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Articles 781 - 810 of 838
Full-Text Articles in Biology
Characterizing And Modeling Antibiotic Resistance Dynamics In Diverse Microbial Communities, Molly Krisann Gibson
Characterizing And Modeling Antibiotic Resistance Dynamics In Diverse Microbial Communities, Molly Krisann Gibson
Arts & Sciences Graduate Student Theses and Dissertations
Complex microbial communities colonize every habitat investigated to date, including soil, animals, water, and humans, as well as the structures we live in. It has been hypothesized that there is network of exchange allowing both bacterial organisms and functions to seamlessly move between and within these environments. These microbial communities often serve essential and beneficial functions for the host organism or environment. This is particularly evident in the human gut, where microbial communities consistently provide a set of services to its human host, including protecting against enteric pathogens, liberating nutrients from food, and signaling immune system regulation. However, these communities …
A Gnotobiotic Mouse Model For Studying The Effect Of Human Gut Community Ecology On A Pathobiont, Bacteroides Fragilis, Vitas Wagner
A Gnotobiotic Mouse Model For Studying The Effect Of Human Gut Community Ecology On A Pathobiont, Bacteroides Fragilis, Vitas Wagner
Arts & Sciences Graduate Student Theses and Dissertations
ABSTRACT OF THE DISSERTATIONA Gnotobiotic Mouse Model for Studying the Effect of Human Gut Community Ecology on a Pathobiont, Bacteroides fragilisbyVitas WagnerDoctor of Philosophy in Biology and Biomedical SciencesEvolution, Ecology, and Population BiologyWashington University in St. Louis, 2015Professor Jeffrey I. Gordon, ChairChildhood undernutrition represents a pressing global health challenge. Epidemiologic studies have shown that undernutrition is not due to food insecurity alone, but rather represents a complex set of interactions between intra- and intergenerational factors. The gut microbiota has been implicated as one such factor. This thesis tested the hypothesis that enteropathogen burden affects the structure and expressed functions of …
Genetic Factors That Contribute To The Pathogenesis Of Amyotrophic Lateral Sclerosis, Janet Elizabeth Cady
Genetic Factors That Contribute To The Pathogenesis Of Amyotrophic Lateral Sclerosis, Janet Elizabeth Cady
Arts & Sciences Graduate Student Theses and Dissertations
Amyotrophic lateral sclerosis (ALS) is fatal neurodegenerative disease for which there is no cure. The only treatment available extends survival by only a matter of months. There are over 20 genes that are known to cause ALS. Over half of the ALS cases with a family history of disease (FALS) can be explained by mutations in known ALS genes with hexanucleotide repeat expansions in C9ORF72 accounting for 40% of families. However roughly 90% of cases have no family history of disease (sporadic ALS or SALS) and a much smaller proportion (10%) of these cases can be explained by mutations in …
Defining The Roles Of Outer Membrane Proteins And Host Cathelicidins In Uropathogenic Escherichia Coli Infection, Elizabeth Sarah Danka
Defining The Roles Of Outer Membrane Proteins And Host Cathelicidins In Uropathogenic Escherichia Coli Infection, Elizabeth Sarah Danka
Arts & Sciences Graduate Student Theses and Dissertations
The Gram-negative bacterium uropathogenic Escherichia coli (UPEC) is the causative agent of up to 85% of community-acquired urinary tract infections (UTIs). This thesis work aimed to better define interactions between UPEC and host antimicrobial peptides (AMPs). The bacterial outer membrane is constantly interacting with the external environment, and contains many integral proteins with defined roles in pathogenesis. The E. coli outer membrane protein OmpA is a highly conserved, integral beta-barrel membrane protein with four extracellular loops. We found that the loops of OmpA individually influence binding and invasion of UPEC during infection. Loop 2 appears to be essential for binding …
Variation And Plasticity Of Dna Methylation In Genome Regulation, Junchen Gu
Variation And Plasticity Of Dna Methylation In Genome Regulation, Junchen Gu
Arts & Sciences Graduate Student Theses and Dissertations
DNA methylation is an important and well-studied epigenetic mark. It plays a pivotal role in imprinting, X-chromosome inactivation and genome stability and regulation in many normal development processes. DNA methylation, along with histone modifications, orchestrates the cell type- and developmental stage-specific chromatin landscapes and influences gene expression in vertebrates. In this thesis, I utilized the latest next-generation sequencing based methods to map DNA methylation levels at a genome-wide scale to investigate two areas of interest: the variation of DNA methylation across a large number of sample types and its functional potentials; the plasticity of DNA methylation in response to environmental …
Mechanisms Underlying Memory Deficits Following West Nile Virus Neuroinvasive Disease, Michael John Vasek
Mechanisms Underlying Memory Deficits Following West Nile Virus Neuroinvasive Disease, Michael John Vasek
Arts & Sciences Graduate Student Theses and Dissertations
Neurocognitive sequelae are observed in >50% of patients who survive neuroinvasive infections with encephalitic arboviruses, such as the mosquito-borne West Nile virus (WNV). Early diagnosis and high survival rates from WNV neuroinvasive disease (WNND) (>90%) have thus led cumulatively to approximately ten thousand patients living with neurocognitive impairments, with 1-3000 cases accruing yearly, yet underlying mechanisms responsible for these deficits have not been investigated.Within the last 15 years, studies have begun uncover many pathways which are utilized both by the developing CNS as well as the immune system, including the use of cytokines in the regulation of progenitor cell …
Functional Characterization Of Putative Rab Geranylgeranyltransferase Subunits In Arabidopsis Thaliana, Wan Shi
Arts & Sciences Graduate Student Theses and Dissertations
Protein prenylation is one of the posttranslational lipid modifications that facilitate protein-membrane association and protein-protein interactions. Three types of heterodimeric protein prenyltransferases, protein farnesyltransferase (PFT), protein geranylgeranyltransferase-I (PGGT-I), and protein geranylgeranyltransferase-II or Rab geranylgeranyltransferase (Rab-GGT), are present in all eukaryotes. In Arabidopsis there are two putative genes encoding Rab-GGT α subunits, termed RGTA1 and RGTA2, and two putative genes encoding β subunits, RGTB1 and RGTB2, but little is known about Arabidopsis Rab-GGT activity. In this dissertation, I demonstrate that four different heterodimers can be formed between RGTA1, RGTA2, RGTB1, and RGTB2, but only RGTA1-RGTB1 and RGTA1-RGTB2 exhibit bona fide Rab-GGT …
Atypical Cadherin Dachsous Regulates The Cytoskeleton And Gastrulation Movements During Zebrafish Development, Nanbing Li
Arts & Sciences Graduate Student Theses and Dissertations
Dachsous (Dchs), an evolutionarily conserved atypical cadherin, regulates planar cell polarity, tissue size, and cell adhesion in Drosophila. However, its functions in vertebrates are just beginning to be elucidated. Inactivating one of two murine homologs, Dchs1, leads to multi-organ defects and postnatal lethality. Recent studies in humans suggest that mutations in DCHS1 cause pleiotropic Van Maldergem syndrome. My thesis work focuses on the functional characterization of zebrafish dchs1b and dchs2 genes. Mutations in dchs1b and dchs2 genes affect several aspects of embryogenesis, including gastrulation. Unexpectedly, dchs1b is also essential for the earliest vertebrate developmental stage, egg activation. We show that …
Neural Basis Of Functional Connectivity Mri, Jingfeng Li
Neural Basis Of Functional Connectivity Mri, Jingfeng Li
Arts & Sciences Graduate Student Theses and Dissertations
The brain is hierarchically organized across a range of scales. While studies based on electrophysiology and anatomy have been fruitful on the micron to millimeter scale, findings based on functional connectivity MRI (fcMRI) suggest that a higher level of brain organization has been largely overlooked. These findings show that the brain is organized into networks, and each network extends across multiple brain areas. This large-scale, across-area brain organization is functionally relevant and stable across subjects, primate species, and levels of consciousness.This dissertation addresses the neural origin of MRI functional connectivity. fcMRI relies on temporal correlation in at-rest blood oxygen level …
Flap Endonuclease 1 Promotes Telomere Replication And Stability By Distinct Mechanisms On The Leading And Lagging Strands, Daniel Cole Teasley
Flap Endonuclease 1 Promotes Telomere Replication And Stability By Distinct Mechanisms On The Leading And Lagging Strands, Daniel Cole Teasley
Arts & Sciences Graduate Student Theses and Dissertations
High fidelity DNA replication is essential for genomic stability and cell survival; this fact is underscored by the redundancy present in DNA replication and repair pathways. The complexity of these pathways is most evident at challenging DNA templates, such as those with repetitive sequence and transcribed loci. Among these challenging templates are telomeres, which are terminal, highly repetitive sequences that maintain genomic stability by preventing aberrant end-to-end chromosome fusions. In the absence of accurate, complete telomere replication, genomic instability results, ultimately leading to cell death or transformation. Here, we describe two unique roles in telomere stability for the DNA replication …
The Role Of Tmem178 In Regulation Of Osteo-Immune Activation And Inflammatory Bone Loss, Corinne Elaine Decker
The Role Of Tmem178 In Regulation Of Osteo-Immune Activation And Inflammatory Bone Loss, Corinne Elaine Decker
Arts & Sciences Graduate Student Theses and Dissertations
Pathological bone loss in human disease such as arthritis is largely due to excessive osteoclast recruitment as a consequence of localized inflammation. Innate immune cells, namely neutrophils and macrophages, infiltrate the joint space and release pro-inflammatory cytokines as well as proteases to drive local tissue damage and inflammation. Importantly, IL-1 and TNF-a in particular act on the synovial fibroblasts as well as directly on osteoclast precursors to potently augment osteoclast differentiation and thus bone resorption. Current therapeutics to treat pathological bone loss are widely unsuccessful at targeting both the resorptive and inflammatory components of disease. We have previously demonstrated that …
Evolutionary Developmental Leaf Morphology Of The Plant Family Araceae, Claudia Liliana Henriquez
Evolutionary Developmental Leaf Morphology Of The Plant Family Araceae, Claudia Liliana Henriquez
Arts & Sciences Graduate Student Theses and Dissertations
Studying the evolutionary developmental morphology of leaves using next-generation phylogenetics, a candidate gene approach and comparative developmental studies in the plant family Araceae is the overarching theme of the dissertation.The plant family Araceae is an ancient lineage from the Early Cretaceous and belongs to the monocotyledons. Members of Araceae display striking variation in leaf development; such variation contradicts traditional models of monocot leaf development. Additionally, dissected leaves, which are rare in monocots, seem to have evolved independently multiple times in Araceae by various developmental mechanisms.Despite extensive efforts to elucidate the evolutionary history of Araceae, phylogenetic ambiguity in the backbone of …
Functional Identification And Characterization Of Cis-Regulatory Elements, Christopher Michael Fiore
Functional Identification And Characterization Of Cis-Regulatory Elements, Christopher Michael Fiore
Arts & Sciences Graduate Student Theses and Dissertations
Transcription is regulated through interactions between regulatory proteins, such as transcription factors (TFs), and DNA sequence. It is known that TFs act combinatorially in some cases to regulate transcription, but in which situations and to what degree is unclear.I first studied the contribution of TF binding sites to expression in mouse embryonic stem (ES) cells by using synthetic cis-regulatory elements (CREs). The synthetic CREs were comprised of combinations of binding sites for the pluripotency TFs Oct4, Sox2, Klf4, and Esrrb. A statistical thermodynamic model explained 72% of the variation in expression driven by these CREs. The high predictive power of …
A Novel Cholesterol-Independent Mode Of Binding Promotes Cytolysin-Mediated Translocation And Pore Formation By Streptolysin O, Cara Mozola Forsberg
A Novel Cholesterol-Independent Mode Of Binding Promotes Cytolysin-Mediated Translocation And Pore Formation By Streptolysin O, Cara Mozola Forsberg
Arts & Sciences Graduate Student Theses and Dissertations
Effector translocation is a common strategy used by bacteria to promote pathogenesis via disruption of the immune response, prevention of phagocytosis, or induction of toxicity in the infected cell. The Gram-positive bacterium Streptococcus pyogenes utilizes a unique effector translocation system termed cytolysin-mediated translocation (CMT) to introduce the NAD+ glycohydrolase SPN into host cells during infection, resulting in cytotoxicity. Host cell membrane recognition by the cholesterol-dependent cytolysin (CDC) Streptolysin O (SLO) is a requisite step in this process, but the canonical cholesterol-dependent pore-forming activity of SLO is unnecessary, indicating that SLO is a bifunctional toxin. SLO exhibits extensive homology to other …
Β-Lactamase Gene Exchange Within The Enterobacteriaceae, Mitchell William Pesesky
Β-Lactamase Gene Exchange Within The Enterobacteriaceae, Mitchell William Pesesky
Arts & Sciences Graduate Student Theses and Dissertations
Antibiotic resistance represents a grave threat to modern medicine’s control over infectious disease. Pathogens of the Enterobacteriaceae have proven particularly problematic as they can cause a wide variety of infections, and they can be, in some cases, resistant to all antibiotics recommended for use against them. A major part of the threat posed by the Enterobacteriaceae is their ability to exchange resistance genes by horizontal gene transfer (HGT). HGT has allowed some Enterobacteriaceae to quickly accumulate resistance against diverse antibiotics, and then to spread their resistance gene collection to other pathogenic strains. I explore three aspects of how HGT has …
Peripheral And Central Mechanisms Of Temporal Pattern Recognition, Christa Ann Baker
Peripheral And Central Mechanisms Of Temporal Pattern Recognition, Christa Ann Baker
Arts & Sciences Graduate Student Theses and Dissertations
Encoding information into the timing patterns of action potentials, or spikes, is a strategy used broadly in neural circuits. This type of coding scheme requires downstream neurons to be sensitive to the temporal patterns of presynaptic inputs. Indeed, neurons with temporal filtering properties have been found in a wide range of sensory pathways. However, how such response properties arise was previously not well understood. The goal of my dissertation research has been to elucidate how temporal filtering by single neurons contributes to the behavioral ability to recognize timing patterns in communication signals. I have addressed this question using mormyrid weakly …
The Role Of Myc And Ap-1 Transcription Factors In The Development And Function Of The Dendritic Cell Lineage, Wumesh K.C.
The Role Of Myc And Ap-1 Transcription Factors In The Development And Function Of The Dendritic Cell Lineage, Wumesh K.C.
Arts & Sciences Graduate Student Theses and Dissertations
Dendritic cells (DCs) orchestrate immune responses to foreign and self proteins by capturing, processing and presenting antigens to naïve CD4+ and CD8+ T cells in specialized regions of lymphoid organs. Consequently, DCs function in many disparate infectious settings, during which their activation can result in both pathogenic and protective responses. The diverse properties of DCs manifest through the actions of a limited set of lineage-specifying DNA-binding proteins called transcription factors (TFs). The precise molecular program controlled by these developmentally important TFs (such as Irf8 and Batf3) is largely unknown because most studies to date have been largely descriptive. We have …
K-Ras, But Not H-Ras Or N-Ras, Hyperactivation Regulates Brain Neural Stem Cell Proliferation In A Raf/Rb-Dependent Manner, R. Hugh F. Bender
K-Ras, But Not H-Ras Or N-Ras, Hyperactivation Regulates Brain Neural Stem Cell Proliferation In A Raf/Rb-Dependent Manner, R. Hugh F. Bender
Arts & Sciences Graduate Student Theses and Dissertations
Neural stem cells (NSCs) give rise to all the major cell types in the brain, including neurons, oligodendrocytes, and astrocytes. However, the intracellular signaling pathways that govern brain NSC proliferation and differentiation have been incompletely characterized to date. Since several neurodevelopmental brain disorders (i.e., Costello syndrome, Noonan syndrome) are caused by germline mutations in the RAS genes, Ras small GTPases are likely critical regulators of brain NSC function. In the mammalian brain, Ras exists as three distinct molecules (H-Ras, K-Ras, and N-Ras), each with different subcellular localizations, downstream signaling effectors, and biological effects. Leveraging a novel series of conditional Ras …
Assessing Vascular Inflammation With Bioluminescence Imaging, Reece Joseph Goiffon
Assessing Vascular Inflammation With Bioluminescence Imaging, Reece Joseph Goiffon
Arts & Sciences Graduate Student Theses and Dissertations
Cardiovascular disease (CVD) is the leading cause of morbidity, mortality, and health care costs in the developed world and is often undiagnosed until clinical presentation with a major adverse cardiovascular event (MACE). Plasma myeloperoxidase (MPO) content is an emerging biomarker for risk, progression, and prognosis at different stages of CVD. Enzyme-linked immunosorbent assays (ELISAs) are currently used to measure clinical plasma MPO concentration, but ELISAs are costly and time-intensive. Luminol is a chemiluminescent compound with specificity for MPO activity in vivo, but is not sensitive enough for use as a bioluminescence reporter of plasma MPO oxidation. The luminol derivative L-012 …
Excessive Complement Activation Due To Genetic Haploinsufficiency Of Regulators In Multiple Human Diseases, Michael Triebwasser
Excessive Complement Activation Due To Genetic Haploinsufficiency Of Regulators In Multiple Human Diseases, Michael Triebwasser
Arts & Sciences Graduate Student Theses and Dissertations
The complement system is an ancient and powerful form of innate immunity. The alternative pathway (AP), a positive feedback loop, is at the core of the complement system. Activating components and regulators of the AP are genetically implicated in atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). aHUS features kidney failure, and often affects young children, but may occur throughout life and can be precipitated by pregnancy. aHUS associated variants are extremely rare and are considered highly penetrant. At the opposite end of the spectrum, AMD affects the retina leading to loss of central vision with a late …
Guanine Nucleotide Synthesis And The Enteric Nervous System, Jonathan Ian Lake
Guanine Nucleotide Synthesis And The Enteric Nervous System, Jonathan Ian Lake
Arts & Sciences Graduate Student Theses and Dissertations
There are currently no prevention strategies for Hirschsprung disease (HSCR), a potentially lethal birth defect caused by the failure of the enteric nervous system (ENS) to develop completely, resulting in an aganglionic segment of intestine. HSCR can result from one or a combination of partially-penetrant mutations in genes affecting the enteric neural crest-derived cells (ENCDCs) that colonize the intestine to form the ENS. While the genetics of HSCR and ENS development has been extensively studied, little is known about environmental risk factors for HSCR. To investigate maternal medication exposure as a possible HSCR risk factor, we conducted a chemical screen …
Functional Consequences Of Cd4+ T Cell Receptor Ligation In The Immune Response To Listeria Monocytogenes, Stephen Phillip Persaud
Functional Consequences Of Cd4+ T Cell Receptor Ligation In The Immune Response To Listeria Monocytogenes, Stephen Phillip Persaud
Arts & Sciences Graduate Student Theses and Dissertations
Interactions between the ab T cell receptor (TCR) and peptide-bound MHC molecules (pMHC) are highly specific and sensitive despite low affinities. The basis of TCR ligand specificity and its functional manifestations during protective immune responses are incompletely understood. To study this, we have generated two TCR transgenic mice called LLO56 and LLO118, which bear CD4+ T cells that recognize the same dominant epitope from the virulence factor Listeriolysin O (LLO) of Listeria monocytogenes. These TCRs were cloned from Listeria-infected B6 mice, and thus represent two solutions to recognizing the same pathogen-derived pMHC. LLO118 T cells expanded better than LLO56 during …
Ketone Body Metabolism Preserves Hepatic Function During Adaptation To Birth And In Overnutrition, David Graham Cotter
Ketone Body Metabolism Preserves Hepatic Function During Adaptation To Birth And In Overnutrition, David Graham Cotter
Arts & Sciences Graduate Student Theses and Dissertations
Mammalian ketone body metabolism partially oxidizes hepatic acyl-chains to ketone body intermediates, which can serve as alternative fuels in extrahapetic tissues during carbohydrate restricted states. Ketone body production (ketogenesis) occurs primarily in liver, due to hepatocyte-specific expression of the fate committing ketogenic enzyme, mitochondrial 3-hydroxymethylglutaryl-CoA synthase (HMGCS2). In contrast, the fate committing enzyme of ketone body oxidation, mitochondrial Succinyl-CoA:3-oxoacid CoA Transferase (SCOT), is expressed ubiquitously, except in liver. Here I demonstrate novel roles for ketone body metabolism during a classically ketogenic period, the transition to birth, and in a classically `non-ketogenic' state, overnutrition, using novel genetic mouse models, high-resolution measures …
How Gains And Losses Influence The Brain And Behavior: Relations To Age, Risk For Depression, And Individual Differences, Katherine R. Luking
How Gains And Losses Influence The Brain And Behavior: Relations To Age, Risk For Depression, And Individual Differences, Katherine R. Luking
Arts & Sciences Graduate Student Theses and Dissertations
Behavioral and neural response to rewards and punishments has been the subject of a growing literature with particular interest within developmental, psychopathology, and individual difference domains. There is now mounting evidence suggesting that adolescents show heightened response to reward relative to adults, and that adolescents with Major Depressive Disorder (MDD), elevated depressive symptoms, or at high-risk for depression show reduced response to reward. However, it is unclear whether similar relations between response to incentives and development/psychopathology are observed during childhood. Here we examine behavioral, neural (functional magnetic resonance imaging - fMRI), and self-reported responsiveness to gain and loss of rewards …
Molecular Characterization Of A Novel, Highly Protective Combination Monoclonal Antibody Therapy Against Chikungunya Virus, Pankaj Pal
Arts & Sciences Graduate Student Theses and Dissertations
Chikungunya virus (CHIKV) is an Aedes mosquito-transmitted alphavirus that causes epidemics of a debilitating, often chronic polyarthritis in humans. Over five million people in Africa and Asia have been infected since 2005, and an outbreak occurred recently in Italy demonstrating the potential for a global epidemic. A strong antibody response is elicited during infection and the aim of this thesis was to develop a better understanding of how the humoral immune response can control CHIKV infection. We identified 230 new anti-CHIKV monoclonal antibodies (MAbs) and tested their ability to inhibit infection of strains representing all three CHIKV genotypes (East/Central/South African, …
Genetic And Cellular Studies Of The Podocyte In Focal Segmental Glomerulosclerosis, Haiyang Yu
Genetic And Cellular Studies Of The Podocyte In Focal Segmental Glomerulosclerosis, Haiyang Yu
Arts & Sciences Graduate Student Theses and Dissertations
The podocyte forms the outer layer of the filtration barrier in the glomerulus to prevent albumin leakage. Podocyte damage leads to focal segmental glomerulosclerosis (FSGS), a leading cause of chronic kidney disease. The cause of the majority of FSGS cases is unknown and referred to as sporadic FSGS. Genetic studies have identified genes as monogenic causes of FSGS in patients with a strong family history, but these cases account for only a small proportion of the FSGS population. Whether genetic susceptibility contributes to sporadic FSGS and which cellular process in the podocyte initiates the pathogenesis of FSGS are important questions …
Molecular Mechanisms Of Plasmodium Red Blood Cell Invasion, Brian Michael Malpede
Molecular Mechanisms Of Plasmodium Red Blood Cell Invasion, Brian Michael Malpede
Arts & Sciences Graduate Student Theses and Dissertations
The malaria parasite Plasmodium utilizes specialized proteins for adherence to cellular receptors in its mosquito vector and human host. Adherence is critical for parasite development, host cell traversal and invasion, and protection from vector and host immune mechanisms. These vital roles have identified several adhesins as vaccine candidates. A deficiency in current adhesin-based vaccines is induction of antibodies targeting non-conserved, non-functional, and decoy epitopes due to the use of full length proteins or binding domains. To alleviate the elicitation of non-inhibitory antibodies, conserved functional regions of proteins must be identified and exploited. Structural biology provides the tools necessary to achieve …
Regulation Of Host And Viral Rna Expression During Gammaherpesvirus Infection, Susan Priscilla Canny
Regulation Of Host And Viral Rna Expression During Gammaherpesvirus Infection, Susan Priscilla Canny
Arts & Sciences Graduate Student Theses and Dissertations
Gammaherpesviruses are oncogenic viruses that establish latent infection and can periodically reactivate. Replication, reactivation from latency and gammaherpesvirus-mediated pathology are regulated by viral and host factors. Long-standing interests in the field include understanding viral gene expression and regulation during lytic and latent infection and the effects of chronic viral infection on the host. Murine gammaherpesvirus 68 (MHV68) is used to model features of human gammaherpesvirus biology.In this dissertation, I investigated: (1) the function of antisense viral transcripts; (2) Stat1 regulation of MHV68 gene 50 promoters; and (3) the effect of chronic infection on host gene expression. Our laboratory identified extensive …
Molecular And Computational Methods For Cellular State Control, Drew Groves Michael
Molecular And Computational Methods For Cellular State Control, Drew Groves Michael
Arts & Sciences Graduate Student Theses and Dissertations
The control of cellular state has many promising applications, including stem cell biology andregenerative medicine, biofuel production, and gene therapy. This dissertation demonstrates acomprehensive approach to cellular state control at the transcriptional level. We introduce anovel algorithm, NetSurgeon, which utilizes genome-wide gene regulatory networks to identifyinterventions that will force a cell toward a desired expression state. Following extensive insilico validation, we applied NetSurgeon to S. cerevisiae biofuel production, generatinginterventions designed to promote a fermentative state during xylose catabolism. Our selectedinterventions successfully promoted a fermentative transcriptional state and generated strainswith higher xylose import rates, improved xylose integration and increased ethanol productionrates. …
Single-Chain Rankl Provides Insights Into Rank Receptor Oligomerization And A Novel Approach To Osteoclast Inhibition, Julia Therese Warren
Single-Chain Rankl Provides Insights Into Rank Receptor Oligomerization And A Novel Approach To Osteoclast Inhibition, Julia Therese Warren
Arts & Sciences Graduate Student Theses and Dissertations
Osteoporosis is a skeletal disease characterized by bone resorption in excess of bone formation. The osteoclast is the sole bone resorbing cell and therefore provides an important avenue for novel therapeutic development. The mature osteoclast is derived from the monocyte/macrophage lineage, and its proper differentiation and function requires the interaction of receptor activator of NF-kB Ligand (RANKL) with its receptor RANK. RANKL exists as a homotrimer, with classical models of receptor activation assuming trimeric clustering of receptor as necessary for signal transduction. We have designed a novel single-chain RANKL (scRANKL) construct to test the assumption that the recruitment of three …