Biopsy Of Melanoma, Ana Eliza Souza Cunha

Yale School of Medicine Physician Associate Program Theses

Background: Current guidelines recommend SLN biopsy (SLNB) among patients with initial Breslow Thickness (BRES) ≥0.8mm at initial screening. However, there is limited guidance regarding SLNB among patients who have deeper final depth after initial biopsy.

Methods: We conducted a retrospective cohort study of 62 thin melanoma patients with primary lesions with initial Breslow Thickness (BRES)

Results: Approximately 55% of patients (n = 34) included in our study underwent SLNB. After adjustment, there was no association between SLNB status and recurrence. Immunosuppressive drug use was associated with higher odds of local (OR= 28.56 CI 1.87- 435.53; p =0.016) and regional recurrence …

Differences In Predicted Risk Of Mortality After Coronary Artery Bypass Graft Between Black And White Patients With Identical Clinical Profiles Using The Society Of Thoracic Surgeons Calculator: An In-Silico Cohort Study, Kiara Marmolejos

Yale School of Medicine Physician Associate Program Theses

Abstract/Summary:

Background: “The Society of Thoracic Surgeons mortality risk calculator”, which includes a race variable, is recommended for estimating Short- term (30 day) predicted risk of mortality after isolated coronary artery bypass graft, with a risk estimate of 3-4% stratifying patients into intermediate risk, a risk estimate above 5% stratifying patients into high risk for surgery and a risk estimate above 8% stratifying patients into the very high-risk category. We compared differences between Black and White individuals in Society of Thoracic Surgeons-predicted risk of mortality across various plausible risk factor combinations with the aim of evaluating if using the predictive …

Data On Deck: A Case Study Of A Historic Undersea Film And Video Digitization Project, Karen Urbec Mlis, Ca, Audrey Mickle Mlis, Lisa Raymond

Journal of Contemporary Archival Studies

In 2021, the Woods Hole Oceanographic Institution (WHOI) Data Library and Archives (DLA), a part of the MBLWHOI (Marine Biological Laboratory Woods Hole Oceanographic Institution) Library, received a grant from the Council on Library and Information Resources (CLIR) Recordings at Risk (RAR) program to catalog, digitize, preserve, and make available historic films and videos of Alvin, the first-of-its-kind manned submersible vessel that has shown us more of the deep ocean than had ever been possible and transformed our understanding of life on Earth.

These moving images have not been accessible to researchers and were far past the intended life cycle …

Platelet Rich Plasma For Women With Recurrent Implantation Failure Undergoing Frozen Embryo Transfer, Gabriela Ortiz

Yale School of Medicine Physician Associate Program Theses

In vitro fertilization with embryo transfer is often considered a solution for infertile women. The proportion of infertile women who fail to become pregnant after an embryo transfer remains high despite advances in assisted reproductive technologies. Use of autologous platelet-rich plasma may have a beneficial effect on implantation. Our objective is to determine if autologous platelet-rich plasma prior to embryo transfer is effective in improving pregnancy rates among women with recurrent implantation failure. We will design a randomized controlled trial such that women will receive an intrauterine infusion of either autologous platelet-rich plasma or saline 48 hours prior to transferring …