Biology Commons^™

Dissemination Of The Apicomplexan Parasite, Toxoplasma Gondii, Lisa L. Drewry

Arts & Sciences Graduate Student Theses and Dissertations

The parasitic protist Toxoplasma gondii is a common pathogen of rodents and felines that also infects humans. The most severe clinical manifestations of toxoplasmosis in humans derive from the systemic dissemination of T. gondii, during which the parasite penetrates biological barriers and accesses protected host compartments such as the central nervous system. T. gondii dissemination is enabled by the intrinsic gliding motility of extracellular parasites, which allows for travel to new host cells and tissues, and also powers the invasion of diverse host cells including migratory leukocytes. Dissemination is further advanced when migrating infected leukocytes shuttle intracellular parasites to new …

Discoidin Domain Receptor 2 As A Therapeutic Target In Breast And Ovarian Cancer, Whitney Grither

Arts & Sciences Graduate Student Theses and Dissertations

Discoidin Domain Receptor 2 (DDR2) is a receptor tyrosine kinase that utilizes the extracellular matrix protein collagen as its ligand. Recently, DDR2 was shown to be critical in facilitating breast cancer metastasis. DDR2 stabilizes protein levels of the epithelial-mesenchymal-transition (EMT) inducing transcription factor, SNAIL1 in basal K14+ epithelial cells that are known to be important for invasive leader cell properties during collective invasion/migration. DDR2 expression is present in a majority of human invasive ductal breast carcinomas, and expression is localized to the tumor-stroma boundary. Additionally, in genetic models of breast cancer, deletion of DDR2 within the stroma (MMTV-PyMT; DDR2 fl/fl; …

Exploring Infant Leukemia Through Exome Sequencing And An In Vitro Model Of Hematopoietic Development, Mark Cannon Valentine

Arts & Sciences Graduate Student Theses and Dissertations

Cancer is a heterogeneous disease with myriad causes and outcomes. Many of the cancers that occur in adult populations have become increasingly well characterized with the advent of affordable high-throughput sequencing. These studies have revealed that cancer is largely a disease of somatic mutation in the adult population. In strong contrast to this, childhood cancers have an exceedingly low rate of somatic mutation. At the extreme end of this spectrum is Infant Leukemia (IL). Sequencing of IL has revealed that these tumors frequently have one or fewer somatic SNP. In the absence of a somatic explanation for IL, many other …

Molecular Mechanisms Responsible For Functional Cortical Plasticity During Development And After Focal Ischemic Brain Injury, Andrew Wiggen Kraft

Arts & Sciences Graduate Student Theses and Dissertations

The cerebral cortex is organized into functional representations, or maps, defined by increased activity during specific tasks. In addition, the brain exhibits robust spontaneous activity with spatiotemporal organization that defines the brain’s functional architecture (termed functional connectivity). Task-evoked representations and functional connectivity demonstrate experience-dependent plasticity, and this plasticity may be important in neurological development and disease. An important case of this is in focal ischemic injury, which results in destruction of the involved representations and disruption of functional connectivity relationships. Behavioral recovery correlates with representation remapping and functional connectivity normalization, suggesting functional organization is critical for recovery and a potentially …

Integrative Analysis To Investigate Complex Interaction In Alzheimer’S Disease, Zeran Li

Arts & Sciences Graduate Student Theses and Dissertations

Alzheimer’s disease (AD) is a neurodegenerative disorder featuring progressive cognitive and functional deficits. Pathologically, AD is characterized by tau and amyloid β protein deposition in the brain. As the sixth leading cause of death in the U.S., the disease course usually last from 7 to 10 years on average before the consequential death. In 2019 there are estimated 5.8 million Americans living with AD affecting 16 million family members. At certain stage of the disease course, patients with inability of maintaining their daily functioning highly depend on caregivers, primarily family caregivers, that incur estimated 18.4 billion unpaid hours of cares, …

Spatio-Temporal Principles Of Infra-Slow Brain Activity, Anish Mitra

Arts & Sciences Graduate Student Theses and Dissertations

In the study of systems where basic laws have eluded us, as is largely the case in neuroscience, the simplest approach to progress might be to ask: what are the biggest, most noticeable things the system does when left alone? Without any perturbations or fine dissections, can regularities be found in the basic operations of the system as a whole? In the case of the brain, it turns out that there is an amazing amount of activity even in the absence of explicit environmental inputs or outputs. We call this spontaneous, or resting state, brain activity. Prior work has shown …

The Role Of Smc3 In Mouse Embryonic And Adult Hematopoiesis, Tianjiao Wang

Arts & Sciences Graduate Student Theses and Dissertations

Acute myeloid leukemia (AML) is a heterogeneous disease, characterized by recurrent genetic mutations. Mutations in the cohesin complex are one of the 8 functional categories of mutations in AML. SMC3 encodes a subunit of the cohesin complex, which has important roles in chromosome segregation, genome instability, and gene expression. In the first chapter of the dissertation, we discuss the genetics of AML, normal functions of the cohesin complex, and the interplay between cohesin mutations and myeloid malignancies.SMC3 is recurrently mutated in AML and other myeloid malignancies. In the second chapter of the dissertation, we compare the consequences of Smc3 deficient …

Mechanics Of Phenotypic Aging Trajectories In C. Elegans And Humans, William Zhang

Arts & Sciences Graduate Student Theses and Dissertations

Overall, my dissertation integrates longitudinal measurements of physiology to investigate the aging process. In the first half, I examine the surprising and largely unexplained degree of variation in lifespan within even homogeneous populations. I sought to understand how physiological aging differs between long- and short-lived individuals within a population of genetically identical C. elegans reared in a homogeneous environment. Using a novel culture apparatus, I longitudinally monitored aspects of aging physiology across a large population of isolated individuals. Aggregating several measures into an overall estimate of senescence, I find that long- and short-lived individuals start adulthood on an equal physiological …

The Role Of The Ascc Complex In The Alkylation Damage Response, Jennifer Soll

Arts & Sciences Graduate Student Theses and Dissertations

DNA alkylation damage is caused by various agents that are present in the environment as well as cellular metabolism and can be induced by certain chemotherapeutic agents. Thus, the repair of damaged DNA is critical for genomic maintenance. The ALKBH family of proteins plays a central role in the repair of specific alkylated lesions, including 1-methyladenine (1meA) and 3-methylcytosine (3meC). A major outstanding question in the field of alkylation repair is the role of associated protein partners in the function of the human AlkB homologues. Here, I demonstrate that the ALKBH3 associated complex ASCC (comprised of ASCC1, ASCC2, and ASCC3) …

Typical And Atypical Development Of The Brain’S Functional Network Architecture, Ashley Nicole Nielsen

Arts & Sciences Graduate Student Theses and Dissertations

The human brain is a complex organ that gives rise to many behaviors. Specialized neural regions cooperate as functional networks that form an intricate functional architecture. Development provides a unique window into how brain functioning and human thinking are affected if the necessary neural features and connections are not fully formed. Similarly, developmental disorders can shed light on atypical trajectories of neural systems that may lead to or be a consequence of symptomatic behavior. A description of the typical and atypical development of functional networks is essential to identify the features of brain organization critical for mature human thinking and …

The Role Of Tumor Stromal Discoidin Domain Receptor 2 (Ddr2) In Breast Cancer Metastasis., Samantha Van Hove Bayer

Arts & Sciences Graduate Student Theses and Dissertations

Characteristics of breast tumor stroma, including altered collagen architecture and increased stiffness, are known to contribute to tumor invasion and metastasis. However, the cellular and molecular mechanisms by which these changes occur are not fully understood. To address this question, we used a mouse genetic model to delete Discoidin Domain Receptor 2 (DDR2) from mouse tumor stromal cells and interrogated breast cancer associated fibroblasts (CAFs) to determine the molecular events downstream of DDR2 action that may lead to changes in the tumor extracellular matrix (ECM). Our work revealed that the action of DDR2 in breast stromal cells is required for …

The Role Of Ifrd1 In The Recruitment And Function Of Reserve Stem Cells In Regeneration And Cancer, Mark Anthony Lewis

Arts & Sciences Graduate Student Theses and Dissertations

Mature cells can reprogram into a proliferative, progenitor-like state to repair tissue following injury and inflammation. Differentiated cells in diverse tissues can become proliferative via a dedicated, evolutionarily conserved program we termed paligenosis. We detailed how paligenosis occurs, in both gastric chief and pancreatic acinar cells, in a step-wise manner that involves: 1) autodegradation of mature cell components; 2) re-expression of progenitor genes; 3) re-entry into the cell cycle. This process is governed by mTORC1, a fundamental cellular energy sensor and regulator of protein translation. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. …

Genetic And Physical Interactions Between The Organellar Mechanosensitive Ion Channel Homologs Msl1, Msl2, And Msl3 Reveal A Role For Inter-Organellar Communication In Plant Development, Josephine S. Lee, Margaret E. Wilson, Ryan A. Richardson, Elizabeth S. Haswell

Biology Faculty Research

Plant development requires communication on many levels, including between cells and between organelles within a cell. For example, mitochondria and plastids have been proposed to be sensors of environmental stress and to coordinate their re- sponses. Here we present evidence for communication between mitochondria and chloroplasts during leaf and root development, based on genetic and physical inter- actions between three Mechanosensitive channel of Small conductance-Like (MSL) proteins from Arabidopsis thaliana. MSL proteins are Arabidopsis homologs of the bac- terial Mechanosensitive channel of Small conductance (MscS), which relieves cellular osmotic pressure to protect against lysis during hypoosmotic shock. MSL1 localizes to …

Anolis Newsletter Vii, James T. Stroud, Anthony J. Geneva, Jonathan B. Losos

Biology Faculty Research

Newsletter for the 7th Anolis Symposium, Fairchild Tropical Botanic Gardens, Miami, Florida, 17-18 March 2018.

It had been nearly a decade since the previous Anolis symposium was held in Cambridge, MA, at the Museum for Comparative Zoology, Harvard. A reunion of anole biologists en masse was long past due and it was decided that this symposium would be slightly different – we were going to hold it somewhere with anoles! And so, on the weekend of 17-18th March, 2018, nearly 70 anole biologists traveled to sunny south Florida to attend the 7th Anolis Symposium held at the beautiful Fairchild Tropical …

Generating Genome Browsers To Facilitate Undergraduate-Driven Collaborative Genome Annotation, Luke Sargent, Yating Liu, Wilson Leung, Nathan Mortimer, David Lopatto, Jeremy Goecks, Sarah C.R. Elgin

Biology Faculty Research

Scientists are sequencing new genomes at an increasing rate with the goal of associating genome contents with phenotypic traits. After a new genome is sequenced and assembled, structural gene annotation is often the first step in analysis. Despite advances in computational gene prediction algorithms, most eukaryotic genomes still benefit from manual gene annotation. Undergraduates can become skilled annotators, and in the process learn both about genes/genomes and about how to utilize large datasets. Data visualizations provided by a genome browser are essential for manual gene annotation, enabling annotators to quickly evaluate multiple lines of evidence (e.g., sequence similarity, RNA-Seq, gene …

Symbiotic Bacteria Can Colonize Closely-Related, But Not Distantly-Related Species Of Its Host Dictyostelium Discoideum, Rory Vu Mather

Undergraduate Research Symposium Posters

Some of the closest interactions between organisms can be found within symbioses, where different individuals live in close physiological contact and either benefit or harm the other. A powerful kind of benefit comes when bacterial symbionts produce amino acids or provide digestive capabilities outside the host’s ability, in essence taking advantage of the other’s genetic catalog. One such symbiosis is that of the social amoeba Dictyostelium discoideum and its bacterial symbionts Burkholderia agricolaris, Burkholderia hayleyella, and Burkholderia bonneia. In this symbiosis, Burkholderia provide the capability of carrying food bacteria to their host, an advantageous trait when bacterial food is rare. …

Grammar And Variation: Understanding How Cis-Regulatory Information Is Encoded In Mammalian Genomes, Dana Michele King

Arts & Sciences Graduate Student Theses and Dissertations

Understanding how genotype leads to phenotype is key to understand both the development and dysfunction of complex organisms. In the context of regulating the gene expression patterns that contribute to cell identity and function, the goal of my thesis research is to how changes in genome sequence may impact impact gene expression by determining how sequence features contribute to regulatory potential. To accomplish this goal, I first leveraged the key regulatory role of pluripotency transcription factors (TFs) in mouse embryonic stem cells (mESCs) and tested synthetically generated and genomic identified combinations of binding site for four TFs, OCT4, SOX2, KLF4, …

Fast Objective Coupled Planar Illumination Microscopy, Cody Jonathan Greer

Arts & Sciences Graduate Student Theses and Dissertations

Among optical imaging techniques light sheet fluorescence microscopy stands out as one of the most attractive for capturing high-speed biological dynamics unfolding in three dimensions. The technique is potentially millions of times faster than point-scanning techniques such as two-photon microscopy. This potential is especially poignant for neuroscience applications due to the fact that interactions between neurons transpire over mere milliseconds within tissue volumes spanning hundreds of cubic microns. However current-generation light sheet microscopes are limited by volume scanning rate and/or camera frame rate. We begin by reviewing the optical principles underlying light sheet fluorescence microscopy and the origin of these …

The Splice Is Not Right: Splice-Site-Creating Mutations In Cancer Genomes, Reyka Glencora Jayasinghe

Arts & Sciences Graduate Student Theses and Dissertations

Accurate interpretation of cancer mutations in individual tumors is a prerequisite for precision medicine. Large-scale sequencing studies, such as The Cancer Genome Atlas (TCGA) project, have worked to address the functional consequences of genomic mutations, with the larger goal of determining the underlying mechanisms of cancer initiation and progression. Many studies have focused on characterizing non-synonymous somatic mutations that alter amino acid sequence, as well as splice disrupting mutations at splice donors and acceptors. Current annotation methods typically classify mutations as disruptors of splicing if they fall on the consensus intronic dinucleotide splice donor, GT, the splice acceptor, AG. Splice …

Modeling The Bioactivation And Subsequent Reactivity Of Drugs, Tyler Brian Hughes

Arts & Sciences Graduate Student Theses and Dissertations

Metabolism can convert drugs to harmful reactive metabolites that conjugate to DNA and off-target proteins. Reactive metabolites are a significant driver of both drug candidate attrition and withdrawal from the market of already approved drugs. Unfortunately, reactive metabolites are difficult to study in vivo, because they are transitory and generally do not circulate. Instead, this work computationally models both metabolism and reactivity. Using deep learning, predictive models were developed for the metabolic formation of quinones and epoxides, which together account for about half of known reactive metabolites. Additionally, an accurate model of DNA and protein reactivity was constructed, which predicts …

Protein Structure-Guided Approaches To Identify Functional Mutations In Cancer, Sohini Sengupta

Arts & Sciences Graduate Student Theses and Dissertations

Distinguishing driver mutations from passenger mutations within tumor cells continues to be a major challenge in cancer genomics. Many computational tools have been developed to address this challenge; however, they rely heavily on primary protein sequence context and frequency/mutation rate. Rare driver mutations not found in many cancer patients may be missed with these traditional approaches. Additionally, the structural context of mutations on tertiary/quaternary protein structures is not taken into account and may play a more prominent role in determining phenotype and function. This dissertation first presents a novel computational tool called HotSpot3D, which identifies regions of protein structures that …

A Mouse Model Of Börjeson-Forssman-Lehmann Syndrome Reveals A Potential Link With Autism Spectrum Disorder, Cheng Cheng

Arts & Sciences Graduate Student Theses and Dissertations

ABSTRACT OF THE DISSERTATIONA Mouse Model of Börjeson-Forssman-Lehmann Syndrome reveals a potential link with Autism Spectrum DisorderByCheng ChengDoctor of Philosophy in Biology and Biomedical SciencesDevelopmental, Regenerative and Stem Cell BiologyWashington University in St. Louis, 2018Dr. Azad Bonni, ChairIntellectual disability (ID) is a prevalent neurodevelopmental disorder that affects 1% to 3% of the general population. ID is characterized by developmental deficiencies in cognitive function and adaptive behaviors. Lacking effective treatments, ID currently presents an immense burden to affected families and the economy. Therefore, there is an urgent need to elucidate the pathogenesis of ID. Human genetic studies have associated ID with …

Combining Footprinting Mass Spectrometry And Molecular Dynamics Simulation For Structural Studies In Membrane Proteins, Fengbo Zhou

Arts & Sciences Graduate Student Theses and Dissertations

Membrane proteins are essential in many cellular processes and represent ~60% of all current drug targets. Due to technical limits, membrane proteins of various types were not studied extensively in the past and the biochemistry and functionality of them remain unclear. The structural biology methodologies require pure isolated protein samples for us to resolve their structure and study their biochemical functions. For such in vitro studies, however, membrane proteins often become unstable when isolated from their native lipid bilayer environment. To overcome the challenge, I employed a novel methodology of solubilizing membrane proteins in solution without detergent. I reconstituted ferroportin, …

The Role Of Fibrillin-1 In Eye Development And Disease, Wendell Brooks Jones

Arts & Sciences Graduate Student Theses and Dissertations

The ciliary zonule of the human eye consists of a circumferential array of fibers that connect the ocular lens to the nonpigmented ciliary epithelium (NPCE) located at the inner wall of the eye. Zonular fibers consist of bundles of beaded filaments called microfibrils. Microfibrils are major structural elements of the extracellular matrix and are present in pure form in the ciliary zonule. Microfibrils are composed principally of fibrillin-1 (FBN-1); a large extracellular matrix glycoprotein. In humans, mutations in FBN1 underlie Marfan syndrome; a pleiotropic connective tissue disorder that profoundly affects the eye. Ocular manifestations include ectopia lentis (dislocated lenses), cataracts, …

Sequence Analysis Methods For The Design Of Cancer Vaccines That Target Tumor-Specific Mutant Antigens (Neoantigens), Jasreet Hundal

Arts & Sciences Graduate Student Theses and Dissertations

The human adaptive immune system is programmed to distinguish between self and non-self proteins and if trained to recognize markers unique to a cancer, it may be possible to stimulate the selective destruction of cancer cells. Therapeutic cancer vaccines aim to boost the immune system by selectively increasing the population of T cells specifically targeted to the tumor-unique antigens, thereby initiating cancer cell death.. In the past, this approach has primarily focused on targeted selection of ‘shared’ tumor antigens, found across many patients. The advent of massively parallel sequencing and specialized analytical approaches has enabled more efficient characterization of tumor-specific …

The Essential Roles Of The Chromatin Factor Gon4l In Heart Development, Terin Elise Budine

Arts & Sciences Graduate Student Theses and Dissertations

Heart development and the genetic pathways underlying it are highly conserved among vertebrates. During heart development, an embryo must induce mesoderm formation, pattern the mesoderm, specify cardiomyocytes, increase the population of cardiomyocytes through proliferation, and pattern the cardiac chambers. It is becoming increasingly clear that chromatin modifications help mediate the complex processes of heart development by providing spatiotemporal regulation of gene expression. My thesis work focuses on characterizing functions of the chromatin factor Gonad-4-like (Gon4l), encoded by the gene ugly duckling (udu), in zebrafish heart development. Previous works established a requirement for Gon4l in the formation of many mesoderm derivatives …

Genetic Basis Of Thermal Divergence In Saccharomyces Species, Xueying C. Li

Arts & Sciences Graduate Student Theses and Dissertations

The genetic architecture of phenotypic divergence is a central question in evolutionary biology. Genetic architecture is impacted by whether evolution occurs through accumulation of many small-effect or a few large-effect changes, the relative contribution of coding and cis-regulatory changes, and the prevalence of epistatic effects. Our empirical understanding of the genetic basis of evolutionary change remains incomplete, largely because reproductive barriers limit genetic analysis to those phenotypes that distinguish closely related species. In this dissertation, I use hybrid genetic analysis to examine the basis of thermal divergence between two post-zygotically isolated species, Saccharomyces cerevisiae and S. uvarum. S. cerevisiae is …

A Recombinant Virus And Reporter Mouse System To Study Chronic Chikungunya Virus Pathogenesis, Alissa Roxanne Young

Arts & Sciences Graduate Student Theses and Dissertations

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that during acute disease causes fever as well as severe joint and muscle pain. Chronic joint and muscle pain persists in a significant subset of patients, yet we still have a poor understanding of what drives this chronic disease. While replicating virus has not been detected in the joints of patients with chronic arthritis or in various animal models at chronic time points, persistent viral RNA can be detected for months after acute infection.To identify the cells that could be contributing to chronic CHIKV pathogenesis, we developed recombinant viruses that express Cre recombinase …

Mechanistic Characterization Of Resistome And Microbiome Dynamics Across Diverse Microbial Habitats, Andrew John Gasparrini

Arts & Sciences Graduate Student Theses and Dissertations

Increasing antibiotic resistance in pathogens is a serious public health challenge, with over two million antibiotic resistant infections in the United States leading to at least 23,000 deaths and an estimated $55 billion in excess healthcare and societal costs. Antibiotic resistance has risen steadily in both pathogenic and benign bacteria since antibiotics’ introduction to agriculture and medicine 70 years ago. A dramatic reduction in the number of antibiotics approved for human use has accompanied this rise in antibiotic resistance, leading to the alarming prospect of a post-antibiotic era. Understanding the evolutionary origins, genetic contexts, and molecular mechanisms of antibiotic resistance …

The Role Of Apolipoprotein E In Regulating Tau Pathogenesis And Neurodegeneration In A Tauopathy Mouse Model, Yang Shi

Arts & Sciences Graduate Student Theses and Dissertations

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 increases brain amyloid-β (Aβ) pathology relative to other APOE isoforms. However, whether APOE independently influences tau pathology, the other pathological hallmark of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human APOE knock in (KI) or APOE knockout (KO) background, we show that the presence of human APOE, regardless of APOE isoforms, leads to various degrees of brain atrophy in 9-month old P301S mice, whereas APOE ablation strongly protects against neurodegeneration. In particular, P301S/E4 mice develop …