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Psychedelic Action On Dendritic Structure And Function, Neil K. Savalia
Psychedelic Action On Dendritic Structure And Function, Neil K. Savalia
Yale Graduate School of Arts and Sciences Dissertations
Psychedelics are amid a scientific renaissance driven by their therapeutic promise for mental illnesses. This dissertation examines the neural mechanisms that underlie the acute and long- term actions of psilocybin, a serotonergic psychedelic found in magic mushrooms and an emerging rapid antidepressant. Here we used cutting-edge in vivo techniques to investigate psilocybin's effects in the medial frontal cortex of mice, with a focus on the structure and function of dendrites. Four key findings emerged. First, a single treatment with psilocybin induces persistent dendritic spinogenesis (Chapter 1). The drug-evoked changes in neuronal structure and function varies for subtypes of excitatory pyramidal …
Kinetic And Thermodynamic Analysis Of Enpp1, Marisa Mary Michalchik
Kinetic And Thermodynamic Analysis Of Enpp1, Marisa Mary Michalchik
Yale Graduate School of Arts and Sciences Dissertations
The Ectonucleotide Pyrophosphatase Phosphodiesterase (ENPP) family members are promiscuous extracellular enzymes that play central roles in human physiology via catalysis of nucleotide and lipid substrates, but remain poorly characterized at the biochemical level. The founding member, ENPP1, is a glycosylated transmembrane enzyme with an extracellular catalytic domain that degrades nucleotide substrates (ATP and cGAMP) into their respective nucleotide monophosphates, playing a key role in both the regulation of biomineralization and innate immune system activation. The ENPP1 ATPase is the major source of extracellular pyrophosphate (PPi), the main chemical inhibitor of calcium phosphate crystal formation in physiology. ENPP1 deficiency lowers systemic …
Investigating The Sequence Requirements For Translation Initiation By Viral Internal Ribosome Entry Sites, Sabrina Gulli Grunseich
Investigating The Sequence Requirements For Translation Initiation By Viral Internal Ribosome Entry Sites, Sabrina Gulli Grunseich
Yale Graduate School of Arts and Sciences Dissertations
Protein synthesis is both essential and highly regulated. This process is complex and requires the concerted effort of many protein factors. Some viruses have evolved ways to co-opt host translation during initiation by using internal ribosome entry sites (IRESs). These structured RNAs allow the virus to bind to the host's ribosome in the absence of canonical requirements. This dissertation focuses on relating the sequence of viral IRES elements to their role in initiating translation. The Cricket Paralysis Virus (CrPV) IRES is short, uses a simple mechanism, and can function in diverse cell-free systems making it a useful tool to study …
Investigation Of How Long Noncoding Rna Pvt1 Regulates Myc Expression, Qiao Li
Investigation Of How Long Noncoding Rna Pvt1 Regulates Myc Expression, Qiao Li
Yale Graduate School of Arts and Sciences Dissertations
Long noncoding RNAs (lncRNAs) play essential roles in both physiological processes and disease, including cancer. A growing body of evidence positions lncRNAs as key regulators and biomarkers in tumorigenesis. Mechanistically, functional lncRNAs can regulate gene expression through epigenetic and transcriptional pathways, acting either via scaffold-like motifs that recruit regulatory complexes or through their abundance, which contributes to RNA-mediated feedback that modulates transcriptional condensates. Within the Plasmacytoma variant translocation 1 (Pvt1) locus, two alternative transcription start site isoforms have been identified: the constitutively expressed Pvt1a and the stress-inducible Pvt1b. While the precise functions of Pvt1a were not well understood, previous studies …
Description’S Displacements: Writing Experience In Musil, Benjamin, And Bachmann, Aida Feng
Description’S Displacements: Writing Experience In Musil, Benjamin, And Bachmann, Aida Feng
Yale Graduate School of Arts and Sciences Dissertations
This dissertation unfolds the ways in which description emerged as an active site for reconfiguring human experience in the writing experiments of the 20th century. Description, as a procedure for presenting and arranging the phenomena of reality, typically constructs an epistemological realm of experience that progresses toward comprehension and internal consistency. Understood in this way, description mediates one kind of experiential reality while foreclosing others. This project enlarges description’s operative capabilities toward a presentational mode that does not merely re-describe the phenomenal objects in this reality. To do so, it foregrounds writers and thinkers who conversed directly with philosophical traditions …
Functional Roles Of Subcellularly Localized Glycolytic Isoforms Of Glucose 6-Phosphate Isomerase, Ian Joseph Gonzalez
Functional Roles Of Subcellularly Localized Glycolytic Isoforms Of Glucose 6-Phosphate Isomerase, Ian Joseph Gonzalez
Yale Graduate School of Arts and Sciences Dissertations
While metabolic pathways are largely conserved across cells and organisms, tissues exhibit metabolic heterogeneity that tailors metabolism to their physiological demands. How the conserved pathways of metabolism achieve metabolic heterogeneity is incompletely understood, particularly in vivo. In this dissertation, I investigate the genetic requirement of glucose 6-phosphate isomerase (GPI-1), a conserved glycolytic enzyme that also regulates the pentose phosphate pathway (PPP). Using CRISPR-Cas9 genome editing, I found that gpi-1 knockout animals display germline defects consistent with impaired PPP, and somatic defects consistent with impaired glycolysis. I discovered that GPI-1 isoforms are differentially expressed and localized: GPI-1A is cytosolic in all …
Epidemiologic And Immunologic Characterization Of The Post-Acute Sequelae Of Covid-19, Christine Marie Miller
Epidemiologic And Immunologic Characterization Of The Post-Acute Sequelae Of Covid-19, Christine Marie Miller
Yale Graduate School of Arts and Sciences Dissertations
Since its emergence in late 2019, SARS-CoV-2 has infected over 15 million people—and the number continues to rise. The global impact of this novel coronavirus has been profound, reshaping not only public health infrastructure but also our understanding of human biology. The full extent of the virus’s effects on the immune system remains incompletely understood and will likely take years to fully unravel. What is already evident, however, is that SARS-CoV-2 uniquely modulates both innate and adaptive immunity, with consequences that span the developmental spectrum—from fetal and pediatric stages through adulthood. While many individuals recover without overt clinical sequelae, an …
Glycolysis-Induced Acidification Links Mitochondrial Deficiency To Axon Degeneration, Hadas Dabas
Glycolysis-Induced Acidification Links Mitochondrial Deficiency To Axon Degeneration, Hadas Dabas
Yale Graduate School of Arts and Sciences Dissertations
Axons extend far from the neuronal soma and depend on local energy metabolism to sustain signaling and structural integrity. Mitochondria are normally abundant in axons, where they provide numerous utilities. In many neurodegenerative diseases, however, mitochondrial function or trafficking is impaired, but the mechanisms linking mitochondrial loss to axon degeneration remain unclear.In this dissertation, I use C. elegans mitochondrial trafficking mutants, in which axons completely lack mitochondria, to define the metabolic basis of degeneration. I find that glycolysis, typically viewed as a protective energy source, unexpectedly promotes axon breakdown. Elevated glycolytic flux in axons without mitochondria leads to accumulation of …
Molecular Investigation Of Signaling Molecules Involved In Cerebrovascular Disorders, Kimberly Jean Vish
Molecular Investigation Of Signaling Molecules Involved In Cerebrovascular Disorders, Kimberly Jean Vish
Yale Graduate School of Arts and Sciences Dissertations
The most common forms of cerebrovascular malformations are brain arteriovenous malformations (AVM), often caused by genetic mutations in the EphB4-p120RasGAP signaling pathway, and cerebral cavernous malformations (CCM), often caused by genetic mutations in the CCM signaling pathway. These pathways are well studied, but there are clear deficiencies in the molecular level understanding of how signals are transduced. Relevant to AVM, the GTPase activating protein (GAP) for Ras, p120RasGAP, is necessary for downregulating Ras signaling during vascular development, and loss of its activity is associated with impaired cerebrovascular development. In my thesis, I investigate how p120RasGAP uses its Src-homology 2 (SH2) …
Studies On The Structural Basis Of Oxygenic Photosynthesis, David Flesher
Studies On The Structural Basis Of Oxygenic Photosynthesis, David Flesher
Yale Graduate School of Arts and Sciences Dissertations
Oxygenic photosynthesis — performed on all seven continents by green plants, algae, and cyanobacteria — supports the global biome through its ability to capture and store light energy. This is achieved through a series of protein complexes collectively known as the photosynthetic apparatus. During my PhD research, I’ve investigated the structural basis for how these protein complexes capture this light energy and transduce it to redox energy. My thesis work, summarized in this dissertation, can be grouped in two broad research themes: (i) structural studies on Nature’s water oxidation reaction, explored in Part I of this dissertation; and (ii) the …
Cell State Dependent Strategies For Resolving Fundamental Properties Of Ligands Via Receptor Processes, Andrew Goetz
Cell State Dependent Strategies For Resolving Fundamental Properties Of Ligands Via Receptor Processes, Andrew Goetz
Yale Graduate School of Arts and Sciences Dissertations
Ligands may carry information through features such as their concentration, identity, and spatial distribution. Cells that can resolve these properties gain access to additional dimensions of information which may be beneficial as certain ligand properties possess unique features (e.g., ligand identity does not disperse with distance the way concentration does). Cells can accomplish this, at least in part, through the use of signaling cascades initiated by membrane receptors which bind to the ligand and activate downstream processes. The properties of these signaling cascades depend on the "state" of the cell (a property encompassing important cell features like protein levels and …
Coordinated Wnt And Shh Signaling In Hair Follicle Mesenchyme Development And Regeneration, Yiqun Jiang
Coordinated Wnt And Shh Signaling In Hair Follicle Mesenchyme Development And Regeneration, Yiqun Jiang
Yale Graduate School of Arts and Sciences Dissertations
Developmental morphogenesis requires cells to balance proliferation with differentiation, often regulated by multiple signaling pathways. While most studies consider these pathways as additive, less is known about how they interact to regulate fate transitions. In this dissertation, I use the hair follicle dermal condensate (DC), the first differentiated mesenchymal population of the skin with the ability to instruct new hair growth, to study morphogens interact to regulate the dermal mesenchyme.Wnt and SHH are necessary and sufficient for DC formation, during which cell cycle exit with molecular DC gene expression occur simultaneously. Interestingly, high Wnt alone is sufficient to induce cell …
Smart Synthesis: Harnessing Electrochemistry To Enhance Catalytic Water Treatment, Aidan Francis Meese
Smart Synthesis: Harnessing Electrochemistry To Enhance Catalytic Water Treatment, Aidan Francis Meese
Yale Graduate School of Arts and Sciences Dissertations
Catalytic water treatment technologies hold great promise for degrading even the most recalcitrant contaminants of emerging concern (CECs). Heterogeneous catalytic processes are especially appealing, providing the benefits of easy catalyst recovery and reduced risk of secondary pollution. However, heterogeneous reactions often suffer from mass transfer limitations, and the development of catalyst materials that are sufficiently active, selective, and stable under the conditions necessary for pollutant degradation remains challenging. Furthermore, synthesis of catalyst materials, particularly those with desirable catalytic properties and novel architectures, are often time- and energy-intensive and involve expensive materials and/or equipment. In this work, we address these challenges …
Nanoporous Inp And Its Application In Short-Wave Infrared Vertical-Cavity Surface Emitting Lasers, Chenziyi Mi
Nanoporous Inp And Its Application In Short-Wave Infrared Vertical-Cavity Surface Emitting Lasers, Chenziyi Mi
Yale Graduate School of Arts and Sciences Dissertations
The Short-Wave Infrared (SWIR) range is a crucial wavelength window with a wide range of applications. Just to name a few, it covers the important telecommunication bands, provides advantages in bio-sensing and there are emerging applications recently such as noninvasive glucose monitoring, eye-safe 3D sensing and Si photonics. The development of SWIR vertical cavity surface emitting lasers (VCSELs) has been ongoing for more than 30 years but has not yet led to commercialization. The main reason is that it hasn't been easy to build highly reflective distributed Bragg reflectors (DBRs). Unlike the GaAs systems, materials lattice-matched to InP suffers from …
Streamlining Drug Discovery With The Aid Of Artificial Intelligence And Physics-Based Modeling, Anastasia Saar
Streamlining Drug Discovery With The Aid Of Artificial Intelligence And Physics-Based Modeling, Anastasia Saar
Yale Graduate School of Arts and Sciences Dissertations
The drug discovery pipeline is both expensive and prone to high attrition rates with many compounds failing in late-stage clinical trials. Computer-aided drug design (CADD) has emerged as a pivotal part of the pipeline to mitigate these challenges by enabling earlier and more cost-effective assessment of compound viability. This work focuses on two major aspects of CADD: absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions and free energy calculations. First, neural network models are developed for the prediction of aqueous solubility and cytotoxicity, two key contributors to late-stage drug attrition. Ensemble models of graph convolutional networks (GCNs) and graph attention …
Development Of The Human Brain Networks During Infancy, Huili Sun
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 …
A Dimensional Approach To Assessing The Effects Of Early-Life Stress On Mental Health Across Development, Emily Meryl Cohodes
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 …
Causal Inference For Environmental And Text-Based Interventions, Megan Ayers
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 …
An Ecological Approach For Understanding The Influence Of Threats In Youth’S Social Environments, May Isabella Conley
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 …
The Roles Of Terrestrial Weathering And Marine Bioturbation In Shaping Earth’S Surface Habitability Across Time, Brian Beaty
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, …
Transition Metal-Catalyzed N–H Functionalization For The Synthesis Of Nitrogen Heterocycles, Jenna Cailin Cordial Molas
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 …
Unraveling The Phenotypic Plasticity In Glioblastoma, Chunxiao Ren
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 …
Molecular Mechanisms Of Kras Regulation And Resistance In Pancreatic Ductal Adenocarcinoma, Xiangyu Ge
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 …
Vaccine-Induced Immunity: Insights Into Sars-Cov-2 And Orthopoxvirus, Valter Monteiro
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 …
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.
Chemosensory Variation Within And Across Bacterial Species, Jeremy Philippe Moore
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 …
Investigations Of Allosteric Mechanisms In Proteins, Brandon C. Allen
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 …
Limbic Circuit Control Of Stress And Neuroinflammation, Alexa Renee Soares
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 …
Neurocognition In Youth With Prediabetes, Jade Ivey Quillian
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 …
Functional Roles Of Histone H3 Lysine 4 Methylation At Regulatory Elements, Haoming Yu
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 …