Chemicals and Drugs Commons^™

Identification Of The Functional Binding Pocket For Compounds Targeting Small-Conductance Ca2+-Activated Potassium Channels, Miao Zhang, John M. Pascal, Marcel Schumann, Roger S. Armen, Ji-Fang Zhang

Pharmacy Faculty Articles and Research

Small- and intermediate-conductance Ca2+-activated potassium channels, activated by Ca2+-bound calmodulin, play an important role in regulating membrane excitability. These channels are also linked to clinical abnormalities. A tremendous amount of effort has been devoted to developing small molecule compounds targeting these channels. However, these compounds often suffer from low potency and lack of selectivity, hindering their potentials for clinical use. A key contributing factor is the lack of knowledge of the binding site(s) for these compounds. Here we demonstrate by X-ray crystallography that the binding pocket for the compounds of the 1-EBIO class is located at the calmodulin-channel interface. We …

Taking Aim At The Start Of Translation, Medha Raina, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

No abstract provided.

Quantification And In Vitro Analysis Of Nanolipoproteins (Nlps) Containing Adjuvants, Purna Venkataraman, Craig Blanchette, Nicholas O. Fischer

STAR Program Research Presentations

Nanolipoprotein particles (NLPs) self-assemble into nanoscale structures that can be used as vaccines or drug delivery agents. Due to the nature of the NLPs, a variety of immune stimulating compounds or adjuvants can be readily incorporated into NLPs: a characteristic difficult to engineer into most other nanoscale platforms. In light of this, a method for quantifying the amount adjuvant actually incorporated into NLPs is a question of high importance. Through the use of reverse phase High-Performance Liquid Chromatography (HPLC) and an Evaporative Light Scattering Detector (ELSD), standard curves can be constructed by analyzing mixtures of NLP components of known concentration, …

Parametric Studies Of Antipsychotic-Induced Sensitization In The Conditioned Avoidance Response Model: Roles Of Number Of Drug Exposure, Drug Dose, And Test–Retest Interval, Natashia Swalve, Ming Li

Department of Psychology: Faculty Publications

Repeated haloperidol and olanzapine treatment produces an enhanced disruption of avoidance responding, a validated measure of antipsychotic activity. Experimental parameters affecting this sensitization-like effect have not been thoroughly examined. The present study investigated the role of three parameters (number of injections, dose, and interval between initial exposure and challenge) in antipsychotic sensitization in the conditioned avoidance response paradigm. Well-trained Sprague–Dawley rats received different numbers of drug treatment (1–5 days) or different doses of haloperidol (0.025–0.10 mg/kg, subcutaneously) or olanzapine (0.5–2.0 mg/kg, subcutaneously). After certain time intervals (4, 10 or 17 days), they were tested for the expression of haloperidol or …

Prolonged Intermediate Syndrome Pue To Prganophosphate Poisoning, Nadeem Ullah Khan, Muhammad Junaid Patel, M. N.M. Hifath, Saima Kamal, Syed Ather Hussain

Department of Emergency Medicine

Organophosphate poisoning can present as acute cholinergic syndrome, Intermediate syndrome and delayed neuropathy. Intermediate syndrome secondary to organophosphate poisoning is a serious health problem leading to increased morbidity and mortality. The incidence of problem varies and range from 8%-84% of organophosphate poisoning cases. The factors account for this difference is nature of organophosphate compound, severity of poisoning and inadequate Oxime therapy. The recognition of this syndrome is important as organophosphate poisoning is common in our country. We presented this case of organophosphate poisoning leading to prolonged intermediate syndrome. The muscle weakness associated with this syndrome generally resolves in 5-18 days …

Effects Of Passive Heat Stress On Thermoregulation In Smokers Versus Non-Smokers, Hannah M. Anderson

Health, Human Performance and Recreation Undergraduate Honors Theses

Context: Maintaining thermal balance under heat-stress depends on appropriate increases in sweating and skin blood flow (cutaneous vasodilation). Given the multiple effects on nicotine on the body, it is unknown if sweating and cutaneous vasodilation are impaired, or possibly enhanced in smokers during heat stress. Objective: To examine the effects of passive heating on thermoregulatory responses (i.e., sweating and cutaneous vasodilation) in smokers versus non-smokers. Design: 1 passive heat trial per subject. Patients or Other Participants: 14 male smokers (26 ± 7 y; 180.0 ± 5.5 cm; 81.2 ± 20.7 kg; 3.2 ± 1.9 packs/week) and 12 male non-smokers (26 …

Expression And Distribution Of Thiol-Regulating Enzyme, Glutaredoxin 2 In Porcine Ocular Tissues, Bijaya Prasad Upadhyaya

School of Veterinary and Biomedical Sciences: Dissertations, Theses, and Student Research

Glutaredoxin 2 (Grx2), a thiol-regulating enzyme of oxidoreductase family and a mitochondrial isozyme of glutaredoxin 1, was discovered 11 years ago in our laboratory. Grx2 is present in the lens where it shows dethiolase, peroxidase, and ascorbate recycling activities. Recently, Grx2 has also been identified to protect the mitochondrial electron transport system with anti-apoptotic function. Since other eye tissues besides the lens are rich in mitochondria and are very sensitive to oxidative stress, we speculate the presence of Grx2 therein as an important redox regulator. This study is to investigate the expression and distribution of Grx2 in ocular tissues using …

Discovery Of Dihydroartemisinin And Dasatinib Drug Combination To Cure Pooroutcome Bcr-Abl+ Acute Lymphoblastic Leukemia, Harpreet Singh

Theses and Dissertations (ETD)

Oncogenic signaling by the Philadelphia chromosome-encoded BCR-ABL fusion kinase initiates and drives both Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Food and Drug Administration (FDA)- approved BCR-ABL-specific kinase inhibitors (BCR-ABL–KIs) imatinib, dasatinib and nilotinib induce prolonged remissions in CML but poor leukemia-reduction and relapse-control in Ph+ ALL. The relative primary BCR-ABL–KI-resistance in Ph+ ALL patients carrying predominantly BCR-ABLWT disease cannot be attributed to drug-resistant BCR-ABL mutations (BCR-ABLMUTANTS), and remains poorly understood.

We established a cell-based platform to evaluate the modulation of anti-Ph+ ALL activity of drugs by both tumor-extrinsic cytokines normally present in the leukemia …

Effects Of Pristane On Growth Of Pink Salmon (Oncorhynchus Gorbuscha), Brielle D. Kemis, Bonita Nelson

STAR Program Research Presentations

Pristane is a naturally occurring hydrocarbon that is generated by copepods in marine ecosystems. Organisms that eat copepods do not readily metabolize pristane, which causes it to accumulate throughout the marine food web. Understanding how pristane affects marine fish is essential because pristane is often used as a bioindicator in lab studies and may be influencing results in those studies. Also, this hydrocarbon may significantly reduce growth of marine fish in the wild. A previous study indicated that pristane is an appetite suppressant and growth retardant in fish. However, the study implemented a feeding regime with unnaturally high levels of …

The Effect Of Pre-Operative Coumadin Therapy On Patients Who Develop Hemorrhagic Events Post Bariatric Surgery, Richard Boorse Md, Peter J. Bechtel Md, Cathleen Webber Rn, Mshs, Suzanne L. Smith Mba, Rrt, Tas, Cathy Fuhrman Rn, Msn

Department of Surgery

No abstract provided.

A Pseudo-Trna Modulates Antibiotic Resistance In Bacillus Cereus, Theresa E. Rogers, Sandro F. Ataide, Kiley Dare, Assaf Katz, Stephanie Seveau, Hervé Roy, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Bacterial genomic islands are often flanked by tRNA genes, which act as sites for the integration of foreign DNA into the host chromosome. For example, Bacillus cereus ATCC14579 contains a pathogenicity island flanked by a predicted pseudo-tRNA, tRNAOther, which does not function in translation. Deletion of tRNAOther led to significant changes in cell wall morphology and antibiotic resistance and was accompanied by changes in the expression of numerous genes involved in oxidative stress responses, several of which contain significant complementarities to sequences surrounding tRNAOther. This suggested that tRNAOther might be expressed as part of a larger RNA, and RACE analysis …

Synthesis Of The Disaccharide Αgal(1,4)Βgal Related To Trypanosoma Cruzi And Its Conjugation To A Protein, Erika Y. Monroy, Igor C. Almeida, Katja Michael*

COURI Symposium Abstracts, Summer 2012

The disaccharide αGal(1,4)βGal was synthesized by Schmidt’s trichloroacetimidate method. α-Stereoselectivity was achieved by the sterically demanding 4,6-di-tert-butyl-silylidene protecting group in the glycosyl donor. The disaccharide was equipped with an allyl group that allowed for the installation of a thiol functionality, which was used for conjugation to the maleimide-derivatized carrier protein keyhole limpet hemocyanin (KLH). Among other oligosaccharides with terminal a-galactosyl moieties this disaccharide could potentially exist on the cell surface of the parasite Trypanosoma cruzi (T. cruzi), which is the causative agent of Chagas disease. As of today no effective vaccine has been developed for Chagas disease. The …

Regulation Of Lipogenesis By Cyclin-Dependent Kinase 8-Mediated Control Of Srebp-1., Xiaoping Zhao, Daorong Feng, Qun Wang, Arian Abdulla, Xiao-Jun Xie, Jie Zhou, Yan Sun, Ellen S Yang, Lu-Ping Liu, Bhavapriya Vaitheesvaran, Lauren Bridges, Irwin J Kurland, Randy Strich, Jian-Quan Ni, Chenguang Wang, Johan Ericsson, Jeffrey E Pessin, Jun-Yuan Ji, Fajun Yang

Department of Cancer Biology Faculty Papers

Altered lipid metabolism underlies several major human diseases, including obesity and type 2 diabetes. However, lipid metabolism pathophysiology remains poorly understood at the molecular level. Insulin is the primary stimulator of hepatic lipogenesis through activation of the SREBP-1c transcription factor. Here we identified cyclin-dependent kinase 8 (CDK8) and its regulatory partner cyclin C (CycC) as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes, and mouse liver. The inhibitory effect of CDK8 and CycC on de novo lipogenesis was mediated through CDK8 phosphorylation of nuclear SREBP-1c at a conserved threonine residue. Phosphorylation by CDK8 enhanced SREBP-1c ubiquitination and protein …

System Dynamics Modeling Of Medical Use, Nonmedical Use And Diversion Of Prescription Opioid Analgesics, Wayne Wakeland, Alexandra Nielsen, Teresa D. Schmidt

Complex Systems Faculty Publications and Presentations

The objective of the study was to develop a system dynamics model of the medical use of pharmaceutical opioids to treat pain, and the associated diversion and nonmedical use of these drugs. The model was used to test the impact of simulated interventions in this complex system. The study relied on secondary data obtained from the literature and from other public sources for the period 1995 to 2008. In addition, an expert panel provided recommendations regarding model parameters and model structure. The behavior of the resulting systems level model compared favorably with reference behavior data (R2=.95). After the base model …

Identification Of Persistent Long Range Interactions In GA95 And GB95 Through Thermal Unfolding Simulations, Milen Redai Tesfamariam

Chemistry & Biochemistry Theses & Dissertations

For over five decades, different experiments have been performed to research how proteins attain their native three dimensional structures. However, the folding problem continues to be a puzzle in modern science. The design of two proteins that have maximal sequence identity but different folds and functions is one method that is being used to study the relationship between protein structure and amino acid sequence. In particular, mutant proteins of Streptococcus protein G, G_A and G_B, have 95% sequence identity and a 3a helix fold and β4/a fold, respectively. Molecular dynamics simulations of G_A95 …

Association Of A Multi-Synthetase Complex With Translating Ribosomes In The Archaeon Thermococcus Kodakarensis, Medha Raina, Sara Elgamal, Thomas J. Santangelo, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

In archaea and eukaryotes aminoacyl-tRNA synthetases (aaRSs) associate in multi-synthetase complexes (MSCs), however the role of such MSCs in translation is unknown. MSC function was investigated in vivo in the archaeon Thermococcus kodakarensis, wherein six aaRSs were affinity co-purified together with several other factors involved in protein synthesis, suggesting that MSCs may interact directly with translating ribosomes. In support of this hypothesis, the aminoacyltRNA synthetase (aaRS) activities of the MSC were enriched in isolated T. kodakarensis polysome fractions. These data indicate that components of the archaeal protein synthesis machinery associate into macromolecular assemblies in vivo and provide the potential …

A Study Of Histone Deacetylase Inhibitors: Determination Of The Binding Energetics Of Suberoylanilide Hydroxamic Acid With Zinc And Cobalt And Preliminary Screening Of Nitric Oxide Donors, Erin Gallagher

College of Science and Health Theses and Dissertations

Inhibiting histone deacetylases (HDACs) can suppress tumor cell growth eventually leading to their death, makeing HDACs an important drug target. Therefore, understanding the mechanism behind inhibiting HDACs is imperative. To determine the thermodynamic parameters for the interaction of a known competitive HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), with zinc(II), the metal ion in the HDAC active site, and cobalt(II), isothermal titration calorimetry (ITC) was used. The results showed that SAHA binds to zinc(II) more strongly than it does to cobalt(II) as the equilibrium binding constants were 4.3 ± 0.5 x 10² M^-1 and 2.0 ± 0.5 x 10 …

Interactive Concept To Aid In Understanding Dimensional Analysis, Alicia Hicks

Symposium 2012

Many students struggle with learning how to utilize dimensional analysis. This confusion is due to not understanding the concept of dose per volume, leading to difficulty when starting the sequencing. This could be one of the contributing causes to medication errors in clinical practice. Does using models, such as Play-doh and pebbles, help students learn the concept of milligrams per milliliters when calculating dosages using dimensional analysis method? A series of pre- and post-tests are used to measure learning growth in each of the treatment groups. Three treatment groups were utilized: Control: one group had no intervention between the pre …

Under The Gun: Ongoing Assaults On Bahrain’S Health System, Richard Sollom, Holly G. Atkinson

Publications and Research

In February 2011, the Government of Bahrain began targeting health professionals who treated protesters. In April 2012, PHR's Richard Sollom, Deputy Director, and Holly Atkinson, MD, FACP, past President of PHR's Board and volunteer expert, authored a report showing the devastation on Bahrain's health system that have resulted from the Government of Bahrain’s continued assault on doctors, patients, and the healthcare system.

Signal Transducer And Activator Of Transcription-5 Mediates Neuronal Apoptosis Induced By Inhibition Of Rac Gtpase Activity., Trisha R Stankiewicz, F Alexandra Loucks, Emily K Schroeder, Marja T Nevalainen, Kenneth L Tyler, Klaus Aktories, Ron J Bouchard, Daniel A Linseman

Department of Cancer Biology Faculty Papers

In several neuronal cell types, the small GTPase Rac is essential for survival. We have shown previously that the Rho family GTPase inhibitor Clostridium difficile toxin B (ToxB) induces apoptosis in primary rat cerebellar granule neurons (CGNs) principally via inhibition of Rac GTPase function. In the present study, incubation with ToxB activated a proapoptotic Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and a pan-JAK inhibitor protected CGNs from Rac inhibition. STAT1 expression was induced by ToxB; however, CGNs from STAT1 knock-out mice succumbed to ToxB-induced apoptosis as readily as wild-type CGNs. STAT3 displayed enhanced tyrosine phosphorylation following …

Structural Basis For Calmodulin As A Dynamic Calcium Sensor, Miao Zhang, Cameron Abrams, Liping Wang, Anthony Gizzi, Liping He, Ruihe Lin, Yuan Chen, Patrick J. Loll, John M. Pascal, Ji-Fang Zhang

Pharmacy Faculty Articles and Research

Calmodulin is a prototypical and versatile Ca2+ sensor with EF-hands as its high-affinity Ca2+ binding domains. Calmodulin is present in all eukaryotic cells, mediating Ca2+-dependent signaling. Upon binding Ca2+, calmodulin changes its conformation to form complexes with a diverse array of target proteins. Despite a wealth of knowledge on calmodulin, little is known on how target proteins regulate calmodulin’s ability to bind Ca2+. Here, we take advantage of two splice variants of SK2 channels, which are activated by Ca2+-bound calmodulin, but show different sensitivity to Ca2+ for their activation. Protein crystal structures and other experiments show that depending on which …

The Effects Of Nicotine Administration On Behavior And Markers Of Brain Plasticity In A Rodent Model Of Psychosis, Marla K. Perna

Electronic Theses and Dissertations

Schizophrenia affects about 1% of the population. A hallmark of the disorder is increased dopamine D2 receptor sensitivity in the brain. Studies have shown that schizophrenics smoke cigarettes at approximately 4 times the rate of the general population. It has been suggested that nicotine use is a form of self-medication for symptoms in schizophrenia. Smoking behaviors typically begin in adolescence. We assessed effects of nicotine on behavior and brain plasticity in an adolescent rodent model of schizophrenia with the goal of identifying targets for smoking cessation. Methods: Rats were neonatally treated with quinpirole (a D2/D3 agonist) or saline and sensitized …

Selectivity Of The Ubiquitin-Binding Modules, Simin Rahighi, Ivan Dikic

Pharmacy Faculty Articles and Research

Ubiquitin-binding modules are constituents of cellular proteins that mediate the effects of ubiquitylation by making transient, non-covalent interactions with ubiquitin molecules. While some ubiquitin- binding modules bind single ubiquitin moieties, others are selective for specific ubiquitin chains of different linkage types and lengths. In recent years, functions of ubiquitin chains that are polymerized through their Lys or N-terminal Met (i.e. linear chains) residues have been linked to a variety of cellular processes. Selectivity of ubiquitin-binding modules for different ubiquitin chain types appears as a key to the distinct regulatory consequences during protein quality control pathways, receptor endocytosis, gene transcription, signaling …

Environmental Friendly Synthesis, Characterization Of Surface Modifiable Starch Encapsulated Gold Nanoparticles With Bactericidal And Catalytic Activity, Dillon Pender

Mahurin Honors College Capstone Experience/Thesis Projects

In the present study, we report the green synthesis of gold nanoparticles (GNPs), using potato starch as a reducing as well as a stabilizing agent in an aqueous buffer medium. The resulting starch-GNPs (St-GNPs) were near spherical in shape with an average diameter of 15 ± 5 nm. In this approach, St-GNPs were characterized and investigated for their antibacterial properties against both gram negative (Escherichia coli) and gram positive (Staphylococcus epidermidis) bacteria. These St-GNPs were found to possess significant dose dependent antibacterial activity against bacteria. Also, St-GNPs showed a significant catalytic activity and can easily be …

Immunizations For Adults And Children, Lynne J. Goebel, Nancy B. Norton, Maurice A. Mufson

Internal Medicine

Vaccines represent the most important medical advance of the twentieth century. The time has passed when large numbers of children and adults suffered serious, life threatening illness from viruses including poliovirus, measles virus, influenza viruses, hepatitis B virus and varicella zoster virus or faced lifelong disability or death from bacterial infections including Hemophilus influenzae, meningococcus and pneumococcus, all infections that can be prevented now by effective vaccines.

The Reaction Of Methionine With A Non-C2-Symmetrical Platinum (Ii) Diamine Compound, Nilesh Sahi

Mahurin Honors College Capstone Experience/Thesis Projects

The research that we have conducted has allowed us to discover that the amino acids, methionine (Met) and N-acetyl methionine (N-AcMet), will react in a 1:1 and 1:2 molar ratio with platinum complexes containing bulky diamine ligands. Previous research has allowed us to gain a plethora of information on the experimentation and results of specific bulky diamine ligands such as N,N,N',N'-tetramethylethylenediamine and N,N-diethylethylenediamine. In the current study, we have investigated the bulky diamine ligand of N,N-dimethylethylenediamine, or Me₂en. With our focus on the bulk of the Me₂en ligand, we have been able to synthesize a platinum …

Oxaliplatin And Oxaliplatin Derivatives: Synthesis, Characterization, And Reactivity With Biologically Relevant Ligands, Amy Poynter

Mahurin Honors College Capstone Experience/Thesis Projects

Oxaliplatin is a third generation anticancer drug that has proven to be successful in fighting ovarian and testicular cancer. We are interested in determining how oxaliplatin and oxaliplatin derivatives interact with proteins, as well as how that interaction is affected by the size and shape of these platinum compounds. We have synthesized oxaliplatin as it is used in cancer treatment, as well as similar platinum compounds with the same diaminocyclohexane ligand as oxaliplatin but with additional bulk added to the nitrogen atoms. We are reacting oxaliplatin with key amino acids, including methionine, and will be comparing the kinetics of this …

Genetic Ablation Of Cav1 Differentially Affects Melanoma Tumor Growth And Metastasis In Mice: Role Of Cav1 In Shh Heterotypic Signaling And Transendothelial Migration., Franco Capozza, Casey Trimmer, Remedios Castello-Cros, Sanjay Katiyar, Diana Whitaker-Menezes, Antonia Follenzi, Marco Crosariol, Gemma Llaverias, Federica Sotgia, Richard G Pestell, Michael P Lisanti

Department of Cancer Biology Faculty Papers

Both cell-autonomous and non-cell-autonomous factors contribute to tumor growth and metastasis of melanoma. The function of caveolin-1 (Cav1), a multifunctional scaffold protein known to modulate several biologic processes in both normal tissue and cancer, has been recently investigated in melanoma cancer cells, but its role in the melanoma microenvironment remains largely unexplored. Here, we show that orthotopic implantation of B16F10 melanoma cells in the skin of Cav1KO mice increases tumor growth, and co-injection of Cav1-deficient dermal fibroblasts with melanoma cells is sufficient to recapitulate the tumor phenotype observed in Cav1KO mice. Using indirect coculture experiments with fibroblasts and melanoma cells …

Biomass Assisted Synthesis Of Antibacterial Gold Nanoparticles And Commentary On Its Future Potential And Applications In Medicine, Chad Willis

Mahurin Honors College Capstone Experience/Thesis Projects

Xylose is a natural monosaccharide found in biomass such as straw, pecan shells, cottonseed hulls, and corncobs. Using this monosaccharide, we report the green synthesis and characterization of biocompatible, biodegradable xylose encapsulated gold nanoparticles (Xyl-GNPs) with potential antibacterial activity. GNPs were synthesized using the bioreduction property of xylose on the chloroaurate anions in an aqueous solution at room temperature and at atmospheric pressure. The characterization of synthesized GNPs was examined by UV-vis spectroscopy; transmission electron microscopy (TEM), energy-dispersive x-ray spectroscopy (EDS) and fourier transform infrared spectroscopy (FTIR). Results indicate that the particles were stable; near spherical in shape with an …

Acetaldehyde And Epithelial Junctions: Role Of Pp2a And Occludin Phosphorylation, Mitzi Dunagan

Theses and Dissertations (ETD)

Chronic alcohol consumption causes health problems including cancers, liver damage, and cirrhosis.These problems are exacerbated by endotoxins from the bacterial population of the colon, which can enter the bloodstream when gastrointestinal tight junctions, protein complexes that prevent paracellular passage of molecules, are compromised. The mechanisms of this barrier disruption are the subject of current study.

Acetaldehyde, produced as a result of ethanol breakdown by intestinal microflora as well as intestinal epithelia, is a known carcinogen. It compromises the barrier function of intestinal epithelial cells by causing irregularities in the phosphorylation of tight junction proteins. It also reacts with proteins, lipids, …