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 …