Systems Biology Commons^™

Epidermal Growth Factor-Like Ligands Regulate Dimer Selection., Jamie S. Rush

Electronic Theses and Dissertations

There are thirteen known endogenous EGF-like ligands. We previously reported that Betacellulin (BTC) increases ligand-mediated corneal wound healing more than Epidermal Growth Factor (EGF) [Peterson et al. (2014) IOVS 55(5):2870-80], although the molecular reason for this is unknown. Despite being better at promoting wound healing via enhanced cell migration, BTC has reduced receptor affinity and weaker induction of EGFR phosphorylation. These data indicate that BTC’s response is not due to enhanced affinity or EGFR-kinase activity. Receptor phosphorylation and proximity ligation assays indicate that BTC treatment significantly increases ErbB3 phosphorylation and EGFR:ErbB3 heterodimers. BTC traffics EGFR at a faster rate than …

Green Tea Polyphenol Epigallocatechin-3-Gallate-Stearate Inhibits The Growth Of Streptococcus Mutans: A Promising New Approach In Caries Prevention, Amy Lynn Melok, Lee Lee, Siti Ayuni Mohamed Yussof, Tinchun Chu

Department of Biology Faculty Scholarship and Creative Works

Streptococcus mutans (S. mutans) is the main etiological bacteria present in the oral cavity that leads to dental caries. All of the S. mutans in the oral cavity form biofilms that adhere to the surfaces of teeth. Dental caries are infections facilitated by the development of biofilm. An esterified derivative of epigallocatechin-3-gallate (EGCG), epigallocatechin-3-gallate-stearate (EGCG-S), was used in this study to assess its ability to inhibit the growth and biofilm formation of S. mutans. The effect of EGCG-S on bacterial growth was evaluated with colony forming units (CFU) and log reduction; biofilm formation was qualitatively determined by Congo red assay, …

Deciphering The Role Of Human Arylamine N-Acetyltransferase 1 (Nat1) In Breast Cancer Cell Metabolism Using A Systems Biology Approach., Samantha Marie Carlisle

Electronic Theses and Dissertations

Background: Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme found in almost all tissues. NAT1 can additionally hydrolyze acetyl-coenzyme A (acetyl-CoA) in the absence of an arylamine substrate. NAT1 expression varies inter-individually and is elevated in several cancers including estrogen receptor positive (ER+) breast cancers. Additionally, multiple studies have shown the knockdown of NAT1, by both small molecule inhibition and siRNA methods, in breast cancer cells leads to decreased invasive ability and proliferation and decreased anchorage-independent colony formation. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. Additionally, consequences …

Computational Analysis Of Genomic Variants Affecting Predicted Microrna:Target Interactions In Prostate Cancer., Angélica Paola Hernández Pérez

KGI Theses and Dissertations

Prostate cancer (PCa) is the most common cancer of men in the United States and is third only to lung and colon as a cause of cancer death. Clinical behavior of the disease is variable and the combination of prostate-specific antigen (PSA) screening and Gleason score staging are currently the best available molecular and pathology tools to predict outcomes. Cancer biology research establishes microRNAs (miRNAs) as key molecular components in both normal and pathological states. Thus, elucidating miRNAs perturbed by genomic alterations will expand our understanding of the molecular taxonomy of PCa with the aim to complement current practices in …

Transcriptional Profiling Reveals Extraordinary Diversity Among Skeletal Muscle Tissues, Erin E. Terry, Xiping Zhang, Christy Hoffmann, Laura D. Hughes, Scott A. Lewis, Jiajia Li, Matthew J. Wallace, Lance A. Riley, Collin M. Douglas, Miguel A. Gutierrez-Monreal, Nicholas F. Lahens, Ming C. Gong, Francisco H. Andrade, Karyn A. Esser, Michael E. Hughes

Physiology Faculty Publications

Skeletal muscle comprises a family of diverse tissues with highly specialized functions. Many acquired diseases, including HIV and COPD, affect specific muscles while sparing others. Even monogenic muscular dystrophies selectively affect certain muscle groups. These observations suggest that factors intrinsic to muscle tissues influence their resistance to disease. Nevertheless, most studies have not addressed transcriptional diversity among skeletal muscles. Here we use RNAseq to profile mRNA expression in skeletal, smooth, and cardiac muscle tissues from mice and rats. Our data set, MuscleDB, reveals extensive transcriptional diversity, with greater than 50% of transcripts differentially expressed among skeletal muscle tissues. We detect …

Modeling And Analyzing An Optogenetic System For Photoactivatable Protein Dissociation, Anvin Thomas, James Schaff

Honors Scholar Theses

Computational modeling of cell-cell interactions can grant clues and can answer questions about an experiment, especially for observations about binding interactions and kinetics. This approach was used to investigate an interaction between a light-oxygen-voltage (LOV) domain and an engineered protein called Zdark (Zdk). The LOV domain is membrane-bound while Zdk is cytosolic. The LOV domain and Zdk bind strongly in dark (K_d 26.2 nM), and weakly upon exposure to blue light (K_d > 4 μM). Total internal reflection fluorescence (TIRF) images are acquired of Zdk, the fluorescent species bound to a mCherry tag, and the loss of fluorescence is …

Superresolution Imaging Identifies That Conventional Trafficking Pathways Are Not Essential For Endoplasmic Reticulum To Outer Mitochondrial Membrane Protein Transport., Kyle Salka, Shivaprasad Bhuvanendran, Kassandra Wilson, Petros Bozidis, Mansi Mehta, Kristin Rainey, Hiromi Sesaki, George H Patterson, Jyoti K. Jaiswal, Anamaris M. Colberg-Poley

Genomics and Precision Medicine Faculty Publications

Most nuclear-encoded mitochondrial proteins traffic from the cytosol to mitochondria. Some of these proteins localize at mitochondria-associated membranes (MAM), where mitochondria are closely apposed with the endoplasmic reticulum (ER). We have previously shown that the human cytomegalovirus signal-anchored protein known as viral mitochondria-localized inhibitor of apoptosis (vMIA) traffics from the ER to mitochondria and clusters at the outer mitochondrial membrane (OMM). Here, we have examined the host pathways by which vMIA traffics from the ER to mitochondria and clusters at the OMM. By disruption of phosphofurin acidic cluster sorting protein 2 (PACS-2), mitofusins (Mfn1/2), and dynamin related protein 1 (Drp1), …

Exploring Biological Heterogeneity And Its Consequences At Tissue And Cellular Scales Through Mathematical And Computational Modeling, Romica Kerketta

Biomedical Sciences ETDs

This dissertation explores the effects of heterogeneity across different biological scales in cancer as well as normal cells. At the tissue scale, we investigated the variability present in the tumor microenvironment and its effect on patient chemotherapeutic outcomes using a mathematical model of drug transport. We found that parameters such as tumor blood perfusion and radius of blood vessel had an impact on the tumor cytotoxicity. This indicated that the physical microenvironment of the tumor is an important regulator of the tumor response to chemotherapy. At the cellular scale, we investigated the heterogeneity present on the membrane landscape of ErbB2 …

Bioethics In The Work Of Ernest Everett Just: + Missing - Some 400 Pages, Theodore Walker

Perkins Faculty Research and Special Events

Biology + ethics = bioethics. Here we see that Howard University biologist Ernest Everett Just (born 1883, died 1941) connected biology to ethics.

According to Just, various forms of specific biology (including especially cell biology) plus “general biology” are necessary for explaining adequately the origin of ethical behaviors. Social ethical behaviors, especially mutual aid and cooperative interactions with others and the environment, are essential to evolutionary advances among living creatures, ranging from humans to cells. Accordingly, theory of ethics (moral theory) should have roots in biology.

Also, Just wrote an unpublished book-length manuscript—“some 400 typed pages” (Just 1940)—on seeking the …

An Amphipathic Trans-Acting Phosphorothioate Rna Element Delivers An Uncharged Phosphorodiamidate Morpholino Sequence In Mdx Mouse Myotube, H. Jain, J. Boehler, D. Verthelyi, Kanneboyina Nagaraju, S. Beaucage

Genomics and Precision Medicine Faculty Publications

An efficient method for the delivery of uncharged polyA-tailed phosphorodiamidate morpholino sequences (PMO) in mammalian cells consists of employing a synthetic 8-mer amphipathic trans-acting poly-2′-O-methyluridylic thiophosphate triester element (2′-OMeUtaPS) as a transfection reagent. Unlike the dTtaPS DNA-based element, this RNA element is potent at delivering polyA-tailed PMO sequences to HeLa pLuc 705 cells or to myotube muscle cells. However, much like dTtaPS, the 2′-OMeUtaPS-mediated internalization of PMO sequences occurs through an energy-dependent mechanism; macropinocytosis appears to be the predominant endocytic pathway used for cellular uptake. The transfected PMO sequences induce alternate splicing of either the pre-mRNA encoding luciferase in HeLa …

Hepatocyte-Specific Deletion Of Tristetraprolin Family Of Rna Binding Proteins Result In The Development Of Hepatocellular Carcinomas, Sonika Patial

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Identification Of Control Targets In Boolean Molecular Network Models Via Computational Algebra, David Murrugarra, Alan Veliz-Cuba, Boris Aguilar, Reinhard Laubenbacher

Mathematics Faculty Publications

Background: Many problems in biomedicine and other areas of the life sciences can be characterized as control problems, with the goal of finding strategies to change a disease or otherwise undesirable state of a biological system into another, more desirable, state through an intervention, such as a drug or other therapeutic treatment. The identification of such strategies is typically based on a mathematical model of the process to be altered through targeted control inputs. This paper focuses on processes at the molecular level that determine the state of an individual cell, involving signaling or gene regulation. The mathematical model type …

Modeling And Analysis Of Germ Layer Formations Using Finite Dynamical Systems, Alexander Garza, Megan Eberle, Eric A. Eager

Spora: A Journal of Biomathematics

The development of an embryo from a fertilised egg to a multicellular organism proceeds through numerous steps, with the formation of the three germ layers (endoderm, mesoderm, ectoderm) being one of the first. In this paper we study the mesendoderm (the tissue that collectively gives rise to both mesoderm and endoderm) gene regulatory network for two species, \textit{Xenopus laevis} and the axolotl (\textit{Ambystoma mexicanum}) using Boolean networks. We find that previously-established bistability found in these networks can be reproduced using this Boolean framework, provided that some assumptions used in previously-published differential equations models are relaxed. We conclude by discussing our …

Identification Of Host Factors Required For Yersinia Pestis Macrophage Intracellular Survival And Their Impact On Vacuole Maturation, Acidification And Trafficking., Michael Graylin Connor

Electronic Theses and Dissertations

Y. pestis is a facultative intracellular pathogen and the causative agent of plague. This bacterium, while most noted or the Black Death during the European 14^th century, is not a historic pathogen but a re-emerging pandemic with both domestic and global impact. Y. pestis is capable of colonizing the macrophage, and actively subverts phagolysosome maturation to establish a replicative niche known as the Yersinia containing vacuole (YCV). The exploited host factors required to support the YCV are unknown. Here we identified a comprehensive list of host factors required for Y. pestis survival through a genome-wide RNAi high-throughput screen. We …

Age-Associated Methylation Suppresses Spry1, Leading To A Failure Of Re-Quiescence And Loss Of The Reserve Stem Cell Pool In Elderly Muscle., Anne Bigot, William J Duddy, Zamalou G Ouandaogo, Elisa Negroni, Virginie Mariot, Svetlana Ghimbovschi, Brennan Harmon, Aurore Wielgosik, Camille Loiseau, Joseph Devaney, Julie Dumonceaux, Gillian Butler-Browne, Vincent Mouly, Stéphanie Duguez

Genomics and Precision Medicine Faculty Publications

The molecular mechanisms by which aging affects stem cell number and function are poorly understood. Murine data have implicated cellular senescence in the loss of muscle stem cells with aging. Here, using human cells and by carrying out experiments within a strictly pre-senescent division count, we demonstrate an impaired capacity for stem cell self-renewal in elderly muscle. We link aging to an increased methylation of the SPRY1 gene, a known regulator of muscle stem cell quiescence. Replenishment of the reserve cell pool was modulated experimentally by demethylation or siRNA knockdown of SPRY1. We propose that suppression of SPRY1 by age-associated …

A Model Of How Different Biology Experts Explain Molecular And Cellular Mechanisms, Caleb M. Trujillo, Trevor R. Anderson, Nancy J. Pelaez

PIBERG Publications

Constructing explanations is an essential skill for all science learners. The goal of this project was to model the key components of expert explanation of molecular and cellular mechanisms. As such, we asked: What is an appropriate model of the components of explanation used by biology experts to explain molecular and cellular mechanisms? Do explanations made by experts from different biology subdisciplines at a university support the validity of this model? Guided by the modeling framework of R. S. Justi and J. K. Gilbert, the validity of an initial model was tested by asking seven biologists to explain a molecular …

Asynchronous Remodeling Is A Driver Of Failed Regeneration In Duchenne Muscular Dystrophy, Sherry Dadgar, Zuyi Wang, Helen Johnston, Akanchha Kesari, Kanneboyina Nagaraju, Yi-Wen Chen, D. Ashley Hill, Terence A. Partridge, Robert J. Freishtat, Javad Nazarian, Jianhua Xuan, Yue Wang, Eric P. Hoffman

Genomics and Precision Medicine Faculty Publications

We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor β-centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are …

Modelling Β2ar Regulation, Sharat J. Vayttaden

Dissertations and Theses (Open Access)

The β2 adrenergic receptor (β2AR) regulates smooth muscle relaxation in the vasculature and airways. Long- and Short-acting β-agonists (LABAs/SABAs) are widely used in treatment of chronic obstructive pulmonary disorder (COPD) and asthma. Despite their widespread clinical use we do not understand well the dominant β2AR regulatory pathways that are stimulated during therapy and bring about tachyphylaxis, which is the loss of drug effects. Thus, an understanding of how the β2AR responds to various β-agonists is crucial to their rational use. Towards that end we have developed deterministic models that explore the mechanism of drug- induced β2AR regulation. These mathematical models …

Adding Upstream Sequence And A Downstream Reporter To The Bile Acid Inducible Promoter Of Clostridium Scindens Vpi 12708, Bryan Patrick Mason

Masters Theses & Specialist Projects

Bile acids in the small intestines of animals serve to breakdown fats and fatsoluble vitamins. Most of the bile acids are reabsorbed into the enterohepatic circulation, but approximately five percent of these bile acids pass into the large intestine. These bile acids are swiftly deconjugated by the bacterial population, and then subjected to further intestinal bacterial chemical modifications. The most significant of these modifications are 7α-dehydroxylations which form secondary bile acids (deoxycholate and lithocholate). Much research has illuminated the 7α-dehydroxylation pathway: of particular interest is the bile acid inducible operon, for which Clostridium scindens VPI 12708 serves as the model …

Drawing Lines In The Sand: Even Skipped Et Al. And Parasegment Boundaries., James B. Jaynes, Miki Fujioka

Department of Biochemistry and Molecular Biology Faculty Papers

The pair-rule segmentation gene even skipped (eve) is required to activate engrailed stripes and to organize odd-numbered parasegments (PSs). The protein product Eve has been shown to be an active repressor of transcription, and recent models for Eve function suggest that activation of engrailed is indirect, but these models have not been fully tested. Here we identify the forkhead domain transcription factor Sloppy-paired as the key intermediate in the initial activation of engrailed by Eve in odd-numbered parasegments. We also analyze the roles of the transcription factors Runt and Odd-skipped in this process. Detailed analysis of engrailed and pair-rule gene …