Chemicals and Drugs Commons^™

Engineering Hyaluronic Acid For Biomedical Applications, Deep S. Bhattacharya

Theses & Dissertations

This work presents research using the naturally available non- sulfated carbohydrate glycosaminoglycan hyaluronic acid (HA) for the synthesis of different chemical derivatives of HA for evaluation of binding kinetics with CD44 and P- selectin proteins for applications in fluorescence image-guided surgery. Chemical derivatives of HA such as deacetylated HA (deHA), sulfated HA (sHA), and deacetylated and sulfated HA (s-deHA) were synthesized by modulating sulfating and deacetylating reagents to alter binding specificities to CD44. Modified HA derivatives and CD44 biophysical interactions were assessed by fluorescence polarization. In silico techniques were also used to determine binding using molecular docking and MM-PBSA approaches. …

Theranostics For Antiretroviral Biodistribution And Pharmacokinetics, Brendan M. Ottemann

Theses & Dissertations

RATIONALE: Our laboratories birthed the field of human immunodeficiency virus (HIV) theranostics. The new field allows simultaneous detection (diagnostics) and treatment (therapeutic) for the identification, treatment and inevitable elimination of virus in cell and tissue compartments. By employing theranostics, antiretroviral drugs (ARVs) can be tracked in lymph nodes, gut, spleen and liver. Cellular viral reservoirs including CD4+ T cell populations and mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) along with subcellular endosomal structures can now be targeted for drug delivery bringing therapeutics to areas where virus replicates. The overarching idea rests in improving precision targeted ARV delivery. …

Alanyl-Trna Synthetase Quality Control Prevents Global Dysregulation Of The Escherichia Coli Proteome, Paul Kelly, Nicholas Backes, Kyle Mohler, Christopher Buser, Arundhati Kavoor, Jesse Rinehart, Gregory Phillips, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Mechanisms have evolved to prevent errors in replication, transcription, and translation of genetic material, with translational errors occurring most frequently. Errors in protein synthesis can occur at two steps, during tRNA aminoacylation and ribosome decoding. Recent advances in protein mass spectrometry have indicated that previous reports of translational errors have potentially underestimated the frequency of these events, but also that the majority of translational errors occur during ribosomal decoding, suggesting that aminoacylation errors are evolutionarily less tolerated. Despite that interpretation, there is evidence that some aminoacylation errors may be regulated, and thus provide a benefit to the cell, while others …

‘Am I Turning Into A Man?’ Experiences Of Pakistani Women With Pcos, Rida E Zehra Zaidi

MSJ Capstone Projects

According to the National Institutes of Health, 20 – 25% of all regularly ovulating women have PCOS. This disorder has a range of visible symptoms including excessive weight gain, hirsutism, acne, and hair loss among others. These symptoms make it difficult for women with the syndrome to fit the femininity ideals of the society, as it demands female bodies to be slim, smart, hair less, and to have porcelain skin and regular menstrual cycles. Women with PCOS and other health problems in Pakistan spend all their lives fighting unnecessary battles. This struggle has severe impacts on their physical and mental …

Alzheimer's And Amyloid Beta: Amyloidogenicity And Tauopathy Via Dyshomeostatic Interactions Of Amyloid Beta, Jordan Tillinghast

Senior Honors Theses

This paper reviews functions of Amyloid-β (Aβ) in healthy individuals compared to the consequences of aberrant Aβ in Alzheimer’s disease (AD). As extraneuronal Aβ accumulation and plaque formation are characteristics of AD, it is reasonable to infer a pivotal role for Aβ in AD pathogenesis. Establishing progress of the disease as well as the mechanism of neurodegeneration from AD have proven difficult (Selkoe, 1994). This thesis provides evidence suggesting the pathogenesis of AD is due to dysfunctional neuronal processes involving Aβ’s synaptic malfunction, abnormal interaction with tau, and disruption of neuronal homeostasis. Significant evidence demonstrates that AD symptoms are partially …

Global Acetylation Dynamics In The Heat Shock Response Of Saccharomyces Cerevisiae, Rebecca E. Hardman

Graduate Theses and Dissertations

All organisms face a constant barrage of environmental stresses. Single-cell organisms such as Saccharomyces cerevisiae, or common Baker’s yeast, must rely solely on cellular responses in order to survive. This response must occur in a rapid and highly coordinated manner to quickly inhibit all unnecessary processes and shuttle all available resources to those necessary for survival. One method that cells utilize for rapid protein regulation is the use of post-translational modifications. Enzymes within the cell add or remove a variety of chemical modifications, thus altering the local chemical environment of a protein. This creates a conformational change in the protein …

Functional Importance Of Lipin Phosphorylation, Stephanie Elizabeth Hood

Graduate Theses and Dissertations

Highly conserved throughout evolution, lipins are dual functioning proteins found from yeast to humans. Functioning in the cytoplasm as phosphatidate phosphatase enzymes (PAP), lipins produce diacylglycerol that serves as a precursor for neutral fats and membrane phospholipids. Alternatively, nuclear lipins are responsible for the regulation of metabolic genes. Interestingly, both the mammalian lipin 1 paralog and the single Drosophila Lipin ortholog are highly phosphorylated proteins. Target of rapamycin (TOR) has previously been identified as one of the kinases that controls the subcellular localization of both lipin 1 and Drosophila Lipin. However, other serine and threonine kinases are predicted to be …

Probing Of Carbohydrate-Protein Interactions Using Galactonoamidine Inhibitors, Jessica B. Pickens

Graduate Theses and Dissertations

Glycoside hydrolases are ubiquitous and one of the most catalytically proficient enzymes known, and thus understanding their mechanisms are crucial. Most research has focused on the interaction of the glycon of substrates and their inhibitors within the active site of glycoside hydrolases. The inhibitors employed to probe these interactions generally had small aglycons (i.e. a hydrogen atom, amidines, small aliphatic groups, or benzyl groups). Here, the interactions of the aglycon with glycoside hydrolases are examined by probing the active sites with a library of 25 galactonoamidines. The studies described in this dissertation aim to increase the understanding of stabilization of …

Toward Understanding The Mechanism Of Protein Targeting In The Chloroplast Signal Recognition Particle Pathway, Mercede Furr

Graduate Theses and Dissertations

Protein targeting is a vital cellular function. The signal recognition particle (SRP) pathway is a universally conserved targeting system present in the cytosol and used to co-translationally target many proteins to the inner membrane of prokaryotes and the endoplasmic reticulum of eukaryotes. The chloroplast has a homologous SRP system which post-translationally targets light harvesting chlorophyll binding proteins (LHCPs) to the thylakoid membrane for integration. The chloroplast SRP (cpSRP) is a heterodimer with a 54 kDa subunit equivalent to SRP54 in the canonical pathway. In addition, cpSRP contains a novel 43 kDa subunit which is a unique and irreplaceable component. cpSRP43 …

Production And Purification Of Basic Fibroblast Growth Factor Fused To Two Collagen Binding Domains Expressed In E. Coli Bl21 Using Flask And Fed-Batch, Hazim Aljewari

Graduate Theses and Dissertations

Delivering effective and non-toxic doses of bioactive materials that can aid in activating tissue regeneration to wounded tissue has proven to be an enormous challenge. This study was designed to produce a potential therapeutic recombinant protein by fusing two collagen binding domains to basic fibroblast growth factors (bFGF) through a collagenase cleavage site linker, so it can release the bFGF in a wound site by the action of this enzyme. The novel fusion protein was expressed in Escherichia coli BL-21 (E. coli) using traditional flask shaker and fed-batch cultivation. Cell lysate was purified by FPLC using Immobilized metal affinity chromatography …

Influence Of Single And Multiple Histidine Residues And Their Ionization Properties On Transmembrane Helix Dynamics, Orientations And Fraying, Fahmida Afrose

Graduate Theses and Dissertations

Since aromatic and charged residues are often present in various locations of transmembrane helices of integral membrane proteins, their impacts on the molecular properties of transmembrane proteins and their interactions with lipids are of particular interest in many studies. In this work, I used solid-state deuterium NMR spectroscopy in designed model peptide GWALP23 [GGALW(LA)6LWLAGA] with selective deuterium labels to addresses the pH dependence and influence of single and multiple “guest” histidine residues in the orientation and dynamic behaviors of transmembrane proteins. The mutations include Gly to His (G2/22 to H2/22), Trp to His (W5/19 to H5/19) and Leu to His …

Single Molecule Fluorescence Studies Of Protein Structure And Dynamics Underlying The Chloroplast Signal Recognition Particle Targeting Pathway, Dustin R. Baucom

Graduate Theses and Dissertations

The work presented in this dissertation explores the structural dynamics in the chloroplast signal recognition particle pathway. Findings include cpSRP shows scanning functionality similar to that in the cytosolic SRP with the ribosome. The intrinsically disordered C-terminal tail of the Albino3 protein has some transient secondary structure. Upon binding to cpSRP43 in solution, separate secondary structure formation was identified in the C-terminal tail of Albino3. Finally, to increase efficiency of analyzing fluorescence time traces for this work, a modular software was produced.

Investigating The Effects Of Excitotoxic Stimuli On The Suprachiasmatic Nucleus, Rachel A. Brandes

Chancellor’s Honors Program Projects

No abstract provided.

A Systematic Comparison Of Lipopolymers For Sirna Delivery To Multiple Breast Cancer Cell Lines: In Vitro Studies, Hamidreza Montazeri Aliabadi, Remant Bahadur Kc, Emira Bousoik, Ashley Barbarino, Bindu Thapa, Melissa Coyle, Parvin Mahdipoor, Hasan Uludağ

Pharmacy Faculty Articles and Research

Small interfering RNA (siRNA) therapy is a promising approach for treatment of a wide range of cancers, including breast cancers that display variable phenotypic features. To explore the general utility of siRNA therapy to control aberrant expression of genes in breast cancer, we conducted a detailed analysis of siRNA delivery and silencing response in vitro in 6 separate breast cancer cell models (MDA-MB-231, MDA-MB-231-KRas-CRM, MCF-7, AU565, MDA-MB-435 and MDA-MB-468 cells). Using lipopolymers for siRNA complexation and delivery, we found a large variation in siRNA delivery efficiency depending on the specific lipopolymer used for siRNA complexation and delivery. Some lipopolymers were …

Evaluating Volatile Organic Compounds For Contact-Independent Antagonism Of Pseudogymnoascus Destructans

Symposium of Student Scholars

White-nose syndrome (WNS), a disease caused by the fungus Pseudogymnoascus destructans, is responsible for the extensive mortality of bats in the United States. In an effort to develop tools to reduce bat mortality attributed to WNS, an in vitro experiment was conducted to quantify the inhibitory effects of select volatile organic compounds (VOCs) as well as explore potential synergistic activities. The experiment involved exposing mycelial plugs of P. destructans to various concentrations of B23 as well as B23 and decanal together at equimolar ratios. Measurements of the plugs were taken over the course of the 13 day experiment allowing …

How Oxygen Availability Affects The Antimicrobial Efficacy Of Host Defense Peptides: Lessons Learned From Studying The Copper-Binding Peptides Piscidins 1 And 3, Adenrele Oludiran, David S. Courson, Malia D. Stuart, Anwar R. Radwan, John C. Putsma, Myriam L. Cotten, Erin B. Purcell

Chemistry & Biochemistry Faculty Publications

The development of new therapeutic options against Clostridioides difficile (C. difficile) infection is a critical public health concern, as the causative bacterium is highly resistant to multiple classes of antibiotics. Antimicrobial host-defense peptides (HDPs) are highly effective at simultaneously modulating the immune system function and directly killing bacteria through membrane disruption and oxidative damage. The copper-binding HDPs piscidin 1 and piscidin 3 have previously shown potent antimicrobial activity against a number of Gram-negative and Gram-positive bacterial species but have never been investigated in an anaerobic environment. Synergy between piscidins and metal ions increases bacterial killing aerobically. Here, we …

Cytochrome P450 Monooxygenase-Mediated Lipid Metabolism In Obesity And Colon Tumorigenesis, Weicang Wang

Doctoral Dissertations

Colon cancer is a major public health issue: it is expected to have 140,250 new cases and 50,630 deaths during 2018, making colon cancer the third most common type of cancer and the second leading cause of cancer death in the United States. Obesity is associated with enhanced colonic inflammation, which is a major risk factor of colorectal cancer. Currently, more than 35% of adults and nearly 17% of children are obese. Considering the obesity and colon cancer epidemic in the United States, there is an urgent need to identify novel therapeutic targets for obesity and colon cancer. Here, using …

Protein Detection And Structural Characterization By Mass Spectrometry Using Supramolecular Assemblies And Small Molecules, Bo Zhao

Doctoral Dissertations

Mass spectrometry (MS) has played an increasingly prominent role in proteomics and structure biology because it shows superior capabilities in identification, quantification and structural characterization of proteins. To realize its full potential in protein analysis, significant progress has been made in developing innovative techniques and reagents that can couple to MS detection. This dissertation demonstrates the use of polymeric supramolecular assemblies for enhanced protein detection in complex biological mixtures by MS. An amphiphilic random co-polymer scaffold is developed to form functional supramolecular assemblies for protein/ peptide enrichment. The influences of charge density and functional group pK_a on host-guest interactions …

Dormant Pathogenic Cd4(+) T Cells Are Prevalent In The Peripheral Repertoire Of Healthy Mice, Anna Cebula, Michal Kuczma, Edyta Szurek, Maciej Pietrzak, Natasha Savage, Wessam R. Elhefnawy, Grzegorz Rempala, Piotr Kraj, Leszek Ignatowicz

Computer Science Faculty Publications

Thymic central tolerance eliminates most immature T cells with autoreactive T cell receptors (TCR) that recognize self MHC/peptide complexes. Regardless, an unknown number of autoreactive CD4+Foxp3⁻ T cells escape negative selection and in the periphery require continuous suppression by CD4+Foxp3⁺ regulatory cells (Tregs). Here, we compare immune repertoires of Treg-deficient and Treg-sufficient mice to find Tregs continuously constraining one-third of mature CD4⁺Foxp3⁻ cells from converting to pathogenic effectors in healthy mice. These dormant pathogenic clones frequently express TCRs activatable by ubiquitous autoantigens presented by class II MHCs on conventional dendritic cells, including selfpeptides that select …

Leaving Ligand Effects On Reactivity And Solubility Of Monofunctional Platinum(Ii) Anticancer Complexes, Heidi Linn Hruska Millay

Masters Theses & Specialist Projects

Monofunctional platinum(II) complexes, such as phenanthriplatin and pyriplatin, have notably different characteristics from the bifunctional anticancer complexes, such as cisplatin and oxaliplatin, which have detrimental toxicities and resistance associated with them. The unique properties of the monofunctional complexes may be exploited to target cancer cells without producing the toxic side effects associated with the current FDA-approved platinum-based anticancer drugs. To advance the understanding of these monofunctional platinum(II) complexes, this study replaced the chloride leaving ligand with an acetate group, which should increase solubility and alter the rate of reactivity with key amino acid and nucleotide targets. Phenanthriplatin and pyriplatin compounds …

The Fitness Landscape Of The African Salmonella Typhimurium St313 Strain D23580 Reveals Unique Properties Of The Pbt1 Plasmid, Rocío Canals, Roy R. Chaudhuri, Rebecca E. Steiner, Siân V. Owen, Natalia Quinones-Olvera, Melita A. Gordon, Michael Baym, Michael Ibba, Jay C. D. Hinton

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

We have used a transposon insertion sequencing (TIS) approach to establish the fitness landscape of the African Salmonella enterica serovar Typhimurium ST313 strain D23580, to complement our previous comparative genomic and functional transcriptomic studies. We used a genome-wide transposon library with insertions every 10 nucleotides to identify genes required for survival and growth in vitro and during infection of murine macrophages. The analysis revealed genomic regions important for fitness under two in vitro growth conditions. Overall, 724 coding genes were required for optimal growth in LB medium, and 851 coding genes were required for growth in SPI-2-inducing minimal medium. These …

Effects Of Dabigatran In Mouse Models Of Aging And Cerebral Amyloid Angiopathy, Neethu Michael, Mher Mahoney Grigoryan, Kelley Kilday, Rachita K. Sumbria, Vitaly Vasilevko, Joanne Van Ryn, David H. Cribbs, Annlia Paganini-Hill, Mark J. Fisher

Pharmacy Faculty Articles and Research

Oral anticoagulants are a critical component of stroke prevention, but carry a risk of brain hemorrhage. These hemorrhagic complications tend to occur in elderly individuals, especially those with predisposing conditions such as cerebral amyloid angiopathy (CAA). Clinical evidence suggests that non-vitamin K antagonist oral anticoagulants are safer than traditional oral anticoagulants. We analyzed whether the anticoagulant dabigatran produces cerebral microhemorrhage (the pathological substrate of MRI-demonstrable cerebral microbleeds) or intracerebral hemorrhage in aged mice with and without hemorrhage-predisposing angiopathy. We studied aged (22 months old) Tg2576 (a model of CAA) and wild-type (WT) littermate mice. Mice received either dabigatran etexilate (DE) …

Chemical Epitope Targeting: Review Of A Novel Screening Technology, Qurrat Ul-Ain, Rene Kandler, Dylan Gillespie, Arundhati Nag

Scholarly Undergraduate Research Journal at Clark (SURJ)

Chemical Epitope Targeting is a novel technology developed for designing peptide ligands with high affinity and specificity against specific regions of a protein that may be inaccessible to small molecules or antibodies. In this review, we summarize the key steps and significant applications of this technology. Operating on the same principles as antibody-antigen interactions, this technique involves chemically synthesizing the region of interest on the protein, called the epitope, as a polypeptide with a biotin detection tag and a strategically placed alkyne or azide presenting amino acid. The constructed epitope is screened against a comprehensive linear or cyclic One Bead …

Association Of Fish Oil And Physical Activity On Mobility Disability In Older Adults, Anoop T. Balachandran

Publications and Research

Purpose: This study aimed to examine whether long-term fish oil (FO) supplementation is associated with a lower risk of mobility disability and enhances benefits of physical activity (PA). Methods: A total of 1635 sedentary adults age 70 to 89 yr from the Lifestyle Interventions and Independence for Elders single-blinded randomized,multicenter clinical trial, which compared a structured PA program to a health education program. Primary outcome was incident major mobility disability (MMD), defined by loss of ability to walk 400 m, measured every 6 months for an average of 2.6 yr. Secondary outcomes included persistent mobility disability, Short Physical Performance Battery, …

Developing A Dissociative Nanocontainer For Peptide Drug Delivery, Michael Patrick Kelly

Dissertations, Theses, and Capstone Projects

The potency and specificity of bioactive peptides have propelled these agents to the forefront of pharmacological research. However, delivery of peptides to their molecular target in cells is a major obstacle to their widespread application. A Trojan Horse strategy of packaging a bioactive peptide within a modified protein cage to protect it during transport, and releasing it at the target site, is a promising delivery method. Recent work has demonstrated that the viral capsid of the P22 bacteriophage can be loaded with an arbitrary, genetically-encoded peptide, and externally decorated with a cell-penetrating peptide, such as HIV-Tat, to translocate across in …

Rare Degs1 Variant Significantly Alters De Novo Ceramide Synthesis Pathway, Nicholas B. Blackburn, Laura F. Michael, Peter J. Meikle, Juan M. Peralta, Marian Mosior, Scott Mcahren, Hai H. Bui, Melissa A. Bellinger, Corey Giles, Satish Kumar, Ana C. Leandro, Marcio Almeida, Jacquelyn M. Weir, Michael C. Mahaney, Thomas D. Dyer, Laura Almasy, John L. Vandeberg, Sarah Williams-Blangero, David C. Glahn, Ravindranath Duggirala, Mark Kowala, John Blangero, Joanne E. Curran

School of Medicine Publications and Presentations

The de novo ceramide synthesis pathway is essential to human biology and health but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry−specific rare functional variant, L175Q, in DEGS1, a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino …

Effective Statistical Energy Function Based Protein Un/Structure Prediction, Avdesh Mishra

University of New Orleans Theses and Dissertations

Proteins are an important component of living organisms, composed of one or more polypeptide chains, each containing hundreds or even thousands of amino acids of 20 standard types. The structure of a protein from the sequence determines crucial functions of proteins such as initiating metabolic reactions, DNA replication, cell signaling, and transporting molecules. In the past, proteins were considered to always have a well-defined stable shape (structured proteins), however, it has recently been shown that there exist intrinsically disordered proteins (IDPs), which lack a fixed or ordered 3D structure, have dynamic characteristics and therefore, exist in multiple states. Based on …

Biological Pathway Involvement In Melanoma Heterogeneity And Drug-Induced Resistance, Sarah V. Pack

STAR Program Research Presentations

Tumors develop resistance to numerous drug therapies, and this remains a major obstacle in treating many types of non-surgical cancers. Melanoma provides a good model system for studying drug resistance in cancer due to its high propensity to incur resistance after a significant initial response to a drug. Genes that are highly expressed in melanoma cancer cells have been studied, but in order to further understand the collective function of these highly expressed genes we must analyze gene sets, or pathways. A single gene’s function is rarely independent of other genes, and pathway analysis takes this into account.

Our objective …

Short Amylin Receptor Antagonist Peptides Improve Memory Deficits In Alzheimer’S Disease Mouse Model, Rania Soudy, Ryoichi Kimura, Aarti Patel, Wen Fu, Kamaljit Kaur, David Westaway, Jing Yang, Jack Jhamandas

Pharmacy Faculty Articles and Research

Recent evidence supports involvement of amylin and the amylin receptor in the pathogenesis of Alzheimer’s disease (AD). We have previously shown that amylin receptor antagonist, AC253, improves spatial memory in AD mouse models. Herein, we generated and screened a peptide library and identified two short sequence amylin peptides (12–14 aa) that are proteolytically stable, brain penetrant when administered intraperitoneally, neuroprotective against Aβ toxicity and restore diminished levels of hippocampal long term potentiation in AD mice. Systemic administration of the peptides for five weeks in aged 5XFAD mice improved spatial memory, reduced amyloid plaque burden, and neuroinflammation. The common residue SQELHRLQTY …

Maternal Nicotine Exposure Induces Congenital Heart Defects In The Offspring Of Mice, Elizabeth Greco

Electronic Thesis and Dissertation Repository

Congenital heart defects are the most prevalent birth defect, and maternal cigarette smoking is a known risk factor. Nicotine replacement therapies are recommended to pregnant women who smoke to aid in smoking cessation, as this alternative is thought to be much safer compared to cigarette smoking. However, these products contain nicotine, and the safety of nicotine on the developing heart is not well known. In this thesis, a mouse model was used to test the hypothesis that maternal nicotine exposure (MNE) during pregnancy leads to congenital heart defects and coronary artery defects in the offspring of mice. MNE resulted in …