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Role Of Lipid Transfer Proteins In Lipid Droplet Dynamics, Neng Wan Apr 2024

Role Of Lipid Transfer Proteins In Lipid Droplet Dynamics, Neng Wan

Yale Graduate School of Arts and Sciences Dissertations

Eukaryotic cells compartmentalize their cellular processes in organelles. Lipid droplets (LDs) are key organelles in energy and membrane lipid homeostasis. It has become evident that LDs form membrane contact sites with other organelles throughout their lifetime, from biogenesis to degradation. Lipid transfer proteins (LTPs) localize to LDs, often at sites of LD-organelle contacts. Several known and newly identified LTPs impact LDs biogenesis and degradation, suggesting a role of protein mediated lipid transport in modulating LDs dynamics. The mechanisms of how lipid transport precisely participates in these functions is largely unclear. I characterized the protein spartin, mutations of which leads to …


Business As Usual: Organizational And Market Responses To The Natural Environment And Magnification Of Inequality, Taylor Martin Holdaway Apr 2024

Business As Usual: Organizational And Market Responses To The Natural Environment And Magnification Of Inequality, Taylor Martin Holdaway

Yale Graduate School of Arts and Sciences Dissertations

Climate change is a multifaceted and insidious grand challenge facing the world. Natural disasters and extreme weather conditions, made more common by climate change, will cause enormous ecological, human, and economic damage across the globe. Businesses, organizations, and markets are critically implicated in climate change due to their culpability for greenhouse gas emissions and their roles in building or hindering adaptive capacity and mediating transfers of wealth resulting from climate change. In my dissertation, I investigate how individuals, businesses, and markets respond to climate-related disasters and extreme weather conditions and how these processes contribute to patterns of inequality in the …


Spatial Multi-Omics Mapping Of The Human Brain Hippocampus, Graham Su Apr 2024

Spatial Multi-Omics Mapping Of The Human Brain Hippocampus, Graham Su

Yale Graduate School of Arts and Sciences Dissertations

With the introduction of next-generation high-throughput DNA sequencing, “Omics” has become staple in biological and biomedical research. Currently, single-cell omics has enabled a wide range of biomolecular assays at single cell level including proteomics, transcriptomics, epigenomics, metabolomics, and more. These techniques have the power to interrogate the different dimensional states of single cells and in parallel with one another. Extensive and rich datasets have been produced with these methods ranging from normal to developing to diseased cells, especially informative in delineating heterogeneous populations. However, the trade-off for high-throughput single-cell Omics is the loss of cellular phenotypic and positional information. When …


High-Dimensional Molecular Quantum Dynamics With Tensor-Trains And Quantum Computation, Ningyi Lyu Apr 2024

High-Dimensional Molecular Quantum Dynamics With Tensor-Trains And Quantum Computation, Ningyi Lyu

Yale Graduate School of Arts and Sciences Dissertations

This thesis introduces numerically exact methods for simulating the quantum dynamics of complex molecular systems beyond the limitations of current models like Transition State Theory and the Born-Oppenheimer approximation. By leveraging tensor-train-based solvers and advancements in quantum hardware, particularly bosonic circuit Quantum Electrodynamics (cQED) processors, we address the computational challenges posed by the "curse of dimensionality" of high-dimensional molecular wavepackets. Our methods demonstrate significant progress in modeling intricate chemical processes such as electron and energy transfer and photochemical reactions across various systems from biological complexes to in-solvent intramolecular charge transfer processes. We specifically focus on the development and application of …


Capturing Membrane Snapshots: A Quantitative Guide For Spatially-Resolved Extraction Of Membrane Proteins On Native Membranes, Caroline Brown Apr 2024

Capturing Membrane Snapshots: A Quantitative Guide For Spatially-Resolved Extraction Of Membrane Proteins On Native Membranes, Caroline Brown

Yale Graduate School of Arts and Sciences Dissertations

Membrane proteins (MPs) stand as pivotal regulators of cellular functions, orchestrating intricate processes vital for organismal homeostasis. However, traditional methodologies employed to study MPs, such as detergent extraction, often fail to accurately preserve the native membrane environment. This deficiency results in the loss of critical biological information, hindering our understanding of MP structure, function, and interactions. To address these limitations, I employ innovative strategies centered around the utilization of membrane active polymers (MAPs). MAPs offer a promising alternative to conventional detergent-based extraction methods by enabling the preservation of the native bilayer environment during MP extraction. Through their unique chemistry, MAPs …


Sacramental Reason: Speculative Thought In Catholic Modernity, Jack Hanson Apr 2024

Sacramental Reason: Speculative Thought In Catholic Modernity, Jack Hanson

Yale Graduate School of Arts and Sciences Dissertations

This dissertation is a study of the position of Catholicism in the conceptual organization of secular modernity. Inspired by the plenitude of roles the Catholic plays in formations of religious and cultural self-narration, I take up three thinkers for whom the Catholic represents above all a means of navigating the contradictory structures of modernity, avoiding both the simple negativity of critique and the delusion of nostalgic reaction. For Charles Péguy, early intimations of a modern mysticism lead him to a paradoxical appreciation of his greatest antagonists, which in turn sets the stage for his return to the Catholicism of his …


Ensuring K-12 School Safety During A Respiratory Viral Pandemic, Dan Li Apr 2024

Ensuring K-12 School Safety During A Respiratory Viral Pandemic, Dan Li

Yale Graduate School of Arts and Sciences Dissertations

In recent times, the world has witnessed an unprecedented global crisis with the outbreak of COVID-19. This pandemic has not only brought about a paradigm shift in our daily lives but has also significantly impacted various sectors of society, including the education system. K-12 schools are a major concern for viral transmission due to the close social interactions between children, crowded institutional environments, and suboptimal vaccine coverage. Children have close interactions with their household members, who are active in all sectors of society. The K-12 educational landscape has faced an array of challenges in the face of managing the COVID-19 …


Data-Driven Methods For Super-Resolution Magnetic Resonance Spectroscopic Imaging, Siyuan Dong Apr 2024

Data-Driven Methods For Super-Resolution Magnetic Resonance Spectroscopic Imaging, Siyuan Dong

Yale Graduate School of Arts and Sciences Dissertations

Magnetic Resonance Spectroscopic Imaging (MRSI) is a non-invasive imaging technique for studying metabolism and has become a crucial tool for understanding neurodegenerative diseases, cancers and diabetes. High spatial resolution MRSI is needed to characterize small lesions and intra-lesion heterogeneity, but in practice MRSI is acquired at low resolution due to time and sensitivity restrictions caused by the low metabolite concentrations. Therefore, there is an imperative need for a post-processing approach to generate high-resolution MRSI from low-resolution data that can be acquired fast and with high sensitivity. In computer vision, enhancing image resolution is known as image super-resolution, which is a …


Fundamental Limits In Large-Scale Multiple Testing And Its Application, Yutong Nie Apr 2024

Fundamental Limits In Large-Scale Multiple Testing And Its Application, Yutong Nie

Yale Graduate School of Arts and Sciences Dissertations

The false discovery rate (FDR) and the false non-discovery rate (FNR), defined as the expected false discovery proportion (FDP) and the false non-discovery proportion (FNP), are the most popular benchmarks for multiple testing. Despite the theoretical and algorithmic advances in recent years, the optimal tradeoff between the FDR and the FNR has been largely unknown except for certain restricted classes of decision rules, e.g., separable rules, or for other performance metrics, e.g., the marginal FDR and the marginal FNR (mFDR and mFNR). In this dissertation, we determine the asymptotically optimal FDR-FNR tradeoff under the two-group random mixture model when the …


Investigating The Sequence Requirements For Specific Ligand Recognition In Variant Riboswitches, Kathryn Barth Apr 2024

Investigating The Sequence Requirements For Specific Ligand Recognition In Variant Riboswitches, Kathryn Barth

Yale Graduate School of Arts and Sciences Dissertations

Recognizing and responding to environmental stimuli is essential for organisms across all domains of life. Riboswitches sense environmental stimuli in the form of a small molecule ligand and then structurally rearrange to modulate gene expression in response. Specific ligand recognition is, therefore, a requirement of a functional riboswitch. This dissertation focuses on relating the primary sequence of a riboswitch to a role in ligand specificity. Unlike structural studies, which are used to identify nucleotides in direct ligand contact, I have taken a mutational approach to determine which nucleotides, when mutated, alter riboswitch function or ligand specificity. I focus on variant …


Uncovering Transkingdom Connectivity Through Mapping Host-Microbiota Interactions, Nicole Sonnert Apr 2024

Uncovering Transkingdom Connectivity Through Mapping Host-Microbiota Interactions, Nicole Sonnert

Yale Graduate School of Arts and Sciences Dissertations

Our microbiota, the trillions of microbes that constitutively colonize every outward-facing surface of our bodies, have diverse impacts on human physiology, yet the molecular bases for these effects remain mostly unknown. Classical pathogens often invade host tissues and modulate immune responses through interactions with human extracellular and secreted proteins (the ‘exoproteome’). Commensal microbes may also facilitate niche colonization and shape host biology by engaging host exoproteins; however, direct microbiota-exoproteome interactions remain largely unexplored. We developed and validated a novel technology, BActerial Selection to Elucidate Host-microbe Interactions in high Throughput (BASEHIT), that enables proteome-scale assessment of human exoproteome-microbiome interactions. Using BASEHIT, …


Transition Metal Complexes For Electrocatalytic Ammonia Oxidation, Hanyu Liu Apr 2024

Transition Metal Complexes For Electrocatalytic Ammonia Oxidation, Hanyu Liu

Yale Graduate School of Arts and Sciences Dissertations

Our rapidly increasing population’s growing need for food, fertilizer, and clean energy necessitates an exploration into the oxidation of ammonia (NH3) for its application as a carbon-free fuel and a precursor for nitrite and nitrate production Traditional ammonia oxidation (AO) techniques, such as the Ostwald process, demand considerable energy and result in greenhouse gas emissions. In contrast, electrochemical AO emerges as an energy-efficient solution. This thesis investigates the development and characterization of copper and iridium-based molecular and heterogeneous catalysts targeting selective electrochemical AO in aqueous environments.Chapter 2 focuses on [Cu(bipyalk)]+, a mononuclear copper electrocatalyst exhibiting selective ammonia oxidation to nitrite …


Exploring Function And Mechanism Through Intuitions, Explanations, & Learning, Amanda Mccarthy Apr 2024

Exploring Function And Mechanism Through Intuitions, Explanations, & Learning, Amanda Mccarthy

Yale Graduate School of Arts and Sciences Dissertations

Imagine learning about a car engine for the first time. You might expect that the person explaining to you how a car engine works would first explain the role that the car engine has within the car (functional information) before diving into how the camshaft, pistons, spark plugs, cylinders, and crankshaft all work together to make the car engine work (mechanistic information). Where might this intuition that functional information should come before mechanistic information come from? Is mechanistic information too convoluted to be understood without function as a cognitive scaffold? This thesis considers the strength of this intuition of explanatory …


Investigating The Cellular Role Of Lama Phosphorylation On Asymmetric Polar Growth In Mycobacteria, Celena Gwin Apr 2024

Investigating The Cellular Role Of Lama Phosphorylation On Asymmetric Polar Growth In Mycobacteria, Celena Gwin

Yale Graduate School of Arts and Sciences Dissertations

From dividing labor within communities to having a flexible response to environmental insults, phenotypic heterogeneity provides numerous benefits to microorganisms. Mycobacteria create this heterogeneity, in part, by their unique pattern of asymmetric growth and division, which generates a population of cells that varies in size, growth rate, and antibiotic susceptibility (1). The deletion of a single gene conserved exclusively in mycobacteria, known as lamA, abrogates a significant amount of this heterogeneity (2). We set out to characterize this protein of relatively unknown function using a combination of genetics, biochemistry, live cell time-lapse microscopy, and super-resolution microscopy.We show that LamA coordinates …


In Situ Characterization Of Electrochemically Intercalated Two-Dimensional Group Vi Transition Metal Dichalcogenides, Shiyu Xu Apr 2024

In Situ Characterization Of Electrochemically Intercalated Two-Dimensional Group Vi Transition Metal Dichalcogenides, Shiyu Xu

Yale Graduate School of Arts and Sciences Dissertations

Two-dimensional (2D) materials display various exotic structural and electronic phases, with layered transition metal dichalcogenides (TMDs) presenting multiple polymorphs featuring distinct physical and chemical properties. Intercalating alkali metal ions stands out as a highly effective method for inducing structural transformations and adjusting the optical and electrical characteristics of 2D group VI TMDs. The resulting novel metastable phases hold transformative potentials for applications in electronic memories, transport devices, hydrogen gas evolution catalysts, and biological sensors. Despite numerous studies on alkali metal intercalation into 2D VI TMDs, a comprehensive understanding of the mechanistic and microscopic aspects of intercalation-induced phase changes remains elusive. …


Mechanical And Transcriptional Roles For Primary Cilia During Intracardiac Cushion Endomt, Kathryn Berg Apr 2024

Mechanical And Transcriptional Roles For Primary Cilia During Intracardiac Cushion Endomt, Kathryn Berg

Yale Graduate School of Arts and Sciences Dissertations

The first organ to develop in vertebrates is the heart, a necessary process for all other organ systems that follow. Proper development of the embryonic heart relies on the ability for intracardiac cells to sense and translate complex mechanical forces into transcriptional signals. Failure to do so results in numerous cardiac abnormalities, such as thinned compact myocardium, stunted trabeculations and atrioventricular canal defects. These structural abnormalities are a common occurrence in congenital heart disease (CHD), which affects more than 1% of all live births. Nonetheless, the mechanism by which mechanical forces are generated, sensed, and integrated into cardiac development remains …


A “Spicy” Molecular Mechanism Of Trpa1 Hyperactivation Conferred By A Disease Mutant And Insights Into C-Terminal Regulatory Components, Avnika Prasad Bali Apr 2024

A “Spicy” Molecular Mechanism Of Trpa1 Hyperactivation Conferred By A Disease Mutant And Insights Into C-Terminal Regulatory Components, Avnika Prasad Bali

Yale Graduate School of Arts and Sciences Dissertations

Roughly one third of Americans suffer from chronic pain and inflammation, yet so far little progress has been made to develop new pain remedies beyond non-steroidal anti-inflammatory agents and opioids, which often harbor deleterious side-effects. The identification and mechanistic analysis of pain-initiating receptors in peripheral nociceptor neurons is therefore an attractive approach to develop new analgesic and anti-inflammatory therapeutics. Transient receptor potential (TRP) ion channels are the largest group of receptors expressed in nociceptor neurons and are capable of transducing noxious thermal and chemical stimuli into cation influx that triggers pain signaling. My thesis work focuses on one such TRP …


Models For Interrogating The Role Of Glutathione Biosynthesis In Pancreatic Islet Development And Function, Emily Ann Davidson Apr 2024

Models For Interrogating The Role Of Glutathione Biosynthesis In Pancreatic Islet Development And Function, Emily Ann Davidson

Yale Graduate School of Arts and Sciences Dissertations

Currently, over 537 million people worldwide have diabetes, a disease characterized by impaired insulin synthesis, and/or utilization. Of diabetics, roughly 90% have type 2 diabetes and develop high blood glucose caused by pancreatic islet dysfunction. The islet is composed of five different endocrine cell types. Sixty - 80% (varies by species) of islet cells are insulin-producing β cells. A hallmark characteristic of dysfunctional β cells is impaired insulin secretion. Among the many factors implicated in islet cell dysfunction is oxidative stress. Oxidative stress is defined as the imbalance between reactive oxygen species (ROS) and cellular antioxidant capacity. During oxidative stress, …


Nuclear Quantum Effects And Proton Transfer Mechanisms In Molecular And Solid- Liquid Interface Systems, Benjamin John Guy Rousseau Apr 2024

Nuclear Quantum Effects And Proton Transfer Mechanisms In Molecular And Solid- Liquid Interface Systems, Benjamin John Guy Rousseau

Yale Graduate School of Arts and Sciences Dissertations

Due to their small mass, protons often exhibit non-classical behavior that can dramatically affect chemical processes. For molecular systems, nuclear quantum effects (NQEs) can be accurately described by electronic structure theory within the nuclear electronic orbital (NEO) framework, wherein select nuclei of interest are treated on the same level of ES theory as the electrons. Within the NEO framework, an affordable and systematically improvable method was developed that produces proton affinities and proton densities of the same quality as a highly accurate and expensive method. In addition to affecting ground state properties of molecules, nuclear quantum effects can also dramatically …


Single-Cell Perturbation Of Human Accelerated Regions In Neural Stem Cells, Mark Alan Noble Apr 2024

Single-Cell Perturbation Of Human Accelerated Regions In Neural Stem Cells, Mark Alan Noble

Yale Graduate School of Arts and Sciences Dissertations

The evolutionary emergence of the uniquely large and complex human brain isunderpinned by the alteration and expansion of the neural stem and progenitor cell (NSC) pool during development. These modifications are the manifestation of numerous regulatory and genetic changes, many of which have yet to be described. One salient set of candidates consists of ~1500 Human Accelerated Regions (HARs), which are noncoding regions of the genome that have been highly constrained throughout evolution until the human lineage, where a significant number of substitutions occur, indicating divergent functions. I designed a direct-capture Perturb-seq screen repressing 180 HARs with evidence of neurodevelopmental …


Bodipy As A Chromophore And An Anchor To Metal Oxides For Solar Fuel Applications, Josephine Anne Jayworth Apr 2024

Bodipy As A Chromophore And An Anchor To Metal Oxides For Solar Fuel Applications, Josephine Anne Jayworth

Yale Graduate School of Arts and Sciences Dissertations

To meet current goals for carbon neutral economies it is important to transition to renewable energy sources and storage solutions. Solar radiation is a cheap and abundant source of renewable energy, but it suffers in grid scale applications due to being intermittent and diffuse. Similar to how plants use sunlight to store energy in the form of sugar via photosynthesis, artificial systems can store solar energy in the form of chemical bonds as solar fuels. One such type of artificial system is a water splitting dye sensitized photoelectrochemical cell (WS-DSPEC), which will be discussed throughout this thesis. WS-DSPECs are introduced …


Utilizing Meta-Analytical And Causal Inference Methods To Evaluate The Impacts Of Environmental Risk Factors On Non-Hodgkin Lymphoma, Xiaoting Shi Apr 2024

Utilizing Meta-Analytical And Causal Inference Methods To Evaluate The Impacts Of Environmental Risk Factors On Non-Hodgkin Lymphoma, Xiaoting Shi

Yale Graduate School of Arts and Sciences Dissertations

Non-Hodgkin lymphoma (NHL) is one of the most common hematologic malignancies in the world. Despite substantial efforts to identify causes and risk factors for NHL over the past few decades, the etiology of NHL is largely unclear. The overarching goal of this three-part dissertation is to use different meta-analytical and causal inference methods to identify and evaluate potential environmental risk factors for NHL. For the first project of this dissertation, we conducted an umbrella review to summarize the range, strength, and consistency of all associations between environmental risk factors and NHL reported in published meta-analyses. We identified 85 meta-analyses of …


Mapping And Functional Characterization Of Hox Gene Expression Patterns In Human Normal Tissue And Solid Tumors, Vadim Kurbatov Apr 2024

Mapping And Functional Characterization Of Hox Gene Expression Patterns In Human Normal Tissue And Solid Tumors, Vadim Kurbatov

Yale Graduate School of Arts and Sciences Dissertations

HOX genes, fundamental in directing embryonic development, are implicated in the spatial organization and functional differentiation of tissues. Their influence, traditionally investigated during early developmental stages, has been noted in a wide variety of malignant processes, albeit at a single gene level in the context of individual cancer types. Given that the HOX genes represent a complex and interrelated network, a unified model evaluating the role of the entire set of HOX genes in cancer has not yet been achieved. Similarly, an overarching model that considers HOX gene patterns in multiple cancer types is absent. This study aims to discover …


Structural Insights Into Group Ii Intron Splicing And Retrotransposition, Kevin Chung Apr 2024

Structural Insights Into Group Ii Intron Splicing And Retrotransposition, Kevin Chung

Yale Graduate School of Arts and Sciences Dissertations

Pre-mRNA processing is a critical metabolic step in eukaryotes. RNA transcripts must be spliced, polyadenylated, and capped, among other modifications, to ensure their proper function. Group II introns are an archetypal splicing system that can catalyze their self-excision and retroelements that invade DNA. They provide a window into understanding the evolution of splicing and have played an important role in shaping the eukaryotic genome as the ancestors of spliceosomal introns, telomerases, and non-LTR retrotransposons. Group II introns consist of a well-folded, large-structured RNA that forms a ribonucleoprotein complex with their encoded maturases to carry out splicing and intron integration functions. …


Deriving Cell And Gene Dynamics From Single-Cell Omics Data, Rihao Qu Apr 2024

Deriving Cell And Gene Dynamics From Single-Cell Omics Data, Rihao Qu

Yale Graduate School of Arts and Sciences Dissertations

Single-cell sequencing techniques have revolutionized our understanding of cellular diversity within tissues and organs. Typically, single-cell data is preprocessed into a feature-by-cell count matrix, where feature values represent gene expression, chromatin accessibility, protein levels, etc. In the realm of computational analysis, cells are conceptualized as points in a high-dimensional feature space. Under distinct conditions or due to experimental perturbations, specific cellular states may exhibit differential abundance. This can be detected by comparing cell density distributions within the feature space. In Chapter 1, we present a novel computational framework by employing a random-walk-based local two-sample test. This approach enables multiscale, cluster-free, …


Integrated Multiscale Mechano-Biological Study Of Lung And Liver Tissues, Hugh Xiao Apr 2024

Integrated Multiscale Mechano-Biological Study Of Lung And Liver Tissues, Hugh Xiao

Yale Graduate School of Arts and Sciences Dissertations

Tissues and bodily fluids undergo continuous changes as a natural life cycle process. Extracellular matrices (ECMs), which provide structural and biochemical support for the cells, and extracellular fluids (ECFs), which transport nutrients, oxygen, and waste products, exhibit several mechanical properties that can impact cell behaviors. These properties include, for example, fibrillar alignment, density, and stiffness of ECMs, and osmolarity and viscosity of ECFs. These mechano-biological cues can impact cell behaviors and change tissue landscapes. Fibrosis is known for thickened extracellular matrix, which involves many changes in mechanical properties of extracellular environment. There is much to be explored as to how …


Genetic Background’S Influence On The Pathogenesis Of Spinocerebellar Ataxia Type 1 (Sca1), Victor Hipolito Olmos Apr 2024

Genetic Background’S Influence On The Pathogenesis Of Spinocerebellar Ataxia Type 1 (Sca1), Victor Hipolito Olmos

Yale Graduate School of Arts and Sciences Dissertations

Spinocerebellar ataxia type 1 (SCA1) is a rare, dominantly inherited monogenic neurodegenerative disease that primarily affects the Purkinje cells (PCs) of the cerebellum. Our lab utilizes SCA1 as a model to unravel the complexity that is neurodegeneration. Neurodegeneration has long been a challenge due to the interactions of multiple cell types, various disease-causing genes, and degeneration beyond a single brain region. We utilized the SCA1 82Q B05 transgenic model (B05) which expresses the disease-causing gene, ATAXIN-1 (ATXN1), only in the PCs of the cerebellum. This mouse model recapitulates the disease phenotypes seen in human patients and allows us to investigate …


Neutrophil Heterogeneity And Transmigration: Decoding Molecular Profiles Through Multi-Omic Analysis And In Vitro Mimicry Of The Venular Wall, Laura C. Morales Apr 2024

Neutrophil Heterogeneity And Transmigration: Decoding Molecular Profiles Through Multi-Omic Analysis And In Vitro Mimicry Of The Venular Wall, Laura C. Morales

Yale Graduate School of Arts and Sciences Dissertations

Neutrophils are crucial innate immune cells that comprise about 50-70% of the white blood cell population in the human peripheral circulation. These polymorphonuclear leukocytes play a pivotal role in the innate immune system, acting as the primary line of defense against pathogens and facilitating tissue repair. Neutrophils exhibit a diverse repertoire of cytotoxic mechanisms to eliminate offending pathogenic agents and promote the resolution of inflammation. These include phagocytosis, degranulation, generating reactive oxygen species, and forming neutrophil extracellular traps, underscoring their versatility in host defense. A critical aspect of neutrophil functionality is their capacity to infiltrate sites of injury or infection, …


Histone Regulation Of The Maternal To Zygotic Transition: The Role Of Histone Modifications On Zygotic Genome Activation, Maria De Jesus Benitez Ortiz Apr 2024

Histone Regulation Of The Maternal To Zygotic Transition: The Role Of Histone Modifications On Zygotic Genome Activation, Maria De Jesus Benitez Ortiz

Yale Graduate School of Arts and Sciences Dissertations

Following fertilization, the zebrafish embryo experiences significant reprogramming events to erase the inherited program of the terminally differentiated gametes, paving the way for the establishment of the zygotic program, which will drive the early steps of embryonic development. An essential step within this process is zygotic genome activation (ZGA), which refers to the time of development when the zygotic genome goes from being largely transcriptionally inactive to a gradual onset of transcriptional activity. In zebrafish, this process coincides with the deposition of many histone modifications associated with the positive regulation of transcription. Here, to explore the function of these transcription-associated …


Expressed Artificial Proteins That Induce Degradation Of The Platelet-Derived Growth Factor Beta Receptor, Emily Branham Apr 2024

Expressed Artificial Proteins That Induce Degradation Of The Platelet-Derived Growth Factor Beta Receptor, Emily Branham

Yale Graduate School of Arts and Sciences Dissertations

Targeted protein degradation (TPD) is a rapidly advancing field with diverse applications spanning from fundamental research to therapeutic interventions. With considerable opportunity for scientific creativity, emerging degradation strategies promise to expand the reach of this field to challenging targets that often elude conventional, small molecule-based degraders. Of particular interest in this report, transmembrane (TM) proteins represent more than half of all drug targets, yet their intrinsic properties present challenges for standard degradation approaches. Here, we describe a novel genetic approach to TPD, presenting the first example of expressible protein degraders: traptamer-based targeting chimeras (TRAPTACs). As their name implies, these innovative …