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Articles 451 - 480 of 1126
Full-Text Articles in Biology
The Role Of Excited States In Determining Β-Lactamase Function And Bacterial Fitness, Catherine Rae Knoverek
The Role Of Excited States In Determining Β-Lactamase Function And Bacterial Fitness, Catherine Rae Knoverek
Arts & Sciences Graduate Student Theses and Dissertations
Proteins are macromolecular machines that play a role in nearly every biological process. They are dynamic molecules which adopt many different conformations as they fold into their 3D structures, interact with their binding partners, and perform their functions. The most probable (lowest energy) protein conformation is referred to as the ground state, and this is often assumed to be the state determined by experimental methods such as x-ray crystallography. However, proteins also adopt higher energy excited states which can have significant probabilities. As these excited states are notoriously difficult to find and study, it is unclear if excited states contribute …
Mechanisms Of Natural Killer Cell Anti-Tumor Function And Homeostasis, Julia Alexandra Wagner
Mechanisms Of Natural Killer Cell Anti-Tumor Function And Homeostasis, Julia Alexandra Wagner
Arts & Sciences Graduate Student Theses and Dissertations
Natural killer (NK) cells are innate lymphoid cells (ILCs) that mediate anti-tumor and anti-viral immune responses. They do so via two primary effector functions: cytokine production and direct cytotoxicity. Unlike adaptive T and B lymphocytes, NK cells do not rearrange their DNA to express a predominant antigen-specific receptor, and instead express a variety of stochastically-expressed, germline DNA-encoded activating and inhibitory receptors whose signals integrate to govern their functional responses. What results is a diverse repertoire of NK cells capable of recognizing a variety of malignantly-transformed or virally-infected cells. Studies from several groups have established the anti-tumor potential of NK cells, …
The Roles Of Capsular Polysaccharides And Diet In The Immune Response To A Bacteroides Thetaiotaomicron Antigen, Samantha Hsieh
The Roles Of Capsular Polysaccharides And Diet In The Immune Response To A Bacteroides Thetaiotaomicron Antigen, Samantha Hsieh
Arts & Sciences Graduate Student Theses and Dissertations
The environment is well recognized to modulate immune responses within the intestinal mucosa in a general fashion. However, the connection between the effects of the environment on the immune response directed towards specific intestinal microbes is unclear. Progress in this area has been hampered by the lack of a model system in which the immune responses to a specific antigen in a gut symbiont can be examined. To this end, we developed a novel CD4+ T cell model, termed BθOM, that is specific for a dominant antigen in the gut symbiont Bacteroides thetaiotaomicron (B. theta). In this work, we use …
Stem Cell Models To Study The Regulation Of Human Cortical Development And Its Disruption In Neurodevelopmental Disorders, Emily Megan Alexandra Lewis
Stem Cell Models To Study The Regulation Of Human Cortical Development And Its Disruption In Neurodevelopmental Disorders, Emily Megan Alexandra Lewis
Arts & Sciences Graduate Student Theses and Dissertations
Abstract of the DissertationStem Cell Models to Study the Regulation of Human Cortical Development and Its Disruption in Neurodevelopmental Disorders by Emily M. A. Lewis Doctor of Philosophy in Biology and Biomedical Sciences Developmental, Regenerative, and Stem Cell Biology Washington University in St. Louis, 2021 Professor Kristen L. Kroll, ChairThe cell state transitions that occur during complex processes, such as development of the human brain, require precisely controlled changes in gene expression. Major regulators of these developmental events include transcription factors (TFs), which bind the genome in a sequence-specific manner, as well as chromatin modifying proteins and complexes that alter …
The Genetic Basis Of Adaptation To Environmental Stress In Two Grass Genomic Model Systems, David Mitchell Goad
The Genetic Basis Of Adaptation To Environmental Stress In Two Grass Genomic Model Systems, David Mitchell Goad
Arts & Sciences Graduate Student Theses and Dissertations
Plants are exposed to a wide variety of environmental stress in the wild and have developed an equally diverse set of adaptations to tolerate them. The evolutionary processes that have led to this functional diversification, and the specific genes and physiological mechanisms involved, are of immense interest to both evolutionary biologists and crop breeders. In this dissertation I investigate adaptation to different types of environmental stress in two economically important grass species, seashore paspalum (Paspalum vaginatum Sw.) and rice (Oryza sativa L.).Seashore paspalum is a halophytic turfgrass that occupies habitats which can dramatically differ in salt concentration. Populations may be …
Retinal Ganglion Cells Underlying Visual Perception And Predation In Mice, Keith Patrick Johnson
Retinal Ganglion Cells Underlying Visual Perception And Predation In Mice, Keith Patrick Johnson
Arts & Sciences Graduate Student Theses and Dissertations
The spike trains of retinal ganglion cells (RGCs) are the sole source of visual information to the brain. In mice, more than 40 RGC types send signals to more than 50 brain areas. RGCs that perform nonlinear operations to extract specific visual features (e.g., the motion of an object against a background) are called feature detectors. Those that linearly integrate local changes in light inten-sity are known as pixel encoders. Most mouse RGC types are feature detectors. In the first part of my dissertation, I discovered a pixel encoder RGC type in mice, the PixON-RGC. I revealed how the unique …
Glial Inflammatory Responses Regulate Neurocognitive Recovery Following Viral Encephalitis, Allison Luen Soung
Glial Inflammatory Responses Regulate Neurocognitive Recovery Following Viral Encephalitis, Allison Luen Soung
Arts & Sciences Graduate Student Theses and Dissertations
The concept of the brain as an immune privileged organ has been slowly shifting as an in-creasing number of studies have demonstrated that even under homeostatic conditions, commu-nication between the nervous and immune system is essential for proper brain function. Given their roles in innate and adaptive immunity, glial cells and infiltrating immune cells have been placed at the center of this communication axis. Microglia, astrocytes, and T cells have all been shown to receive and convey information to all neural cell types in a coordinated effort to re-spond to injury and infection and initiate reparative mechanisms as well as …
Characterizing A Novel Metabolic Pathogenic Mechanism In Familial Hemiplegic Migraine, Sarah Elizabeth Smith
Characterizing A Novel Metabolic Pathogenic Mechanism In Familial Hemiplegic Migraine, Sarah Elizabeth Smith
Arts & Sciences Graduate Student Theses and Dissertations
Migraine, an episodic neurological disorder, afflicts about 1 in 10 people at least monthly, yet the underlying pathophysiological mechanisms remain poorly understood. The prototypical monogenic migraine disorder, Familial Hemiplegic Migraine, theoretically presents an excellent opportunity for preclinical modeling, but thus far animal models of migraine have failed to recapitulate the severe migraine aura symptoms of episodic paralysis and ataxia. Mutations that cause Familial Hemiplegic Migraine occur in one of three genes, two neuronal ion channels, and interestingly, the astrocytic α2-Na/K ATPase. In the case of α2-Na/K ATPase, mutations primarily result in loss of protein function. As migraine is thought to …
Dissecting The Role And Regulation Of Transcription Factor Zeb2 In Hematopoiesis, Xiao Huang
Dissecting The Role And Regulation Of Transcription Factor Zeb2 In Hematopoiesis, Xiao Huang
Arts & Sciences Graduate Student Theses and Dissertations
A potent immune response requires crosstalk and collaboration between the innate and adaptive immune systems, both of which contain highly specialized immune lineages. All immune lineages arise during adult life are generated from the differentiation of hematopoietic stem cells (HSCs) in the process of hematopoiesis. Normal hematopoiesis under steady state and emergency hematopoiesis during immune response are orchestrated precisely by transcriptional networks formed by transcription factors (TFs) to direct multipotent progenitors into specific fate. TFs required for the development of single or multiple lineages within the hematopoietic system has been identified, such as Irf8 for type I classical dendritic cells …
Transcriptional And Epigenetic Regulation Of Cerebellar Development And Function, Shahriyar Majidi
Transcriptional And Epigenetic Regulation Of Cerebellar Development And Function, Shahriyar Majidi
Arts & Sciences Graduate Student Theses and Dissertations
Compensation among paralogous transcription factors (TFs) confers genetic robustness of cellular processes. Despite the prevalence of this phenotypic phenomenon, an in vivo genome-scale understanding of how TFs dynamically respond within the chromatin context to paralog depletion is still lacking. We explore this question in the mammalian brain by studying the highly conserved MEF2 family of TFs, which confer phenotypic robustness for neuronal processes across multiple brain regions. The paralogous TFs MEF2A and MEF2D are strongly co-expressed in granule neurons of the cerebellum, the most abundant neurons in the brain. Employing single and double conditional knockout of MEF2A and MEF2D in …
Dedicated Interneuronal Microcircuits Regulated By Behavioral State, Moises William Arriaga
Dedicated Interneuronal Microcircuits Regulated By Behavioral State, Moises William Arriaga
Arts & Sciences Graduate Student Theses and Dissertations
The hippocampus is a critical brain structure for learning and memory. Neuronal inhibition within the hippocampus, performed by a wide variety of inhibitory interneuron subtypes, is required to organize and regulate the cell activity and circuit operations which underly memory formation. Despite the importance of inhibitory interneurons to the function of the hippocampus, detailed descriptions of the role of interneurons in the regulation of network activity have been limited by difficulties associated with identifying and recording from these cells using traditional electrophysiology techniques, especially in awake, behaving animals. To better investigate the function of hippocampal interneurons in awake, behaving animals, …
Transcriptional Control Of Dendritic Cell Function And Development, David Alexander Anderson Iii
Transcriptional Control Of Dendritic Cell Function And Development, David Alexander Anderson Iii
Arts & Sciences Graduate Student Theses and Dissertations
Dendritic cells (DCs) are innate immune cells of the myeloid lineage that are specialized at pathogen recognition, cytokine production, and antigen presentation. Their functions and developmental pathways are largely conserved between mice and humans and mice. The DC lineage is composed of two major subsets, known as plasmacytoid DCs (pDCs) and classical DCs (cDCs). Research conducted to date suggests that the function of pDCs, limited to viral antigen recognition and type I interferon production, can be compensated by other immune cell lineages. On the other hand, there is a consensus that diversified subsets cDCs in mice and humans are essential …
Rhoa Mediated Juxtacrine Regulation Of Glucagon Secretion, Yong Hee Chung
Rhoa Mediated Juxtacrine Regulation Of Glucagon Secretion, Yong Hee Chung
Arts & Sciences Graduate Student Theses and Dissertations
Glucagon is secreted from pancreatic islet alpha-cells in response to hypoglycemia. The regulation of this secretion likely involves multiple interacting molecular pathways. There are three general types of proposed models for glucose-dependent regulation of glucagon secretion: direct regulation by glucose mediated modulation of cell electrophysiology, paracrine regulation by other endocrine cell types within the islets of Langerhans, and juxtacrine regulation by surface protein interactions from neighboring beta-cells. This work is focused on one pathway of juxtacrine regulation that occurs through signaling from EphA4 receptors on the surface of α-cells upon interaction with ephrin-A5 ligands on the surface of beta-cells. In …
Potentiation Of Tmem16a Currents By Clca1 In Cystic Fibrosis Airway, Kayla Berry
Potentiation Of Tmem16a Currents By Clca1 In Cystic Fibrosis Airway, Kayla Berry
Arts & Sciences Graduate Student Theses and Dissertations
In the airway, proper activity of the anion channel cystic fibrosis transmembrane conductance regulator (CFTR) contributes to innate immune defense by maintaining a hydratedand alkaline mucus layer through the conductance of chloride and bicarbonate ions. This allows potentially pathogenic microorganisms to be trapped, quickly killed, and cleared via mucociliary clearance, thus preventing microbial colonization of the lungs. In cystic fibrosis (CF), this activity is impaired, resulting in repeated pulmonary infections that damage the lung and, if severe and prolonged, may lead to premature death without lung transplantation. Available therapies remain focused on targeted rescue of the CFTR mutation. However, given …
The Role Of Soil Microbes In Improving Tallgrass Prairie Restoration And Rare Plant Reintroduction, Rachel Ellen Becknell
The Role Of Soil Microbes In Improving Tallgrass Prairie Restoration And Rare Plant Reintroduction, Rachel Ellen Becknell
Arts & Sciences Graduate Student Theses and Dissertations
We are currently in the midst of an ecological crisis with many species and ecosystems threatened with extinction. Less than 1% of the original extent of the incredibly biodiverse tallgrass prairie ecosystem remains and other grassland ecosystems such as the limestone cedar glade complex that is home to many endemic plant species are threatened by development, woody plant encroachment, and trash dumping. Restoration practitioners have been acting to restore these degraded ecosystems for over a century and rare plant reintroductions have steadily increased over the past few decades, yet many plant restorations and reintroductions are often not successful. Prairie restorations …
Polygenic And Transcriptomic Studies In Neurodegeneration: Towards More Precise Medicine., Umber Dube
Polygenic And Transcriptomic Studies In Neurodegeneration: Towards More Precise Medicine., Umber Dube
Arts & Sciences Graduate Student Theses and Dissertations
Precision medicine defines both health and disease in terms of high dimensional data. In my thesis work, I apply current knowledge and tools of precision medicine to better understand the etiopathogenesis of neurodegenerative diseases (NDs).Genome-wide association studies (GWAS) have demonstrated that genetic susceptibility for NDs and other diseases is mediated by many common genetic variants of modest effect size which contribute to disease risk in a polygenic or even omnigenic manner. These complex genetics render prioritizing genes to better understand the disease and potentially identify therapeutic targets, challenging. In the first half of this thesis, I address this challenge by …
Regulation Of Genome Architecture By Chromatin Remodeling In The Brain, Jared Vega Goodman
Regulation Of Genome Architecture By Chromatin Remodeling In The Brain, Jared Vega Goodman
Arts & Sciences Graduate Student Theses and Dissertations
Brain development requires exquisite control of gene expression to establish and refine the proper circuitry of the nervous system. Gene expression control is under the purview of several cellular processes, including chromatin regulation in the form of DNA modification, histone modification, and nucleosome remodeling. Chromatin remodeling enzymes are the major effectors of nucleosome remodeling. These enzymes are clearly involved in brain development – mutations in chromatin remodeling enzymes are likely causative for neurodevelopmental disorders of cognition. Chromatin remodeling enzymes have discrete molecular functions and binding profiles and similarly control distinct phases of nervous system maturation. Chd4 is a Chd family …
Modeling Small Molecule Metabolism In Human Liver Microsome To Better Predict Toxicity Risk, Na Le Dang
Modeling Small Molecule Metabolism In Human Liver Microsome To Better Predict Toxicity Risk, Na Le Dang
Arts & Sciences Graduate Student Theses and Dissertations
Adverse drug reactions (ADRs) are a serious problem with increasing morbidity, mortality, and health care costs worldwide. In the U.S., ADRs are responsible for more than 50% of acute liver failure cases and are the fourth most common cause of death, costing 100,000 lives annually.Idiosyncratic adverse drug reactions (IADRs) are immune-mediated hypersensitivity ADRs that are difficult to foresee during drug development. IADRs are often caused by reactive metabolites produced during drug metabolism. These reactive metabolites covalently attach to cellular components, and the resulting conjugates may provoke toxic immune response. Because reactive metabolites are short-lived, they can be difficult to detect. …
Analysis Of Structural Variation And Mtdna Copy Number In Finns, Liron Ganel
Analysis Of Structural Variation And Mtdna Copy Number In Finns, Liron Ganel
Arts & Sciences Graduate Student Theses and Dissertations
Cardiovascular disease (CVD) is a complex disease responsible for more deaths worldwide than any other cause according to the World Health Organization. Genetic association studies for CVD and related risk factors have successfully identified hundreds of loci associated with these complex diseases and traits, although much of their heritability remains unexplained. Structural variants (SVs) - including insertions, deletions, duplications, and inversions - are an understudied class of genomic variation that have the potential to explain much of the missing heritability of CVD and other complex traits. Here, we discuss advances emerging from the study of SVs in the context of …
Sex Differences In The Role Of Cornichon Homolog-3 On Spatial Memory And Synaptic Plasticity, Hannah Elizabeth Frye
Sex Differences In The Role Of Cornichon Homolog-3 On Spatial Memory And Synaptic Plasticity, Hannah Elizabeth Frye
Arts & Sciences Graduate Student Theses and Dissertations
Cornichon homolog-3 (CNIH3) is an AMPA receptor (AMPAR) auxiliary protein highly expressed in the dorsal hippocampus (dHPC), a region where AMPARs are critical for spatial memory and synaptic plasticity. A 2016 genome-wide association study (GWAS) by Nelson et al. identified single nucleotide polymorphisms (SNPs) in the gene CNIH3 to be associated with reduced individual risk for the development of opioid use disorder (OUD) in individuals with prior opioid exposure. We previously demonstrated a key role for AMPARs in the dHPC in opioid-associated learning and memory, therefore we hypothesized that CNIH3 in the dHPC may mediate learning and memory processes through …
Understanding Immune Responses With Single-Cell Rna Sequencing And Cytof Across Different Diseases And Model Organisms, Ekaterina Esaulova
Understanding Immune Responses With Single-Cell Rna Sequencing And Cytof Across Different Diseases And Model Organisms, Ekaterina Esaulova
Arts & Sciences Graduate Student Theses and Dissertations
The immune system is an integral part of a healthy functioning organism. Immune responses during the disease are complex and include the interplay of many cell subsets. Integrated genomics and bioinformatics usage can yield unique insights into the immune system’s function in health and disease at a single-cell resolution. Here we utilize complimentary single-cell profiling technologies, scRNA-seq and CyTOF, to explore immune responses across diseases and model organisms. Our approach included leveraging scRNA-seq on few samples to understand the immune response landscape and select key markers for a follow-up protein level validation using an appropriate number of replicates by FACS …
The Role Of Cd53 In Hematopoietic Development, Stress, And Malignancy, Zev Joshua Greenberg
The Role Of Cd53 In Hematopoietic Development, Stress, And Malignancy, Zev Joshua Greenberg
Arts & Sciences Graduate Student Theses and Dissertations
For a cell to function properly, it must be able to interact with and respond to environmental cues; however, expression of surface molecules, proteins, and receptors is not always sufficient to execute a cellular response. Proper organization of the plasma membrane is necessary to facilitate these highly regulated protein interactions, such that a cell can respond to stressors, growth factors, and other signaling molecules. Tetraspanins are a family of transmembrane proteins which help correctly orient surface molecules on the cell membrane, often through tetraspanin enriched microdomains, a membrane structure similar to lipid rafts. As a family, tetraspanins are known to …
Etv2/Myct1 Axis In The Regulation Of Tumor Angiogenesis And Anti-Tumor Immunity, Ashraf Ul Kabir
Etv2/Myct1 Axis In The Regulation Of Tumor Angiogenesis And Anti-Tumor Immunity, Ashraf Ul Kabir
Arts & Sciences Graduate Student Theses and Dissertations
Angiogenesis is a critical determinant of neoplastic growth and metastatic spread. As such, anti-angiogenic approaches have long been tried to throttle down tumor progression. However, current anti-angiogenic treatments so far have produced modest clinical benefits. Further in-depth research has provided rationales behind these disappointing and apparent perplexing clinical outcomes. It is now established that VEGF (vascular endothelial growth factor) and other prominent current angiogenic targets are neither specific to the vascular system nor the pathological conditions explaining the sub-optimal angiogenic control following the existing treatments. This suggests that anti-angiogenesis could still be a viable strategy for cancer patients should there …
Single-Cell Resolution Mechanistic Analyses Of Direct Lineage Reprogramming, Chuner Guo
Single-Cell Resolution Mechanistic Analyses Of Direct Lineage Reprogramming, Chuner Guo
Arts & Sciences Graduate Student Theses and Dissertations
End-stage organ failures remain a clinical challenge with an unmet need for medical therapies, with transplantation often being the only curative option. Despite advances in transplantation outcomes, organ shortage continues to limit the availability of cures to patients in need. The direct lineage reprogramming of one cell type to another is a promising avenue for therapy with the following advantages: (1) patient-specific cell sources, (2) direct conversion without reverting to pluripotency and the associated risk of teratoma formation, and (3) utilization of the cell type responsible for fibrotic scar formation for the engineering towards the desired cell fate. Nonetheless, many …
The Phylogeography Of Rare Central Tennessee Glade Endemics Trifolium Calcaricum And Viola Egglestonii, Rachel Ann Lyman
The Phylogeography Of Rare Central Tennessee Glade Endemics Trifolium Calcaricum And Viola Egglestonii, Rachel Ann Lyman
Arts & Sciences Graduate Student Theses and Dissertations
Endemic species are range-restricted to a particular type of habitat and generally occur in a few small populations. Often endemic species are threatened or endangered due to their geographic isolation and limited habitat breadth. Despite the fact that understanding factors that may have shaped the evolutionary history of a species with a narrow distribution can provide important insights for their management and conservation, little is known about the historical forces that gave rise to many endemic species. Endemic species can arise because of factors such as variation in climate, geographic barriers, and habitat specificity, or the combination of several of …
Gut Reactions: Quantitative Predictions Of The Responses Of Human Gut Microbiota To Medical Interventions, Amy Elizabeth Langdon
Gut Reactions: Quantitative Predictions Of The Responses Of Human Gut Microbiota To Medical Interventions, Amy Elizabeth Langdon
Arts & Sciences Graduate Student Theses and Dissertations
The collection of microbes known as the human microbiome perform vital functions for their host, and when this community becomes unhealthy, its dysbiosis is implicated in a myriad of diseases. The gut microbiota in particular are known to suppress colonization of opportunistic pathogens, regulate the immune system, aid in nutrient breakdown, produce vitamins, and a growing number of other functions. In order to intervene in a dysbiotic microbial ecology, we can try to remove unwanted microbes or try to recolonize the gut with microbes expected to be beneficial. This dissertation provides an overview of the state of medical interventions for …
Dissecting The Neural Circuits Mediating Pain-Induced Negative Affect And Drug-Seeking Behaviors, Tamara Markovic
Dissecting The Neural Circuits Mediating Pain-Induced Negative Affect And Drug-Seeking Behaviors, Tamara Markovic
Arts & Sciences Graduate Student Theses and Dissertations
Understating the function of neural circuits and the state-depended adaptations within them is one of the fundamental aims in the field of neuroscience. With recent technical developments in monitoring circuit dynamic, such as calcium (Ca2+) imaging, visualizing synaptic connections using viral approaches and manipulating neuronal activity in cell-specific manner such as optogenetic and chemogenetics, we are now able to mechanistically link the activity and function of neural circuits with behavioral outcomes.Using the above-mentioned techniques, I demonstrate that pain induces somatic adaptations in the Ventral Tegmental Area (VTA) dopamine (DA) neurons to drive anhedonia-like behaviors. Pain is a complex phenomenon composed …
Deep Learning Deleterious Small Molecule Biochemistry From The Lab To The Clinic, Matthew Matlock
Deep Learning Deleterious Small Molecule Biochemistry From The Lab To The Clinic, Matthew Matlock
Arts & Sciences Graduate Student Theses and Dissertations
Small molecules are key tools in biology and medicine. In biology, small molecules are used to probe biological systems and gain insight into their structure and function. In medicine, this role is further refined to reverse the biological conditions that contribute to human disease. Developing new small molecules into biological probes or drugs can be a daunting scientific task. These projects often begin with many thousands of potential candidates, which are progressively screened and eliminated from consideration by high-throughput experimental assays. Those molecules that emerge from this process as candidate drugs are also subject to extensive in vitro, in vivo, …
A Novel Function Of Plasmacytoid Dendritic Cells In Regulating Type 2 Immune Responses, Hannah Leigh Miller
A Novel Function Of Plasmacytoid Dendritic Cells In Regulating Type 2 Immune Responses, Hannah Leigh Miller
Arts & Sciences Graduate Student Theses and Dissertations
The generation of an allergic response is particularly perplexing, as the mucosal immune system is exposed to a myriad of antigens on a daily basis, the majority of which do not elicit inflammation. However, for the growing population of patients impacted by allergic diseases, there is a clear breakdown of normal tolerance to innocuous antigens, resulting in symptoms mediated by antigen specific T helper 2 (Th2) cells. In addition to their well-established role in early antiviral immunity via production of type I interferon, plasmacytoid dendritic cells (pDC) have been implicated in the generation of immune tolerance in a variety of …
The Role Of Subclonal Gene Mutations During Progression From Myelodysplastic Syndrome To Secondary Acute Myeloid Leukemia, Andrew John Menssen
The Role Of Subclonal Gene Mutations During Progression From Myelodysplastic Syndrome To Secondary Acute Myeloid Leukemia, Andrew John Menssen
Arts & Sciences Graduate Student Theses and Dissertations
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal bone marrow disorders characterized by ineffective hematopoiesis. Approximately 30% of MDS patients progress to secondary acute myeloid leukemia (AML). MDS is caused by somatic mutations in hematopoietic stem/progenitor cells and progression to secondary AML is associated with the acquisition and/or expansion of at least one subclone. We hypothesized that specific gene mutations would be enriched in subclones compared to founding clones, and that the order of mutation acquisition would be critical for clonal evolution and progression from MDS to secondary AML. Sequencing of paired MDS and secondary AML samples from 44 …