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Computational Systems Biology Approach For The Study Of Rheumatoid Arthritis: From A Molecular Map To A Dynamical Model, Vidisha Singh, Marek Ostaszewski, George D. Kalliolias, Gilles Chiocchia, Robert Olaso, Elisabeth Petit-Teixeira, Tomáš Helikar, Anna Niarakis 2018 Universite Paris-Saclay

Computational Systems Biology Approach For The Study Of Rheumatoid Arthritis: From A Molecular Map To A Dynamical Model, Vidisha Singh, Marek Ostaszewski, George D. Kalliolias, Gilles Chiocchia, Robert Olaso, Elisabeth Petit-Teixeira, Tomáš Helikar, Anna Niarakis

Biochemistry -- Faculty Publications

In this work we present a systematic effort to summarize current biological pathway knowledge concerning Rheumatoid Arthritis (RA). We are constructing a detailed molecular map based on exhaustive literature scanning, strict curation criteria, re-evaluation of previously published attempts and most importantly experts’ advice. The RA map will be web-published in the coming months in the form of an interactive map, using the MINERVA platform, allowing for easy access, navigation and search of all molecular pathways implicated in RA, serving thus, as an on line knowledgebase for the disease. Moreover the map could be used as a template for Omics data ...


The Colomoto Interactive Notebook: Accessible And Reproducible Computational Analyses For Qualitative Biological Networks, Aurelien Naldi, Celine Hernandez, Nicolas Levy, Gautier Stoll, Pedro T. Monteiro, Claudine Chaouiya, Tomáš Helikar, Andrei Zinovyev, Laurence Calzone, Sarah Cohen-Boulakia, Denis Thieffry, Loic Pauleve 2018 PSL Université

The Colomoto Interactive Notebook: Accessible And Reproducible Computational Analyses For Qualitative Biological Networks, Aurelien Naldi, Celine Hernandez, Nicolas Levy, Gautier Stoll, Pedro T. Monteiro, Claudine Chaouiya, Tomáš Helikar, Andrei Zinovyev, Laurence Calzone, Sarah Cohen-Boulakia, Denis Thieffry, Loic Pauleve

Biochemistry -- Faculty Publications

Analysing models of biological networks typically relies on workflows in which different software tools with sensitive parameters are chained together,many times with additional manual steps. The accessibility and reproducibility of such workflows is challenging, as publications often overlook analysis details, and because some of these tools may be difficult to install, and/or have a steep learning curve. The CoLoMoTo Interactive Notebook provides a unified environment to edit, execute, share, and reproduce analyses of qualitative models of biological networks. This framework combines the power of different technologies to ensure repeatability and to reduce users’ learning curve of these technologies ...


A Mechanistic Computational Model Reveals That Plasticity Of Cd4+ T Cell Differentiation Is A Function Of Cytokine Composition And Dosage, Bhanwar Lal Puniya, Robert G. Todd, Akram Mohammed, Deborah M. Brown, Matteo Barberis, Tomáš Helikar 2018 University of Nebraska - Lincoln

A Mechanistic Computational Model Reveals That Plasticity Of Cd4+ T Cell Differentiation Is A Function Of Cytokine Composition And Dosage, Bhanwar Lal Puniya, Robert G. Todd, Akram Mohammed, Deborah M. Brown, Matteo Barberis, Tomáš Helikar

Biochemistry -- Faculty Publications

CD4+ T cells provide cell-mediated immunity in response to various antigens. During an immune response, naïve CD4+ T cells differentiate into specialized effector T helper (Th1, Th2, and Th17) cells and induced regulatory (iTreg) cells based on a cytokine milieu. In recent studies, complex phenotypes resembling more than one classical T cell lineage have been experimentally observed. Herein, we sought to characterize the capacity of T cell differentiation in response to the complex extracellular environment. We constructed a comprehensive mechanistic (logical) computational model of the signal transduction that regulates T cell differentiation. The model’s dynamics were characterized and analyzed ...


Simulation Of Stimulation: Cytokine Dosage And Cell Cycle Crosstalk Driving Timing-Dependent T Cell Differentiation, Matteo Barberis, Tomáš Helikar, Paul Verbruggen 2018 University of Amsterdam

Simulation Of Stimulation: Cytokine Dosage And Cell Cycle Crosstalk Driving Timing-Dependent T Cell Differentiation, Matteo Barberis, Tomáš Helikar, Paul Verbruggen

Biochemistry -- Faculty Publications

Triggering an appropriate protective response against invading agents is crucial to the effectiveness of human innate and adaptive immunity. Pathogen recognition and elimination requires integration of a myriad of signals from many different immune cells. For example, T cell functioning is not qualitatively, but quantitatively determined by cellular and humoral signals. Tipping the balance of signals, such that one of these is favored or gains advantage on another one, may impact the plasticity of T cells. This may lead to switching their phenotypes and, ultimately, modulating the balance between proliferating and memory T cells to sustain an appropriate immune response ...


Towards The Synthetic Design Of Camelina Oil Enriched In Tailored Acetyl-Triacylglycerols With Medium-Chain Fatty Acids, Sunil Bansal, Hae Jin Kim, GunNam Na, Megan E. Hamilton, Edgar B. Cahoon, Chaofu Lu, Timothy P. Durrett 2018 Lovely Professional University

Towards The Synthetic Design Of Camelina Oil Enriched In Tailored Acetyl-Triacylglycerols With Medium-Chain Fatty Acids, Sunil Bansal, Hae Jin Kim, Gunnam Na, Megan E. Hamilton, Edgar B. Cahoon, Chaofu Lu, Timothy P. Durrett

Biochemistry -- Faculty Publications

The ability to manipulate expression of key biosynthetic enzymes has allowed the development of genetically modified plants that synthesise unusual lipids that are useful for biofuel and industrial applications. By taking advantage of the unique activities of enzymes from different species, tailored lipids with a targeted structure can be conceived. In this study we demonstrate the successful implementation of such an approach by metabolically engineering the oilseed crop Camelina sativa to produce 3-acetyl-1,2-diacyl-sn-glycerols (acetyl-TAGs) with medium-chain fatty acids (MCFAs). Different transgenic camelina lines that had been genetically modified to produce MCFAs through the expression of MCFA-specific thioesterases ...


Single-Molecule Unbinding Forces Between The Polysaccharide Hyaluronan And Its Binding Proteins, Fouzia Bano, Markku I. Tammi, David W. Kang, Edward N. Harris, Ralf P. Richter 2018 University of Leeds

Single-Molecule Unbinding Forces Between The Polysaccharide Hyaluronan And Its Binding Proteins, Fouzia Bano, Markku I. Tammi, David W. Kang, Edward N. Harris, Ralf P. Richter

Biochemistry -- Faculty Publications

The extracellular polysaccharide hyaluronan (HA) is ubiquitous in all vertebrate tissues, where its various functions are encoded in the supramolecular complexes and matrices that it forms with HA-binding proteins (hyaladherins). In tissues, these supramolecular architectures are frequently subjected to mechanical stress, yet how this affects the intermolecular bonding is largely unknown. Here, we used a recently developed single-molecule force spectroscopy platform to analyze and compare the mechanical strength of bonds between HA and a panel of hyaladherins from the Link module superfamily, namely the complex of the proteoglycan aggrecan and cartilage link protein, the proteoglycan versican, the inflammation-associated protein TSG-6 ...


Endosomal Escape Of Antisense Oligonucleotides Internalized By Stabilin Receptors Is Regulated By Rab5c And Eea1 During Endosomal Maturation, Colton M. Miller, W. Brad Wan, Punit P. Seth, Edward N. Harris 2018 University of Nebraska - Lincoln

Endosomal Escape Of Antisense Oligonucleotides Internalized By Stabilin Receptors Is Regulated By Rab5c And Eea1 During Endosomal Maturation, Colton M. Miller, W. Brad Wan, Punit P. Seth, Edward N. Harris

Biochemistry -- Faculty Publications

Second-generation (Gen 2) Antisense oligonucleotides (ASOs) show increased nuclease stability and affinity for their RNA targets, which has translated to improved potency and therapeutic index in the clinic. Gen 2 ASOs are typically modified using the phosphorothioate (PS) backbone modification, which enhances ASO interactions with plasma, cell surface, and intracellular proteins. This facilitates ASO distribution to peripheral tissues and also promotes cellular uptake after injection into animals. Previous work identified that Stabilin receptors specifically internalize PS-ASOs in the sinusoidal endothelial cells of the liver and the spleen. By modulating expression of specific proteins involved in the trafficking and maturation of ...


Purification Of Hepatocytes And Sinusoidal Endothelial Cells From Mouse Liver Perfusion, Fatima Cabral, Colton M. Miller, Katrina M. Kudrna, Blake E. Hass, Jocelyn G. Daubendiek, Brianna M. Kellar, Edward N. Harris 2018 University of Nebraska - Lincoln

Purification Of Hepatocytes And Sinusoidal Endothelial Cells From Mouse Liver Perfusion, Fatima Cabral, Colton M. Miller, Katrina M. Kudrna, Blake E. Hass, Jocelyn G. Daubendiek, Brianna M. Kellar, Edward N. Harris

Biochemistry -- Faculty Publications

This protocol demonstrates a method for obtaining high yield and viability for mouse hepatocytes and sinusoidal endothelial cells (SECs) suitable for culturing or for obtaining cell lysates. In this protocol, the portal vein is used as the site for catheterization, rather than the vena cava, as this limits contamination of other possible cell types in the final liver preparation. No special instrumentation is required throughout the procedure. A water bath is used as a source of heat to maintain the temperature of all the buffers and solutions. A standard peristaltic pump is used to drive the fluid, and a refrigerated ...


A Tlr/Akt/Foxo3 Immune Tolerance–Like Pathway Disrupts The Repair Capacity Of Oligodendrocyte Progenitors, Taasin Srivastava, Parham Diba, Justin M. Dean, Fatima Banine, Daniel Shaver, Matthew Hagen, Xi Gong, Weiping Su, Ben Emery, Daniel L. Marks, Edward N. Harris, Bruce Baggentoss, Paul H. Weigel, Larry S. Sherman, Stephen A. Back 2018 Oregon Health and Science University

A Tlr/Akt/Foxo3 Immune Tolerance–Like Pathway Disrupts The Repair Capacity Of Oligodendrocyte Progenitors, Taasin Srivastava, Parham Diba, Justin M. Dean, Fatima Banine, Daniel Shaver, Matthew Hagen, Xi Gong, Weiping Su, Ben Emery, Daniel L. Marks, Edward N. Harris, Bruce Baggentoss, Paul H. Weigel, Larry S. Sherman, Stephen A. Back

Biochemistry -- Faculty Publications

Cerebral white matter injury (WMI) persistently disrupts myelin regeneration by oligodendrocyte progenitor cells (OPCs). We identified a specific bioactive hyaluronan fragment (bHAf) that downregulates myelin gene expression and chronically blocks OPC maturation and myelination via a tolerance-like mechanism that dysregulates pro-myelination signaling via AKT. Desensitization of AKT occurs via TLR4 but not TLR2 or CD44. OPC differentiation was selectively blocked by bHAf in a maturation-dependent fashion at the late OPC (preOL) stage by a noncanonical TLR4/TRIF pathway that induced persistent activation of the FoxO3 transcription factor downstream of AKT. Activated FoxO3 selectively localized to oligodendrocyte lineage cells in white ...


3-O Sulfation Of Heparin Leads To Hepatotropism And Longer Circulatory Half-Life, Colton M. Miller, Yongmei Xu, Katrina M. Kudrna, Blake E. Hass, Brianna M. Kellar, Andrew W. Egger, Jian Liu, Edward N. Harris 2018 University of Nebraska- Lincoln

3-O Sulfation Of Heparin Leads To Hepatotropism And Longer Circulatory Half-Life, Colton M. Miller, Yongmei Xu, Katrina M. Kudrna, Blake E. Hass, Brianna M. Kellar, Andrew W. Egger, Jian Liu, Edward N. Harris

Biochemistry -- Faculty Publications

Introduction: Heparins are common blood anticoagulants that are critical for many surgical and biomedical procedures used in modern medicine. In contrast to natural heparin derived from porcine gut mucosa, synthetic heparins are homogenous by mass, polymer length, and chemistry.

Materials & methods: Stable cell lines expressing the human and mouse Stabilin receptors were used to evaluate endocytosis of natural and synthetic heparin. We chemoenzymatically produced synthetic heparin consisting of 12 sugars (dodecamers) containing 14 sulfate groups resulting in a non-3-O sulfated structure (n12mer). Half of the n12mer was modified with a 3-O sulfate on a single GlcNS sugar producing the 3-O ...


Reactive Oxygen Species In Chronic Obstructive Pulmonary Disease, Samia Boukhenouna, Mark A. Wilson, Karim Bahmed, Beata Kosmider 2018 Temple University

Reactive Oxygen Species In Chronic Obstructive Pulmonary Disease, Samia Boukhenouna, Mark A. Wilson, Karim Bahmed, Beata Kosmider

Biochemistry -- Faculty Publications

Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis and emphysema. Environmental exposure, primarily cigarette smoking, can cause high oxidative stress and is the main factor of COPD development. Cigarette smoke also contributes to the imbalance of oxidant/antioxidant due to exogenous reactive oxygen species (ROS). Moreover, endogenously released ROS during the inflammatory process and mitochondrial dysfunction may contribute to this disease progression. ROS and reactive nitrogen species (RNS) can oxidize different biomolecules such as DNA, proteins, and lipids leading to epithelial cell injury and death. Various detoxifying enzymes and antioxidant defense systems can be involved in ROS removal. In this ...


Characterization Of A Recurrent Missense Mutation In The Forkhead Dna-Binding Domain Of Foxp1, Tyler B. Johnson, Keegan Mechels, Ruth Ellen Anderson, Jacob T. Cain, David A. Sturdevant, Stephen Braddock, Hailey Pinz, Mark A. Wilson, Megan Landsverk, Kyle J. Roux, Jill M. Weimer 2018 Sanford Research

Characterization Of A Recurrent Missense Mutation In The Forkhead Dna-Binding Domain Of Foxp1, Tyler B. Johnson, Keegan Mechels, Ruth Ellen Anderson, Jacob T. Cain, David A. Sturdevant, Stephen Braddock, Hailey Pinz, Mark A. Wilson, Megan Landsverk, Kyle J. Roux, Jill M. Weimer

Biochemistry -- Faculty Publications

Haploinsufficiency of Forkhead box protein P1 (FOXP1), a highly conserved transcription factor, leads to developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features. Most of the reported FOXP1 mutations occur on the C-terminus of the protein and cluster around to the forkhead domain. All reported FOXP1 pathogenic variants result in abnormal cellular localization and loss of transcriptional repression activity of the protein product. Here we present three patients with the same FOXP1 mutation, c.1574G>A (p.R525Q), that results in the characteristic loss of transcription repression activity. This mutation, however, represents the first reported FOXP1 mutation ...


Editorial: Structure And Function Of Chloroplasts, Rebecca L. Roston, Juliette Jouhet, Fei Yu, Hongbo Gao 2018 University of Nebraska- Lincoln

Editorial: Structure And Function Of Chloroplasts, Rebecca L. Roston, Juliette Jouhet, Fei Yu, Hongbo Gao

Biochemistry -- Faculty Publications

The primary energy resource of life on earth is the sun, whose energy is captured in the form of usable carbons by a process called photosynthesis. Photosynthesis occurs within a cellular organelle adapted to that purpose, called the chloroplast. Chloroplasts are unique metabolic and sensory organelles restricted to plants, algae, and a few protists. In this special topic, we aimed to gather new research, hypotheses, and reviews that would help us to better understand the important role of chloroplasts in all photosynthetic organisms. We were fortunate enough to have submissions from many talented chloroplast researchers. This topic contains a total ...


Mouse Genome-Wide Association Studies And Systems Genetics Uncover The Genetic Architecture Associated With Hepatic Pharmacokinetic And Pharmacodynamic Properties Of A Constrained Ethyl Antisense Oligonucleotide Targeting Malat1, Elaine Pirie, Shayoni Ray, Calvin Pan, Wuxia Fu, Andrew F. Powers, Danielle Polikoff, Colton M. Miller, Katrina M. Kudrna, Edward N. Harris, Aldons J. Lusis, Rosanne M. Crooke, Richard G. Lee 2018 Ionis Pharmaceuticals

Mouse Genome-Wide Association Studies And Systems Genetics Uncover The Genetic Architecture Associated With Hepatic Pharmacokinetic And Pharmacodynamic Properties Of A Constrained Ethyl Antisense Oligonucleotide Targeting Malat1, Elaine Pirie, Shayoni Ray, Calvin Pan, Wuxia Fu, Andrew F. Powers, Danielle Polikoff, Colton M. Miller, Katrina M. Kudrna, Edward N. Harris, Aldons J. Lusis, Rosanne M. Crooke, Richard G. Lee

Biochemistry -- Faculty Publications

Antisense oligonucleotides (ASOs) have demonstrated variation of efficacy in patient populations. This has prompted our investigation into the contribution of genetic architecture to ASO pharmacokinetics (PK) and pharmacodynamics (PD). Genome wide association (GWA) and transcriptomic analysis in a hybrid mouse diversity panel (HMDP) were used to identify and validate novel genes involved in the uptake and efficacy of a single dose of a Malat1 constrained ethyl (cEt) modified ASO. The GWA of the HMDP identified two significant associations on chromosomes 4 and 10 with hepatic Malat1 ASO concentrations. Stabilin 2 (Stab2) and vesicle associated membrane protein 3 (Vamp3) were identified ...


Identification Of Genes Encoding Enzymes Catalyzing The Early Steps Of Carrot Polyacetylene Biosynthesis, Lucas Busta, Won Cheol Yim, Evan William LaBrant, Peng Wang, Lindsey Grimes, Kiah Malyszka, John C. Cushman, Patricia Santos, Dylan K. Kosma, Edgar B. Cahoon 2018 University of Nebraska - Lincoln

Identification Of Genes Encoding Enzymes Catalyzing The Early Steps Of Carrot Polyacetylene Biosynthesis, Lucas Busta, Won Cheol Yim, Evan William Labrant, Peng Wang, Lindsey Grimes, Kiah Malyszka, John C. Cushman, Patricia Santos, Dylan K. Kosma, Edgar B. Cahoon

Biochemistry -- Faculty Publications

Polyacetylenic lipids accumulate in various Apiaceae species after pathogen attack, suggesting that these compounds are naturally occurring pesticides and potentially valuable resources for crop improvement. These compounds also promote human health and slow tumor growth. Even though polyacetylenic lipids were discovered decades ago, the biosynthetic pathway underlying their production is largely unknown. To begin filling this gap and ultimately enable polyacetylene engineering, we studied polyacetylenes and their biosynthesis in the major Apiaceae crop carrot (Daucus carota subsp. sativus). Using gas chromatography and mass spectrometry, we identified three known polyacetylenes and assigned provisional structures to two novel polyacetylenes. We also quantified ...


Rates And Patterns Of Evolution In A Duplicated Genome In The Family Catostomidae, Megann Michelle Schmidt 2018 University of Northern Iowa

Rates And Patterns Of Evolution In A Duplicated Genome In The Family Catostomidae, Megann Michelle Schmidt

Honors Program Theses

First and foremost, I would like to thank Dr. Gary and Myrna Floyd for financial support through their Undergraduate Research Assistantship, and I would also like to thank the University of Northern Iowa Biology Department for their support of undergraduate research. I would like to express my utmost gratitude towards Dr. Peter Berendzen and Zachary Sperstad for their support and guidance throughout this entire project. Additionally, thanks to the Iowa EPSCoR for funding collection of the data set, and thanks to Andrew Simons at the University of Minnesota and Jonathan Armbruster at Auburn University for help in data collection and ...


Recently Discovered Benzo(A)Pyrene Induced Health Effects And Their Threat To The Inland Empire, Quinn Navarro 2018 University of Redlands

Recently Discovered Benzo(A)Pyrene Induced Health Effects And Their Threat To The Inland Empire, Quinn Navarro

Armacost Library Undergraduate Research Award (ALURA)

This study investigated recent discoveries of Benzo(a)Pyrene (BaP) in order to determine the current threat BaP poses to residents of Southern California. Literature reviews comprise the research done on BaP-induced health effects. Primary articles reviewed include “Adverse Effect of Sub-Chronic Exposure to Benzo(a)Pyrene and Protective Effect of Butylated Hydroxyanisole on Learning and Memory Ability in Male

Sprague-Dawley Rat” by Xiao Liang (2014), and “Bioaccumulation and oxidative damage in juvenile scallop Chlamys farreri exposed to benzo[a]Pyrene, benzo[b]Fluoranthene and chrysene” by Meng Xiu (2014). These studies conclude that BaP potentially impairs memory and learning ...


Structural Features And Domain Movements Controlling Substrate Binding And Cofactor Specificity In Class Ii Hmg-Coa Reductase, Bradley R. Miller, Yan Kung 2018 Bryn Mawr College

Structural Features And Domain Movements Controlling Substrate Binding And Cofactor Specificity In Class Ii Hmg-Coa Reductase, Bradley R. Miller, Yan Kung

Chemistry Faculty Research and Scholarship

The key mevalonate pathway enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) uses the cofactor NAD(P)H to reduce HMG-CoA to mevalonate in the production of countless metabolites and natural products. Although inhibition of HMGR by statin drugs is well-understood, several mechanistic details of HMGR catalysis remain unresolved, and the structural basis for the wide range of cofactor specificity for either NADH or NADPH among HMGRs from different organisms is also unknown. Here, we present crystal structures of HMGR from Streptococcus pneumoniae (SpHMGR) alongside kinetic data of the enzyme’s cofactor preferences. Our structure of SpHMGR bound with its kinetically ...


Can A Comprehensive Transition Plan To Barefoot Running Be The Solution To The Injury Epidemic In American Endurance Runners?, Michael A. Scarlett 2018 Claremont McKenna College

Can A Comprehensive Transition Plan To Barefoot Running Be The Solution To The Injury Epidemic In American Endurance Runners?, Michael A. Scarlett

CMC Senior Theses

Fossils belonging to the genus Homo, dating as far back as two million years ago, exhibit uniquely efficient features suggesting that early humans had evolved to become exceptional endurance runners. Although they did not have the cushion or stability-control features provided in our modern day running shoes, our early human ancestors experienced far less of the running-related injuries we experience today. The injury rate has been estimated as high as 90% annually for Americans training for a marathon and as high as 79% annually for all American endurance runners. There is an injury epidemic in conventionally shod populations that does ...


Mutations In Rhodopsin Transmembrane Helix 5 And Dimerization Interface, Margaret Pinkevitch 2018 The University of Akron

Mutations In Rhodopsin Transmembrane Helix 5 And Dimerization Interface, Margaret Pinkevitch

Williams Honors College, Honors Research Projects

G protein coupled receptors (GPCRs) are membrane proteins with many functional roles. This family of receptors is expansive, with several subfamilies. Here, a member of subfamily A, rhodopsin (Rho) is studied. Mutations in rhodopsin have been linked to the disease retinitis pigmentosa (RP). Some of these mutations have been found to disrupt the dimerization/oligomerization of Rho at the TM4/TM5 proposed dimerization interface, causing pathogenesis of RP. In this study, two mutations of transmembrane helix 5 were investigated for changes in dimerization and stability, cell trafficking, and signaling. It was found that the V209M and F220C mutations did not ...


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