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Human Engineered Pulsatile Conduits Using Engineered Heart Tissue Of Defined Composition And Fiber Orientation, Christopher William Anderson Apr 2022

Human Engineered Pulsatile Conduits Using Engineered Heart Tissue Of Defined Composition And Fiber Orientation, Christopher William Anderson

Yale Graduate School of Arts and Sciences Dissertations

Tissue engineering and regenerative medicine are relatively new fields that aim to combine principals of chemistry, physics and biology to recreate tissues of the body within lab settings. By utilizing these concepts, novel tissues can be created from entirely biologic material for use as therapeutic replacement tissues. The advent of stem cell technology has been an incredible enabling factor for tissue engineering as a field, especially that of human induced pluripotent stem cells (hiPSCs). hiPSCs are a class of stem cell that may be readily produced using non-invasively derived patient samples that are subsequently transfected with what are commonly known …

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Regulation Of Pi3k/Akt Signaling By The Exocyst Complex, Alexander Michael Anneken Apr 2022

Regulation Of Pi3k/Akt Signaling By The Exocyst Complex, Alexander Michael Anneken

Yale Graduate School of Arts and Sciences Dissertations

The exocyst is a conserved hetero-octameric protein complex responsible for tethering secretory vesicles to the plasma membrane prior to vesicle fusion. The exocyst associates with various factors on both the vesicular and plasma membranes throughout the process of tethering, including small GTPases and the SNARE proteins themselves. As such, these interactions influence not only where the exocyst tethers the vesicle on the plasma membrane, but also how the vesicle ultimately fuses. This theme of conferring spatial control to exocytosis has been central to decades of exocyst research, which over time has implicated the exocyst in myriad cellular processes. Consequently, genetic …

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Evolutionary Dynamics Of Rapid, Microgeographic Adaptation In An Amphibian Metapopulation, Adam Zachary Andis Arietta Apr 2022

Evolutionary Dynamics Of Rapid, Microgeographic Adaptation In An Amphibian Metapopulation, Adam Zachary Andis Arietta

Yale Graduate School of Arts and Sciences Dissertations

Wild organisms can rapidly adapt to changing environments, even at fine spatial scales. This fact prompts hope that contemporary local adaptation may buffer some of the negative anthropogenic impacts to ecosystems. However, there are limits to the pace of adaptation. Understanding the adaptive potential—and limitations—of individual species at fine-resolution is an important task if we hope to accurately predict the repercussions of future climate and landscape change on biodiversity. My dissertation takes advantage of an uncommonly long-observed and closely-studied system to paint a comprehensive picture of evolution over time in association with shifts in ecological contexts. In this dissertation, I …

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Archival Phonetics & Prosodic Typology In Sixteen Australian Languages, Sarah Babinski Apr 2022

Archival Phonetics & Prosodic Typology In Sixteen Australian Languages, Sarah Babinski

Yale Graduate School of Arts and Sciences Dissertations

In naturalistic speech, the phonetic instantiation of phonological categories is often highly variable. Speakers have been observed to converge on patterns of phonetic variation that are consistent within languages but variable cross-linguistically for the same phonological phenomenon. Speakers are evidently sensitive to these sorts of patterns and learn the phonetic variation in a consistent way. Furthermore, the systematicity of this variation suggests that these patterns should change over time systematically as well. Most Australian languages assign lexical stress consistently on the first syllable of the word, raising the question of how the phonetics of stress varies across languages with this …

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Structural Basis Of Flagellar Filament Asymmetry And Supercoil Templating By Leptospira Sheath Factors, Megan Rose Brady Apr 2022

Structural Basis Of Flagellar Filament Asymmetry And Supercoil Templating By Leptospira Sheath Factors, Megan Rose Brady

Yale Graduate School of Arts and Sciences Dissertations

The spirochete family of bacteria, including pathogens such as Borrelia burgdorferi (Lyme disease), Treponema pallidum (syphilis), and Leptospira interrogans (leptospirosis), generates a unique, corkscrew-like form of motility that is crucial for pathogenicity. This motility is driven by flagella that are periplasmic rather than extracellular in nature and are composed of a FlaB core and a FlaA sheath. Purified Leptospira flagellar filaments form tight coils and contain the coiling proteins FcpA and FcpB, in addition to two FlaA isoforms. Loss of either the FlaA or Fcp proteins results in straighter flagella and bacteria that are non-motile and non-pathogenic. I have used …

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Deep Learning For Embedding And Integrating Multimodal Biomedical Data, Matthew Amodio Apr 2022

Deep Learning For Embedding And Integrating Multimodal Biomedical Data, Matthew Amodio

Yale Graduate School of Arts and Sciences Dissertations

Biomedical data is being generated in extremely high throughput and high dimension by technologies in areas ranging from single-cell genomics, proteomics, and transcriptomics (cytometry, single-cell RNA and ATAC sequencing) to neuroscience and cognition (fMRI and PET) to pharmaceuticals (drug perturbations and interactions). These new and emerging technologies and the datasets they create give an unprecedented view into the workings of their respective biological entities. However, there is a large gap between the information contained in these datasets and the insights that current machine learning methods can extract from them. This is especially the case when multiple technologies can measure the …

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Functional Profiling Of Human Commensal Metabolites In Colorectal Cancer And Pain Sensation, Yiyun Cao Apr 2022

Functional Profiling Of Human Commensal Metabolites In Colorectal Cancer And Pain Sensation, Yiyun Cao

Yale Graduate School of Arts and Sciences Dissertations

The gastrointestinal tract contains the largest number and greatest diversity of microbes which are referred to collectively as the gut microbiota. Alterations in microbiota dysbiosis are associated with diverse disease states, including colorectal cancer (CRC), inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). However, the causative mechanisms mediated by the gut microbiota are still to be illustrated. Particularly, the gut commensals encode ~150 times more genes than the human genome and thousands of metabolites that mostly lack functional annotations or structural identification. Therefore, the functional profiling of human commensal metabolites is promising to reveal the molecular mechanisms of the …

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The Role Of Mink1 In Congenital Heart Disease: Regulation Of Spemann Organizer Cell Fate And Multiciliated Cell Specification, Vaughn Colleluori Apr 2022

The Role Of Mink1 In Congenital Heart Disease: Regulation Of Spemann Organizer Cell Fate And Multiciliated Cell Specification, Vaughn Colleluori

Yale Graduate School of Arts and Sciences Dissertations

Congenital Heart Disease (CHD) is the most common birth defect and leading cause of infant mortality, yet molecular mechanisms explaining CHD remain mostly unknown. Sequencing studies are identifying CHD candidate genes at a brisk rate including MINK1, a serine/threonine kinase. However, a plausible molecular mechanism connecting CHD and MINK1 is unknown. Here, we reveal that mink1 is required for proper heart development due to its role in left-right patterning. Mink1 regulates canonical Wnt signaling to define the cell fates of the Spemann organizer and the Left-Right Organizer, a ciliated structure that breaks bilateral symmetry in the vertebrate embryo. To identify …

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Ecosystem Structure And Function In Semiarid Drylands: Exploring The Effects Of Water And Nitrogen Availability In The Great Plains Of The Western United States, Christopher Beltz Apr 2022

Ecosystem Structure And Function In Semiarid Drylands: Exploring The Effects Of Water And Nitrogen Availability In The Great Plains Of The Western United States, Christopher Beltz

Yale Graduate School of Arts and Sciences Dissertations

The global soil carbon (C) pool contains more than twice as much C as the atmosphere, and a large portion of terrestrial C as a whole. Within the global soil C pool, drylands contain 20% of the soil C, in addition to covering 40% of the earth’s surface. Because they are both widespread and a significant reservoir of C, drylands are an important component of the global C cycle. Despite the importance of drylands, ecosystem function can be difficult to predict, with drylands switching from a C source to sink on an interannual basis. This uncertainty in net C flux …

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Evaluating The Role Of The Alzheimer’S Disease Risk Factor Pyk2 In Tau Phosphorylation, Pathology And Related Dysfunction, Alex Harrison Brody Apr 2022

Evaluating The Role Of The Alzheimer’S Disease Risk Factor Pyk2 In Tau Phosphorylation, Pathology And Related Dysfunction, Alex Harrison Brody

Yale Graduate School of Arts and Sciences Dissertations

Alzheimer’s disease (AD), the most common cause of dementia, is the 6th leading cause of death in the US and the 5th leading cause of death in individuals 65 and older. As the global population ages, current projections suggest that AD may overwhelm existing healthcare infrastructure in the 21st century, with cases in the US expected to surpass 13.8 million by 2060. The need for additional disease modifying therapies is paramount, though the development of novel therapeutic strategies for the treatment of AD is limited by our current understanding of AD pathophysiology. The vast majority of AD cases are sporadic …

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Regulation Of Trio Gef1 Activity By The Spectrin Repeats And Cellular Factors, Josie Evelyn Bircher Apr 2022

Regulation Of Trio Gef1 Activity By The Spectrin Repeats And Cellular Factors, Josie Evelyn Bircher

Yale Graduate School of Arts and Sciences Dissertations

The Trio family of proteins consists of Trio, Kalirin, UNC-73 (in Caenorhabditis elegans) and dTrio (in Drosophila). Trio proteins are key regulators of cell morphogenesis and migration, tissue organization, and secretion and protein trafficking in many biological contexts. Recent discoveries have linked Trio and Kalirin to human disease, including neurological disorders and cancer. The genes for Trio family proteins encode a series of large multidomain proteins with up to three catalytic activities and multiple scaffolding and protein-protein interaction domains. As such, Trio family proteins engage a wide array of cell surface receptors, substrates, and interaction partners to coordinate changes in …

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Sick Time: Medicine, Management, And Slavery In Louisiana And Cuba, 1763-1868, Liana Demarco Apr 2022

Sick Time: Medicine, Management, And Slavery In Louisiana And Cuba, 1763-1868, Liana Demarco

Yale Graduate School of Arts and Sciences Dissertations

Modern, capitalist ideas of productivity became central to medicine under slavery. They shaped how physicians treated enslaved patients, crafted a scientific basis for medicine, and conceived of themselves as a profession. Between the late eighteenth century and the mid-nineteenth century, white male physicians in Louisiana and Cuba distinguished themselves from other healers: first, by aligning with Spanish colonialism, and then, by making themselves essential to a new form of plantation management that used clock-time discipline, hierarchical divisions of labor, and complex accounting systems. As these technologies became widespread in sugar and cotton production, they helped planters precisely interpret enslaved health …

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Quantifying Membrane Topology At The Nanoscale, Zachary Ryan Connerty-Marin Apr 2022

Quantifying Membrane Topology At The Nanoscale, Zachary Ryan Connerty-Marin

Yale Graduate School of Arts and Sciences Dissertations

Changes in the shape of cellular membranes are linked with viral replication, Alzheimer's, heart disease and an abundance of other maladies. Some membranous organelles, such as the endoplasmic reticulum and the Golgi, are only 50 nm in diameter. As such, membrane shape changes are conventionally studied with electron microscopy (EM), which preserves cellular ultrastructure and achieves a resolution of 2 nm or better. However, immunolabeling in EM is challenging, and often destroys the cell, making it difficult to study interactions between membranes and other proteins. Additionally, cells must be fixed in EM imaging, making it impossible to study mechanisms of …

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The Role Of Γ-Secretase In Human Papillomavirus Infection, Mac Crite Apr 2022

The Role Of Γ-Secretase In Human Papillomavirus Infection, Mac Crite

Yale Graduate School of Arts and Sciences Dissertations

Human papillomaviruses (HPV) are important pathogens that cause 5% of all human cancers worldwide, including essentially all cases of cervical cancer. Prophylactic vaccines against HPV exist, however these are not widely utilized in all communities, cannot cure existing infection, and do not protect against all subtypes. Therefore, study of HPV infection may lead to important new therapeutics to reduce the spread of the virus and disease burden. In addition, thorough investigation of HPV infection is likely to provide new insights into many aspects of cell biology and biochemistry, as the study of viruses has in the past. HPV requires multiple …

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T Cell Regulation Of Antibody Responses To Infection And Immunization, Jennifer Shuen Chen Apr 2022

T Cell Regulation Of Antibody Responses To Infection And Immunization, Jennifer Shuen Chen

Yale Graduate School of Arts and Sciences Dissertations

T follicular helper (Tfh) cells are the conventional drivers of protective, germinal center (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Even though Tfh-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high-affinity, durable, and reactive against diverse spike-derived epitopes …

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Systematic Screen Of Histone H4 In Arabidopsis Thaliana, Emma Tung Corcoran Apr 2022

Systematic Screen Of Histone H4 In Arabidopsis Thaliana, Emma Tung Corcoran

Yale Graduate School of Arts and Sciences Dissertations

Histones regulate diverse processes in eukaryotes and consequently, can have widespread effects on organismal fitness and development. Histones are a dynamic target for a variety of post-translational modifications (PTMs) and the assessment of histone function has typically been accomplished by mutating enzymes that catalyze and/or recognize these PTMs (i.e., writers and readers, respectively). Although considerable information has been gained in the past several decades by using this strategy, multiple issues such as writer/reader redundancy, unidentified writers/readers of histone PTMs, and writers/readers with additional non-histone targets can preclude the identification of new roles for histones and complicate the assessment of mutant …

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Widespread Association Of The Argonaute Protein Ago2 With Meiotic Chromatin Suggests A Distinct Nuclear Function In Mammalian Male Reproduction, Kimberly Nicole Griffin Apr 2022

Widespread Association Of The Argonaute Protein Ago2 With Meiotic Chromatin Suggests A Distinct Nuclear Function In Mammalian Male Reproduction, Kimberly Nicole Griffin

Yale Graduate School of Arts and Sciences Dissertations

A variety of mechanisms in different compartments of the cell cooperate to regulate gene expression. Some mechanisms are specific to certain compartments, such as the regulation of transcription by changes in histone modifications in the nucleus or protein translation repression in the cytoplasm. Other mechanisms, such as gene regulation by Argonaute proteins, span multiple compartments. Argonaute 2 (AGO2) is the best characterized member of the Argonaute family. It is a ubiquitously expressed, key protein in the cytoplasmic regulation of RNA transcripts, vital to the development and homeostasis of organisms. Recent studies in lower organisms have implicated AGO2 function in the …

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Spatial And Prediction Models For Addressing Challenges In Pediatric Tuberculosis Control And Care, Kenneth Suranga Gunasekera Apr 2022

Spatial And Prediction Models For Addressing Challenges In Pediatric Tuberculosis Control And Care, Kenneth Suranga Gunasekera

Yale Graduate School of Arts and Sciences Dissertations

Tuberculosis (TB) is among the leading causes of global mortality among children <5 years. Each year, over 1 million TB cases occur among children <15 years worldwide, and nearly one quarter of those children die; approximately 80% of those deaths occur among children <5 years. Alleviating the burden of pediatric TB and mortality requires 1) enhanced efforts to prevent transmission to children and 2) treating more children for TB. Targeting resources to children with a known TB exposure has been a cornerstone of the public health response to prevent transmission and detect cases early. Infectious adults must be diagnosed and treated earlier to prevent transmission to their child contacts. Modeling studies suggest that targeting community-level active case-finding to areas with high local transmission intensity may demonstrate population-level reductions in TB incidence. However, obtaining conclusive evidence of concentrated transmission requires access to spatial and genomic data, which is often only available under research conditions in high TB-incidence settings. In chapter 1, I use Bayesian spatial modeling methods to probe routinely collected, age-disaggregated TB notification data to demonstrate that overrepresentation of young child cases co-locate with areas of high local transmission intensity, identified by molecular evidence of transmission from a prospective cohort study in the same setting. This finding suggests that the use of models that leverage widely available notification data should be explored as tools to target case-finding and treatment efforts in high-transmission locations to maximize the direct and indirect benefits of active screening approaches. In chapter 2, I leverage data from a large prevalence survey to investigate a poorly understood form of TB that may frustrate symptom-based active case-finding efforts. Given that modeling estimates suggest that 96% of global childhood mortality due to TB occurs among children not receiving antituberculosis treatment, identifying and treating more cases of pediatric TB provide an opportunity to reduce child mortality. Diagnostic tools for pediatric pulmonary TB are limited by paucibacillary disease in children as well by resource constraints in many high TB-incidence settings. This contributes to poorer treatment outcomes through missed diagnoses and treatment delays. In chapter 3, I describe the analysis of a cohort of children being evaluated for TB from Cape Town, South Africa to demonstrate that a majority of antituberculosis treatment-decisions could be made using clinical evidence alone, without the need for additional diagnostic testing. In chapter 4, I describe the assembly of a large cohort of pediatric TB diagnostic evaluation data sourced from multiple geographically diverse, high TB-incidence settings to develop a prediction model for TB and investigate its validity and generalizability. As part of this work, I describe efforts in partnership with the World Health Organization to operationalize the prediction model as a treatment-decision algorithm to guide the evaluation of children with presumptive pulmonary TB.

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Catalytic Stereoselective Construction Of Terphenyl And Imide Atropisomers By Brønsted Basic Guanidinylated Peptides, Omar Mustapha Beleh Apr 2022

Catalytic Stereoselective Construction Of Terphenyl And Imide Atropisomers By Brønsted Basic Guanidinylated Peptides, Omar Mustapha Beleh

Yale Graduate School of Arts and Sciences Dissertations

This dissertation describes our studies on the development of tetramethylguanidine (TMG)-based peptides as a new class of Brønsted basic catalysts and their application to challenging atroposelective reactions. The enhanced basicity of these peptides has enabled us to access novel reactivity to synthesize scaffolds of interest containing one or more stereogenic axes with high levels of catalyst control.Chapter 1 serves as an introduction to the concept of chirality, with a focus on its connection to the functional role of natural and synthetic molecules. An important subset of chirality is atropisomerism, which arises from restricted bond rotation most commonly between sp2–sp2 atoms. …

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Spectroscopic Probes Of Low-Barrier Proton-Transfer Dynamics, Lidor Foguel Apr 2022

Spectroscopic Probes Of Low-Barrier Proton-Transfer Dynamics, Lidor Foguel

Yale Graduate School of Arts and Sciences Dissertations

The diverse discipline of molecular spectroscopy, which has profited tremendously from the advent of tunable laser sources, has transformed the scientific community’s knowledge of the microscopic world, allowing the study of perplexing quantum-chemical phenomena. Classically-hindered proton transfer, a multidimensional process mediated by nuclear-quantum effects (e.g., potential-barrier tunneling), is a chemical transformation that forms the crux of all acid/base chemistry. Although extensive research efforts have aimed to establish the paradigms that govern this transformation, a full understanding has proven elusive with questions continuing to emerge.Exploring the proton-transfer reaction, and the related concept of hydrogen bonding, has benefitted greatly from investigations of …

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Two Projects Informed By Work On Glucosepane, Robert Donald Hale Apr 2022

Two Projects Informed By Work On Glucosepane, Robert Donald Hale

Yale Graduate School of Arts and Sciences Dissertations

Part 1: Having developed a reaction to synthesize the protein-sugar crosslink glucosepane, we sought to apply our lessons to the synthesis of structurally similar molecules. Marine alkaloids containing a diaminoimidazole-derived core possess intriguing chemical structures and have displayed promising antimicrobial activity in preliminary screens. However, these compounds generally contain densely functionalized multicyclic cores and relatively large numbers of nitrogen atoms. For these reasons, they have proven difficult to synthesize. In this work, we report a novel total synthesis of the marine alkaloid (±)-dibromoagelaspongin. Our key intermediate is a 2,5-diaminoisoimidazole accessed in one step from a suitably protected guanylhydrazine and an …

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Inflammatory Stress Disrupts Endothelial Cell Cholesterol Homeostasis And Increases Srebp2-Dependent Gene Expression To Amplify The Acute Inflammatory Response, Joseph Wayne Montano Fowler Apr 2022

Inflammatory Stress Disrupts Endothelial Cell Cholesterol Homeostasis And Increases Srebp2-Dependent Gene Expression To Amplify The Acute Inflammatory Response, Joseph Wayne Montano Fowler

Yale Graduate School of Arts and Sciences Dissertations

Immunometabolism is a growing field that centers on a core paradigm:perturbations in metabolism alter a cell’s biological response in immunity and, likewise, inflammatory signals, such as cytokines and pathogens, can directly influence cellular metabolism. Although the carbons within cholesterol cannot be used for catabolic energy production, there is a growing appreciation that a similar relationship exists between cholesterol homeostasis and immunity. The majority of this literature is focused on cholesterol dynamics in the context of leukocyte immunobiology. However, the endothelium also plays an important role during the acute inflammatory response. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as …

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Collared Men: Ethnographic Essays On Navigating Race And Status In Everyday Live, Craig Holloway Apr 2022

Collared Men: Ethnographic Essays On Navigating Race And Status In Everyday Live, Craig Holloway

Yale Graduate School of Arts and Sciences Dissertations

The demands of the American society are changing as it develops into a more plural anddiverse society that is characterized by an increasingly specialized economy. Many are willing to say that we are in both a post-industrial and post-racial society that renders equal opportunity for all people. Yet, black men continue to be in relatively peculiar circumstances as people from varied statuses. Status is fluid. And their narrations of their everyday lives and the lives of their counterparts through their own status can at times be strikingly different from mainstream society. These men navigate the demands of race, family and …

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Quantitative Methods For Improving Medical Decision-Making, Margret Erlendsdottir Apr 2022

Quantitative Methods For Improving Medical Decision-Making, Margret Erlendsdottir

Yale Graduate School of Arts and Sciences Dissertations

Innovation in causal inference and implementation of electronic health record systems are rapidly transforming medical care. In this dissertation, we present three examples in which use of methods in causal inference and large electronic health record data address existign challenges in medical decision-making. First, we use principles of causal inference to examine the structure of randomized trials of biomarker targets, which have produced divergent results and controversial clinical guidelines for management of hypertension and other chronic diseases. We discuss four key threats to the validity of trials of this design. Second, we use methods in causal inference for adjustment of …

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The Parkinson’S Gene Vps13c Encodes An Er-Lysosome Lipid Transfer Protein Linking Lysosomal Lipid Homeostasis And Cgas/Sting-Mediated Innate Immunity, William Franklin Hancock-Cerutti Apr 2022

The Parkinson’S Gene Vps13c Encodes An Er-Lysosome Lipid Transfer Protein Linking Lysosomal Lipid Homeostasis And Cgas/Sting-Mediated Innate Immunity, William Franklin Hancock-Cerutti

Yale Graduate School of Arts and Sciences Dissertations

Biallelic loss-of-function mutations in VPS13C cause early-onset Parkinson’s Disease (PD), and the VPS13C locus is a GWAS hit for sporadic PD risk. VPS13C is a member of the VPS13 family, which in humans contains three other proteins, VPS13A, VPS13B, and VPS13D, all with ties to neurological diseases. Mutations in VPS13A cause chorea-acanthocytosis a Huntington’s like syndrome with dysmorphic erythrocytes, mutations in VPS13B cause the neurodevelopmental disorder Cohen syndrome, and mutations in VPS13D cause spastic ataxia with varying presentation. The molecular function of these proteins, why their loss cause neurological diseases, and why they are each associated with distinct diseases despite …

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Does Soil Carbon Support Climate Resilient Agricultural Systems? Searching For Evidence And Developing New Measurement Tools, Daniel Kane Apr 2022

Does Soil Carbon Support Climate Resilient Agricultural Systems? Searching For Evidence And Developing New Measurement Tools, Daniel Kane

Yale Graduate School of Arts and Sciences Dissertations

2022Increasing soil organic carbon (SOC) is frequently promoted as a “win-win” strategy for agricultural management in the face of a changing climate. This framing is based on the notion that building SOC both reduces yield losses/variability by improving soil water dynamics, and that building SOC can contribute to climate change mitigation by reducing atmospheric carbon. While this framing may be useful, relationships between SOC and such outcomes are often poorly described and not quantitative. That is, it’s unclear how much of an improvement to SOC is needed to reduce yield losses, whether or not that effect translates across soil types …

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Stresses Within The Actin Meshwork Control The Turnover Of Fimbrin During Clathrin-Mediated Endocytosis, Xiaobai Li Apr 2022

Stresses Within The Actin Meshwork Control The Turnover Of Fimbrin During Clathrin-Mediated Endocytosis, Xiaobai Li

Yale Graduate School of Arts and Sciences Dissertations

In this dissertation, I investigated the molecular mechanism of clathrin-mediated endocytosis (CME) in fission yeast with a sparse labeling strategy to track endocytic proteins at the single molecule level. CME is involved in a variety of biological processes, such as nutrient internalization and receptor recycling. CME is also a well-conserved biological process from yeast to mammalian cells. During clathrin-mediated endocytosis, about 60 different endocytic proteins are recruited to the endocytic site in a highly reproducible order. During the endocytic event, endocytic proteins assemble into endocytic structures, contributing to membrane invagination and endocytic vesicle formation. Based on the single molecule endocytic …

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Modulating Innate Immunity Via Cd40-Based Myeloid Targeting Can Overcome Anti-Pd1 Therapy Resistance, Irina Krykbaeva Apr 2022

Modulating Innate Immunity Via Cd40-Based Myeloid Targeting Can Overcome Anti-Pd1 Therapy Resistance, Irina Krykbaeva

Yale Graduate School of Arts and Sciences Dissertations

Melanoma is the most aggressive skin cancer and is estimated to have caused 7180 deaths in the United States in 2021. Immune checkpoint inhibitors have revolutionized melanoma treatment over the past decade and dual therapy with anti-PD-1 and anti-CTLA4 inhibitors is currently the standard of care for advanced melanoma. Despite the success of this treatment regimen, resistance remains a significant clinical challenge. Many tumors either do not respond to checkpoint inhibition or develop resistance and ultimately patients experience disease progression. Options for these patients are limited and there is a critical need for new therapies to adequately treat anti-PD1 non-responders. …

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Essays In Financial Economics, Canyao Liu Apr 2022

Essays In Financial Economics, Canyao Liu

Yale Graduate School of Arts and Sciences Dissertations

In my dissertation, I dive into three specific areas in financial economics. Chapter 1 of my Ph.D. dissertation studies how the boom in off-exchange trading at the market close affects the close price discovery. In recent years, investment banks like Goldman Sachs have started a "guaranteed close" business where investors looking to buy or sell shares of a certain stock can get a guarantee from the bank to execute their orders at the close price set on the primary exchange. Using the TAQ data and a quasi-experimental shock from NYSE fee cut, we find that when the fraction of trades …

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An Intellectual History Of Black Literary Discourse 1910-1956, Shayne Mcgregor Apr 2022

An Intellectual History Of Black Literary Discourse 1910-1956, Shayne Mcgregor

Yale Graduate School of Arts and Sciences Dissertations

This dissertation examines the first forty-six years of black literary discourse in the American twentieth century. Beginning with Benjamin Brawley’s The Negro in Literature and Art (1910), I begin the dissertation by identifying black literary discourse’s original goal. In the parlance of the time, the goal of black literary discourse was to solve the “Negro Problem.” I then discuss how further into the twentieth century other critics and artists like James Weldon Johnson and Sterling Brown expanded on Brawley’s ideas in ways that attempted to get at the underlying philosophical thought that underpinned the Problem. By the 1930s a competing …

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