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Spink1-Col18a1 Crosstalk Shapes Epigenome And Drives Cancer Stemness In Pancreatic Ductal Adenocarcinoma, Haoyu Tang

Yale Graduate School of Arts and Sciences Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an increasing incidence and extremely dismal prognosis, due to early metastasis and the limited understanding of the mechanisms driving its progression. In this dissertation, by analyzing bulk transcriptomic profiles from PDAC patients with substantial differences in survival and deconvoluting the results using a single-cell transcriptome dataset of human PDAC, we identified serine protease inhibitor Kazal type 1 (SPINK1) as a crucial modulator of PDAC progression and patient survival. At the patient level, higher SPINK1 expression is correlated with shorter survival, and at the single cell level, SPINK1 expression showed dynamical changes …

Rasa3 Identified As A Potential Effector Of The Brain G Protein G⍺o By Mass Spectrometry, Halie Adesin Bell

Yale Graduate School of Arts and Sciences Dissertations

G⍺o, the alpha subunit of the most abundant heterotrimeric G protein in the brain, mediates signaling by opioids and by many neuromodulators to inhibit neural function. An open question is whether activated G⍺o-GTP directly binds to and regulates effector molecules, like all other animal G⍺ proteins, or if it signals solely by releasing Gβ�� subunits. Using mouse brain lysates as native source of G⍺o and its potential effectors, I analyzed immunopurified G⍺o protein complexes by mass spectrometry. I identified several proteins that interact preferentially with inactive or active G⍺o. I focused my analysis on proteins that are significantly upregulated in …

Nap-Trap Reveals 5'Utr-Mediated Translation Regulation During Zebrafish Development, Ethan C. Strayer

Yale Graduate School of Arts and Sciences Dissertations

The cis-regulatory elements encoded in an mRNA determine its stability and translational output. While there has been a considerable effort to understand the factors driving mRNA stability, the regulatory frameworks governing translational control remain more elusive. We have developed a novel massively parallel reporter assay (MPRA) to measure mRNA translation, named Nascent Peptide Translating Ribosome Affinity Purification (NaP-TRAP). NaP-TRAP measures translation in a frame-specific manner through the immunocapture of epitope tagged nascent peptides of reporter mRNAs. We benchmark NaP-TRAP to polysome profiling and use it to quantify Kozak strength and the regulatory landscapes of 5’ UTRs in the developing zebrafish …

Investigating The Plasticity And Role Of Peripherally Derived Cd4 T Cells In The Brain At Homeostasis, Tomomi Marie Yoshida

Yale Graduate School of Arts and Sciences Dissertations

Specialized immune cells residing in tissues orchestrate diverse biological functions through communication with parenchymal cells. The contribution of the innate immune compartment in the meninges and central nervous system (CNS) is well-characterized, however, whether T cells as part of the adaptive immune system reside in the brain and are involved in homeostasis is poorly understood. Here, we identify that the subfornical organ (SFO) region of the brain is a nucleus for parenchymal T cells in the steady-state brain in both mice and humans. Using unbiased transcriptomics, we found that these extravascular T cells in the mouse brain are distinct from …

Host Defense Inside & Outside Of The Immune System: Modeling Antimicrobial Immunity By Gbps, Zhongyu Yuan

Yale Graduate School of Arts and Sciences Dissertations

Traditional views of host defense often focus on antibody-mediated neutralization, cytotoxic T-cell plus NK-cell-mediated killing, and phagocytic activities by cell populations originating in the bone marrow as part of the classical immune system. Additional effector activities, however, also operate in non-immune cells which compose the stroma or parenchyma of host tissues. These latter cell populations often mobilize antimicrobial activities in response to cytokines such as type II IFN (IFN-gamma; IFN-) against a wide variety of intracellular pathogens.

Among the most prominent IFN--stimulated genes are a family of immune dynamin-like GTPases termed the Guanylate Binding Proteins (GBPs). GBPs are widely expressed …

Deep Learning Methods For Protein - Small Molecule Interactions With Applications To Early-Stage Drug Discovery, Gregory William Kyro

Yale Graduate School of Arts and Sciences Dissertations

Drug discovery is a challenging endeavor for multiple reasons including the complexity of protein-ligand interactions at the molecular-level, the vastness of chemical space, and safety constraints related to unintended biological effects. In this dissertation, I present a suite of novel deep learning approaches that address these challenges from multiple angles. I first introduce HAC-Net— a deep learning model that, at the time, was the state of the art for predicting protein-ligand binding affinity—which was used to identify a potential inhibitor of a G protein-coupled receptor whose overexpression leads to cancer, diabetes, and multiple sclerosis, as well as a potential antivirulence …

Spaced Learning Approaches To Attitude Change: Impressions Of Individuals, Outgroup Prejudice, And Policy Endorsement, Emily Grace Ritchie

Yale Graduate School of Arts and Sciences Dissertations

How does the schedule of information delivery influence attitude change? While decades of research highlights the cognitive benefits of spaced learning for memory, little is known about whether these same principles extend to the domain of persuasion— particularly for socially meaningful or politically charged attitudes. This dissertation bridges cognitive and social psychological approaches by investigating whether spacing persuasive content over time enhances its ability to revise attitudes. Across three empirical chapters, I test the effects of spaced versus massed presentation of new information on evaluative judgements in three distinct domains: person impressions, social group attitudes, and policy support. In Chapter …

Evaluating Saliva Based Glucose Testing For Accessible Diabetes Care In Tanzania, Shannon Dhindsa

Public Health Theses

Background: In Tanzania, limited healthcare infrastructure and reliance on invasive diagnostic methods significantly hinder effective diabetes screening and management. Individuals with diabetes often go undetected and have lower immune systems that make them prone to further infectious complications. Thus, properly managing this chronic condition can prevent additional infectious diseases. Salivary glucose testing offers a non-invasive, innovative alternative with the potential to transform the early detection and management of diabetes, especially in resource-constrained settings.

Design: This cross-sectional study, conducted at Muhimbili National Hospital's Diabetes Clinic in Dar es Salaam, evaluates the feasibility of salivary glucose testing using a colorimetric glucose-oxidase-peroxidase point-of-care …

Statistical Methods For Investigating Cell-Type Specificity And Genetic Regulation Of Dna Methylation In Complex Traits, Youshu Cheng

Yale Graduate School of Arts and Sciences Dissertations

DNA methylation is one of the most widely studied epigenetic modifications that capture the cumulative effects of environmental exposures and inheritable effects and regulates gene expression. DNA methylation occurs at CpG sites, where the cytosine and guanine bases are connected by a phosphate group. Over the past decades, DNA methylation have been useful resources to understand the etiology and mechanisms of complex diseases. Multiple studies have linked DNA methylation with diseases to identify differentially methylated CpGs that associated with complex traits. In addition, another research direction is to focus on the single nucleotide polymorphisms (SNPs) associated with DNA methylation levels, …

Understanding Generative Models, From Theory To Applications, Zehao Dou

Yale Graduate School of Arts and Sciences Dissertations

Generative models - statistical and machine learning frameworks capable of producing new data samples - have emerged as powerful tools for modern artificial intelligence. This dissertation explores the theoretical underpinnings of generative modeling and examines their real-world impact across various domains. The work begins by delving into the mathematical foundations of probability distributions and latent variable methods, emphasizing concepts such as maximum likelihood estimation, variational inference, and adversarial training. Building on these core principles, it presents a unified perspective on popular architectures, including Variational Autoencoders (VAEs), Generative Adversarial Networks (GANs), and score-based diffusion models. Empirical studies highlight how these models …

The Pulse And Press Of Change: Consequences Of Shifting Climate Regimes And Extreme Events In Big Sagebrush Plant Communities, Scott Carpenter

Yale Graduate School of Arts and Sciences Dissertations

Dryland ecosystems cover over 40% of Earth’s terrestrial surface and are critical to both biodiversity and human livelihoods, yet they are increasingly vulnerable to the interacting pressures of climate variability and land use. Effective management of these systems requires a deeper understanding of how chronic pressures and acute disturbances shape plant communities. This dissertation examines the interplay between climate variability, livestock grazing, and plant community dynamics in big sagebrush ecosystems of the Upper Green River Basin, Wyoming. Through three complementary studies, I demonstrate that while livestock grazing influences plant structure, its effects are consistently subordinate to climatic and edaphic factors, …

Tau-Connectome Predictive Modeling And Subtyping In Preclinical Alzheimer's Disease, Hamid Abuwarda

Yale Graduate School of Arts and Sciences Dissertations

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-? and tau, yet clinical progression varies widely across individuals. The central aim of this dissertation was to evaluate whether functional brain connectivity derived from resting-state fMRI can serve as a clinically meaningful predictive tool in the asymptomatic phase of the disease, preclinical AD. In Chapter 2, I develop connectome-based predictive models linking whole-brain functional connectivity to regional tau positron emission tomography (PET) signal in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study. These models predicted tau burden, particularly in regions vulnerable to tau deposition in Braak stages IV/V. In …

Genetic Variants Linked To Neurodevelopmental Disorders Within The Beta3-Beta4 Loop Of The Trio Ph 2 Domain Release Autoinhibition Of The Trio Gef2 Activity, Melissa Carrizales

Yale Graduate School of Arts and Sciences Dissertations

The TRIO family of proteins, which includes Trio, Kalirin, UNC-73 (in Caenorhabditis elegans), and dTrio (in Drosophila), are key regulators of cell morphogenesis, migration, tissue organization, and neuronal development through their regulation of Rho GTPases. These proteins feature multiple catalytic and scaffolding domains that mediate GTPase activation and cellular localization. TRIO proteins are essential for processes like actin dynamics, cell migration, and synaptic function, and disruptions in their activity have been linked to neurodevelopmental and neuropsychiatric disorders. This study focuses on Trio, specifically its regulatory mechanisms and how disease-related mutations disrupt its catalytic activity, contributing to various human diseases.

In …

Individual-Level Large-Scale Circuit Modelling Of Human Cortex, Rachel Ann Cooper

Yale Graduate School of Arts and Sciences Dissertations

Individuality is a defining feature of human existence. Yet the neural mechanisms underlying such individual variation are not fully understood. Prior research has suggested that variation in the balance between excitation and inhibition within the brain may contribute to these differences. To investigate this hypothesis, we employed a large-scale, biophysically-based model of the human cortex. This model is governed by a small set of biologically interpretable parameters, allowing for a focused analysis of how shifts in excitation and inhibition shape individual brain function. Using this modelling framework, this thesis examined patterns of variation across both healthy individuals and clinical populations. …

Interpretable And Data-Driven Machine Learning Models For Analyzing High-Dimensional Biological Data, Junchen Yang

Yale Graduate School of Arts and Sciences Dissertations

High-dimensional biological data, including single-cell omics, are prevalent in modern biology for characterizing a wide range of biological processes and phenomena. Although our capacity to generate such data has expanded at an unprecedented pace, significant challenges remain in extracting the informative features and the underlying biological signals. In particular, these datasets not only exhibit high dimensionality but also suffer from issues including inherent noise, low signal-to-noise ratio, and intrinsic heterogeneity. While machine learning models hold great promise for analyzing such data, their complexity and sensitivity to data characteristics often impede biological interpretability. To address these interconnected challenges, this thesis develops …

Aberrant Splicing Exonizes C9orf72 Repeat Expansion In Als/Ftd, Suzhou Yang

Yale Graduate School of Arts and Sciences Dissertations

A nucleotide repeat expansion (NRE) (GGGGCC)n in the first annotated intron of the C9ORF72 (C9) gene is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While previous studies have shown that C9 NRE produces several toxic dipeptide repeat (DPR) proteins, how an intronic RNA segment can access the cytoplasmic translation machinery remains unclear.

By capturing and sequencing NRE-containing RNAs from patient-derived fibroblasts and neurons, I found that C9 NRE became part of an alternatively spliced exon 1 through the usage of various downstream 5ʹ splice sites. These NRE-containing splice isoforms accumulate in C9 ALS/FTD brains, …

Movement Public Health: Addressing The Links Between Public Health And Carceral Systems, Marie Fatima Hyacinthe

Yale Graduate School of Arts and Sciences Dissertations

This dissertation is an interdisciplinary exploration of the links between public health and carceral systems, the connections between academic scholarship and advocacy, and the role of public health research in social justice movements. This dissertation begins with in-depth interviews with academic researchers and anti-carceral organizers, as well as analyses of my own experiences taking part in protests and mutual aid work, which ground conversations on the meaning of safety and care, and the role of public health. The second chapter is a systematic literature review and synthesis where I analyze academic literature about public health and carceral systems, assessing it …

Dynamical Mechanisms Of Neural Computation, Frederick Michael Berl

Yale Graduate School of Arts and Sciences Dissertations

The brain is one of the most complex dynamical systems in the universe and despite our everyday familiarity with it, the intricacies of how it functions remain a mystery to us. It is enormously powerful, continuously learning, and able to perform computations flexibly and adapt to novel situations. Although science presently has an understanding of how individual neurons work and a general idea of what the functions of each region in the brain are, how the computations of each neuron are modulated by context and how the various regions work together to produce behavior are unclear. Here, we explore the …

A Possible Mechanism Of Miwi2-Mediated Dna Methylation By De Novo Dna Methyltransferases, Tianshu Liu

Yale Graduate School of Arts and Sciences Dissertations

Epigenetic information refers to inheritable information that is not directly encoded in the genomic locus. Among various epigenetic mechanisms, DNA methylation play a crucial role in development and homeostasis and undergoes dynamic remodeling during mouse embryogenesis. In the mouse germline, primordial germ cells experience a global erasure of DNA methylation, a process important for the re-establishment of parent-specific methyl-imprint in the late stage of gametogenesis. However, how DNA methylation occurs at specific genomic loci remains an open question. Miwi2, one of three murine PIWI proteins, has been implicated in guiding de novo DNA methylation, yet the molecular machinery of Miwi2-mediated …

The Gnda Microprotein Supports Atp Homeostasis In Escherichia Coli During Heat Shock, Jessica Jayne Mohsen

Yale Graduate School of Arts and Sciences Dissertations

Same-strand overlapping, or nested, open reading frames (ORFs) can optimize the information content of size-constrained viral genomes by increasing the number of proteins expressed from a limited nucleotide sequence. However, nested small open reading frames (sORFs) were previously omitted from prokaryotic and eukaryotic genome annotations. It was therefore surprising when numerous nested sORFs were recently discovered in bacteria and eukaryotes. Our case study of the GndA microprotein in Escherichia coli provides evidence of an emerging model that overlapping genes can be expressed from bacterial genomes to contribute to cellular fitness. GndA interacts with the electron transport chain and ATP synthase …

Adaptation Of Learning Dynamics And Feature Representations Via The Neural Kernel, Lianghui Peng

Yale Graduate School of Arts and Sciences Dissertations

The ability to learn from experience is essential for both biological and artificial agents. To learn efficiently in complex, high-dimensional environments, agents must generalize strategically from limited data by focusing on features relevant for the task. The generalization strategy, known as inductive bias, shapes the dynamics of learning. Previous works have established the theory of neural tangent kernels that describes the learning dynamics of artificial neural networks. However, a comparable framework for understanding and quantifying inductive bias in biological systems performing behavioral tasks remains underdeveloped. Here, we introduce a neural kernel framework to characterize inductive biases of humans and artificial …

Exploring Squamate Evolution Through Focused Taxonomic And Anatomic Lenses: A Taxon-Character Approach To A Taxon-Character Problem, Dalton Meyer

Yale Graduate School of Arts and Sciences Dissertations

Among the living terrestrial vertebrates, the greatest diversity of verifiable species is seenamong the squamates, the group which contains the lizards and snakes. With a global distribution limited only by their general intolerance to long periods of cold temperatures, they are a ubiquitous component of modern ecosystems. Furthermore, over their roughly 180-million-year evolutionary history they have achieved tremendous morphological disparity and a range of body sizes that spans three orders of magnitude. However, our understanding of the origins and early evolution of squamates remains obscured due to persistent conflict in hypotheses generated from morphological and molecular data. This discordance is …

A Second Wave Of Notch Signaling Diversifies The Intestinal Secretory Lineage, Eleanor Zagoren

Yale Graduate School of Arts and Sciences Dissertations

The small intestine is well known for its nutrient-absorbing enterocytes; yet equally crucial for homeostasis is a diverse set of secretory cells, all presumed to originate from the same intestinal stem cell. Despite their major roles in intestinal function and health, understanding how the full spectrum of secretory cell types arises remains a longstanding challenge, largely due to their comparative rarity. Here, I investigate the specification of a rare population of small intestinal epithelial cells found in rats and humans but not mice: CFTR high expressers (CHEs). Using pseudotime trajectory analysis of single-cell RNA-sequencing data from rat jejunum, I provide …

Bridging Behavior And Neural Activity: Neural Dynamics Leading To Self-Initiated And Task-Driven Movements, Yongxu Zhang

Yale Graduate School of Arts and Sciences Dissertations

Understanding how populations of neurons generate behavior remains a fundamental question in neuroscience. While single-neuron analyses have provided valuable insights, behavior emerges from the coordinated dynamics of large neural ensembles that evolve over time and across states. A major difficulty is that neural population activity is non-stationary: it exhibits temporal distributional shifts, transitions between distinct dynamical regimes, and modulation by external or inter-regional inputs. Advances in artificial intelligence offer new opportunities to address this challenge. Yet, conventional models, such as standard recurrent neural networks, often fail to capture such complexity, limiting both predictive performance and mechanistic interpretability. This motivates the …

The Organization Of Autophagic Membranes And Proteins At The Phagophore Assembly Site, Devin Michael Fuller

Yale Graduate School of Arts and Sciences Dissertations

Autophagosomes are transient organelles which grow from a seed vesicle to encapsulate a target cargo and subsequently fuse with the lysosome to degrade its contents. This process occurs rapidly and requires the concerted effort of a host of unique membranes and proteins in a complicated cascade, which I detail in chapter I. Deletion of the lipid transport proteins ATG2A and ATG2B results in the accumulation of most of the preceding autophagic membranes and proteins in a large compartment. The ATG2 DKO compartment is advantageous as a model for the phagophore assembly site (PAS) for the following reasons: it is not …

Visible-Light Mediated, Diastereoselective Epimerization Of Endocyclic, Exocyclic And Acyclic Amines, Maria Antonieta Vargas-Rivera

Yale Graduate School of Arts and Sciences Dissertations

Light-mediated stereochemical editing has become increasingly explored as a method for the stereoselective synthesis of compounds. This dissertation describes the work towards the stereoselective epimerization of amines. The first chapter describes the highly diastereoselective epimerization of endocyclic amines, which are commonly found in pharmaceuticals. The second chapter demonstrates the expansion of this light-mediated epimerization method to include exocyclic amines. Finally, chapter three details current advances towards the diastereoselective epimerization of acyclic amines.

Incorporating Environmental Information Into Genetic Studies Of Psychiatric Disorders, Yue Hu

Yale Graduate School of Arts and Sciences Dissertations

Psychiatric disorders are among the most common diseases of humans, affecting a large number of individuals worldwide and contributing to a considerable burden of disease and disability. With a lifetime prevalence ranging from 5% to 17%, depression – characterized by a persistent low mood or loss of interest in activities for extended periods – is prominent amongst psychiatric disorders. Despite the availability of new medications developed over the past decade to treat depression, long-term treatment response remains disappointing; the risk of death by suicide is over 8-times national averages. Depression is multifactorial with both genetic and environmental factors, including demographic …

Warm Life, Cold Stones: The Effigial Tomb In Late Medieval English Literature, Maia Ruth Béar

Yale Graduate School of Arts and Sciences Dissertations

The effigial tomb is one of the defining features of Gothic sacred art. Tombs topped with grand effigies populated the churches, cathedrals, and chapels of late medieval England and many survive to this day. This dissertation explores the encounter with these tombs as represented in the literature of the period, in particular hagiography, romance, and narrative poetry. Although it literally demarcates the boundary between dead and living, the tomb is a powerful site of boundary-breaking in these texts at which the distinctions between life and death, flesh, and natural and artistic bodies are tested and often complicated. I consider various …

Advancing Neuroimaging Brain-Behavior Machine Learning Biomarkers, Brendan Adkinson

Yale Graduate School of Arts and Sciences Dissertations

Machine learning models trained on human neuroimaging data are increasingly used as tools for predicting individual behavioral phenotypes and enhancing precision medicine. However, multiple limitations hinder their current scientific and future clinical utility. In this dissertation, I address key challenges surrounding "brain-behavior" predictive model interpretability, generalization, and bias. In Chapters 2 and 3, I show that prevalent feature selection practices overlook features that are meaningful for both prediction and neurobiological interpretation. This suggests that prevailing approaches lead to feature overinterpretation and a misrepresentation of the neurobiological bases of brain-behavior associations. In Chapters 4 and 5, I demonstrate that brain-behavior predictions …

Distrust Of Psychotherapy For Biologically Explained Mental Disorders: A Validation Of Beliefs Underlying This Distrust And Interventions To Mitigate This Distrust, Annalise Perricone

Yale Graduate School of Arts and Sciences Dissertations

Lay and scientific communities alike increasingly attribute mental disorders to biological causes (e.g., genetic risk or neurobiological abnormalities). Biological explanations of mental disorders have some beneficial consequences, including reduced personal blame of individuals affected by such disorders. One adverse consequence, however, is that upon learning that a mental disorder has a biological etiology, people tend to show reduced trust in the effectiveness of psychotherapy. Given that the combination of psychotherapy and pharmacotherapy is often optimal for many mental disorders, reduced trust of psychotherapy could result in poorer clinical outcomes, if people elect not to receive such treatment. Although this distrust …