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Integrating Life History And Ecological Adaptation: Evolution In The Desert-Alpine Plant Lineage Cistantheae, Anri Chomentowska

Yale Graduate School of Arts and Sciences Dissertations

Understanding the mechanisms underlying evolution and adaptation - particularly among traits that evolve correlatively, like those that make up life history strategies - requires an integrative approach across evolutionary, ecological, and genomic scales. This dissertation focuses on the desert-alpine lineage Cistantheae (Montiaceae), a clade of herbaceous plants distributed across arid and montane habitats in western North and South America. The three chapters, at different scales, explore how climate niche, mating system, and photosynthetic physiology are correlated to life history strategies through evolutionary history. Chapter 1 presents the first densely-sampled molecular phylogeny of Cistantheae, inferred using reduced-representation genome sequencing (ddRADSeq). This …

Light Sheet Microscopy For 3d Nanoscale Imaging, Hannahmariam Mekbib

Yale Graduate School of Arts and Sciences Dissertations

Advances in expansion microscopy, a super resolution microscopy technique in which samplesare expanded up to ~8,000 times their original volume, require new microscope modalities to image the large sample sizes. These new techniques should be suitable for imaging large sample volumes, yet need to maintain the high 3D resolution of 250-500 nm of high-end confocal microscopy to provide the maximum level of detail and thereby reveal nanoscale cellular ultrastructure. Axially Swept Light Sheet Microscopy (ASLM) has emerged as a promising technique for generating high-resolution images at high-throughput. However, current designs struggle with the trade-off between limited resolution and field-of-view (FOV) …

The Independent And Redundant Roles Of Tbx16 And Msgn1 In Mesodermal Differentiation, Guoyu Zhu

Yale Graduate School of Arts and Sciences Dissertations

Tbx16 and msgn1 genes are key genes responsible for the mesodermal progenitor cells to undergo mesodermal fate transition during zebrafish embryonic body elongation. Here we elucidated their previously unclear independent and redundant roles of mesodermal fate regulation. Using heat-shock induced tbx16 and msgn1 overexpression, in situ hybridization, quantitative PCR, RNA sequencing, and systematic analysis of differentially expressed genes, we found that tbx16 and msgn1 promotes mesodermal differentiation by repressing the progenitor niche that maintains the mesodermal progenitor cell state. Tbx16 and msgn1 repress the expression of many of the same genes in the mesodermal progenitor niche, but tbx16 also represses …

Programming Cell States With Emage And Engineered Allosteric Crispr Effectors In Saccharomyces Cerevisiae, Peter Ciaccia

Yale Graduate School of Arts and Sciences Dissertations

Cells are self-replicating information processing systems that maintain control of internal state by gathering and expending chemical energy. Programming these cellular states requires complementary technological paradigms: genome editing methods define the phase space of possible cellular behaviors by modifying an underlying genetic blueprint, and transcriptional and allosteric control systems enable precise navigation within that defined space through spatiotemporal and environmentally responsive regulation. In this sense, genome editing and gene regulation tools work synergistically to expand ability to perturb, control, and monitor cellular function. No single genome editing or control paradigm optimally addresses all applications: eukaryotic MAGE (eMAGE) excels at generating …

Circuit And Cell Class Specific Effects Of Psilocybin And Serotonergic Psychedelics, Pasha Davoudian

Yale Graduate School of Arts and Sciences Dissertations

Psychedelics are compounds that can alter perception and cognition and are being explored as treatments for depression, anxiety, and substance-use disorders. Yet, the mechanisms by which they reshape brain function remain poorly understood. This dissertation presents four studies in rodent models examining how psychedelics act across synapses, microcircuits, and whole-brain networks. Chapter 1 shows that a single dose of psilocybin promotes plasticity in the frontal cortex. Chapter 2 maps brain-wide activity induced by psilocybin and ketamine, linking shared and distinct effects to gene expression. Chapter 3 extends this approach to multiple psychiatric drugs, using machine learning to classify drug-specific circuit …

Evaluation Of Passive Sampling And Emerging Bulk Air Disinfection Technologies To Monitor And Mitigate Airborne Viral Exposure In Indoor Environments, Darryl Marissa Angel

Yale Graduate School of Arts and Sciences Dissertations

The COVID-19 pandemic demonstrated the significance of understanding the airborne route of transmission for respiratory viruses and clarified the need to monitor and mitigate the presence of respiratory viral aerosols in indoor congregate settings. The goal of this dissertation is to evaluate the ability of emerging technologies to detect and reduce infectious viral aerosols within occupied indoor spaces. This work first explores the ability of a wearable passive sampler to collect viral aerosols for personal exposure assessments to SARS-CoV-2. The sampling material, polydimethylsiloxane (PDMS), efficiently collected enveloped viral aerosols, with a calculated uptake rate commensurate with previously developed passive aerosol …

Roles For The Planar Cell Polarity Pathway In Postnatal Intestinal Patterning And Architecture, Rebecca Frances Lee

Yale Graduate School of Arts and Sciences Dissertations

The coordination and patterning of cells required for proper tissue architecture play a critical role in organ development and function. This process is especially important in the small intestine, which relies heavily on its unique architecture of “hills” (villi) and “valleys” (crypts) to maximize nutrient absorption. Stem cells from a single crypt generate daughter cells that migrate up the villus in a linear ribbon pattern to form villus ribbons, while progressively differentiating into zonated cell states. This differentiation is tightly correlated to distinct digestive functions through compartmentalized expression of nutrient transporters. Despite the implicit reliance of intestinal tissue physiology on …

The Science Of Not Knowing: Systems Thinking Between Vienna And The United States, 1900-1972, Libby S. O'Neil

Yale Graduate School of Arts and Sciences Dissertations

This dissertation is a history of the interdisciplinary field of systems theory from the perspective of Central European scientists and intellectuals who migrated to North America during the 20th century. It is a story about how people, ideas, and techniques circulated in new ways across a period of global upheaval, about how the philosophy of science became a stage for urgent political questions, and about how scientists tried to grasp the whole without surrendering authority over its constituent parts. This project reveals how European interwar debates were encoded into technical practices of control and communication in the postwar United States, …

Cross-Stack Design Space Exploration For Energy-Efficient Ai Systems, Abhishek Moitra

Yale Graduate School of Arts and Sciences Dissertations

The growing complexity of neural networks—from spiking neural networks (SNNs) to vision transformers (ViTs) and large language models (LLMs)—has posed major challenges for deployment on edge devices with limited compute and memory resources. This thesis addresses these challenges by proposing a suite of co-optimization strategies that span device, circuit, architecture, and algorithm layers to enable efficient AI inference on both analog and digital compute-in-memory (CiM) platforms. The first contribution, SpikeSim, presents an end-to-end simulation framework for evaluating SNNs on CiM hardware, uncovering key tradeoffs in neuronal memory, latency, and crossbar mapping. XPert introduces a differentiable co-search framework that jointly optimizes …

Inference Of Somatic Selection In Cancer: Methods And Applications, Jeffrey Mandell

Yale Graduate School of Arts and Sciences Dissertations

Cancers are predominantly understood as diseases in which somatic tissue lineagesacquire genetic or epigenetic alterations that confer traits which lead to aberrant cell growth. Such phenotypes include maintenance of proliferative signaling, resistance of apoptotic signaling, and immune suppression. In a microcosm of classical evolution, which progresses via random genetic drift and natural selection, somatic cells accumulate mutations throughout the life course. The small subset of mutations (or other heritable alterations) that provide proliferative advantages to the cells in which they occur tend to gain prevalence in subsequent generations, which may eventually lead to clonal evolution of cancer cell traits. While …

Unveiling The Spatial Cellular Dynamics And Regulatory Network In Glioblastoma, Shuozhen Bao

Yale Graduate School of Arts and Sciences Dissertations

Glioblastoma (GBM) is a grade IV astrocytoma, the most common malignant brain tumor in adults, which has a poor prognosis and high recurrence. To better understand the disease's fundamental mechanism, tremendous effort has been made to investigate the molecular and cellular interactions between malignant cells and the tumor microenvironment using single-cell technology. However, the spatial intra-tumoral information of GBM, including the disease progression regulatory network and cellular dynamics, has yet to be widely constructed. Our investigation undertakes a novel approach to address the challenges. Specifically, we employ different spatial omics technologies at all levels from epigenetics, transcriptomics, post-transcriptomics, and proteomics, …

Extending And Improving The Study Of Gene Expression Regulatory Mechanisms, Isaac William Vock

Yale Graduate School of Arts and Sciences Dissertations

Gene expression levels are a product of RNA synthesis and degradation kinetics. In addition, the bulk rates of RNA synthesis and decay are a function of the rates of several highly regulated biochemical steps, from transcription initiation, productive elongation, RNA processing, export from the nucleus, and degradation in either the cytoplasm or nucleus. When gene expression levels need to be regulated, cells can tune any combination of these kinetic parameters to achieve the desired change. If one only studies the levels of mature RNA and their fluctuations, one misses out on understanding the intricate kinetic regulation underlying gene expression. Because …

Elucidating Mechanisms Of Selective Ion Transport In Nanoporous Membranes, Camille Violet

Yale Graduate School of Arts and Sciences Dissertations

Membranes that can separate ionic species of similar size and valency are needed to advance resource recovery for battery and electronic waste recycling, lithium harvesting, and water reuse. Insights from ion channels in biological cell membranes indicate that simultaneous confinement and preferential interactions with binding sites are critical for fast and selective ion transport. However, these specific, localized chemical interactions have yet to be translated to synthetic membrane design. This dissertation attempts to bridge the gap between molecular-level selectivity mechanisms of biological ion channels and the design of ion-selective membranes through systematic investigations of ion transport in precision-model systems. The …

Discovery Of Direct-Acting Small-Molecule Rig-I Agonists Through Creation Of A Selective Card Activation Platform, Rong Guo

Yale Graduate School of Arts and Sciences Dissertations

Retinoic acid-inducible gene I (RIG-I) is a human pattern recognition receptor (PRR) that plays a key role in the innate immune response against RNA viruses, including influenza viruses, coronaviruses, and flaviviruses. As a ubiquitously expressed protein in nearly all nucleated cells, RIG-I resides primarily in the cytoplasm, where it detects foreign RNA. Although RIG-I can bind to a variety of RNA molecules, it is selectively activated by viral RNAs that have specific structural features—such as blunt-ended double-stranded regions and 5′-triphosphates. Beyond its antiviral role, RIG-I has emerged as a promising target in cancer immunotherapy, largely due to its ability to …

Identifying Quantitative Trait Loci Of Genetically Regulated Molecules To Reveal Biological Mechanisms In Complex Traits, Chen Lin

Yale Graduate School of Arts and Sciences Dissertations

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex traits and diseases, but most of these variants reside in non-coding regions, making their biological functions challenging to study and interpret. To investigate the potential roles of these variants, expression quantitative trait locus (eQTL) analyses associate genetic variants with gene expression, providing insights into their regulatory roles. Integrating eQTL results with GWAS summary statistics has motivated transcriptome-wide association studies (TWAS), which focus on testing associations between imputed genetically regulated gene expression (GReX) and complex traits, offering a powerful gene-level view of genetic contributions to disease. Despite substantial …

Exploration Of The Mechanisms Regulating Genomic Stability In Plants, Wenxin Yuan

Yale Graduate School of Arts and Sciences Dissertations

Genomic stability is a cornerstone of cellular integrity, with implications spanning genetic engineering, epigenetic regulation, and disease modeling. However, most studies rely on yeast or mammalian models, leaving significant gaps in our understanding of plant chromatin biology and genome stability mechanisms. Exploring the conserved and divergent processes regulating genome stability in plants has become increasingly important, especially as global climate change threatens crop yields and biodiversity. Furthermore, the developmental resilience of plants provides a unique opportunity to study genes essential in mammals, offering translational insights for agriculture and human health. This dissertation investigates the molecular and genetic mechanisms underpinning T-DNA …

Mechanistic Insights Into Respiratory Tract Susceptibility In Whim Syndrome, Yawen Jiang

Yale Graduate School of Arts and Sciences Dissertations

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare congenital immunodeficiency caused by gain-of-function (GOF) mutations in CXCR4. Although respiratory infections are common in WHIM patients, the underlying mechanisms of susceptibility remain unclear. Using a mouse model of WHIM syndrome, we show that myelokathexis does not impair lung immune surveillance under homeostatic conditions. During acute viral and bacterial respiratory infections, neutrophils and monocytes are efficiently recruited from circulation into the lung vasculature and parenchyma. However, these cells fail to reach the airways due to their retention in adventitial cuffs enriched with CXCL12-producing fibroblasts, where potentially function as niches typically …

Development Of Quantum Machine Learning Methods Applied To Drug Discovery, Anthony Michael Smaldone

Yale Graduate School of Arts and Sciences Dissertations

At the intersection of quantum computing and machine learning, quantum machine learning (QML) has the potential to drive major breakthroughs in chemistry and drug discovery. This dissertation explores the development of quantum neural networks and their application within drug discovery tools, navigating a deliberate path from current methodologies towards quantum enhancement under progressively more practical assumptions. Initially, we present novel Quantum Convolutional Neural Network (QCNN) architectures for multi-channel supervised learning (Chapter 2), laying the groundwork for use in a wide variety of drug discovery tasks such as protein-ligand binding affinity and structure prediction. Despite state-of-the-art performance among QCNNs on benchmark, …

Investigating The Seasonal And Interannual Evolution Of Dissolved Oxygen In The Arctic Ocean’S Canada Basin, Ashley Arroyo

Yale Graduate School of Arts and Sciences Dissertations

This dissertation examines the evolution of dissolved oxygen in the waters of the Arctic Ocean's Canada Basin. Dissolved oxygen concentrations in the ocean are initially set at the surface through air-sea exchange and subsequently modified by physical and biogeochemical processes as waters circulate and mix. The variability of dissolved oxygen in the Arctic Ocean across seasonal and interannual timescales provides valuable insight into the broader evolution of water masses in the Arctic Ocean. As dissolved oxygen concentrations are gradually depleted in deeper waters via biological consumption, and only replenished when waters return to the surface, their distribution provides a valuable …

From Individuals To Ecosystems: The Role Of Intraspecific Variation And Phenotypic Plasticity In Ecosystem Function, Nathalie Rose Sommer

Yale Graduate School of Arts and Sciences Dissertations

Understanding how organisms shape ecosystems is a central goal of ecology, particularly in an era of rapid environmental change. While ecosystem models have traditionally emphasized species-level diversity and abiotic controls, this dissertation provides evidence that trait variation within species—driven by phenotypic plasticity and transgenerational effects—can have consequences for ecosystem structure and function. Intraspecific variation is increasingly recognized as a key component of biodiversity-ecosystem function relationships, yet its effects remain underrepresented in empirical studies and predictive frameworks. By integrating multigenerational field experiments, multi-trait assessments, and detailed ecosystem measurements in a long-term, well-characterized study system, this dissertation bridges evolutionary ecology and ecosystem …

Cryo-Em Reveals The Mechanochemical Cycle Of Reactive Full-Length Human Dynein-1, Pengxin Chai

Yale Graduate School of Arts and Sciences Dissertations

Dynein is a microtubule-based motor protein complex that generates force and drives movement toward the minus ends of microtubules. Despite extensive structural, biochemical, and biophysical studies, key questions remain about how dynein achieves its unidirectional stepping and force-generating powerstroke through its ATP-dependent mechanochemical cycle. In this dissertation, I leverage recent advances in cryo-electron microscopy (cryo-EM) and develop novel cryo-EM image processing methods to elucidate the atomic-level details of the mechanochemical cycle of full-length cytoplasmic dynein-1. I directly visualize the conformational landscape of dynein both on and off microtubules, uncovering several novel and important reactive intermediates. These findings include the discovery …

Defining The Genetic Basis Of Autosomal Dominant Polycystic Liver Disease With Whole Exome Sequencing, Xinmiao Meng

Public Health Theses

Polycystic liver and kidney diseases are inherited disorders marked by progressive cyst formation in hepatic and renal tissues, leading to significant morbidity through organ enlargement, impaired function, and eventual kidney failure or painful hepatic enlargement. While several genes—including PKD1, PKD2, GANAB, and PRKCSH—are implicated, a substantial proportion of cases remain genetically unexplained, limiting diagnostic precision and therapeutic development. This thesis aims to refine the genetic understanding of polycystic liver diseases through whole exome sequencing of 292 individuals with liver and/or kidney cysts. We first identify pathogenic variants in known disease genes in 133 individuals (46%), confirming the recurrent involvement of …

The Immunological Pathogenesis Of Persistent Lyme Disease And Babesiosis, Evan Navori

Public Health Theses

Post-Treatment Lyme Disease Syndrome (PTLDS) and persistent babesiosis are late-stage manifestations of two tick-borne diseases. Both are characterized by protracted symptoms despite the use of standard antimicrobial treatment. PTLDS is thought to be associated with immune dysregulation rather than active infection, while persistent and relapsing babesiosis is due to long-lasting infection caused by host immunodeficiency, pathogen antimicrobial resistance, and immune evasion. This thesis examines the immunological host deficits underlying both conditions, one too strong and the other too weak, and explores the mechanisms that contribute to prolonged disease states. Numerous studies suggest that Borrelia burgdorferi, the causative bacteria of Lyme …

An Analysis Of The Impact Of Genetic Diversity In Pfsec13 And Pfendo Genes On Pre-Clinical Drug Response To Med6-189 Analogs: A Novel Potent Class Of Antimalarial Compounds, Don-Pedro Ume

Public Health Theses

Malaria is a deadly disease responsible for 263 million cases and 597,000 deaths in 2023, with the majority being from the WHO African Region. While resistance to chloroquine and sulfadoxine-pyrimethamine (SP) emerged decades ago, there have been records of partial resistance to artemisinin-based combination therapies (ACTs) in African countries like Rwanda, Uganda, and Ethiopia. Given that ACTs are the main malaria drug of choice in Africa, there is a need to develop novel antimalarial agents that target pathways not explored by the current antimalarial therapies. Mutations in coding genes (PfSec13 and Pfendoplasmin or PfEndo) have been previously associated with resistance …

Prevalence, Management, And Outcomes Associated With Obstructive Sleep Apnea In The Medical Icu, Madeline Lilly Ehrenberg

Yale Medicine Thesis Digital Library

The prevalence of Obstructive Sleep Apnea (OSA) in the general adult population has been estimated to be between 9-17% in women and 25-30% in men. However, the prevalence of OSA among medical intensive care unit (MICU) patients is unknown. A 2015 systematic review by Knauert et al demonstrated the associations of OSA with many chronic diseases commonly seen in MICU patients (for instance, hypertension, type II diabetes mellitus, and congestive heart failure). This same review also shed light on the gaps in knowledge surrounding OSA, including underdiagnosis, undertreatment, and lack of research. Given the overall prevalence of OSA and the …

Trends In Missing Race And Ethnicity Data In A National Surgical Database, Kevin Gao Hu

Yale Medicine Thesis Digital Library

Accurate data collection on race and ethnicity is critical to detecting and characterizing disparities in surgical care. This study explores the prevalence and impact of missing race and ethnicity data in the National Surgical Quality Improvement Project Pediatric (NSQIP Pediatric) database. NSQIP Pediatric from 2016-2020 was assessed for patients who were missing data for race (RM), ethnicity (EM), or both (BM). Changes in proportion of RM, EM, and BM patients were assessed with Cochran-Armitage tests. Surgical outcomes were modeled using linear mixed-effects models, treating CPT codes as random effects. Models were bootstrapped with 1000 iterations for each outcome. Of 596,571 …

The Effects Of New Onset Medicare Eligibility At Age 65 On Access To Surgical Care At A Large Non-Profit Health System, A Single-Center Regression Discontinuity Analysis, Amanda R. Jankelovits

Yale Medicine Thesis Digital Library

ASSOCIATION OF MEDICARE ELIGIBILITY ON SURGICAL CARE ACCESS, A REGRESSION DISCONTINUITY DESIGN

Amanda Jankelovits, Julian Zhao, Hugo He, Hung-Mo Lin, Robert B. Schonberger, Department of Anesthesiology, Yale University, School of Medicine, New Haven, CT

The widespread onset of Medicare eligibility at age 65 has expanded access to healthcare, particularly among those previously uninsured. However, disparities in healthcare coverage still exist, especially for underrepresented minorities and low-income individuals. In this analysis, we utilize a regression discontinuity design to understand the effects of new onset Medicare eligibility at age 65 on access to surgical care at a large non-profit health system, focusing …

Maternal Prenatal Anxiety And Child Epigenetic Aging: A Longitudinal Analysis From Childhood To Mid-Adolescence, Shashwat Kala

Yale Medicine Thesis Digital Library

The developmental origins of health and disease posits that in utero exposures and early life experiences increases susceptibility to a host of pathologies. Maternal psychopathology, specifically maternal prenatal anxiety, has been studied as an in utero stressor that can affect childhood development and epigenetic aging. In the current study, we analyzed the longitudinal effects of maternal prenatal anxiety on epigenetic aging, assessed sex-specific effects, and tested the contribution of cellular heterogeneity to these findings. Using the longitudinal Basal Influences on Baby Development (BIBO) cohort, we performed a mixed model for repeated measures to determine how prenatal and postnatal anxiety (State-Trait …

Investigating The Cooccurrence Of Papillary Thyroid Carcinoma Among Patients With Oncocytic Pathology: Is There Evidence Of Causation?, Forest Seely Mahoney

Yale Medicine Thesis Digital Library

Thyroid neoplasms, both benign and malignant, significantly contribute to healthcare burden in the United States. Oncocytic neoplasms (ON), previously classified as Hürthle-cell neoplasms and comprising oncocytic adenoma (OA) and oncocytic carcinomas (OC), represent a rare subset of follicular cell-derived thyroid pathology, accounting for 3–7% of all thyroid malignancies. OC are considered more aggressive with worse prognosis due to higher rates of recurrence as well as inherent resistance to radioactive iodine, the first line of adjunct therapy for well-differentiated thyroid cancers. Conversely, papillary thyroid carcinoma (PTC), another follicular cell-derived thyroid cancer, constitutes over 90% of thyroid cancer cases and is characterized …

International Structural Magnetic Resonance Imaging Of Cortical Thickness In Older Adults With Bipolar Disorder, Rebecca Brynn Marks

Yale Medicine Thesis Digital Library

The presentation of bipolar disorder (BD) seems to change over the course of a lifetime. In older adults, BD seems to pose novel challenges including decreased cognitive functioning, psychiatric and medical comorbidities, increased susceptibility to medication side effects, and possibly even a shift toward more depressive symptoms. Despite these clinical findings, research into older adults with BD has lagged behind that of adolescents and young adults. As the global population ages, so too do individuals with BD. In fact, it is predicted that by 2030, 50% of patients with BD will be over the age of 60. This emphasizes why …