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Lrg1 Is An Adipokine That Mediates Obesity-Induced Hepatosteatosis And Insulin Resistance, Sijia He, Jiyoon Ryu, Juanhong Liu, Hairong Luo, Ying Lv, Paul R. Langlais, Jie Wen, Feng Dong, Zhe Sun, Ravindranath Duggirala

School of Medicine Publications

Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet–induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared with their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid β-oxidation. LRG1 …

Antibody-Drug Conjugates Plus Janus Kinase Inhibitors Enable Mhc-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation, Stephen P Persaud, Julie K Ritchey, Sena Kim, Sora Lim, Peter G Ruminski, Matthew L Cooper, Michael P Rettig, Jaebok Choi, John F Dipersio

Open Access Publications

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT …

Finland, A Package Deal: Disciplinary Climate In Science Classes, Science Dispositions And Science Literacy, Larry J. Grabau, Jari Levonen, Kalle Juuti

Plant and Soil Sciences Faculty Publications

Finland’s educational prowess, though tempered by recent international assessments, has remained intact. This report focused on lessons that could be learned regarding secondary-level science education from the Program for International Student Assessment (PISA) 2015, science-focused assessment. That PISA iteration included not only science literacy but also students’ science dispositions (epistemology, enjoyment, interest, and self-efficacy) and the schools’ science climate measures (disciplinary climate and teaching support). Due to the hierarchical nature of the PISA data, multilevel models were employed in this Finnish study, involving 5582 students from 167 schools. Science dispositions (as outcome measures) were differently associated with teaching support and …

Human Plcg2 Haploinsufficiency Results In A Novel Immunodeficiency, Joshua Brandon Alinger

Arts & Sciences Graduate Student Theses and Dissertations

NK cells are critical for the recognition and lysis of herpesvirus-infected cells. Patients with NK cell immunodeficiency may suffer from unusually severe and/or recurrent herpesvirus infections; however, the genetic cause is frequently unknown. PLCG2 encodes a signaling protein in NK cell and B cell receptor signaling, in which dominant-negative or gain-of-function mutations may cause cold urticaria, antibody deficiency, or autoinflammation. However, loss-of-function mutations and PLCG2 haploinsufficiency have never been reported in human disease. We examined 2 families with autosomal dominant NK cell immunodeficiency with dual high-dimensional techniques, mass cytometry and whole-exome sequencing, to identify the cause of disease. We identified …

Slo2.1 Channels: A New Molecular Mechanism To Regulate Uterine Excitability, Juan Jose Ferreira

Arts & Sciences Graduate Student Theses and Dissertations

At the end of pregnancy, the uterus transitions from a non-contractile state to a highly contractile state. Two processes primarily drive this transition. First, from the 28th week of pregnancy until labor, the resting membrane potential of uterine (myometrial) smooth muscle cells (MSMCs) gradually becomes more positive (depolarizes) (Parkington et al. 1999). Second, at the end of pregnancy, MSMCs express more oxytocin receptors and become more sensitive to oxytocin (Kimura et al. 1996). However, the detailed mechanisms by which these processes occur have not been determined. My central hypothesis was that the Na+-activated K+ channel SLO2.1 plays a key role …

Mass Spectrometry-Based Protein Footprinting: High-Throughput Maldi Platform And Large Protein Complexes Of Baf, Ruidong Jiang

Arts & Sciences Graduate Student Theses and Dissertations

Human’s advances in understanding biological processes rely heavily on the breakthroughs in biophysical tools. Mass spectrometry (MS)-based protein footprinting, which interrogates protein structures by measuring protein solvent assessable surface area (SASA), has grown rapidly in the last decade, successful in providing valuable data for numerous protein systems. This thesis focuses mainly on this technology.We set out to push the boundary of MS-based protein footprinting further into the new areas, preparing it for potential future applications including large-scale experiments that require high-throughput analysis the structure of large, complicated protein complexes. This thesis devotes five chapters to the method development of MS-based …

Regulatory Effects Of The E. Coli Recbcd Nuclease Domain On Dna Unwinding Kinetics, Nicole Fazio

Arts & Sciences Graduate Student Theses and Dissertations

I have examined the effects of deleting the nuclease domain of the E. coli helicase RecBCD on the rates of ATP-independent DNA melting, single stranded (ss) DNA translocation, and double stranded (ds) DNA unwinding by RecBCD. The canonical role of the nuclease domain is DNA degradation, but the removal of this domain showed unexpected effects on other RecBCD activities including DNA binding, melting, and unwinding. This thesis presents a mechanistic study of DNA unwinding by RecBCD and a RecBCD variant with the nuclease domain deleted (RecBΔnucCD). I examined the rates of ssDNA translocation and dsDNA unwinding by RecBCD and RecBΔnucCD …

Paleo-Environmental Pollution Of The Bronze Production During The Shang Period At Anyang, Henan Province, China, Yi-Ling Lin

Arts & Sciences Graduate Student Theses and Dissertations

Paleo-environmental pollution is invested in both identifying anthropogenic activities and evaluating the environmental condition and its impact on humans to understand human-environment relationships and the human experience of the past. This project first investigates the environmental and health consequences of bronze production during the Shang period at Anyang. As a contribution to the growing scholarship in paleo-environmental and archaeological studies, this dissertation uses Shang bronze production in Anyang as a case study into how paleo- environmental pollution study can inform us about the on environmental and health conditions of lives in the Bronze Age China. Through geochemical analysis (ICP-MS, ICP-OES) …

Cyclodextrin-Based Supramolecular Drug-Delivery Nanomaterials And Shear-Thinning Hydrogels Using Ring-Opening Metathesis Polymerization, Ruihan Li

Arts & Sciences Graduate Student Theses and Dissertations

Cyclodextrins (CD) are a family of oligosaccharides that can non-covalently and precisely bind small hydrophobic drug molecules, such as antibiotics and anticancer drugs, through well-defined host-guest interactions inside the inner cavity of the macrocycle. Ring-opening metathesis polymerization (ROMP) is a versatile, functional group tolerant method of polymerization that is underexplored in biomedical applications relative to the more common controlled chain-growth polymerizations. In this dissertation, I describe my efforts to combine the supramolecular chemistry of CDs with that of ROMP using specialized functional monomers to synthesize several CD-based polymeric drug delivery nanomaterials. For example, in Chapter 2, a new type of …

On The Challenges And Rewards Of Analyzing Molecular Dynamics At The Terabyte And Millisecond Scale, Justin Roy Porter

Arts & Sciences Graduate Student Theses and Dissertations

Molecular Dynamics (MD) and Markov state models (MSMs) are powerful tools for estimating and concisely representing the conformational ensemble accessible to biological macromolecules, particularly proteins. Conformational ensembles are of special importance biological function, both in health and disease, because biology derives from molecules’ entire conformational distribution rather than any single structure. Consequently, MD is poised to become a powerful tool for personalized medicine and for the study of molecular sequence-function relationships generally. However, because of their hyperdimensionality and size, just generating MD datasets and Markov state models (MSMs) that represent biologically relevant molecules is a substantive technical challenge. Then, even …

Causal Function And Bias Correlation Of The Orbitofrontal Cortex In Economic Choices, Shi Weikang

Arts & Sciences Graduate Student Theses and Dissertations

Economic choices entail two mental processes, value calculation and value comparison (Niehans, 1990). Studies in the last twenty years have shown that neurons in the orbitofrontal cortex (OFC) could support both processes. Namely, in the studies in which monkeys chose between two juice options with various amounts, three functional cell groups had been found in the OFC: offer value cells encode the value of individual juices, chosen juice cells encode the choice in a binary way and chosen value cells encode the value of the chosen juice (Padoa-Schioppa and Assad, 2006). These results suggest a decision circuit within OFC with …

Influence Of Focal Activity On Macroscale Brain Dynamics In Health And Disease, Zachary Pollack Rosenthal

Arts & Sciences Graduate Student Theses and Dissertations

Macroscopic recordings of brain activity (e.g. fMRI, EEG) are a sensitive biomarker of the neural networks supporting neurocognitive function. However, it remains largely unclear what mechanisms mediate changes in macroscale networks after focal brain injuries like stroke, seizure, and TBI. Recently, optical neuroimaging in animal models has emerged as a powerful tool to begin addressing these questions. Using widefield imaging of cortical calcium dynamics in mice, this dissertation investigates the mechanisms by which focal disruptions in activity alter brain-wide functional dynamics. In two chapters, I demonstrate 1) that focal sensory stimulation elicits state-dependent, global slow waves propagating from primary somatosensory …

Regulation Of Metabolic Stress By The Snhg3 Locus, Arthur Curtis Sletten

Arts & Sciences Graduate Student Theses and Dissertations

Dyslipidemia and lipotoxicity are pathologic signatures of the metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not fully understood. To identify novel genes involved in metabolic stress, our group performed an unbiased forward genetic screen for lipotoxicity resistance. My studies focused on characterizing one of the mutant cell lines isolated from this screen, in which promoter trap mutagenesis disrupted one allele of the small nucleolar RNA hosting gene 3 (Snhg3). I demonstrate that diminished expression …

Role Of Interferon Receptors In Sting-Associated Autoinflammatory Disease In Mice, William Alexander Stinson

Arts & Sciences Graduate Student Theses and Dissertations

Over the past decade, the cGAS-STING pathway has emerged as a principal component of innate DNA sensing. Its activation of type I interferon (IFN) elicits host immune activation and in the absence of cGAS or STING, mice are rendered critically susceptible to infection by viruses and bacteria. Breakdowns in the molecules that regulate this pathway can promote unrestrained cGAS-STING activation and the development of various forms of autoimmune disease. For instance, gain-of-function mutations in STING cause autoinflammatory lung disease in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. However, our understanding of the mechanisms that underlie STING-dependent …

Genetic Risk Factors For Neurodevelopmental Disorders: Insights From Hipsc-Cerebral Organoids, Michelle L. Wegscheid

Arts & Sciences Graduate Student Theses and Dissertations

Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder (NDD) characterized by remarkable phenotypic variability, where affected children manifest a spectrum of central nervous system (CNS) abnormalities, including brain tumors, impairments in attention, behavior, learning disabilities, and an increased incidence of autism spectrum disorder (ASD). A significant barrier to the implementation of precision medicine strategies for children with NF1 is a lack of prognostic risk factors to guide clinical management. However, emerging population-based genotype-phenotype association studies have suggested that the germline NF1 gene mutation may represent one clinically actionable risk factor for NF1-associated neurodevelopmental abnormalities. As a critical step in …

Weedy Rice As A Model System For The Study Of Microevolutionary Interactions In Agricultural Contexts, Marshall Jon Wedger

Arts & Sciences Graduate Student Theses and Dissertations

Just under one-half of the global population relies on cultivated rice (Oryza sativa) astheir primary source of calories, making the optimization of rice agriculture immensely important. One of the primary constraints to rice agriculture is the de-domesticated (feral) form of rice known as ‘weedy rice’ that aggressively competes for space, soil nutrients, and light. Heavy infestation can reduce crop yields by as much as 80%. As a closely-related weedy descendant of cultivated rice, chemical control is difficult in rice fields, and physical weeding is labor intensive, time consuming, and largely ineffective due to early life-stage mimicry of the crop. Weedy …

The Role Of Neuronal Atp-Sensitive Potassium Channels In Learning And Memory, Shaul Vladimir Yahil

Arts & Sciences Graduate Student Theses and Dissertations

ATP-sensitive potassium (KATP) channels link cellular metabolism and membrane excitability in many tissues, including brain and pancreas. Gain-of-function (GOF) mutations to KATP channels cause neonatal diabetes, with some patients exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Diabetic symptoms have been attributed to loss of membrane excitability and insulin secretion in pancreatic β-cells, though the origin of neurological deficits and the effects of neuronal KATP-GOF mutations more generally remain elusive. In this dissertation, I will present evidence that mice expressing KATP-GOF mutations pan-neuronally (nKATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP-GOF mice exhibited predominantly learning and memory deficits. …

Cancer Epigenome Reprogramming, Jennifer Ann Karlow

Arts & Sciences Graduate Student Theses and Dissertations

The identification of recurrent genetic mutations in cancer and their functionalcharacterization has provided a strong foundation for our understanding of tumorigenesis. The more recent observation of recurrent and specific epigenetic changes also present in cancer has widened this view, now establishing cancer as a disease of both genetic and epigenetic misregulation. Enhancers, genomic regions primarily responsible for tissue-specific gene expression, have been shown to be frequent targets of both genetic and epigenetic abnormalities. The observation that DNA methylation within regulatory regions has traditionally correlated with reduced gene expression, coupled with the known role of enhancers in regulating tissuespecific gene expression, …

Developments In Proteomics, Trans-Splicing Technology And Endogenous Transcript Manipulation, Justin Alexander Melendez

Arts & Sciences Graduate Student Theses and Dissertations

Technological innovation drives scientific discovery, unlocks new avenues of research, and allows us to ask questions in ways that were previously unavailable. With each technological advance, our ability to perturb and explore biological systems has grown in ways previously unimagined. The theme of my thesis is the development of new technologies in biology. To this end, I have worked on three technologies that contribute to the areas of protein sequencing, RNA barcoding for trans-splicing and single-cell applications, and a new method for transcriptional knockdown. In my first project, digital analysis of proteins by end sequencing (DAPES), we set out to …

Deep Learning For Automatic Microscopy Image Analysis, Shenghua He

McKelvey School of Engineering Graduate Student Theses & Dissertations

Microscopy imaging techniques allow for the creation of detailed images of cells (or nuclei) and have been widely employed for cell studies in biological research and disease diagnosis in clinic practices.Microscopy image analysis (MIA), with tasks of cell detection, cell classification, and cell counting, etc., can assist with the quantitative analysis of cells and provide useful information for a cellular-level understanding of biological activities and pathology. Manual MIA is tedious, time-consuming, prone to subject errors, and are not feasible for the high-throughput cell analysis process. Thus, automatic MIA methods can facilitate all kinds of biological studies and clinical tasks. Conventional …

Defining The Epigenetic And Transcriptional Regulatory Mechanisms By Which Hrsv Ns1 Alters Host Transcriptional Response, Nina Rose Beri

Arts & Sciences Graduate Student Theses and Dissertations

No abstract provided.

Dissecting The Molecular Mechanism Of Familial Cardiomyopathies, Sarah Ruth Clippinger Schulte

Arts & Sciences Graduate Student Theses and Dissertations

Familial cardiomyopathies, including hypertrophic (HCM), restrictive (RCM) and dilated cardiomyopathy (DCM), are the leading cause of sudden cardiac death in young people. These diseases, which are characterized by altered cardiac contractility and remodeling of the heart, can lead to heart failure. These diseases are primarily caused by point mutations in sarcomeric proteins that generate or regulate heart contraction, such as troponin T. In the heart, the troponin complex together with tropomyosin lie along the actin filament and regulate myosin’s ability to bind actin and produce force. Here I show how mutations in troponin T affect contractility at the molecular level …

Influence Of Aging And Cerebrovascular Disease On Neuroimaging Measures Of Alzheimer Disease, Lauren Nicole Koenig

Arts & Sciences Graduate Student Theses and Dissertations

The overall goal of this dissertation is to gain a better understanding of how Alzheimer disease relates to normal aging and cerebrovascular disease to impact neuroimaging measures in a clinically meaningful way. Both aging and cerebrovascular disease are known to influence measures of Alzheimer disease, making it difficult to separate what changes are attributable specifically to Alzheimer disease. We hypothesize that a better understanding of these relationships will allow future studies to appropriately take these factors into account. In Chapters 2 and 3 we attempt to separate out the influences of normal aging and Alzheimer disease on measures of atrophy. …

Structural Variants Are A Major Source Of Gene Expression Differences In Humans And Often Affect Multiple Nearby Genes, Alexandra Jane Scott

Arts & Sciences Graduate Student Theses and Dissertations

Structural variants (SVs), including copy number variants (CNVs), balanced rearrangements, and mobile element insertions (MEIs), are an important source of diversity in the human genome but their functional effects are not well understood. SVs are technically difficult to detect and genotype1, and mapping is dependent on deep whole genome sequencing (WGS) which was, until recently, unaffordable for large cohorts. For these reasons SVs are not included in most genome-wide studies of functional variants, despite the fact that SVs are known causal agents in multiple clinical disorders2-16. However, recent advancements in high-throughput sequencing technologies that allow for widespread use of WGS, …

Deep Multi-Omics Investigations Elucidate Novel Oncogenesis Paradigms, Therapeutic Targets, And Mechanisms Of Treatment Resistance In Cancer, Daniel Cui Zhou

Arts & Sciences Graduate Student Theses and Dissertations

No abstract provided.

A Systematic Study Of Neutron Production In Two Versions Of The Mevion Proton-Therapy System, Nima Tatari

Arts & Sciences Graduate Student Theses and Dissertations

This thesis presents a study of neutron production in two types of proton-therapy systems: passive scattering Mevion S250, and active scanning Mevion S250i. The scattering system has been operating at Washington University in St. Louis since 2013. The scanning system was installed in the same building in 2020. The scanning system has the advantage of producing fewer neutrons due to a focused scanned beam and the absence of beam scatterers, collimators, and a static brass aperture. A systematic particle transport Monte Carlo analysis using the Geant4 toolkit has been performed to track the neutrons produced in various components of each …

Regional Reprogramming And The Small Intestine: Analysis And Modeling Of Adaptive Regeneration Of The Epithelium, Sarah Elizabeth Waye

Arts & Sciences Graduate Student Theses and Dissertations

The small intestine in homeostasis is capable of regular regeneration, but in cases of massive injury like Short Bowel Syndrome, the innate human response often fails to fully compensate for the loss of nutrient absorptive surface area that accompanies bowel resection. Murine models display an active compensatory reaction deemed “adaptation” in which the surface area of the bowel is increased to accommodate nutrient absorptive needs. This observation has highlighted several gaps in knowledge regarding bowel adaptation. Firstly, what occurs on a molecular level in murine models during adaptation? Secondly, how can the findings in mice be applied to humans in …

Identification Of Multi-Tissue Protein Quantitative Trait Loci And Causal Inference Of Protein Effects In Neurological And Other Complex Human Diseases Via Mendelian Randomization, Chengran Yang

Arts & Sciences Graduate Student Theses and Dissertations

Alzheimer disease (AD) is the most common neurodegenerative disease, affecting 6.2 million people mostly aged 65 years or older in the United States as of early 2021. AD has been widely studied and characterized worldwide, but there is still no effective treatment or cure. Even the latest FDA-approved treatment, Aducanumab, cannot stop decline or improve cognition. To develop a truly effective treatments, researchers keep discovering genetic and molecular mechanisms underlying the disease. Protein biomarkers are keys to bridge the mechanisms to disease. Here, I first used a high-throughput proteomic dataset from three tissues (CSF, plasma, and brain) with array-based genotype …

Development And Application Of A Novel Acoustic Microfluidic Technology For Single Cell Per Well Trapping And High-Resolution Analysis Of Cilia Motion In Chlamydomonas Reinhardtii, Mingyang Cui

McKelvey School of Engineering Graduate Student Theses & Dissertations

Acoustic manipulation of cells and microorganisms is a label-free and contact-free technique with promise for biological and biomedical applications. When exposed to an ultrasonic standing wave field, particles suspended in microfluidic channels will be moved to pressure minima (nodes) or maxima (antinodes) due to the acoustic impedance mismatch between particles and the suspension medium. Cilia motion is fundamental to understanding biological and biomedical problems related to dysfunctional human cilia, including primary ciliary dyskinesia, blindness, and male infertility. However, in vivo and ex vivo mammalian ciliated cell research is laborious and time-consuming due to difficulty in growing, maintaining, and imaging these …

On The Study Of Age-Related Physiological Decline In C. Elegans, Drew Benjamin Sinha

McKelvey School of Engineering Graduate Student Theses & Dissertations

Aging decline is a universal and unescapable phenomenon; as organisms reach maturity and continue living, physiological function inevitably declines, resulting in mortality. While the study of mortality has been long studied, technical and practical challenges have limited the equally important study of how/when individuals deteriorate and what types of factors affect that deterioration. This gap in knowledge is not only evident in a relative lack of empirical data on physiological decline, but considerable debate around the analysis and conceptual interpretations of the little data that is available.

In this dissertation, I use quantitative reasoning and analysis of longitudinal data to …