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2,4-Disulfonyl Phenyl Butyl Nitrone, Its Salt And Their Use As Pharmaceuticals, John M. Carney

Pharmacology and Nutritional Sciences Faculty Patents

2,4-disulfonyl α-phenyl-tert-butyl nitrone and its pharmaceutically acceptable salts are disclosed. These materials are useful as pharmaceutical agents for oral or parenteral, e.g. intravenous administration to patients suffering from acute central nervous system oxidation as occurs in a stroke or from gradual central nervous system oxidation which can exhibit itself as progressive central nervous system function loss. The materials are also used to ameliorate the side effects of oxidative-damage causing antineoplastic disease treatments.

Phenyl Butyl Nitrone Compositions And Methods For Treatment Of Oxidative Tissue Damage, John M. Carney, Robert A. Floyd

Pharmacology and Nutritional Sciences Faculty Patents

Compositions for treating tissue damage from ischemia contain PBN, or active derivatives thereof, which are active during ischemia in preventing ATP depletion of the cells which predisposes them to subsequent injury during reperfusion, and which are active during reperfusion as oxygen radical scavengers, in a suitable pharmaceutical carrier for systemic or local administration, especially to the CNS, spinal column and eyes. Based on animal studies, the dosage for treating damage due to stroke is in the range of 10 to 300 mg/kg. Similar dosages are useful in treating damage resulting from free radical generation during inflammation, either as a product …

The Effect Of Dietary Supplemented Vitamin E And Selenium On Experimental Chagas' Disease, Brenda Bennett

Masters Theses & Specialist Projects

Dietary supplementation with increased levels of vitamin E can enhance the immune system of C3HeB/FeJ mice to enable many of them to survive an otherwise lethal dose of Trypanosoma cruzi, the causative agent of Chagas' disease. To study the role of diet on the course of experimental Chagas' disease, C3HeB/FeJ mice were fed pelleted, synthetic food containing no vitamin E and selenium, 800 IU/kg vitamin E, 2 ppm selenium, or food containing 800 IU/kg vitamin E plus 2 ppm selenium. Mice on synthetic food were compared to control mice fed a commonly used Purina rodent chow # 5001. After diet …

Asbestos Induces Nuclear Factor Kappa B (Nf-Kappa B) Dna-Binding Activity And Nf-Kappa B-Dependent Gene Expression In Tracheal Epithelial Cells., Yvonne M. Janssen, Aaron Barchowsky, Melinda Treadwell, Kevin E. Driscoll, B T. Mossman

Dartmouth Scholarship

Nuclear factor kappa B (NF-kappa B) is a transcription factor regulating expression of genes intrinsic to inflammation and cell proliferation--features of asbestos-associated diseases. In studies here, crocidolite asbestos caused protracted and dose-responsive increases in proteins binding to nuclear NF-kappa B-binding DNA elements in hamster tracheal epithelial (HTE) cells. This binding was modulated by cellular glutathione levels. Antibodies recognizing p65 and p50 protein members of the NF-kappa B family revealed these proteins in two of the DNA complexes. Transient transfection assays with a construct containing six NF-kappa B-binding DNA consensus sites linked to a luciferase reporter gene indicated that asbestos induced …

The Role Of Fibrinogen D Domain Intermolecular Association Sites In The Polymerization Of Fibrin And Fibrinogen Tokyo Ii (Γ275 Arg→Cys), Michael W. Mosesson, Kevin R. Siebenlist, James P. Diorio, M. Matsuda, James F. Hainfeld, J. S. Wall

Biomedical Sciences Faculty Research and Publications

Intermolecular end-to-middle domain pairing between a thrombin-exposed 'A' polymerization site in the central 'E' domain of fibrin, and a constitutive complementary 'a' site in each outer 'D' domain ('D:E'), is necessary but not alone sufficient for normal fibrin assembly, as judged from previous studies of a congenital dysfibrinogen, Tokyo II (gamma 275 arg-->cys), which showed defective fibrin clot assembly and a normal D:E interaction (Matsuda, M., M. Baba, K. Morimoto, and C. Nakamikawa, 1983. J. Clin. Invest. 72:1034-1041). In addition to the 'a' polymerization site, two other constitutive intermolecular association sites on fibrinogen D domains have been defined: between …

Increased Abundance Of The Receptor-Type Protein-Tyrosine Phosphatase Lar Accounts For The Elevated Insulin Receptor Dephosphorylating Activity In Adipose Tissue Of Obese Human Subjects, Falyaz Ahmad, Robert V. Considine, Barry J. Goldstein

Department of Medicine Faculty Papers

Protein-tyrosine phosphatases (PTPases) have an essential role in the regulation of the steady-state phosphorylation of the insulin receptor and other proteins in the insulin signalling pathway. To examine whether increased PTPase activity is associated with adipose tissue insulin resistance in human obesity we measured PTPase enzyme activity towards the insulin receptor in homogenates of subcutaneous adipose tissue from a series of six lean and six nondiabetic, obese (body mass index > 30) subjects. The obese subjects had a mean 1.74-fold increase in PTPase activity (P < 0.0001) with a striking positive correlation by linear regression analysis between PTPase activity and body mass index among all of the samples (R = 0.918; P < 0.0001). The abundance of three candidate insulin receptor PTPases in adipose tissue was also estimated by immunoblot analysis. The most prominent increase was a 2.03-fold rise in the transmembrane PTPase LAR (P < 0.001). Of the three PTPase examined, only immunodepletion of LAR protein from the homogenates with neutralizing antibodies resulted in normalization of the PTPase activity towards the insulin receptor, demonstrating that the increase in LAR was responsible for the enhanced PTPase activity in the adipose tissue from obese subjects. These studies suggest that increased PTPase activity towards the insulin receptor is a pathogenetic factor in the insulin resistance of adipose tissue in human obesity and provide evidence for a potential role of the LAR PTPase in the regulation of insulin signalling in disease states.

A Tef-1-Independent Mechanism For Activation Of The Simian Virus 40 (Sv40) Late Promoter By Mutant Sv40 Large T Antigens., Paul Casaz, Phillip W. Rice, Charles N. Cole, Ulla Hansen

Dartmouth Scholarship

Simian virus 40 (SV40) large tumor antigen (T antigen) stimulates the activity of the SV40 late promoter and a number of cellular and other viral promoters. We have characterized the ability of T antigens with mutations in the DNA-binding domain and within the N-terminal 85 residues to activate the SV40 late promoter. T antigens lacking both nonspecific and sequence-specific DNA-binding activities were able to induce the late promoter. Mutations within the N-terminal 85 residues of T antigen diminished activation by less than twofold. Activation by wild-type and most of the mutant T antigens required intact binding sites for the cellular …

Heterozygosity Mapping Of Partially Congenic Lines: Mapping Of A Semidominant Neurological Mutation, Wheels ( Whl), On Mouse Chromosome 4, Patrick M. Nolan, Patricia J. Sollars, Barbara A. Bohne, Warren J. Ewens, Gary E. Pickard, Maja Bucan

School of Veterinary and Biomedical Sciences: Faculty Publications

We identified a semidominant, chemically induced, mouse use mutation with a complex array of abnormal behaviors including bidirectional circling and hyperactivity, abnormal circadian rhythmicity and abnormal responses to light. In this report, we genetically and phenotypically characterized the circling/ waltzing component of the abnormal behavior. We mapped the locus controlling this trait by heterozygosity mapping of partially congenic lines carrying the mutagenized chromosome outcrossed to different inbred strains for three generations. Analysis of 68 PCR-based markers in 13 affected individuals indicated that the mutant locus, named Wheels (Whl), resides in the subcentromeric portion of mouse chromosome 4. The …

The Leukemic Core Binding Factor Beta-Smooth Muscle Myosin Heavy Chain (Cbf Beta-Smmhc) Chimeric Protein Requires Both Cbf Beta And Myosin Heavy Chain Domains For Transformation Of Nih 3t3 Cells., Amitav Hajra, Pu Liu, Qing Wang, Christine Kelley

Dartmouth Scholarship

An inversion of chromosome 16 associated with the M4Eo subtype of acute myeloid leukemia produces a chimeric protein fusing the beta subunit of the transcription factor core binding factor (CBF beta) to the tail region of smooth muscle myosin heavy chain (SMMHC). We investigated the oncogenic properties of this CBF beta-SMMHC chimeric protein using a 3T3 transformation assay. NIH 3T3 cells expressing CBF beta-SMMHC acquired a transformed phenotype, as indicated by their ability to form foci, grow in soft agarose, and form tumors in nude mice. Cells expressing normal CBF beta or the SMMHC tail domain did not become transformed. …

A Novel Translational Regulation Function For The Simian Virus 40 Large-T Antigen Gene., Prithi Rajan, Sathyamagalam Swaminathan, Jiyue Zhu, Charles N. Cole

Dartmouth Scholarship

Cells use the interferon-induced, double-stranded-RNA-dependent protein kinase PKR as a defense against virus infections. Upon activation, PKR phosphorylates and thereby inactivates the protein synthesis initiation factor eIF-2, resulting in the cessation of protein synthesis. Viruses have evolved various strategies to counteract this cellular defense. In this paper, we show that simian virus 40 (SV40) large-T antigen can antagonize the translational inhibitory effect resulting from the activation of PKR in virus-infected cells. Unlike the situation with other virus-host cell interactions, SV40 large-T antigen does not block the activation of PKR, suggesting that SV40 counteracts the cellular antiviral response mediated by PKR …

A Family Of Putative Receptor-Adenylate Cyclases From Leishmania Donovani, Marco A. Sanchez, David Zeoli, Elizabeth M. Klamo, Michael Kavanaugh, Scott M. Landfear

Biomedical and Pharmaceutical Sciences Faculty Publications

Leishmania parasites are exposed to pronounced changes in their environment during their life cycle as they migrate from the sandfly midgut to the insect proboscis and then into the phagolysosomes of the vertebrate macrophages. The developmental transformations that produce each life cycle stage of the parasite may be signaled in part by binding of environmental ligands to receptors which mediate transduction of extracellular signals. We have identified a family of five clustered genes in Leishmania donovani which may encode signal transduction receptors. The coding regions of two of these genes, designated rac-A and rac-B, have been sequenced and shown …

Site-Directed Mutagenesis Of Southern Bean Mosaic Virus (Cowpea Strain): In Search Of A Viral Protease, Alan Simmons

Masters Theses & Specialist Projects

The second and largest open reading frame within the southern bean mosaic virus (SBMV) genome encodes a 105 kDa polyprotein. Following translation, the polyprotein is cleaved to liberate various proteins necessary for SBMV replication. The elements within polyproteins of the picornavirus superfamily members have a conserved order: Vpg (viral protein, genome-linked)-protease-replicase. Amino acid sequence homologies indicate that the 105 kDa protein of SBMV contains a replicase very similar to those identified in polyproteins of the picorna-like viruses. The presence of a VPg covalently attached to the 5' end of the SBMV genome further suggests that SBMV may be considered a …

Characterization Of The On And Off Pathways In Human Vision, Luisa Roveri

Master's Theses

No abstract provided.

Faculty Publications 1994, Lsu Health Sciences Center New Orleans

Historical Faculty Publications

This Faculty bibliography contains 565 publications.

The Gtp-Bound Form Of The Yeast Ran/Tc4 Homologue Blocks Nuclear Protein Import And Appearance Of Poly(A)+ Rna In The Cytoplasm., Gabriel Schlenstedt, Claudio Saavedra, Jonathan D. Loeb, Charles N. Cole, Pamela A. Silver

Dartmouth Scholarship

Ran/TC4, a Ras-like GTP-binding protein, and its nucleotide exchanger, RCC1, have been implicated in control of protein movement into the nucleus and cytoplasmic accumulation of mRNA. Saccharomyces cerevisiae contains two homologues of the mammalian Ran/TC4, encoded by the GSP1 and GSP2 genes. We have constructed yeast strains that overproduce either wild-type Gsp1 or a form of Gsp1 with glycine-21 converted to valine (Gsp1-G21V), which we show stabilizes the GTP-bound form. Cells producing Gsp1-G21V have defects in localization of nuclear proteins; nuclear proteins accumulate in the cytoplasm following galactose induction of Gsp1-G21V. Similarly, cells producing Gsp1-G21V retain poly(A)+ RNA in their …

Sidedness Of H+ Action On K-Cl Cotransport In Dids Ph(I)-Clamped Low K Sheep Red Blood Cells With Reduced Mg(I), Peter K. Lauf, Norma C. Adragna

Pharmacology and Toxicology Faculty Publications

No abstract provided.

A Study Of Euplotes Crassus Telomere Proteins And Related Genes, John Scott Perez

Department of Chemistry: Dissertations, Theses, and Student Research

A novel PCR technique used to amplify Euplotes crassus macronuclear chromosomes was developed to provide scientific proof that an Euplotes crassus 1.0 kb gene is not genetically related to an Oxytricha nova 1.8 kb β-telomere protein gene. Theories and experimental procedures associated with the development of this PCR technique were the product of research that will have a profound impact on future studies of telomere protein genes and telomeric DNA in a multitude of eukaryotic cells. The hypothesis that a β-telomere protein does not exist in Euplotes crassus was supported by the result of this study.

Expression of the recombinant …

Update - September 1994, Loma Linda University Center For Christian Bioethics

Update

In this issue:

-- Ritualized Genital Mutilation the Procedure
-- A Cultural Perspective
-- Female Genital Mutilation: A Question of Fundamental Human Rights
-- Ethics When Cultures Clash
-- Ethics Consultation (Review)

Peculiar Histopathological Features Of Giardiasis In Distal Duodenal Biopsies, Z Abbas, A A. Qureshi, H Sheikh, S M. Jafri, A H. Khan

Department of Pathology and Laboratory Medicine

Histological changes in 20 Giardia positive duodenal biopsies (Group A) were compared with 50, Giardia negative duodenal biopsies (Group B), taken during the same period. Stool examinations in Group B were negative for Giardia. Surface epithelium, villous and crypt architecture and cellular infiltrates were examined and compared between the groups. Atrophic changes in the villi were more common in Group A as compared to B(P < 0.0001). Intraepithelial neutrophil infiltration (P < 0.001), infiltration of the lamina propria with plasma cells (P < 0.5), and presence of eosinophils in the lamina propria (P < 0.001) were significant findings in group A. Some of the changes were related to the density of Giardia colonization e.g., the goblet cell depletion (P < 0.05) and the density of plasma cell infiltration in lamina propria (P < 0.01). Erosions and ulcerations were less commonly seen in group A. Thus we conclude that giardiasis manifests its peculiar features in the distal duodenal mucosa and a biopsy of this region is an important diagnostic tool for detection of this disease.

A Thyroid Hormone-Regulated Gene In Xenopus Laevis Encodes A Type Iii Iodothyronine 5-Deiodinase., Donald L. St Germain, Robert Schwartzman, Walburga Croteau, Akira Kanamori, Zhou Wang, Donald D. Brown, Valerie Galton

Dartmouth Scholarship

The type III iodothyronine 5-deiodinase metabolizes thyroxine and 3,5,3'-triiodothyronine to inactive metabolites by catalyzing the removal of iodine from the inner ring. The enzyme is expressed in a tissue-specific pattern during particular stages of development in amphibia, birds, and mammals. Recently, a PCR-based subtractive hybridization technique has been used to isolate cDNAs prepared from Xenopus laevis tadpole tail mRNA that represent genes upregulated by thyroid hormone during metamorphosis. Sequence analysis of one of these cDNAs (XL-15) revealed regions of homology to the mRNA encoding the rat type I (outer ring) 5'-deiodinase, including a conserved UGA codon that encodes selenocysteine in …

High Rates Of Frameshift Mutations Within Homo-Oligomeric Runs During A Single Cycle Of Retroviral Replication, Dawn P. Wooley, H. M. Temin

Neuroscience, Cell Biology & Physiology Faculty Publications

Homo-oligomeric runs were inserted into a spleen necrosis virus-based retrovirus vector to determine the nature and rate of mutations within runs of 10 to 12 identical nucleotides during a single replication cycle. Clones of helper cells containing integrated copies of retroviral vectors were used to produce virus for infection of target (nonhelper) cells. Proviral sequences from target cell clones were compared with proviral sequences from helper cell clones to study mutations that occurred during a single cycle of replication. In addition to the internal region spanning the homo-oligomeric inserts, a naturally occurring run of 10 T's in the long terminal …

Update - March 1994, Loma Linda University Center For Christian Bioethics

Update

In this issue:

-- The Human Genome Project: A Molecular Approach to Defining Humanity
-- Some Legal Ramifications for Newborns
-- Ethical and Legal Ramifications of Predictive Genetic Information
-- Graduate program combines biomedical and clinical ethics

The Amino-Terminal Functions Of The Simian Virus 40 Large T Antigen Are Required To Overcome Wild-Type P53-Mediated Growth Arrest Of Cells., Robin S. Quartin, Charles N. Cole, James M. Pipas, Arnold J. Levine

Dartmouth Scholarship

High levels of the p53 tumor suppressor protein can block progression through the cell cycle. A model system for the study of the mechanism of action of wild-type p53 is a cell line (T64-7B) derived from rat embryo fibroblasts transformed by activated ras and a temperature-sensitive murine p53 gene. At 37 to 39 degrees C, the murine p53 protein is in a mutant conformation and the cells actively divide, whereas at 32 degrees C, the protein has a wild-type conformation and the cells arrest in the G1 phase of the cell cycle. Wild-type simian virus 40 large T antigen and …

Cd40 Ligand Expression Is Defective In A Subset Of Patients With Common Variable Immunodeficiency., Mary Farrington, Laura S. Grosmaire, Shigeaki Nonoyama, Susanna H. Fischer, Diane Hollenbaugh, Jeffrey A. Ledbetter, R. J. Noelle

Dartmouth Scholarship

Common variable immunodeficiency (CVI) is characterized by hypogammaglobulinemia and recurrent bacterial infections due to failure of CVI B cells to differentiate in vivo into immunoglobulin-secreting plasma cells. We hypothesized that T-cell dysfunction resulting in abnormal contact-mediated B-cell activation may play a prominent role in the failure of CVI B cells to produce specific antibody. We have previously shown that B-cell proliferation and IgE production after stimulation with anti-CD40 and interleukin (IL) 4 were normal in 22 CVI patients evaluated, indicating that CVI B cells respond to signals delivered via CD40. Here we report that CD40 ligand (gp39) mRNA expression by …

Control Of Cationic Amino Acid Transport And Retroviral Receptor Functions In A Membrane Protein Family, Michael Kavanaugh, Hao Wang, Zheng Zhang, Weibin Zhang, Yan-Na Wu, Esther Dechant, R. Alan North, David Kabat

Biomedical and Pharmaceutical Sciences Faculty Publications

A partial cDNA sequence indicated that the T lymphocyte early-activation gene (Tea) encodes a protein related to the dual-function ecotropic retrovirus receptor/cationic amino acid transporter (ecoR/CAT1), and RNA blots suggested highest Tea expression in T lymphocytes and liver (MacLeod, C.L., Finley, K., Kakuda, D. Kozad, C.A., and Wilkinson, M.F. (1990) Mol. Cell. Biol. 7, 3663-3674). The sequence of full-length Tea cDNA from liver (3683 bases) predicts a 657-amino-acid protein (CAT2 alpha) with 12-14 transmembrane domains. A long (515 base) region with six initiation codons and termination codons precedes the translation start codon. The liver Tea cDNA is identical to Tea …

Functional Expression Of Two Glucose Transporter Isoforms From The Parasitic Protozoan Leishmania Enriettii, Chris K. Langford, Brian M. Little, Michael Kavanaugh, Scott M. Landfear

Biomedical and Pharmaceutical Sciences Faculty Publications

The parasitic protozoan Leishmania enriettii contains a family of tandemly repeated genes, designated Pro-1, that encode proteins with significant sequence similarity to mammalian facilitative glucose transporters. Pro-1 mRNAs are expressed almost exclusively in the promastigote or insect stage of the parasite life cycle. The Pro-1 tandem repeat encodes two isoforms of the putative transporter, iso-1 and iso-2, which have identical predicted amino acid sequences except for their NH2-terminal hydrophilic domains. We have now expressed both iso-1 and iso-2 by microinjecting their RNAs into Xenopus oocytes and assaying these oocytes for transport of various radiolabeled ligands. Both iso-1 and iso-2 transport …

Functional Comparisons Of Three Glutamate Transporter Subtypes Cloned From Human Motor Cortex, Jeffrey L. Arriza, Wendy A. Fairman, Jacques I. Wadiche, Geoffrey H. Murdoch, Michael Kavanaugh, Susan G. Amara

Biomedical and Pharmaceutical Sciences Faculty Publications

Reuptake plays an important role in regulating synaptic and extracellular concentrations of glutamate. Three glutamate transporters expressed in human motor cortex, termed EAAT1, EAAT2, and EAAT3 (for excitatory amino acid transporter), have been characterized by their molecular cloning and functional expression. Each EAAT subtype mRNA was found in all human brain regions analyzed. The most prominent regional variation in message content was in cerebellum where EAAT1 expression predominated. EAAT1 and EAAT3 mRNAs were also expressed in various non- nervous tissues, whereas expression of EAAT2 was largely restricted to brain. The kinetic parameters and pharmacological characteristics of transport mediated by each …

Accessing Genomic Information For Nonmedical Purposes, George P. Smith Ii

Scholarly Articles

No abstract provided.

Genetic Determinism Or Genetic Discrimination, George P. Smith Ii

Scholarly Articles

The first part of this essay evaluates the contemporary focus of the genetic revolution seen as such through the Human Genome Initiative - a project which brings not only great hope for new advancements of genetic knowledge designed to control disease and minimize human suffering, but raises real fears of unabated invasions of personal privacy that in turn would lead to discrimination for those found to be genetically handicapped. The extent to which this central fear is justified or rational is justified within the present context of the Genome Initiative, together with the past practices of genetic screening, will then …

Enhanced Immunogenicity Of Protein-Dextran Conjugates: I. Rapid Stimulation Of Enhanced Antibody Responses To Poorly Immunogenic Molecules, Andrew Lees, Fred Finkelman, John K. Inman, Kim Witherspoon, Penny Johnson, Jasiri Kennedy, James J. Mond

Microbiology, Immunology, and Molecular Genetics Faculty Publications

In view of our observation that anti-immunoglobulin antibody conjugated to high-molecular-weight dextran stimulates high levels of B-cell activation (Brunswick et al. J. Immunol . 1989, 143, 1239), we coupled T cell-dependent antigens to dextran. When mice were immunized, in the absence of adjuvant, with a BSA-dextran conjugate (BSA-dex), a persistent, high-titre anti-BSA IgG1 response was induced. Titres were dose-dependent and seen with as little as 10 I~g of conjugated protein. Anti-BSA titres were detected as early as day 7, usually peaked at about day 14 and persisted for at least 4 weeks. Anti-hapten antibodies were also elicited in mice that …