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Statistical Methods For Genetic Prediction Of Complex Traits In Single And Multiple Populations, Geyu Zhou Apr 2022

Statistical Methods For Genetic Prediction Of Complex Traits In Single And Multiple Populations, Geyu Zhou

Yale Graduate School of Arts and Sciences Dissertations

Genetic prediction of complex traits, also known as polygenic risk score (PRS), is constructed by combining the estimated effect sizes of genetic markers across the genome for an individual. PRS has shown great promise in biomedical and clinical research for disease prevention, monitoring and treatment. However, the development of accurate prediction models is challenging due to the wide diversity of genetic architecture, limited access to individual level data, and the demand for computational resources. The broader application of PRS to the general population is further hindered by the poor transferability of PRS developed in Europeans to non-European populations. In this …

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A Robotic Skin-Based Approach To Soft Robotics, Dylan Shah Apr 2022

A Robotic Skin-Based Approach To Soft Robotics, Dylan Shah

Yale Graduate School of Arts and Sciences Dissertations

Typical robots are designed to achieve a single function in a controlled environment and lack the ability to generalize to new tasks. In their quest to build more capable robots, engineers have explored many avenues, including artificial intelligence, reconfigurable robots, and leveraging deformable materials that naturally absorb impacts and conform to objects. In this dissertation, I build upon these latter two bodies of work and introduce reconfigurable robotic skins, working toward the long-term vision of general-purpose robots. By applying the skins to different objects, new functionalities can be obtained, and this layer-based approach to robot design allows engineers to endow …

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Specification And Function Of Developmental Programmed Cell Death, Alison Kochersberger Apr 2022

Specification And Function Of Developmental Programmed Cell Death, Alison Kochersberger

Yale Graduate School of Arts and Sciences Dissertations

Programmed cell death is a crucial process for animal development. Within the developing nervous system neurons are removed through developmental programmed cell death (dPCD), altering neuronal architecture. In the central nervous system (CNS) where dPCD is controlled intrinsically, it is not clear how or why these particular cells are choosing to die since the decision is independent of their context within the nervous system. A similar intrinsically regulated dPCD is found in C. elegans. These cell deaths occur across the lineage and are highly stereotyped, so that the same 131 cells are removed in each individual. We have developed a …

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Development And Delivery Of Genome-Editing Therapies For Improved Glioblastoma Treatment, Ann Tai Chen Apr 2022

Development And Delivery Of Genome-Editing Therapies For Improved Glioblastoma Treatment, Ann Tai Chen

Yale Graduate School of Arts and Sciences Dissertations

Glioblastoma (GBM) is the most common and aggressive type of primary brain cancer. Even with the current standard of care, which consists of surgical resection, radiotherapy, and chemotherapy, GBM patients have a five-year survival rate of only two percent. Several characteristics of GBM hinder the development of effective treatments. First, GBM is highly invasive by nature, making complete surgical resection of the tumor impossible and tumor recurrence inevitable. Second, a subpopulation of cells within GBM, known as cancer stem cells (CSCs), significantly contributes to patient mortality. CSCs are capable of tumor initiation, invasion, and self-renewal, and are resistant to conventional …

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Making The Most Of Polygenic Risk Scores: Risk Decomposition, Cross-Population Prediction, And Clinical Application, Yixuan Ye Apr 2022

Making The Most Of Polygenic Risk Scores: Risk Decomposition, Cross-Population Prediction, And Clinical Application, Yixuan Ye

Yale Graduate School of Arts and Sciences Dissertations

An essential component of human genetics research and precision medicine is to develop robust and accurate disease risk prediction models from genetic data together with other risk factors. Accurate prediction models will have great impacts on disease prevention and early and effective treatment. With the remarkable success achieved by genome-wide association studies (GWAS) in the past 17 years, numerous single-nucleotide polymorphisms (SNPs) associated with complex human traits and diseases have been identified, and various methods, broadly called polygenic risk scores (PRS), have been proposed to utilize GWAS data to predict genetic risk. Compared to risk prediction models that require individual-level …

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Precisely-Engineered Brush Active-Layer And Biomimetic Membranes For Aqueous Separations, Cassandra Porter Apr 2022

Precisely-Engineered Brush Active-Layer And Biomimetic Membranes For Aqueous Separations, Cassandra Porter

Yale Graduate School of Arts and Sciences Dissertations

Currently, a third of the world lives in areas with inadequate or unsafe water supply, with a projected shortage for at least half the population by 2025. With 97% of the Earth’s water contained in the ocean, improving desalination technology and other aqueous separations could be a solution. At present, the best polyamide thin film composite reverse osmosis (TFC-RO) membranes require 2 times the theoretical minimum energy to desalinate. Furthermore, these membranes cannot sufficiently reject in one pass certain solutes, like boron and chloride, to stringent regulatory levels. Additionally, other aqueous separations are important for the pursuit of environmentally sustainable …

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Discovery Of Novel Cancer Immunotherapy Targets With Next Generation Genome Engineering Methods, Jonathan Joon-Young Park Apr 2022

Discovery Of Novel Cancer Immunotherapy Targets With Next Generation Genome Engineering Methods, Jonathan Joon-Young Park

Yale Graduate School of Arts and Sciences Dissertations

Recent advances in immuno-oncology have led to remarkable clinical benefits in a variety of different cancers; however, a large fraction of patients encounter resistance. Identifying novel targets that can improve T cell functionality can therefore broaden the potential of cancer immunotherapy. We developed methods for discovering such targets using CRISPR gene editing technology. First, we created a hybrid genetic screening system where Sleeping Beauty (SB) transposons and single guide RNA cassettes are nested in an adeno-associated virus (AAV) to enable in vivo AAV-SB-CRISPR screens for membrane protein targets in CD8+ T cells in mouse models of glioblastoma. Second, we developed …

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Exploring The Regulation Of Transcriptional Noise In Nf-Κb-Inducible Genes Across Chromatin Environments, Margaret Elise Bullock Apr 2022

Exploring The Regulation Of Transcriptional Noise In Nf-Κb-Inducible Genes Across Chromatin Environments, Margaret Elise Bullock

Yale Graduate School of Arts and Sciences Dissertations

There is a significant amount of cell-to-cell heterogeneity inherent in gene expression. One source of this heterogeneity in eukaryotes is transcriptional bursting, in which a gene promoter infrequently transitions from an inactive state to an active state, producing bursts of transcripts. Cell to cell variations lead to phenotypic differences downstream, which are implicated in immunological function. One model often used to study transcriptional bursting and its phenotypic consequences is human immunodeficiency virus (HIV). The HIV provirus integrates into the host genome, and in a subset of genomic locations, remains silent, or latent, until a perturbation stochastically reactivates viral transcription. Work …

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Cell- And Extracellular Matrix-Based Approaches To Investigate Diabetic Fibroblasts And Improve Wound Healing, Hao Xing Apr 2022

Cell- And Extracellular Matrix-Based Approaches To Investigate Diabetic Fibroblasts And Improve Wound Healing, Hao Xing

Yale Graduate School of Arts and Sciences Dissertations

Chronic wounds are a major complication associated with diabetes. Often presented as foot ulcers, diabetic chronic wounds have a 5-7% prevalence among patients and can lead to serious consequences such as sepsis and amputation. Despite the devastating impact of such complications on patients’ health, current clinical interventions have limited efficacy, in part, due to 1) a limited understanding of the underlying cellular mechanism and 2) the lack of effective engineering solutions that can improve therapy. This thesis addresses these two issues by first investigating dysfunctions and altered molecular mechanisms in diabetic fibroblasts and then creating a novel, decellularized biomaterial enriched …

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Transcriptomic And Cellular Reorganization Of The Human Prefrontal Cortex, Shaojie Ma Apr 2022

Transcriptomic And Cellular Reorganization Of The Human Prefrontal Cortex, Shaojie Ma

Yale Graduate School of Arts and Sciences Dissertations

The expansion and evolutionary specializations of the cerebral cortex, and especially the prefrontal cortex (PFC), are thought to underlie the rich and complex nature of primate and human cognition. The PFC is larger and anatomically more complex in anthropoid primates compared to other analyzed mammals, covering the entire dorsolateral two-thirds of the frontal lobe with a well-defined granular layer 4. The granular dorsolateral PFC (dlPFC) exhibits a broad connectivity with other brain regions. In this setting, dysfunction of the dlPFC also has been implicated in the etiology of many neuropsychiatric disorders. Accordingly, nonhuman primates have been used as model species …

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Biogeochemical And Hydrologic Dynamics In Urban Watersheds: Dissolved Organic Matter Quantity And Quality Changes Across An Urbanization Gradient During Baseflow And Stormflow Conditions In Temperate River Networks, Lisa Christina Weber Apr 2022

Biogeochemical And Hydrologic Dynamics In Urban Watersheds: Dissolved Organic Matter Quantity And Quality Changes Across An Urbanization Gradient During Baseflow And Stormflow Conditions In Temperate River Networks, Lisa Christina Weber

Yale Graduate School of Arts and Sciences Dissertations

Dissolved organic matter (DOM) is a pivotal variable in aquatic ecosystems that can influence multiple factors, including pH, light penetration, stream metabolism, contaminant mobility, and water-treatment efficiency. Past studies on headwaters during baseflow have shown that urbanization is leading to DOM compositional changes; however, more research is needed across a range of stream orders with various upstream land influences, including urban point and nonpoint sources, during baseflow and stormflow to better understand urban DOM dynamics. Urban DOM sources can include leaky septic/sewer systems, treated wastewater effluent, and stormwater runoff. This dissertation examined changes in dissolved organic matter quantity and quality …

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The Brain Bases Of Adaptive And Effortful Goal Pursuit, Lauren M. Patrick Apr 2022

The Brain Bases Of Adaptive And Effortful Goal Pursuit, Lauren M. Patrick

Yale Graduate School of Arts and Sciences Dissertations

Effortful goal pursuit is a complex process relying on the widespread engagement of a distributed set of large-scale brain systems. To date, investigations of the neural mechanisms underlying effortful goal pursuit have primarily focused on cortico-striatal regions of interest, leaving the role of large-scale networks unclear. To address this gap in our understanding, Chapter 1 provides an overview of the current state of knowledge of the brain bases of goal pursuit, examining the circuits and networks implicated, the role of effort costs, persistence and uncertainty, and the underlying structure that may support observed functional patterns. Chapters 2 through 4 report …

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The Dead Receptor Paradox: Insights Into Receptor Tyrosine Kinases With Intracellular Pseudokinase Domains, Joshua B. Sheetz Apr 2022

The Dead Receptor Paradox: Insights Into Receptor Tyrosine Kinases With Intracellular Pseudokinase Domains, Joshua B. Sheetz

Yale Graduate School of Arts and Sciences Dissertations

Receptor tyrosine kinases, or RTKs, are key transducers of cellular signals in metazoans. All RTKs utilize a common architecture—an extracellular ligand binding region, a single-pass transmembrane helix, and an intracellular kinase domain—to control diverse biological processes from cellular metabolism to migration. Our understanding of how most receptors relay signals, however, remains incomplete. A particular puzzle is the collection of ~10% of RTKs that lack catalytic activity in their intracellular kinase homology domains, owing to altered amino acid residues thought necessary for phosphorylation. These so-called pseudokinases are highly evolutionarily conserved and are mutated, overexpressed, or otherwise dysregulated in certain cancers or …

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Riboswitches As Versatile Scaffolds For Ligand Recognition And As Tools For Drug Discovery, Harini Sadeeshkumar Apr 2022

Riboswitches As Versatile Scaffolds For Ligand Recognition And As Tools For Drug Discovery, Harini Sadeeshkumar

Yale Graduate School of Arts and Sciences Dissertations

Riboswitches are highly structured, noncoding RNAs that bind specific ligands to regulate gene expression. To date, over fifty riboswitch classes have been validated to control fundamental biological processes and recognize various coenzymes, nucleotides, signaling molecules, ions, and other important ligands. As described in Chapter 1, careful study of these various riboswitches reveals an incredible diversity in their structural and biochemical characteristics as well as their function. Herein is detailed the efforts to validate long-standing orphan riboswitch classes involved in essential cellular functions such as maintaining nucleotide pools, managing ion toxicity, osmoregulation, and ATP production.The ykkC family of riboswitches are a …

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Spirit Disfigured: The Persistence Of Freedom In The Modernist Novel, Jensen Suther Apr 2022

Spirit Disfigured: The Persistence Of Freedom In The Modernist Novel, Jensen Suther

Yale Graduate School of Arts and Sciences Dissertations

The modernist novel has often been read as an apolitical expression of dissatisfaction with bourgeois modernity. From Kafka to Beckett, the modernists are taken to champion a transcendent condition beyond the straitjacket of society, body, and self. Against this interpretive tradition, my dissertation draws on recent work in philosophy on conceptuality and affect as well as animality and social recognition to develop a new account of the politics of form in modernist fiction. First, the project shows that the idea of a free, self-determining subjectivity is not—as has often been argued—defeated in or left behind by the modernist novel. Rather, …

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Manipulating Neural Dynamics To Tune Motion Computation In Drosophila, Aneysis De Las Mercedes Gonzalez Apr 2022

Manipulating Neural Dynamics To Tune Motion Computation In Drosophila, Aneysis De Las Mercedes Gonzalez

Yale Graduate School of Arts and Sciences Dissertations

Virtually every neuron integrates inputs from excitatory and inhibitory presynaptic cells toproduce its output response. Despite this, it remains poorly understood how the dynamics of these inputs influence the neuron’s output. This is in part due to the difficulty of manipulating neural response dynamics with high specificity. Previous studies have used temperature and pharmacology to alter circuit dynamics (Arenz et al., 2017; Long and Fee, 2008; Suver et al., 2012; Tang et al., 2010), but these methods affect entire circuits, making it difficult to investigate how the dynamics of single excitatory and inhibitory input neurons drive computation. In this study, …

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Towards Tumor Cell Specific Proteolysis Targeting Chimeras: Identification Of Oncogenic Krasg12c, Dcps, And Mage-A3 Degraders, Michael Joseph Bond Apr 2022

Towards Tumor Cell Specific Proteolysis Targeting Chimeras: Identification Of Oncogenic Krasg12c, Dcps, And Mage-A3 Degraders, Michael Joseph Bond

Yale Graduate School of Arts and Sciences Dissertations

Targeted Protein Degradation (TPD) is a nascent, rapidly evolving field in which cellular proteolysis pathways are co-opted to induce degradation of disease-causing proteins. PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional small molecules that recruit an E3 ubiquitin ligase to induce protein degradation. This pioneering technology has paved the way for other bifunctional modalities, like lysosome targeting chimeras (LYTACs) and autophagy targeting compounds (AUTAC/ATTEC), as well as monovalent “glue” degraders, and has drastically changed the drug discovery landscape. In Chapter 1 I review important PROTAC discovery milestones and provide an outlook on the future of PROTAC design. After a general introduction I …

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Imaging Cholinergic And Dopaminergic Systems In Cigarette Smoking And Withdrawal, Katina Constantina Calakos Apr 2022

Imaging Cholinergic And Dopaminergic Systems In Cigarette Smoking And Withdrawal, Katina Constantina Calakos

Yale Graduate School of Arts and Sciences Dissertations

Tobacco smoking continues to be a leading cause of preventable disease and death. Individuals face challenges in quitting smoking due to negative experiences in early abstinence such as changes in mood and cognition, as well as the onset of cigarette craving, irritability, and other adverse withdrawal symptoms. Elucidation of neural systems involved in tobacco use and withdrawal may help predict cessation outcomes. The cholinergic and dopaminergic systems of the brain are involved in the reinforcing properties of cigarette smoking. Animal studies demonstrate that chronic nicotine exposure induces changes in beta2-subunit containing nicotinic acetylcholine receptor (beta2*-nAChR) expression and dopamine responsivity to …

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Leveraging Omics Data For Better Treatment: Computational Methods For Biomarker Identification, Drug Repositioning, And Polypharmacy Risk Assessment, Zhaolong Yu Apr 2022

Leveraging Omics Data For Better Treatment: Computational Methods For Biomarker Identification, Drug Repositioning, And Polypharmacy Risk Assessment, Zhaolong Yu

Yale Graduate School of Arts and Sciences Dissertations

With the advancement of high-throughput sequencing and massively parallel technologies, more and more omics data are available for biomedical research. Genomics, transcriptomics, proteomics, metabolomics and microbiomics data help biomedical researchers delve into the complex biological systems and dissect the underlying mechanisms of genetics from different perspectives. Despite the huge success in molecular biology research, the potential value of omics data has not been fully realized, especially for treatment discovery. This thesis is focused on the computational method development for biomarker identification, drug repositioning, and polypharmacy risk assessment, which are three substantial tasks in treatment discovery and development. The first contribution …

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Am I That Easy To Forget?: The Sounds And Forms Of Black Women’S Labor In The Mid-Twentieth-Century Music Industry, Clara Wilson Hawken Apr 2022

Am I That Easy To Forget?: The Sounds And Forms Of Black Women’S Labor In The Mid-Twentieth-Century Music Industry, Clara Wilson Hawken

Yale Graduate School of Arts and Sciences Dissertations

Am I That Easy to Forget?: The Sounds and Forms of Black Women’s Labor in the Mid-Twentieth-Century Music Industry argues that the history of Black popular music’s commodification during the latter half of the twentieth century cannot be adequately understood without accounting for the myriad forms of social and economic labor that Black women undertook. The project excavates historically neglected musicians, managerial figures, and musical institutions within and between key urban sites of Black musical innovation in order to analyze the work of Black women throughout all corners of the music industry—from radio disc jockey to record label executive, talent …

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Extracellular Elastin Assembly And Vascular Hyperproliferation: Connections For Treatment And Tissue Engineering, Matthew Ellis Apr 2022

Extracellular Elastin Assembly And Vascular Hyperproliferation: Connections For Treatment And Tissue Engineering, Matthew Ellis

Yale Graduate School of Arts and Sciences Dissertations

Elastin is the load-bearing extracellular matrix protein complex that endows the aorta with the recoil necessary to propagate blood to the peripheral circulation following systolic ejection from the heart. The assembly of the elastin complex occurs early in perinatal development and degrades over the course of a human lifetime, leading to arterial stiffening and elevated blood pressure. Although this complex assembly process occurs seamlessly in vivo, it has been a large obstacle in the field to replicate this process in vitro, hampering efforts to engineer elastin-rich grafts for transplantation and to study and develop curative treatments for elastin-associated pathologies. Herein, …

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Studying Disease Dynamics With Manifold Learning, Manik Razdan Kuchroo Apr 2022

Studying Disease Dynamics With Manifold Learning, Manik Razdan Kuchroo

Yale Graduate School of Arts and Sciences Dissertations

In an effort to computationally predict causal genetic networks and derive biological pathways empirically, biomedical scientists have begun to design increasingly complicated single cell experiments. A single study can now sequence millions of cells from hundreds of patient samples across different chronological timepoints or stages of disease progression with multiple measurement modalities. None of these additional complexities, however, are adequately addressed by the current state-of-the-art computational tools. Current machine learning techniques ignore these valuable sources of information by either downsampling the number of cells to a computationally tractable number or discarding experimental information, like stage of disease, modality or timepoint, …

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Discovery Of Selective Binding Molecules For The Pseudokinase Domain Of Janus Kinase 2, Maria-Elena Liosi Apr 2022

Discovery Of Selective Binding Molecules For The Pseudokinase Domain Of Janus Kinase 2, Maria-Elena Liosi

Yale Graduate School of Arts and Sciences Dissertations

Janus Kinase 2 (JAK2) is a nonreceptor tyrosine kinase that plays an important role in the regulation of hematopoiesis through the JAK-STAT pathway. JAK2 is comprised of seven Janus Homology (JH) domains, including a C-terminal kinase domain (JH1) responsible for the catalytic activity, and an adjacent pseudokinase domain (JH2). The pseudokinase domain adopts a prototypical protein-kinase fold and can bind ATP, but it lacks critical residues for phosphorylation catalysis. Its primary role is to regulate the function of the JH1 domain, and according to recent insights, it also plays critical role in cytokine receptor dimerization. V617F, the most frequently occurring …

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Combining High Performance Mass Spectrometry And Cryogenic Ion Spectroscopy For Structure Determinations Of Exotic Molecules And Reaction Intermediates, Evan Hunt Perez Apr 2022

Combining High Performance Mass Spectrometry And Cryogenic Ion Spectroscopy For Structure Determinations Of Exotic Molecules And Reaction Intermediates, Evan Hunt Perez

Yale Graduate School of Arts and Sciences Dissertations

High-performance mass spectrometry is a staple for analytical chemistry in a vast number of industries and academic settings. In recent years, gas-phase analysis of highly reactive species has become prevalent, as isolation of these intermediates provides fundamental chemical insight. Collision-induced dissociation (CID) is a technique that is leveraged to generate these reactive species. Paired with mass spectrometry, cryogenic ion spectroscopy provides sharp vibrational spectra that allows for accurate structural comparison to electronic structure calculations. The combination of these two techniques enables the structure determination of a new class of ions and complexes. In this dissertation, the details of the integration …

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Co-Option Of Alveolar Macrophage Homeostatic Metabolic Networks In Lung Adenocarcinoma, Alexandra Kuhlmann Apr 2022

Co-Option Of Alveolar Macrophage Homeostatic Metabolic Networks In Lung Adenocarcinoma, Alexandra Kuhlmann

Yale Graduate School of Arts and Sciences Dissertations

Cancer, fundamentally a disease of deregulated tissue homeostasis, substantially alters the composition of the surrounding tumor microenvironment (TME). The metabolic demands for rapid cellular growth and proliferation result in abnormally high rates of glucose and amino acid consumption in cancer cells. We propose a model in which nutrient competition creates a metabolic checkpoint engendering a suppressive TME. Failure to acquire adequate nutrients is compounded by the accumulation of nutritionally—and therefore immunologically—permissive immune cells. In Chapter 2, using a genetically induced mouse model of lung adenocarcinoma, we observed a striking expansion in resident alveolar macrophages (AM). AM accumulation was dependent upon …

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Comprehensive Identification And Characterization Of Cajal Body Components, Dahyana Arias Escayola Apr 2022

Comprehensive Identification And Characterization Of Cajal Body Components, Dahyana Arias Escayola

Yale Graduate School of Arts and Sciences Dissertations

Each cell’s nucleus is a safe harbor for the genome (DNA), ensuring the integrity of all of the genes that contribute to development and health of an organism. What’s more, the 3-dimensional (3D) organization of the cell nucleus regulates how genes are expressed to give each cell its unique characteristics. In addition to chromosomes, the nucleus contains nuclear bodies, which are functionally distinct yet membraneless compartments that likely form through liquid-liquid phase separation (LLPS). Nuclear bodies concentrate specific proteins and RNAs on distinct chromosomal DNA regions to regulate gene expression. One of these nuclear bodies, the Cajal Body (CB), is …

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Regulation Of Th17 Cells During Inflammatory Disorders, Hao Xu Apr 2022

Regulation Of Th17 Cells During Inflammatory Disorders, Hao Xu

Yale Graduate School of Arts and Sciences Dissertations

A balance between immunity against pathogens and tolerance to non-harmful stimuli is carefully maintained by our immune system under homeostatic conditions. Effector CD4+ T cells, particularly TH17 cells, are one of the major immune cell types that surveil mucosal homeostasis by producing pro-inflammatory cytokines, including IL-17A and IFN. However, when the immune balance is disrupted, massive numbers of TH17 cells infiltrate different tissues and organs, leading to a series of inflammatory disorders, such as inflammatory bowel diseases (IBDs) and multiple sclerosis (MS). Therefore, TH17 cells must be carefully monitored by multiple regulatory machineries, which are compromised or overridden by other …

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Trinity Of Geobacter Filaments: Discovery And Characterization Of Omcs, Omcz, And Pili Filaments, Yangqi Gu Apr 2022

Trinity Of Geobacter Filaments: Discovery And Characterization Of Omcs, Omcz, And Pili Filaments, Yangqi Gu

Yale Graduate School of Arts and Sciences Dissertations

Common soil bacterium Geobacter sulfurreducens is actively involved in a wide range of globally important phenomena, including element recycling, bioremediation, corrosion, and energy conversion. Their outstanding ability to engage long-range extracellular electron transfer (EET) has invoked great interest from researchers around the world. It was proposed 15 years ago that EET in Geobacter is supported by the filamentous appendages, usually referred to as “microbial nanowires”, which deliver electrons from inside the cell to the extracellular environment. Based on the genome organization and genetic studies, the identity of the nanowires was speculated to be type IV pili made up of a …

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Identifying Novel Strategies To Augment Anti-Melanoma Immunity, Meaghan K. Mcgeary Apr 2022

Identifying Novel Strategies To Augment Anti-Melanoma Immunity, Meaghan K. Mcgeary

Yale Graduate School of Arts and Sciences Dissertations

Melanoma is the deadliest form of skin cancer and caused the deaths of over 7,000 people in the United States in 2021. While immunotherapies have revolutionized care and extended survival for melanoma patients, most will either not respond or eventually develop resistance to these treatment options. Therefore, there is an urgent need to improve our understanding of the biology underlying the immune response to melanoma, and indeed to all cancers. We performed a whole-genome CRISPR screen in an immunogenic mouse model of melanoma to identify tumor intrinsic-factors that modulate the anti-tumor immune response. We identified several pathways of interest, including …

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On The Surveillance And Spread Of Drug Resistant Malaria In Sub-Saharan Africa, Hanna Y. Ehrlich Apr 2022

On The Surveillance And Spread Of Drug Resistant Malaria In Sub-Saharan Africa, Hanna Y. Ehrlich

Yale Graduate School of Arts and Sciences Dissertations

Artemisinin-based combination therapies (ACTs) are among the most important tools in our arsenal to treat and control malaria. ACTs and other antimalarial drugs have contributed to significant declines in global malaria-attributed morbidity and mortality over the past few decades. However, progress is the effort to eradicate the disease has not been equally distributed: sub-Saharan Africa continues to experiences the vast majority of the burden of the disease. Recent reports of ACT resistance in Rwanda and Uganda confirm longstanding expectations that artemisinin-resistant parasites will eventually emerge in Africa. To delay the spread of artemisinin resistance across the malaria endemic sub-continent, it …

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