Pharmacology, Toxicology and Environmental Health Commons^™

Arsenic Analysis: Comparative Arsenic Groundwater Concentration In Relation To Soil And Vegetation, Rominna E. Valentine Vecorena

Electronic Theses, Projects, and Dissertations

Arsenic (As) is a toxic semi-metallic element found in groundwater, soils, and plants. Natural and anthropogenic sources contribute to the distribution of arsenic in the environment. Arsenic’s toxic and mobile behavior is associated with its speciation ability. There are two types of arsenic available to the environment, inorganic and organic arsenic. Of the two, inorganic arsenic is more toxic to humans and more mobile in the environment. Two inorganic compounds responsible for arsenic contamination are trivalent arsenite, As (III), and pentavalent arsenate, As (V). Trivalent arsenate is considered to be more soluble, toxic, and mobile than pentavalent arsenate. Arsenic’s absorptive …

Glyphosate Induces Neurotoxicity In Zebrafish, Nicole M. Roy, Bruno Carneiro, Jeremy Ochs

Biology Faculty Publications

Glyphosate based herbicides (GBH) like Roundup^® are used extensively in agriculture as well as in urban and rural settings as a broad spectrum herbicide. Its mechanism of action was thought to be specific only to plants and thus considered safe and non-toxic. However, mounting evidence suggests that GBHs may not be as safe as once thought as initial studies in frogs suggest that GBHs may be teratogenic. Here we utilize the zebrafish vertebrate model system to study early effects of glyphosate exposure using technical grade glyphosate and the Roundup^® Classic formulation. We find morphological abnormalities including cephalic and …

Extracorporeal Membrane Oxygenation (Ecmo) For Severe Toxicological Exposures: Review Of The Toxicology Investigators Consortium (Toxic)., G S. Wang, R Levitan, T J. Wiegand, Jennifer Lowry, R F. Schult, S Yin, Toxicology Investigators Consortium

Manuscripts, Articles, Book Chapters and Other Papers

Although there have been many developments related to specific strategies for treating patients after poisoning exposures, the mainstay of therapy remains symptomatic and supportive care. One of the most aggressive supportive modalities is extracorporeal membrane oxygenation (ECMO). Our goal was to describe the use of ECMO for toxicological exposures reported to the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC). We performed a retrospective review of the ACMT ToxIC Registry from January 1, 2010 to December 31, 2013. Inclusion criteria included patients aged 0 to 89 years, evaluated between January 2010 through December 2013, and received ECMO for …

Chemical Investigation Of Antarctic Marine Organisms & Their Role In Modern Drug Discovery, Jacqueline Lee Fries

USF Tampa Graduate Theses and Dissertations

The chemicals produced by biological systems, whether proteins, peptides, or terpenes, will always provide an intriguing topic for researchers. Invisibly controlling every aspect of nature, these molecules are responsible for life, evolution, and death. Specifically, here is described the secondary metabolites produced by Antarctic marine organisms as well as others, and how they are used to defend or attract other animals while potentially providing health benefits to mankind. This is done through collection, extraction, and separation of individual specimens. The respective mixtures of compounds after isolation are then analyzed via spectroscopic methods such as nuclear magnetic resonance spectroscopy, mass spectrometry, …

Β-Thujaplicin: A Soil Antifungal, Dennis J. Baumgardner

Dennis J. Baumgardner, MD

Background: β-thujaplicin (β-Th), also known as hinokitiol, naturally occurs in cedar mulch, is found in personal care products and has in vitro antitumor activities. It is antibacterial and antifungal, but has not been tested on soil. Scedosporium apiospermum (Sce) is an emerging “extremophile” fungal pathogen found in built outdoor environments. Purpose: Pilot β-Th as “natural” soil antimicrobial or for isolation of extremophiles, and to explore β-Th resistance as selective advantage to Sce in mulched landscape. Methods: A variety of outdoor and indoor environments were used for 2 sets of 24 paired soil samples. Soil/H20 slurry (0.1 ml) was spread on …

Acellular Reactivity Of Polymeric Dendrimer Nanoparticles As An Indicator Of Oxidative Stress In Vitro, Marcus Maher, Humza Khalid, Hugh Byrne

Articles

The need for rapid and cost effective pre-screening protocols of the toxicological response of the vast array of emerging nanoparticle types is apparent and the emerging consensus on the paradigm of oxidative stress by generation of intracellular reactive oxygen species as a primary source of the toxic response suggests the development of acellular assays to screen for nanoparticle surface reactivity. This study explores the potential of the monoamine oxidase A (MAO-A) enzyme based assay with polymeric dendrimers as cofactors and serotonin as substrate, which generates H₂O₂, quantified by the conversion of the Carboxy-H₂DCFDA dye …

Gene Expression Microarray Data From Human Microvascular Endothelial Cells Supplemented With A Low Concentration Of Niacin, Nica M. Borradaile, Jennifer M. Hughes-Large

Physiology and Pharmacology Publications

The systemic lipid modifying drug, niacin, can directly improve human microvascular endothelial cell angiogenic function under lipotoxic conditions, possibly through activation of niacin receptors [1]. Here we provide accompanying data collected using Affymetrix GeneChip microarrays to identify changes in gene expression in human microvascular endothelial cells treated with 10 μM niacin. Statistical analyses of robust multi-array average (RMA) values revealed that only 16 genes exhibited greater than 1.3-fold differential expression. Of these 16, only 5 were identified protein coding genes, while 3 of the remaining 11 genes appeared to be small nuclear/nucleolar RNAs. Altered expression of EFCAB4B, …

Blockade Of Astrocytic Calcineurin/Nfat Signaling Helps To Normalize Hippocampal Synaptic Function And Plasticity In A Rat Model Of Traumatic Brain Injury, Jennifer L. Furman, Pradoldej Sompol, Susan D. Kraner, Melanie M. Pleiss, Esther J. Putman, Jacob Dunkerson, Hafiz Mohmmad Abdul, Kelly N. Roberts, Stephen William Scheff, Christopher M. Norris

Pharmacology and Nutritional Sciences Faculty Publications

Increasing evidence suggests that the calcineurin (CN)-dependent transcription factor NFAT (Nuclear Factor of Activated T cells) mediates deleterious effects of astrocytes in progressive neurodegenerative conditions. However, the impact of astrocytic CN/NFAT signaling on neural function/recovery after acute injury has not been investigated extensively. Using a controlled cortical impact (CCI) procedure in rats, we show that traumatic brain injury is associated with an increase in the activities of NFATs 1 and 4 in the hippocampus at 7 d after injury. NFAT4, but not NFAT1, exhibited extensive labeling in astrocytes and was found throughout the axon/dendrite layers of CA1 and the dentate …

Tom Curran, Phd, Frs, Named Executive Director Of Children's Research Institute, Children's Mercy Hospital

Our Story Continues

Tom Curran, PhD, FRS, has been named Chief Scientific Officer and Executive Director of the Children’s Mercy Children’s Research Institute (CRI), effective Feb. 1 [2016]

The Children’s Research Institute at Children’s Mercy Kansas City was established last year to build on the hospital’s century-long history in pediatric research and to focus the hospital’s future research efforts in four key areas:

• Pediatric Genomic Medicine
• Clinical Pharmacology
• Health Services and Outcomes
• Health Care Delivery

Nitrogen And Phosphorus Availability From Various Composted Wastes For Use In Irish Agriculture And Horticulture, Alan Lee

Doctoral

Current environmental EU legislation promotes recycling and recovery from organic waste products. Compost has been identified as an alternative to inorganic fertilisers and animal slurries as a nutrient source for crop plants. This study aimed to investigate nitrogen (N) and phosphorus (P) availability from various composted waste through detailed characterisations, complemented by short term lab incubations and long term plant growth experiments. Twenty-five composts were selected and classified by their groups. The composts were characterised by multiple different analytical techniques. Two incubation studies were conducted. One investigating N and P mineralisation potential of the composts and the second on the …

Role Of Pharmacogenetics In Improving The Safety Of Psychiatric Care By Predicting The Potential Risks Of Mania In Cyp2d6 Poor Metabolizers Diagnosed With Bipolar Disorder., Santiago Sánchez-Iglesias, Virginia García-Solaesa, Belén García-Berrocal, Almudena Sanchez-Martín, Carolina Lorenzo-Romo, Tomás Martín-Pinto, Andrea Gaedigk, José Manuel González-Buitrago, María Isidoro-García

Manuscripts, Articles, Book Chapters and Other Papers

One of the main concerns in psychiatric care is safety related to drug management. Pharmacogenetics provides an important tool to assess causes that may have contributed the adverse events during psychiatric therapy. This study illustrates the potential of pharmacogenetics to identify those patients for which pharmacogenetic-guided therapy could be appropriate. It aimed to investigate CYP2D6 genotype in our psychiatric population to assess the value of introducing pharmacogenetics as a primary improvement for predicting side effects.A broad series of 224 psychiatric patients comprising psychotic disorders, depressive disturbances, bipolar disorders, and anxiety disorders was included. The patients were genotyped with the AmpliChip …

Structural Dependence Of The In Vitro Cytotoxicity, Oxidative Stress And Uptake Mechanisms Of Poly(Propylene Imine) Dendritic Nanoparticles, Humza Khalid, Sourav Prasanna Mukherjee, Luke O'Neill, Hugh Byrne

Articles

The in vitro cytotoxic and intracellular oxidative stress responses to exposure to poly (propylene imine) (PPI) dendritic nanoparticles of increasing generation (number of repeated branching cycles) (G0-G4) were assessed in an immortal non-cancerous human keratinocyte cell-line (HaCaT). Confocal fluorescence microscopy with organelle staining was used to explore the uptake and intracellular trafficking mechanisms. A generation and dose dependent cytotoxic response was observed, increasing according to generation and therefore number of surface amino groups. A comparison of the cytotoxic response of G4 PPI and the related G4 Poly (amido amine) dendrimer indicates that the PPI with the same number of surface …

Pharmacogenetic Allele Nomenclature: International Workgroup Recommendations For Test Result Reporting., L V. Kalman, Jag Agúndez, M Lindqvist Appell, J L. Black, G C. Bell, S Boukouvala, C Bruckner, E Bruford, K Caudle, S A. Coulthard, A K. Daly, Al Del Tredici, J T. Den Dunnen, K Drozda, R E. Everts, D Flockhart, R R. Freimuth, Andrea Gaedigk, H Hachad, T Hartshorne, M Ingelman-Sundberg, T E. Klein, V M. Lauschke, D R. Maglott, H L. Mcleod, G A. Mcmillin, U A. Meyer, D J. Müller, D A. Nickerson, W S. Oetting, M Pacanowski, V M. Pratt, M V. Relling, A Roberts, W S. Rubinstein, K Sangkuhl, M Schwab, S A. Scott, S C. Sim, R K. Thirumaran, L H. Toji, R F. Tyndale, Rhn Van Schaik, M Whirl-Carrillo, Ktj Yeo, U M. Zanger

Manuscripts, Articles, Book Chapters and Other Papers

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

The Shellfish Corner -- Water Quality And Culture Of Shellfish In Prohibited Waters, Michael A. Rice

Michael A Rice

The Ssdna Mutator Apobec3a Is Regulated By Cooperative Dimerization, Markus-Frederik Bohn, Shivender Shandilya, Tania Silvas, Ellen Nalivaika, Takahide Kouno, Brian Kelch, Sean Ryder, Nese Yilmaz, Mohan Somasundaran, Celia Schiffer

Celia A. Schiffer

Deaminase activity mediated by the human APOBEC3 family of proteins contributes to genomic instability and cancer. APOBEC3A is by far the most active in this family and can cause rapid cell death when overexpressed, but in general how the activity of APOBEC3s is regulated on a molecular level is unclear. In this study, the biochemical and structural basis of APOBEC3A substrate binding and specificity is elucidated. We find that specific binding of single-stranded DNA is regulated by the cooperative dimerization of APOBEC3A. The crystal structure elucidates this homodimer as a symmetric domain swap of the N-terminal residues. This dimer interface …

Structure Of The Vif-Binding Domain Of The Antiviral Enzyme Apobec3g, Takahide Kouno, Elizabeth Luengas, Megumi Shigematsu, Shivender Shandilya, Jingying Zhang, Luan Chen, Mayuko Hara, Celia Schiffer, Reuben Harris, Hiroshi Matsuo

Celia A. Schiffer

The human APOBEC3G (A3G) DNA cytosine deaminase restricts and hypermutates DNA-based parasites including HIV-1. The viral infectivity factor (Vif) prevents restriction by triggering A3G degradation. Although the structure of the A3G catalytic domain is known, the structure of the N-terminal Vif-binding domain has proven more elusive. Here, we used evolution- and structure-guided mutagenesis to solubilize the Vif-binding domain of A3G, thus permitting structural determination by NMR spectroscopy. A smaller zinc-coordinating pocket and altered helical packing distinguish the structure from previous catalytic-domain structures and help to explain the reported inactivity of this domain. This soluble A3G N-terminal domain is bound by …

Simultaneously Targeting The Ns3 Protease And Helicase Activities For More Effective Hepatitis C Virus Therapy, Jean Ndjomou, M Corby, Noreena Sweeney, Alicia Hanson, Cihan Aydin, Akbar Ali, Celia Schiffer, Kelin Li, Kevin Frankowski, Frank Schoenen, David Frick

Celia A. Schiffer

This study examines the specificity and mechanism of action of a recently reported hepatitis C virus (HCV) nonstructural protein 3 (NS3) helicase-protease inhibitor (HPI), and the interaction of HPI with the NS3 protease inhibitors telaprevir, boceprevir, danoprevir, and grazoprevir. HPI most effectively reduced cellular levels of subgenomic genotype 4a replicons, followed by genotypes 3a and 1b replicons. HPI had no effect on HCV genotype 2a or dengue virus replicon levels. Resistance evolved more slowly to HPI than telaprevir, and HPI inhibited telaprevir-resistant replicons. Molecular modeling and analysis of the ability of HPI to inhibit peptide hydrolysis catalyzed by a variety …

Structural Basis For Mutation-Induced Destabilization Of Profilin 1 In Als, Sivakumar Boopathy, Tania Silvas, Maeve Tischbein, Silvia Jansen, Shivender Shandilya, Jill Zitzewitz, John Landers, Bruce Goode, Celia Schiffer, Daryl Bosco

Celia A. Schiffer

Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the …

Inhibition Of Apobec3g Activity Impedes Double-Stranded Dna Repair, Ponnandy Prabhu, Shivender Shandilya, Elena Britan-Rosich, Adi Nagler, Celia Schiffer, Moshe Kotler

Celia A. Schiffer

The cellular cytidine deaminase APOBEC3G (A3G) was first described as an anti-HIV-1 restriction factor, acting by directly deaminating reverse transcripts of the viral genome. HIV-1 Vif neutralizes the activity of A3G, primarily by mediating degradation of A3G to establish effective infection in host target cells. Lymphoma cells, which express high amounts of A3G, can restrict Vif-deficient HIV-1. Interestingly, these cells are more stable in the face of treatments that result in double-stranded DNA damage, such as ionizing radiation and chemotherapies. Previously, we showed that the Vif-derived peptide (Vif25-39) efficiently inhibits A3G deamination, and increases the sensitivity of lymphoma cells to …

Rediii: A Pipeline For Automated Structure Solution, Markus-Frederik Bohn, Celia Schiffer

Celia A. Schiffer

High-throughput crystallographic approaches require integrated software solutions to minimize the need for manual effort. REdiii is a system that allows fully automated crystallographic structure solution by integrating existing crystallographic software into an adaptive and partly autonomous workflow engine. The program can be initiated after collecting the first frame of diffraction data and is able to perform processing, molecular-replacement phasing, chain tracing, ligand fitting and refinement without further user intervention. Preset values for each software component allow efficient progress with high-quality data and known parameters. The adaptive workflow engine can determine whether some parameters require modifications and choose alternative software strategies …