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Full-Text Articles in Entire DC Network
Mechanistic Insights Into Protein-Mediated Lipid Transfer, Zhouping Hong
Mechanistic Insights Into Protein-Mediated Lipid Transfer, Zhouping Hong
Yale Graduate School of Arts and Sciences Dissertations
In eukaryotes, most lipids are synthesized in the endoplasmic reticulum (ER) and then redistributed from there to other organelles, each of which has a distinct membrane lipid composition. We have long known that lipids can be trafficked between organelles by vesicles. More recently, it has become clear that there is another major means of lipid redistribution mediated by lipid transport proteins (LTPs) that localize to so-called membrane contact sites (MCSs), where two organelles come into close apposition. LTPs have a hydrophobic cavity to solubilize the lipid fatty acyl tail. They work as either shuttles that ferry 1-2 lipid molecules at …
Integrative Analysis Of Bulk And Single Cell Rna-Seq Modalities In The C. Elegans Nervous System, Alec Barrett
Integrative Analysis Of Bulk And Single Cell Rna-Seq Modalities In The C. Elegans Nervous System, Alec Barrett
Yale Graduate School of Arts and Sciences Dissertations
Nervous systems are complex networks, which requires a diverse set of neurons to detect, process, learn from, and respond to external stimuli. This neuronal diversity is directly tied to diversity of gene expression networks across the nervous system. Here I present my work, as part of the CeNGEN consortium, mapping gene expression across the entire nervous system in the hermaphroditic nematode C. elegans. I outline a strategy for sequencing RNA from individual neurons using bulk RNA-seq after cell sorting, and demonstrate a species-specific reagent for ribosomal depletion for ultra-low input RNA-seq library preparation. I describe a collaborative effort to sequence …
Environmental Exposures From The Local To The Global: A Comparison Of The Experiences And Consequences Of Exposure Among The Qom Of Formosa, Argentina, And Residents Of New Haven, Connecticut, Carlye Chaney
Yale Graduate School of Arts and Sciences Dissertations
Exposure to endocrine disrupting chemicals and other environmental contaminants is globally ubiquitous and can have adverse consequences on health throughout the lifespan. In this project, I investigated the experiences and consequences of environmental contaminant exposure for maternal and infant health in two places that differ environmentally, politically, and socioeconomically –Namqom in Formosa, Argentina, and New Haven, Connecticut. Specifically, I hypothesized that environmental contaminant exposure influences human well-being and physiology, as assessed from the human milk and urine metabolome, through changes in the hypothalamic-pituitary-gonadal (HPG) axis in both infancy and adulthood.I first investigated the local context, both historical and present, that …
Machine Learning For Ordinal Time Series To Understand Disease Progression, Jonathan D. Koss
Machine Learning For Ordinal Time Series To Understand Disease Progression, Jonathan D. Koss
Yale Graduate School of Arts and Sciences Dissertations
Measuring symptoms over time is an essential part of clinical research. Differencesin symptom progression are often used to better understand diseases and identify treatment targets. In clinical trials, change in symptoms is always a key finding. Many symptoms, however, are often difficult to measure empirically, particularly in neurological and psychiatric conditions. In these cases, clinical questionnaires which measure symptoms on ordinal scales are used. When longitudinal clinical studies use these questionnaires, noisy ordinal time series are created. Current approaches to the analysis of these questionnaires do not properly account for the noise or the ordinality and often all questions are …
Disentangling Sequence Constraints On The Cofilin N-Terminal Phosphorylation Site, Joel Andrew Sexton
Disentangling Sequence Constraints On The Cofilin N-Terminal Phosphorylation Site, Joel Andrew Sexton
Yale Graduate School of Arts and Sciences Dissertations
Eukaryotic cells require cofilin, also known as actin depolymerizing factor (ADF), to regulate the severing and rapid reorganization of actin filaments during processes such as cell division and migration. Cofilin severing activity is facilitated by a binding interaction between actin and the cofilin N-terminus. The cofilin N-terminus contains a phosphorylation site that reversibly inhibits actin severing when phosphorylated by members of the LIM kinase (LIMK) family. These two functions of the N-terminus, actin severing and phospho-regulation, converge to promote strict evolutionary conservation of a Ser-Gly-Val/Ile/Met/Thr motif, but how the N-terminal motif conforms and contributes to these two requirements has remained …
The Role Of Laminin In A Model Of Maternal Antiviral Immune Activation During Early Placental Development, Emily Kay Condiff
The Role Of Laminin In A Model Of Maternal Antiviral Immune Activation During Early Placental Development, Emily Kay Condiff
Yale Graduate School of Arts and Sciences Dissertations
During pregnancy, the maternal immune system must strike a delicate balance between immune tolerance to prevent rejection of the allogeneic fetus and immune activation to support tissue remodeling and anti-pathogen responses. From the first days of pregnancy and implantation to the development of the mature placenta, fetal trophoblasts rapidly invade the maternal uterine decidua and facilitate tissue reorganization through closely regulated mechanisms of maternal-fetal crosstalk. The extracellular matrix, and particularly the basement membrane protein laminin, is an essential mediator of this process. In this thesis, I describe a model of γδ T cells responding to viral inflammation and causing changes …
Meaning And Meaninglessness: The Global Standup Explosion, Adam Valen Levinson
Meaning And Meaninglessness: The Global Standup Explosion, Adam Valen Levinson
Yale Graduate School of Arts and Sciences Dissertations
This dissertation investigates the social and cultural significance of the global standup explosion. An unignorable social fact — viewers of more than ten standup specials jumped 60% just between 2018-19, at least half of Netflix users have watched at least one, comedy clubs are their own pandemic — the live comedy phenomenon offers a novel chance to analyze large-scale cultural attitudes and trends. The analysis explores distinct aspects (scales) of humor in three chapters. Chapter One statistically analyzes specific jokes and their reception, surveying whether they are found funny and offensive by respondents. The study reveals that individual reactions to …
The Essential Protein Sts1 Facilitates 26s Proteasome Nuclear Import By A Unidirectional Mechanism In Saccharomyces Cerevisiae, Carolyn Allain Breckel
The Essential Protein Sts1 Facilitates 26s Proteasome Nuclear Import By A Unidirectional Mechanism In Saccharomyces Cerevisiae, Carolyn Allain Breckel
Yale Graduate School of Arts and Sciences Dissertations
Maintenance of the delicate balance between protein translation and degradation is imperative to preserving proper cellular homeostasis. The ubiquitin-proteasome system represents one of the major pathways for protein quality control and is conserved across eukaryotes. The proteasome is a large protein complex that is responsible for proteolysis of various degradation target proteins, and most cellular proteasomes are localized to the cell nucleus. In the budding yeast Saccharomyces cerevisiae, proper localization of the proteasome to the nucleus is essential to viability; therefore, the mechanism by which proteasomes enter the nucleus is also of considerable interest. Here, we show that the essential …
Ship164 Is A Lipid Transfer Protein That Coordinates Membrane Trafficking In The Endolysosomal System, Patreece H. Suen
Ship164 Is A Lipid Transfer Protein That Coordinates Membrane Trafficking In The Endolysosomal System, Patreece H. Suen
Yale Graduate School of Arts and Sciences Dissertations
A defining feature of cells are membrane bilayers that separate them from their environment and, in eukaryotic cells, delineate intracellular organelles with specialized functions. In eukaryotes, the lipid composition of different organellar membranes varies both in terms of bulk and signaling lipids, lending these membranes different biochemical and biophysical characteristics. Yet most lipids are synthesized in the endoplasmic reticulum (ER), then redistributed asymmetrically from there via mechanisms that remain poorly understood. Lipid redistribution is mediated in part by lipid transport proteins that operate at membrane contact sites, where organelles are closely apposed but do not fuse, moving lipids between their …
A Novel Microbial Source Of Stochasticity In Microbiota-Driven Diseases, Yi Yang
A Novel Microbial Source Of Stochasticity In Microbiota-Driven Diseases, Yi Yang
Yale Graduate School of Arts and Sciences Dissertations
Gut commensals with the capacity to translocate across the intestinal barrier can drive the development of diverse immune-mediated diseases. However, the key factors that dictate bacterial translocation remain unclear. Recent studies have revealed that gut microbiota strains can adapt and evolve throughout the lifetime of the host, raising the possibility that changes in individual commensals themselves over time may impact their propensity to elicit inflammatory disease. Here we show that within-host evolution of the model gut pathobiont Enterococcus gallinarum facilitates bacterial translocation and initiation of chronic inflammation. Using a combination of in vivo experimental evolution and comparative genomics, we found …
Context Dependency Of Eco-Evolutionary Feedbacks In Alewife (Alosa Pseudoharengus), Matthew Michael Dougherty
Context Dependency Of Eco-Evolutionary Feedbacks In Alewife (Alosa Pseudoharengus), Matthew Michael Dougherty
Yale Graduate School of Arts and Sciences Dissertations
Eco-evolutionary feedbacks describe how ecology and evolution reciprocally act upon each other to bring about adaptive evolution over ecological timescales. Two conditions or steps define eco-evolutionary feedbacks: (1) an organism’s phenotype must interact strongly with its environment so as to construct or structure it, and subsequently, (2) the newly constructed environment must introduce new selection pressures that result in the population’s adaptive evolution. Eco-evolutionary feedbacks have been discovered in numerous taxa, including fish, bacteria, cancer cells, and plants. Despite the growing number of examples, the prevalence of eco-evolutionary feedbacks in nature is still unknown. Each step of an eco-evolutionary feedback …
Spatiotemporal Regulation Of Atypical B Cell Memory, Wenzhi Song
Spatiotemporal Regulation Of Atypical B Cell Memory, Wenzhi Song
Yale Graduate School of Arts and Sciences Dissertations
The immune system functions as the major defender against pathogenic challenges but can also cause damage to host tissues. Humoral immunity, mediated by diverse B cell subsets, is a crucial component of immunological memory and forms the basis of long-lasting immunological protection induced by most existing vaccines. On the flip side, B cell response is a key link in the cascade of events leading to autoimmunity and immunopathology. Atypical memory B cells (also known as age-associated B cells, hereafter ABCs) is a recently described population of B cells strongly associated with pathological immune functions, both in patients with autoimmune diseases …
Children's Intuitive Theories Of Group Collaboration, Emory Richardson
Children's Intuitive Theories Of Group Collaboration, Emory Richardson
Yale Graduate School of Arts and Sciences Dissertations
Cumulative culture has amplified human knowledge far beyond what any individual learner could teach themselves or even be taught in a single lifetime: a doctor can learn to drive a car without having to literally reinvent the wheel. In some cases, complex artifacts can be produced through the accumulation of incremental improvements over time; but frequently, they’re a product of more or less direct collaboration. But collaboration comes with costs of its own. This thesis is about the cognitive capacities individuals need for collaborative learning to be worth the trouble. I first describe a set of interrelated obstacles to the …
Spectroscopic Studies Of Photochemical Proton-Coupled Electron Transfer Reactions, Laura Fei Cotter
Spectroscopic Studies Of Photochemical Proton-Coupled Electron Transfer Reactions, Laura Fei Cotter
Yale Graduate School of Arts and Sciences Dissertations
Proton-coupled electron transfer (PCET) reactions are integral to numerous energy conversion processes, including photosynthesis, fuel cells, and cellular respiration. The coupling of proton transfer (PT) with electron transfer (ET) influences the overall energetic landscape and mechanism of the PCET reaction. Developing a better understanding of the thermodynamics and kinetics of PCET reactions could enable the design of more efficient technologies for energy storage and conversion. However, it is often challenging to study PCET within naturally occurring systems, as many of these reactions are part of larger, complex biological processes. Well-defined, small molecule model systems, where variables such as reaction driving …
Pig Induced Pluripotent Stem Cells As A Preclinical Model For Cardiovascular Tissue Engineering, Luke Daniel Batty
Pig Induced Pluripotent Stem Cells As A Preclinical Model For Cardiovascular Tissue Engineering, Luke Daniel Batty
Yale Graduate School of Arts and Sciences Dissertations
The leading cause of death in the United States and worldwide is heart disease, a category that includes a variety of cardiovascular diseases both inherited and acquired. Because of the urgency and complexity of the problem, copious research has been conducted on the causes and progression of these diseases with an eye towards therapeutic solutions to their manifestations. For diseases that require tissue replacement, such as vessel implantation in coronary artery blockage or single ventricle disease, cardiovascular tissue engineering (CVTE) has emerged as an attractive way to provide high quality implantable therapeutics. CVTE is a field using chemistry, biology, and …
Evaluating The Impact Of Perceived Discrimination On Patient-Reported Outcomes, Outpatient Care Utilization, Inflammatory Markers, And Lipid Profiles In Young Adults Hospitalized For Acute Myocardial Infarction (Ami), Andrew Arakaki
Yale Graduate School of Arts and Sciences Dissertations
Perceived discrimination, defined as experiences of indignities, microaggressions, and other types of mistreatments that privileged groups enact towards members of disadvantaged groups, is a chronic stressor that has been shown to be associated with risk factors for cardiovascular disease and incident cardiovascular events. Previous studies have hypothesized that perceived discrimination adversely affects cardiovascular health through multiple physiological, behavioral, and psychosocial pathways. However, the impact of perceived discrimination on outcomes and healthcare utilization among young adults (age 18 – 55 years) hospitalized for acute myocardial infarction (AMI) is largely unknown. This work leveraged data from the VIRGO study (Variation in Recovery: …
The Shape Of Things: Reading Culture Through Form In The Wilhelmine And Weimar Republic, Sophie Duvernoy
The Shape Of Things: Reading Culture Through Form In The Wilhelmine And Weimar Republic, Sophie Duvernoy
Yale Graduate School of Arts and Sciences Dissertations
This dissertation explores the historical transformation of the concept of form in Germany between 1850 and 1930 into a dynamic term that intellectually enabled the project of liberal cultural critique. It describes how form was reconceived from a static shaping force with Platonic overtones into a mobile, dynamic means of structuration that allowed for internal difference and change. The dynamization of form allowed it to become a central term in the renewal of epistemology, and in turn, allowed philosophy to move into the study of culture and its material products. The project is based around three key figures – the …
Host Immunity And Receptor Expression Determine Rna Virus Pathogenesis, Madison Scott Strine
Host Immunity And Receptor Expression Determine Rna Virus Pathogenesis, Madison Scott Strine
Yale Graduate School of Arts and Sciences Dissertations
Identifying host factors essential for viral infections has the potential to reveal novel mechanisms of viral pathogenesis and immune escape. Here, we use two mucosal positive-sense RNA viruses – murine norovirus (MNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – as probes to investigate mechanisms of viral pathogenesis at mucosal barrier surfaces. Among noroviruses, murine norovirus (MNV) is a model for human norovirus and a tractable system to elucidate fundamental mechanisms of viral tropism and immune evasion. The strain MNVCR6 infects rare chemosensory epithelial cells called tuft cells, which are dispensable for the canonical non-persistent strain MNVCW3. Herein, we …
Delineating Novel Checkpoints In Metabolic Syndromes, Jonathan Sun
Delineating Novel Checkpoints In Metabolic Syndromes, Jonathan Sun
Yale Graduate School of Arts and Sciences Dissertations
The global rise in obesity and overnutrition has rapidly increased diagnosedmetabolic syndromes, including fatty liver disease and hypercholesterolemia. This growing burden of metabolic diseases elicits an immense health and economic burden on society, as metabolic syndromes are significant risk factors for co-morbidities such as cancer and heart failures, leading to an attributable cost of $147 billion in US healthcare spending. Given this, it is of high importance to uncover the dynamic metabolic programs that drive the progression of these metabolic syndromes toward end-stage diseases. Metabolic rewiring during overnutrition can regulate the expression of feedback loops, referred hereupon as metabolic checkpoints, …
Internal And External State-Dependent Modulation Of Visual Perception And Cortical Processing, Mitchell Paul Morton
Internal And External State-Dependent Modulation Of Visual Perception And Cortical Processing, Mitchell Paul Morton
Yale Graduate School of Arts and Sciences Dissertations
The ability of humans and other animals to perceive and understand stimuli in the visual world is substantially modulated by internal and external states. Internal states, such as arousal and attention, influence how we can perceive stimuli even when the physical characteristics of that stimulus are constant. Additionally, external configuration of objects in the visual world can influence our perceptual abilities, even when other characteristics remain unchanged. We first studied internal state-dependent modulation of perception by examining what states were associated with accurate perception at threshold, a condition in which the physical properties of a stimulus remain constant, and a …
Cpg Island Turnover Predicts Evolutionary Change In Enhancer Activity, Acadia Kocher
Cpg Island Turnover Predicts Evolutionary Change In Enhancer Activity, Acadia Kocher
Yale Graduate School of Arts and Sciences Dissertations
Enhancers play a crucial role in specifying when and where genes are expressed, and changes in their function have been shown to influence trait evolution. However, it remains challenging to determine the sequence features that contribute to variation in enhancer function across species. Here I assessed the contribution of orphan CpG islands (oCGIs), which are intronic and intergenic regions enriched in CpG dinucleotides, to enhancer evolution. I identified oCGIs in nine mammalian species and integrated them with maps of enhancer activity-associated histone modifications (H3K27ac, H3K4me3, H3K4me2, and H3K4me1), finding that active enhancers are overrepresented at oCGIs. I found widespread turnover …
Helicobacter Pylori Catabolism Of Host Glutathione: An Emerging Mechanism Of Nutritional Virulence, Maia Joi Baskerville
Helicobacter Pylori Catabolism Of Host Glutathione: An Emerging Mechanism Of Nutritional Virulence, Maia Joi Baskerville
Yale Graduate School of Arts and Sciences Dissertations
Mammalian cells synthesize the antioxidant glutathione (GSH) to shield cellular biomolecules from oxidative damage. Certain bacteria, including the gastric pathogen Helicobacter pylori, can perturb host GSH homeostasis. H. pylori infection significantly decreases GSH levels in host tissues, which has been attributed to the accumulation of reactive oxygen species in infected cells. However, the precise mechanism of H. pylori-induced GSH depletion remains unknown, and tools for studying this process during infection are limited. We developed an isotope-tracing approach to quantitatively monitor host-derived GSH in H. pylori-infected cells by mass spectrometry. Using this method, we determined that H. pylori catabolizes reduced GSH …
Robotic Fabrics Enabled By Functional Fibers And Responsive Materials, Trevor Luke Buckner
Robotic Fabrics Enabled By Functional Fibers And Responsive Materials, Trevor Luke Buckner
Yale Graduate School of Arts and Sciences Dissertations
The burgeoning field of soft robotics brings with it a wave of new and nontraditional materials to the robotics repertoire. New advances are being made using elastomers, foams, and gels as the core robotic substrate, giving rise to entirely new avenues of robot capability. Now more than ever, machines can be designed with extreme flexure, stretch, and even volume change as key functions, opening up a design space that rigid machinery cannot easily occupy. In this dissertation, I build upon the use of atypical materials, introducing fabrics as a new soft robotics platform. Fabrics are thin, have a fiber-based structure, …
Developing E-Covery, An App-Based Intervention To Support Individuals With Co-Occurring Problem Alcohol And Opioid Use, Adam Viera
Yale Graduate School of Arts and Sciences Dissertations
Background: Co-occurring alcohol and opioid use are an under-addressed factor associated with increased drug overdose mortality. There are many challenges in the treatment of co-occurring alcohol and opioid use with most individuals in need of substance use treatment not receiving treatment services. Those that do have a high likelihood of returning to use, with resumption of use following treatment episodes increasing risk for overdose. Contextual factors have been recognized as triggers of cravings to return to use. Few interventions work to address the effect these factors have on individuals in early recovery, with locations serving as a particularly challenging trigger. …
Peptidic Environments For Site- And Enantioselective Nitrene Transfer, Naudin Van Den Heuvel
Peptidic Environments For Site- And Enantioselective Nitrene Transfer, Naudin Van Den Heuvel
Yale Graduate School of Arts and Sciences Dissertations
Metal-catalyzed nitrene transfer remains one of the most powerful methods to introduce nitrogen into minimally functionalized organic frameworks. In recent years, there have been significant advances in the development of catalytic systems to achieve these transformations selectively in increasingly complex environments. Despite this, full site- and stereocontrol remains challenging in many cases. This work describes our contributions to the field of selective metal-catalyzed nitrene transfer, which involve the use of peptide- based environments surrounding the catalytic metal. Chapter 1 places this work in a larger context, introduces the topics of homogeneous catalysis and nitrene transfer, and discusses methods to enable …
Necroptotic Cell Death Sensing Directly Promotes Fibroblast And Macrophage Inflammatory Effector Responses, Lindsey Demaree Hughes
Necroptotic Cell Death Sensing Directly Promotes Fibroblast And Macrophage Inflammatory Effector Responses, Lindsey Demaree Hughes
Yale Graduate School of Arts and Sciences Dissertations
Programmed cell death is carried out by a wide array of molecularly executed pathways. We postulated that the ensuing tissue effector response to cellular corpses reflects this diversity in cell death modalities. Importantly, the demise of a cell does not immediately coincide with the termination of its capacity to relay information to the surrounding tissue. We have previously described that apoptotic cell death in the lung, in the context of helminth infection and an IL-4-rich environment, is sensed by macrophages to direct the resolution of inflammation and induction of a tissue repair gene expression program. In organs like the gut, …
Socially Responsible Operations: Essays On Public Sector Management, Yu Shi
Socially Responsible Operations: Essays On Public Sector Management, Yu Shi
Yale Graduate School of Arts and Sciences Dissertations
This dissertation studies a range of topics in social responsibility and the operations of public sector. The three essays presented in this dissertation are intended to provide normative recommendations to better inform public-policy decisions, through the examination of private-public sector interactions. Chapter 1 focuses on the enforcement of environmental/labor regulations and highlights the role of self-inspection by the regulated entity. Chapters 2 and 3 focus on the management of the Australian blood bank. The chapters identify a causal relationship between blood age and hospital demand, and propose novel remedies to improve the blood bank's supply chain. Chapter 1, "Competing to …
Pediatric Cerebral Arachnoid Cysts Are Genetically-Encoded Harbingers Of Neurodevelopmental Pathology, Garrett Allington
Pediatric Cerebral Arachnoid Cysts Are Genetically-Encoded Harbingers Of Neurodevelopmental Pathology, Garrett Allington
Yale Graduate School of Arts and Sciences Dissertations
Cerebral arachnoid cysts (ACs) are among the most common human developmental brain lesions, yet, because ACs are not possible to reliably model in lower mammals, the pathogenic mechanisms driving AC formation remain poorly understood. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 proband-parent exome trios, 152,898 brain and meningeal single-cell transcriptomes, and artificially-intelligent natural language processor data of proband medical records. We found damaging de novo variants (DNVs) were highly enriched in AC probands versus controls (P = 1 .57 × 10-33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes are enriched for …
Human Cerebral Organoids For Modeling Neurodevelopmental And Infectious Disease, Ce Zhang
Human Cerebral Organoids For Modeling Neurodevelopmental And Infectious Disease, Ce Zhang
Yale Graduate School of Arts and Sciences Dissertations
Human cerebral organoids are three-dimensional cultures of brain-like tissue that model early human fetal cortical development. They recapitulate important neurodevelopmental events, including neural progenitor cell expansion, formation of a well-defined outer radial glia layer resembling the human outer subventricular zone, neurogenesis, and neuronal migration. In this study, I utilize cerebral organoids generated from induced pluripotent stem cells as a human-specific platform to investigate the mechanisms underlying neurodevelopmental and infectious central nervous system disease. The immediate application for cerebral organoids is to address the global healthpandemic of COVID-19 and its associated neurological manifestations. I demonstrate that exposure of cerebral organoids to …
Evaluating Novel Diagnostics In Covid-19 And Malaria, Jillian Armstrong
Evaluating Novel Diagnostics In Covid-19 And Malaria, Jillian Armstrong
Yale Graduate School of Arts and Sciences Dissertations
Although there have been significant improvements in recent decades, emerging and established infections continue to represent a significant contribution to the global burden of disease. Diagnostics play a critical role at the population level for infectious disease surveillance and at the individual level for patient care decisions. However, adequate diagnosis can be challenging in high-risk populations and resource-limited settings. In my dissertation, I present work on repeat positive SARS-CoV-2 testing in nursing home residents and the detection and differentiation of hemozoin, a parasite-derived biomarker, produced by human malaria species. In the first year of the COVID-19 pandemic, little was known …