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Development Of The Human Brain Networks During Infancy, Huili Sun Jan 2025

Development Of The Human Brain Networks During Infancy, Huili Sun

Yale Graduate School of Arts and Sciences Dissertations

In early infancy, the human brain undergoes rapid network construction and remodeling. Advances in neuroimaging have made non-invasive, in-vivo observation of these brain changes possible during the perinatal period. However, how the brain develops to support dynamic activity and cognitive function remains unclear. In this thesis, I leverage the network control theory to model brain controllability - the capacity to drive activity changes - and examine its role in neurodevelopment. I first outline the developmental trajectories of controllability during the perinatal period and link them to synaptogenesis with cross-species models. Next, I introduce a machine-learning framework to explore how white …

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A Dimensional Approach To Assessing The Effects Of Early-Life Stress On Mental Health Across Development, Emily Meryl Cohodes Jan 2025

A Dimensional Approach To Assessing The Effects Of Early-Life Stress On Mental Health Across Development, Emily Meryl Cohodes

Yale Graduate School of Arts and Sciences Dissertations

Decades of research inform our understanding of the pernicious effects of exposure to stress for individuals across the lifespan. This research underscores that exposure to stressful contexts places individuals at increased risk for developing cognitive, social, emotional, and physical health problems. However, exposure to stress does not have a universal effect on all individuals across development, likely due in part to the extreme heterogeneity in experiential, environmental, and temporal aspects of stress. Recent advances in the study of the psychobiological effects of stress have focused on better understanding how heterogeneity in exposure may account for heterogeneity in developmental and clinical …

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Causal Inference For Environmental And Text-Based Interventions, Megan Ayers Jan 2025

Causal Inference For Environmental And Text-Based Interventions, Megan Ayers

Yale Graduate School of Arts and Sciences Dissertations

Causal inference provides statistical tools for generating empirical evidence about causal relationships. In conventional settings, randomized experiments can enable estimation of causal effects with simple methods and under weak assumptions, but many pressing causal questions concern complex systems where standard approaches break down. This dissertation presents advances and insights for such cases, first in the context of carbon markets and conservation programs, and then in settings where text serves as treatment. In the first chapter, we develop a generalized causal inference framework for analyzing forest carbon protocols. Recent work has questioned the credibility of forest carbon offsets as an environmental …

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An Ecological Approach For Understanding The Influence Of Threats In Youth’S Social Environments, May Isabella Conley Jan 2025

An Ecological Approach For Understanding The Influence Of Threats In Youth’S Social Environments, May Isabella Conley

Yale Graduate School of Arts and Sciences Dissertations

A central question motivating developmental research for decades has been how threats in youth’s social environments influence development. In particular, researchers have focused on understanding how threats in different contexts in youth’s social environments increase risk for adverse outcomes and why some youth exposed to threats appear more susceptible to adverse outcomes than others. Increasingly, researchers have identified cognitive and neurobiological factors that are thought to contribute to youth’s susceptibility to threats. Despite these advances, our understanding of the influence of threats on development remains incomplete due to a few critical limitations. Notably, while foundational ecological theories emphasize youth’s social …

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The Roles Of Terrestrial Weathering And Marine Bioturbation In Shaping Earth’S Surface Habitability Across Time, Brian Beaty Jan 2025

The Roles Of Terrestrial Weathering And Marine Bioturbation In Shaping Earth’S Surface Habitability Across Time, Brian Beaty

Yale Graduate School of Arts and Sciences Dissertations

The existence of life on Earth for over 3.8 billion years implies continuously habitable conditions despite major changes to the planet’s climate and surface geochemistry. In this thesis, I explore two Earth surface processes – terrestrial weathering and marine bioturbation – and their roles in shaping environmental habitability across various timescales. Weathering has long been recognized as a fundamental component of the Earth system. On multi-million-year timescales, it is the primary source for limiting nutrients to the biosphere and primary sink for atmospheric CO2. This concept underlies recent interest in artificially accelerating global weathering rates to mitigate near-future warming. However, …

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Transition Metal-Catalyzed N–H Functionalization For The Synthesis Of Nitrogen Heterocycles, Jenna Cailin Cordial Molas Jan 2025

Transition Metal-Catalyzed N–H Functionalization For The Synthesis Of Nitrogen Heterocycles, Jenna Cailin Cordial Molas

Yale Graduate School of Arts and Sciences Dissertations

Nitrogen heterocycles are privileged scaffolds found in 82% of FDA approved pharmaceuticals approved from 2013 – 2023. Thus, modular and efficient methods to synthesize these motifs are valuable for drug discovery and development. Chapters 1 and 2 will discuss the use of Cp*Rh(III)-catalyzed N–H functionalization to synthesize two types of non-aromatic nitrogen heterocycles. Chapter 3 discusses ongoing work for a Cu(I)-catalyzed three-component synthesis of piperazines. Chapter 1 describes a three-component synthesis of piperazinones from readily available amino amides, aldehydes, and diazo compounds. This method proceeds by a new mode of reactivity: imine directed Cp*Rh(III)-catalyzed N–H functionalization/annulation. This method represents the …

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Unraveling The Phenotypic Plasticity In Glioblastoma, Chunxiao Ren Jan 2025

Unraveling The Phenotypic Plasticity In Glioblastoma, Chunxiao Ren

Yale Graduate School of Arts and Sciences Dissertations

Cell plasticity enables cancer cells to transition between distinct phenotypic states, driving heterogeneity and therapeutic resistance. Here, I present the RACE (Rapid Analysis of Cell phenotypic Extremes) assay, a longitudinal in vitro experimental model designed to functionally isolate and enrich fast- and slow-migrating glioblastoma (GBM) cell subpopulations in response to mechanical input imposed by an extracellular matrix (ECM)-mimicking nanofabricated platform with pro-migratory property. I tracked these phenotypically distinct subpopulations and characterized their dynamic evolution through bulk and single-cell transcriptomic profiling. I found that fast- and slow-migrating cells corresponded to mesenchymal- and proneural-like transcriptional programs, respectively, and were regulated by a …

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A Study Of Math 1 Students At Two Eastern High Schools In North Carolina, Employing An Explanatory Design, Anthony Mark Tracey Jan 2025

A Study Of Math 1 Students At Two Eastern High Schools In North Carolina, Employing An Explanatory Design, Anthony Mark Tracey

Doctor of Education Dissertations

This study examined the instructional experiences of Math 1 students in the Green Valley (pseudonym) County School District during the 2022-2023 academic year. Using an explanatory sequential mixed methods approach grounded in constructivism (Bruner, 1960; Vygotsky, 1978), behaviorism (Skinner, 1938), universal design for learning (CAST, 2021; Meyer et al., 2014), multiple intelligences (Gardner, 1983), and Piaget's (1954) stages of development, this study explored how students' lived instructional experiences impact academic outcomes. Data, analyzed descriptively and thematically in Qualtrics, revealed a widespread dissatisfaction among students regarding engagement, instructional pace, preparation, and classroom disruptions. Qualitative insights particularly underscore issues with a passive, …

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Molecular Mechanisms Of Kras Regulation And Resistance In Pancreatic Ductal Adenocarcinoma, Xiangyu Ge Jan 2025

Molecular Mechanisms Of Kras Regulation And Resistance In Pancreatic Ductal Adenocarcinoma, Xiangyu Ge

Yale Graduate School of Arts and Sciences Dissertations

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive human malignancies, with a five-year survival rate of less than 13%. Oncogenic KRAS mutations occur in over 90% of cases and drive tumor initiation and progression, making KRAS a desirable therapeutic target. Despite the development of direct KRAS inhibitors, clinical efficacy has been modest due to rapid adaptive resistance. This thesis primarily investigates the molecular mechanisms by which PDAC cells adapt to KRAS inhibition, while also uncovering co-vulnerabilities that can be therapeutically exploited. Chapter 1 provides a comprehensive literature review of KRAS biology in PDAC, summarizing historical and contemporary findings …

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Vaccine-Induced Immunity: Insights Into Sars-Cov-2 And Orthopoxvirus, Valter Monteiro Jan 2025

Vaccine-Induced Immunity: Insights Into Sars-Cov-2 And Orthopoxvirus, Valter Monteiro

Yale Graduate School of Arts and Sciences Dissertations

Emerging infectious diseases like SARS-CoV-2 and re-emergent pathogens such asmpox (formally known as monkeypox) have posed substantial challenges to global health, often due to immune escape and antigenic variability. My research addresses these challenges by evaluating and designing vaccine strategies to enhance immune responses and cross-protection, focusing on SARS-CoV-2 variants and members of the Orthopoxvirus family. The central aim of my research is to understand and overcome limitations in immune responses to antigenically variable pathogens. My studies focus on humoral responses to SARS-CoV-2 variants through targeted booster regimens, exploring cross-protective immunity in Orthopoxvirus vaccines, and testing new mRNA vaccines to …

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Fine Particulate Air Pollution Exposure Burden And Sociodemographic Health Disparities In The United States: Impacts From Energy Transitions And Temporal Variation In Mortality Risk, Rory Stewart Jan 2025

Fine Particulate Air Pollution Exposure Burden And Sociodemographic Health Disparities In The United States: Impacts From Energy Transitions And Temporal Variation In Mortality Risk, Rory Stewart

Yale Graduate School of Arts and Sciences Dissertations

Climate change, the defining environmental crisis of our time, has been shown to impact concentration, distribution, and composition of tropospheric air pollutants, including particulate matter. Economic patterns greatly shape the generation of particulate matter as well as greenhouse gases that enhance climatic changes. Substantial evidence shows that exposure to fine particulates, particulate matter with aerodynamic diameter <2.5 µm (PM2.5), contributes to premature mortality and morbidity. These detrimental health outcomes have been shown to be experienced unequally across population groups, with disparities in the level of exposure and in the magnitude of health response for marginalized populations that have higher vulnerability to air pollution exposure. It is also possible that these health responses are not static, but dynamic over time due to changes in population health and composition of air pollution exposures, warranting deeper investigation into the directionality and shape of these health responses. Modeling potential future energy scenarios by using existing knowledge on health responses to air pollutants allows researchers and policymakers to understand how changes to air pollution can impact population health before policies are implemented. Thus, inclusion of appropriate modelling techniques and analyses of energy policy impacts is essential to understanding health impacts from climate mitigation and adaptation across population groups within the United States. This dissertation contributes to the growing knowledge base on climate mitigation, health co-benefits from air pollution concentration changes and health response changes across time to air pollution exposures. Chapter two presents work investigating whether energy policies that aim to reduce greenhouse gas emissions have a secondary impact of reducing health burden in the United States (U.S.) and if any changes to mortality and hospitalizations differ across subpopulations. I explored four future sector-specific energy policy scenarios (electrification of ports and marine shipping, low long-term natural gas pricing, high electric vehicle uptake, and innovations in building energy efficiency) and a business-as-usual scenario to determine how changes to ambient PM2.5 levels impact health within the continental U.S. by region, race/ethnicity, urbanicity, and income. I also investigated how methodological assumptions impact findings. I found projected avoided premature mortalities from energy transition policies range from 67,011 (95% CI: 45,692, 82,397) to 81,003 (55,286, 99,532) individuals in 2050 and 11,577 (1,332, 19,918) to 13,552 (1,560, 23,303) avoided cardiorespiratory hospitalizations in 2050, showing substantial health co-benefits from greenhouse gas mitigation policy implementation. These benefits vary by region and subpopulation, with Black, suburban, and less wealthy Americans experiencing the highest percent reduction in mortalities across all energy policy scenarios. Analysis into how population assumption specificity (such as using race-specific incidence rates instead of total population rates) influences the results proved that more specific population assumptions can make substantial differences to overall health projections. This research demonstrates the vast health benefits of climate mitigation strategies and how they differ across subpopulations, with some environmental justice populations benefiting more relative to the overall population. In chapter three, I investigated how PM2.5-mortality associations vary over time (2001-2016) in North Carolina and Michigan, while considering how temporality of these associations varies by sociodemographic variables. Results indicate that the direction of PM2.5– mortality health effects varies by location. The odds ratio (OR) for mortality per 10?g/m3 PM2.5 differed across time from 2001-2008 to 2009-2016, increasing by 0.28% in Michigan and decreasing 0.78% in North Carolina. Non-linear models show steadily increasing PM2.5-mortality odds over time for Michigan but an “S” shape for North Carolina. I also found suggestive evidence of widening disparities in PM2.5-mortality odds over time by age, race/ethnicity, urbanicity, sex, and education, although the magnitude of those changes varies across subpopulations and state. This research shows that mortality impacts of PM2.5 are changing over time, with different trends by location and subpopulation, potentially exacerbating environmental justice. This dissertation research underscores the importance of analysis to determine sociodemographic population health disparities when modeling co-benefits of energy and air pollution policies as overall estimates may obscure important differences across subpopulations. Better projections on local health effects on vulnerable communities can enhance equity considerations for climate mitigation actions, as well as provide a more holistic analysis on benefits of cost to implement versus avoided exposure and health costs. Further, this research shows that concentration-response functions may vary temporally and that such trends vary across location. This suggests that applications of historical concentration-response estimates may be obscuring the actual health impact on populations through over- or underestimates of health responses to a certain level of exposure. Improvements in the methodological assumptions of exposure and health response by introducing temporal variation provide researchers with a more accurate representation of the association between air pollution and health, which should be more widely considered in epidemiologic research. These results can inform policymakers and public health professionals in evaluating which communities are at highest risk from particulate exposures in the present day and into the future, especially in relation to temporal trends and projected changes in emissions, particulate composition, and population vulnerability.

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Chemosensory Variation Within And Across Bacterial Species, Jeremy Philippe Moore Jan 2025

Chemosensory Variation Within And Across Bacterial Species, Jeremy Philippe Moore

Yale Graduate School of Arts and Sciences Dissertations

Bacteria use a highly conserved sensory pathway to navigate chemical gradients. In particular, the chemotactic signaling pathway of Escherichia coli is one of the best-characterized systems in biology. However, despite decades of study, there are still open questions about bacterial chemotaxis, including how clusters of receptors cooperatively amplify signals, how variability in the composition of these arrays affects behavioral diversity, and how findings in E. coli generalize to diverse motile behaviors across bacteria. In this thesis, we explore diversity in chemosensory capabilities within and across bacteria species. First, we characterize the distribution of sensitivities to various chemical attractants in populations …

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Investigations Of Allosteric Mechanisms In Proteins, Brandon C. Allen Jan 2025

Investigations Of Allosteric Mechanisms In Proteins, Brandon C. Allen

Yale Graduate School of Arts and Sciences Dissertations

This dissertation examines how allosteric communication governs the dual catalytic and immunomodulatory functions of the macrophage migration inhibitory factor (MIF) superfamily, with an emphasis on D-dopachrome tautomerase (MIF-2). Despite limited primary sequence identity, MIF and MIF-2 share a conserved trimeric fold centered on a solvent-accessible channel that connects their catalytic N-terminal proline to distant receptor-binding loops. Experimental work using NMR spin relaxation, site-directed mutagenesis, and in vivo inflammatory assays suggest that single-residue mutations near this channel can dramatically alter tautomerase activity of MIF-2 and its ability to recruit neutrophils in murine lung models, thereby cementing the link between local perturbations …

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Limbic Circuit Control Of Stress And Neuroinflammation, Alexa Renee Soares Jan 2025

Limbic Circuit Control Of Stress And Neuroinflammation, Alexa Renee Soares

Yale Graduate School of Arts and Sciences Dissertations

Individuals are constantly subjected to various forms of stress, which shape the brain in different ways. The brain, in turn, must coordinate a response to adapt to the demands of the stressor. This response is coordinated via interactions between several neuromodulatory and neuroinflammatory signaling pathways. The limbic system, particularly the amygdala and hippocampus, has been highlighted as an important site for integration of these signals. These areas are critical for engaging neural, autonomic, and behavioral responses to acute stress and for plasticity-driven learning that can shape future responses to stress through a process called allostasis. Chronic exposure to stress can …

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Neurocognition In Youth With Prediabetes, Jade Ivey Quillian Jan 2025

Neurocognition In Youth With Prediabetes, Jade Ivey Quillian

Yale Graduate School of Arts and Sciences Dissertations

The association between type 2 diabetes (T2D) and cognitive impairment has been well established. This is critical because T2D is a key risk factor for Alzheimer’s disease. However, these studies often fail to account for adiposity and other co-morbid conditions that accompany T2D in older adults. As a result, the mechanisms linking connecting T2D and cognitive impairment consequently remain unclear. The overall aim of this dissertation is to understand the precise effects of dysfunctional glucose metabolism on neurocognition. To do this I capitalized on a unique opportunity to study dysregulated glucose in youth from the Pathogenesis of Youth Onset Diabetes …

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Functional Roles Of Histone H3 Lysine 4 Methylation At Regulatory Elements, Haoming Yu Jan 2025

Functional Roles Of Histone H3 Lysine 4 Methylation At Regulatory Elements, Haoming Yu

Yale Graduate School of Arts and Sciences Dissertations

Histone H3 lysine 4 methylation (H3K4me) is a highly conserved histone post-translational modification linked to active transcription. Although the enzymes that regulate this mark are essential for development, the direct functional role of H3K4me itself remains unclear. To provide a comprehensive overview, I first reviewed evidence from histone residue mutations, histone modifier perturbations, and epigenetic editing studies in yeast, Drosophila, and mammalian systems. This analysis highlights that H3K4me3 instructs transcription initiation and Pol II pause-release at promoters, and H3K4me1 and H3K4me3 may have convergent functions in establishing open chromatin. However, the functional role of H3K4me3 at intergenic site remains poorly …

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Integrating Life History And Ecological Adaptation: Evolution In The Desert-Alpine Plant Lineage Cistantheae, Anri Chomentowska Jan 2025

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 …

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Light Sheet Microscopy For 3d Nanoscale Imaging, Hannahmariam Mekbib Jan 2025

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) …

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The Independent And Redundant Roles Of Tbx16 And Msgn1 In Mesodermal Differentiation, Guoyu Zhu Jan 2025

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 …

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Programming Cell States With Emage And Engineered Allosteric Crispr Effectors In Saccharomyces Cerevisiae, Peter Ciaccia Jan 2025

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 …

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Circuit And Cell Class Specific Effects Of Psilocybin And Serotonergic Psychedelics, Pasha Davoudian Jan 2025

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 …

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Evaluation Of Passive Sampling And Emerging Bulk Air Disinfection Technologies To Monitor And Mitigate Airborne Viral Exposure In Indoor Environments, Darryl Marissa Angel Jan 2025

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 …

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Roles For The Planar Cell Polarity Pathway In Postnatal Intestinal Patterning And Architecture, Rebecca Frances Lee Jan 2025

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 …

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The Science Of Not Knowing: Systems Thinking Between Vienna And The United States, 1900-1972, Libby S. O'Neil Jan 2025

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, …

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Cross-Stack Design Space Exploration For Energy-Efficient Ai Systems, Abhishek Moitra Jan 2025

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 …

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Inference Of Somatic Selection In Cancer: Methods And Applications, Jeffrey Mandell Jan 2025

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 …

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Unveiling The Spatial Cellular Dynamics And Regulatory Network In Glioblastoma, Shuozhen Bao Jan 2025

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, …

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Extending And Improving The Study Of Gene Expression Regulatory Mechanisms, Isaac William Vock Jan 2025

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 …

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Elucidating Mechanisms Of Selective Ion Transport In Nanoporous Membranes, Camille Violet Jan 2025

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 …

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Discovery Of Direct-Acting Small-Molecule Rig-I Agonists Through Creation Of A Selective Card Activation Platform, Rong Guo Jan 2025

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 …

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