CYSTEINE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Cysteine: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00327-9 1. Cysteine-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on cysteine. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CYSTEINE .................................................................................................. 3 Overview........................................................................................................................................ 3 Federally Funded Research on Cysteine......................................................................................... 3 E-Journals: PubMed Central ....................................................................................................... 61 The National Library of Medicine: PubMed ................................................................................ 66 CHAPTER 2. NUTRITION AND CYSTEINE....................................................................................... 115 Overview.................................................................................................................................... 115 Finding Nutrition Studies on Cysteine ..................................................................................... 115 Federal Resources on Nutrition ................................................................................................. 117 Additional Web Resources ......................................................................................................... 117 CHAPTER 3. ALTERNATIVE MEDICINE AND CYSTEINE ................................................................ 123 Overview.................................................................................................................................... 123 National Center for Complementary and Alternative Medicine................................................ 123 Additional Web Resources ......................................................................................................... 134 General References ..................................................................................................................... 143 CHAPTER 4. DISSERTATIONS ON CYSTEINE .................................................................................. 145 Overview.................................................................................................................................... 145 Dissertations on Cysteine .......................................................................................................... 145 Keeping Current ........................................................................................................................ 147 CHAPTER 5. PATENTS ON CYSTEINE ............................................................................................. 149 Overview.................................................................................................................................... 149 Patents on Cysteine.................................................................................................................... 149 Patent Applications on Cysteine................................................................................................ 174 Keeping Current ........................................................................................................................ 199 CHAPTER 6. BOOKS ON CYSTEINE ................................................................................................. 201 Overview.................................................................................................................................... 201 Book Summaries: Federal Agencies............................................................................................ 201 Book Summaries: Online Booksellers......................................................................................... 202 CHAPTER 7. PERIODICALS AND NEWS ON CYSTEINE ................................................................... 203 Overview.................................................................................................................................... 203 News Services and Press Releases.............................................................................................. 203 Academic Periodicals covering Cysteine.................................................................................... 204 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 207 Overview.................................................................................................................................... 207 U.S. Pharmacopeia..................................................................................................................... 207 Commercial Databases ............................................................................................................... 208 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 211 Overview.................................................................................................................................... 211 NIH Guidelines.......................................................................................................................... 211 NIH Databases........................................................................................................................... 213 Other Commercial Databases..................................................................................................... 215 APPENDIX B. PATIENT RESOURCES ............................................................................................... 217 Overview.................................................................................................................................... 217 Patient Guideline Sources.......................................................................................................... 217 Finding Associations.................................................................................................................. 219 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 221 Overview.................................................................................................................................... 221 Preparation................................................................................................................................. 221 Finding a Local Medical Library................................................................................................ 221 Medical Libraries in the U.S. and Canada ................................................................................. 221
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ONLINE GLOSSARIES................................................................................................................ 227 Online Dictionary Directories ................................................................................................... 227 CYSTEINE DICTIONARY ........................................................................................................... 229 INDEX .............................................................................................................................................. 321
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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with cysteine is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about cysteine, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to cysteine, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on cysteine. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to cysteine, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on cysteine. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON CYSTEINE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on cysteine.
Federally Funded Research on Cysteine The U.S. Government supports a variety of research studies relating to cysteine. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to cysteine. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore cysteine. The following is typical of the type of information found when searching the CRISP database for cysteine: •
Project Title: AGONIST-DRIVEN CONFORMATIONAL CHANGES IN NACHRS Principal Investigator & Institution: Rosenberg, Robert L.; Professor; Pharmacology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2004; Project Start 15-MAY-2004; Project End 31-MAR-2009
2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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Summary: (provided by applicant): Understanding the molecular mechanisms of agonist binding and agonist-dependent conformational changes during activation of neuronal nicotinic acetylcholine receptors (nAChRs) is essential for our understanding nicotine addiction, certain forms of epilepsy, Alzheimer's disease, and other neurological disorders. The research in this proposal focuses on alpha7 neuronal nAChRs because they are important in modulating neurotransmitter release. Specific residues that are important for ligand binding have been identified and characterized, but the conformational changes that couple agonist binding to channel gating are unclear. We use a homology model of the alpha7 receptors based on the crystal structure of the ACh Binding Protein to identify amino acids that may play important roles in agonist- or antagonist-dependent conformational changes. The specific goals of this research are to: (1) test the hypothesis that agonist binding causes a contraction or partial collapse of the ligand-binding pocket; (2) test the hypothesis that the beta9-beta10 hairpin structure, connecting the ligand-binding pocket to the transmembrane pore domain, undergoes conformational changes following the binding of agonists; and (3) determine whether lateral movement of the beta9-beta10 hairpin and/or rotational movements of subunits participate in agonist-driven activation. Several complementary experimental approaches will be employed. We will express alpha7 receptors in Xenopus oocytes and use electrophysiological approaches to probe functional properties. We will use the substituted cysteine accessibility method to identify residues that change accessibility during ligand binding. In addition, we will introduce electrostatic constraints and form disulfides or cysteine cross-links in (and near) the beta9-beta10 hairpin to limit movement and alter receptor activation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALDO/KETO REDUCTASES AND DIABETIC COMPLICATIONS Principal Investigator & Institution: Gabbay, Kenneth H.; Professor of Pediatrics and Molecular &; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 01-JUN-1995; Project End 31-JUL-2004 Summary: (Adapted from applicant's abstract): Aldose and aldehyde reductase are closely related members of the aldo-keto reductase superfamily. Aldose reductase is implicated in the pathogenesis of diabetic cataracts, retinopathy, neuropathy and nephropathy. Aldose reductase inhibitors, proposed for the prevention and therapy of those diabetic complications, are not specific and inhibit both enzymes as well as other members of the superfamily. The objectives of this proposal are to compare the atomic structure and the catalytic and inhibitory mechanisms of these two enzymes so as to obtain a better understanding of the enzymatic mechanism(s) in order to rationally develop highly specific inhibitors unique to each enzyme, as well as to better understand the normal operation of aldose reductase in the whole organism. It is proposed to: (1) investigate the joint role of the NADP-binding and C-terminal loops of aldose reductase in the regulation of catalysis and co-factor exchange, and particularly, the potential role of cysteine 298 in the thiol-mediated regulation of the enzyme; (2) determine the mechanism, structure, and inhibition of human aldehyde reductase in comparison to aldose reductase; (3) use the kinetic and crystallographic information obtained to design specific inhibitors for aldose and aldehyde reductase, respectively, using organic solvent mapping of enzyme surface, proprietary peptidomimetic compounds and knowledge of the mechanistic pathway; and (4) determine the basis for the significant decrease in activity of murine recombinant wild-type aldose reductase in preparation for future testing of the role of aldose reductase in diabetic retinopathy and other complications by introduction of appropriate mutations into the mouse germ-line.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALS, SOD AND PEROXYNITRITE Principal Investigator & Institution: Beckman, Joseph S.; Professor & Director; None; Oregon State University Corvallis, or 973391086 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 31-JUL-2004 Summary: Over 60 different dominant missense mutations to the Cu, Zn superoxide dismutase gene are associated with motor neuron death in amyotrophic lateral sclerosis (ALS). The apparent gain-of-function conferred by these SOD mutations remains elusive. Four broad theories have been proposed to account for the gain-of-function: an amyloid effect due to aberrant protein folding unrelated to free radicals; toxicity due to reactions of SOD with hydrogen peroxide; the loss of zinc leading to altered redox reactions by SOD; and increased tyrosine nitration. Our preliminary data suggests that zinc-deficient SOD causes increased tyrosine nitration and apoptosis in motor neurons. In the present application, we propose to test these four general theories utilizing new lines of ALS- SOD transgenic mice where mutant ALS SOD expression is controlled by a tetracycline- inducible promoter. The inducible expression will allow us to determine how long expression of mutant SOD is necessary to induce motor neuron death and whether down regulating expression of ALS SOD allows motor neurons to be rescued. Other transgenic lines expressing ALS-SODs with additional mutations to eliminate zinc and copper binding will be made to determine the roles of these metals in the development of motor neuron disease. We have developed novel assays to measure formation of hydrogen peroxide, accumulation of zinc-deficient SOD and tyrosine nitration in vivo, which will be used to determine whether expression of these mutant SODs affects these factors as mice develop disease. From in vitro expression experiments, we have discovered that one cysteine residue renders the ALS-SOD mutant proteins vulnerable to aggregation. We will determine whether mutation of this cysteine residue increases or decreases the toxicity of ALS-SODs in transgenic mice and how it affects intracellular aggregation. These experiments will critically test the contributions of protein aggregation, metal ions and oxidative stress in SOD-induced degeneration of motor neurons in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: APOLIPOPROTEIN LIPOPROTEIN
A-I
STRUCTURE
IN
HIGH
DENSITY
Principal Investigator & Institution: Davidson, W. Sean.; Associate Professor; Pathology and Lab Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): High density lipoprotein (HDL) and its major protein constituent, apolipoprotein (apo)A-I, may play critical roles in the prevention of cholesterol accumulation in blood vessels that can lead to human cardiovascular disease, which claims nearly a million lives per year in the United States. Unfortunately, relatively little is known about the molecular basis for the cardio-protective effects of HDL. A prominent obstacle in the way of a detailed understanding of these effects is the lack of information on the structure of apoA-I in HDL. We propose to test the hypothesis that the structure of apoA-I in spherical human plasma HDL particles is related to that in the simplest discoidal particles that can be created in vitro. The approach will be to take advantage of the geometric constraints inherent to the edge of reconstituted discoidal MDL particles to generate a highly detailed model of apoA-I
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organization on these particles. Using this structure as a benchmark, changes in spatial relationships between regions of apoA-I will then be monitored as the complexity of the particles is systematically increased from discs, to well-defined reconstituted spherical particles, and finally to isolated human HDL particles. Two complementary approaches will be used to monitor the distance parameters within and between apoA-I molecules on the particles. These are: A) the use of a comprehensive battery of tryptophan and cysteine mutants of apoA-I to study fluorescence energy transfer, and B) the application of a novel mass spectrometry/peptide mapping technique that takes advantage of reversible thiol cross-linkers to determine the proximity of various regions of apoA-I in lipoproteins. These methods will be used to generate a detailed "proximity map" of HDL-bound apoA-I in different particle morphologies. This information will provide a basis for highly targeted mutagenesis strategies resulting in apoA-I variants that can be used in vivo to dissect out the cardio-protective functions of apoA-I. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APOPTOSIS AND NECROSIS IN PANCREATITIS Principal Investigator & Institution: Gukovskaya, Anna S.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Inflammation and parenchymal tissue damage are hallmarks of pancreatitis. In particular, severe necrosis is a major complication of the disease. Over the past decade, significant progress has been achieved in understanding the mechanisms of the inflammatory response of pancreatitis. In contrast, very little is known about the mechanisms of pancreatic acinar cell death. Mechanisms of necrosis are largely unknown. Key signals mediating apoptosis have been established; however, their roles in disease processes remain obscure, and they have not been investigated in pancreatitis. The role of cell death pathways in pathologic trypsin activation, an important marker of tissue damage in pancreatitis, has not been explored. Our preliminary data indicate that key necrotic and apoptotic mechanisms: poly (ADPribose) polymerase (PARP), mitochondrial dysfunction, caspases (specific cysteine proteases), and the transcription factor NFkappaB are activated in experimental models of pancreatitis and in pancreatic acinar cells stimulated with cholecystokinin (CCK). For the present application, we hypothesize that in pancreatitis, necrotic and apoptotic signaling pathways are interrelated. Activation of PARP and mitochondrial deenergization leads to ATP depletion and necrosis. On the other hand, effector caspases mediate apoptosis and limit necrosis by inactivating PARP and trypsin. NFkappaB negatively regulates effector caspases and, thus plays an anti-apoptotic role in pancreatitis. Thus PARP, mitochondrial dysfunction, caspases, and NFkappaB play central roles in determining the balance between apoptotic versus necrotic type of acinar cell death and the severity of pancreatitis. We propose the following specific objectives for the present application: 1). Determine the role of PARP in necrosis and apoptosis in experimental pancreatitis and in vitro, in pancreatic acini stimulated with CCK. 2). Determine the role of mitochondrial dysfunction in necrosis and apoptosis in experimental pancreatitis and in vitro, in pancreatic acini stimulated with CCK. 3) Determine the role of caspases in necrosis, apoptosis, and trypsin activation in experimental pancreatitis and in vitro, in pancreatic acini stimulated with CCK. 4). Determine the role of NFkappaB in necrosis and apoptosis in experimental pancreatitis and in vitro, in pancreatic acini stimulated with CCK. Measurements to achieve these goals will include measures of pancreatitis, morphologic characterization of apoptosis and necrosis, intrapancreatic activation of caspases and trypsin, cytochrome c release,
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mitochondrial membrane potential, ATP levels, and NFkappaB activation by using Western blot and gel shift analyses, enzymatic and fluorimetric assays. The result of the experiments in the proposed specific objectives will be delineation of key molecular mechanisms regulating necrosis and apoptosis in acute pancreatitis, which will lead to novel therapeutic strategies to treat the disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APOPTOSIS IN SHIGELLA INFECTIONS Principal Investigator & Institution: Basilico, Claudio; Professor and Chairman; Microbiology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2004; Project Start 01-MAR-1996; Project End 31-MAY-2005 Summary: Shigellae are the etiological agents of bacillary dysentery, a severe form of diarrhea that is often fatal in infants. Shigellosis is an acute inflammatory disease. Here we propose to investigate the role of apoptosis in the initiation of inflammation. We have demonstrated that Shigella induces apoptosis in macrophages in vitro and in vivo. Shigella first invades cells and then escapes from the phagocytic vacuole into the cytoplasm. In the cytoplasm, Shigella secretes the plasmid-encoded virulence factor Invasion Plasmid Antigen (Ipa) B which is necessary to induce cell death. IpaB binds to caspase (Casp)-1, a host cysteine protease that is required for Shigella induced apoptosis. Apoptosis mediated by Casp-1 appears to be pro- inflammatory in Shigella infections, since Casp-1 proteolytically activates the cytokines pro-Interleukin (IL)-1beta and pro-IL-18. Macrophages infected with Shigella release mature IL-1beta and IL-18. Furthermore, casp-1 knock-out mice do not mount an acute inflammation in response to Shigella infection. In vivo, some apoptotic cells are localized to regions of the lymphoid follicle where Shigella is not detectable. This difference in distribution suggested that Shigella possesses a second cytotoxic molecule, not IpaB, that can diffuse within infected tissue. We identified the novel diffusible cytotoxic activity in Shigella culture supernatants as Bacterial Lipoproteins (BLP). We also demonstrated that BLP activates both apoptosis and the host cell transcription factor Nuclear Factor - kappa B (NFkappaB) through the Toll Like Receptor (TLR)2. In this application we propose to further understand the significance of apoptosis in Shigella infections. More specifically we will determine: (1) the role of Casp-1 activated cytokines in acute inflammation and whether apoptosis is required for the release of mature IL-1beta and IL-18 and (2) the signal transduction pathway activated by TLR2 after treatment with BLP and the role of BLP and TLR2 in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BCR-ABL-MEDIATED INHIBITORS OF APOPTOSIS Principal Investigator & Institution: Deming, Paula B.; Pharmacology and Cancer Biology; Duke University Durham, Nc 27710 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): The BCR-Abl oncoprotein is directly linked to the pathogenesis of chronic myeloid leukemia and a subset of acute lymphocytic leukemias. BCR-Abl promotes tumorigenesis by increasing cellular proliferation and inhibiting cell death (apoptosis). However, the mechanism by which BCR-Abl prevents apoptosis remains largely unknown. In response to DNA damage, apoptotic signaling pathways converge on the mitochondria to release cytochrome c into the cytosol where it binds to a proapoptotic regulator, Apaf1. The cytochrome c/Apaf1 complex recruits and
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activates the cysteine protease caspase 9 to form an active proteolytic complex known as the apoptosome. Although BCR-Abl has been shown to exert its anti-apoptotic effects by preventing cytochrome c release, addition of purified BCR-Abl to an in vitro apoptosis system inhibited caspase activity after mitochondrial release of cytochrome c. Furthermore, caspase activity was inhibited when cytochrome c was added to lysates from BCR-Abl-expressing mammalian cells. Therefore, it is hypothesized that BCR-Abl directly modulates the apoptosome to inhibit apoptosis. The goal of this proposal is to elucidate the mechanism by which BCR-Abl inhibits the apoptosome to block cell death. The results from this study will reveal new apoptotic regulators that can eventually be targeted to sensitize resistant cells to chemotherapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BENZENE METABOLITES AND HEMATOTOXICITY Principal Investigator & Institution: Monks, Terrence J.; Professor and Chair; Div/Pharmoacology & Toxicology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: (Adapted from applicant's abstract): Benzene, a major industrial chemical and environmental pollutant, causes a variety of hematological disorders in man, including aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia. While it is clear that benzene must be metabolized to cause its acute hematotoxic effects, no single metabolite of benzene reproduces these effects in vivo. Coadministration of hydroquinone (HQ) and phenol (PHE), however, does lead to bone marrow suppression in rodents. A pharmacokinetic interaction between these two benzene metabolites results in increased concentrations of both metabolites in bone marrow. Peroxidase and/or phenoxy-radical mediated oxidation of HQ then initiates redox cycling and formation of the reactive electrophile, 1,4-benzoquinone, which is considered the ultimate hematotoxic metabolite of benzene. However, 1,4-benzoquinone readily undergoes glutathione (GSH) conjugation to form 2-(glutathion-Syl)hydroquinone, 2,5-bis-(glutathion-S-yl)hydroquinone, 2,6-bis-(glutathion-Syl)hydroquinone, and 2,3,5-tris-(glutathion-S-yl)hydroquinone. Preliminary data indicate that these GSH conjugates are present in the bone marrow of rats and mice following coadministration of hydroquinone and phenol. Moreover, the majority of HQGSH conjugates present in bone marrow are formed in situ and are metabolized to more reactive thiol conjugates via a previously unidentified mercapturic acid pathway. Because these quinol-thioether metabolites have enhanced capability to both redox cycle and arylate tissue macromolecules, we hypothesize that quinol-thioether metabolites contribute to benzene-mediated hematotoxicity and that the mechanism(s) likely involve the production of reactive oxygen species and/or interaction with proteins that specifically recognize GSH/cysteine and GSH/cysteine containing molecules. Such metabolite specific interactions interfere with growth- and differentiation-related signaling. We therefore propose to (i) assess the acute hematotoxicity of HQ-GSH conjugates in rodent hematopoietic tissue, (ii) determine changes in the production and/or function of hematopoietic growth factors in response to HQ-GSH conjugates, (iii) test the hypothesis that metabolite-induced changes in gamma-glutamyl transpeptidase activity (GGT), dipeptidase activity, cysteine transport, and GSH concentrations, precipitate sphingolipid turnover, the generation of ceramide and the induction of apoptosis, and (iv) test the hypothesis that specific proteins involved in the synthesis (GST), transport (GS-X pump), and metabolism (GGT, dipeptidases) of the peptidyl leukotrienes are targets of HQ-GSH conjugates and interfere with granulocytic
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cell differentiation. Because benzene reduces the number of myeloid stem cells in bone marrow and induces incomplete granulocytic differentiation, our studies will provide a comprehensive understanding of the mechanisms by which reactive polyphenolic metabolites of benzene cause perturbations in growth- and differentiation-related signaling and how such changes culminate in benzene-mediated hematotoxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOMOLECULAR INTERACTIONS AND ENZYMATIC PROCESSES Principal Investigator & Institution: Gao, Jiali; Professor; Chemistry; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2004; Project Start 30-SEP-1992; Project End 31-MAR-2008 Summary: (provided by applicant): A multi-faceted research project is directly aimed at computational studies of enzymatic processes in aqueous solution. The theoretical approach centers on molecular dynamics simulations of enzymatic systems using combined quantum mechanical and molecular mechanical (QM/MM) methods. To achieve greater accuracy, we propose to further develop a mixed molecular orbitalvalence bond (MOVB) method for simulation of enzyme reactions and sampling of the reaction pathway. In addition, we plan to implement a semi-empirical density functional theory for combined QM/MM calculations, which will significantly expand the scope of QM/MM applications to enzymatic systems, including metailoenzymes. A major thrust is to provide a deeper understanding of the remarkable catalytic power of enzymes. Our approach is to seek general catalytic principles, by examining individual enzymatic systems that share common features, but have different biological functions. In particular, the hydrolytic cysteine protease, human cathepsin K, and alanine and glutamate racemases, will be investigated in detail to understand substrate binding, reaction mechanism, and free energy profiles. Inhibitors of cathepsin K can reduce bone resorption, providing a promising therapeutic target for the treatment of osteoporosis and rheumatoid arthritis, while amino acid racemases are essential in the synthesis of the peptidoglycan layer of bacteria cell walls, rendering them attractive targets for inhibitors. The proposed computational study will provide insight into the mechanism of acid/base catalysis of these two important classes of enzymes. In addition, the dynamic conformational changes in thymidylate synthase (TS), that take place throughout the many-steps of the enzymatic reaction, will be studied. TS catalyzes the de novo synthesis of dTMP nucleotide for DNA synthesis, which has been extensively investigated experimentally. The proposed study will provide a deeper understanding of the roles of protein dynamic conformation change in the function of thymidylate synthase, and the results will be of general importance in enzyme catalysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOPTERIN, CATECHOLAMINES, & NO IN REGULATING APOPTOSIS Principal Investigator & Institution: Levine, Robert A.; Professor; Neurology; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp-046 Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 28-APR-2000; Project End 31-MAR-2004 Summary: (Verbatim from the Applicant's Abstract) Dopamine neurons in the substantia nigra die prematurely in Parkinson's disease, and apoptotic death has been detected postmortem. The cause of apoptosis is unknown. Two prominent, yet unsubstantiated hypotheses are that apoptosis is mediated by oxidative stress or
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inappropriate reentry into the cell cycle; both conditions may be initiated by insufficient neurotrophic support from striatal target cells. We will address this knowledge gap by studying mechanisms underlying apoptosis in cultured catecholamine cells, where conditions can me more tightly controlled than in animals. Cells to be studied include pheochromocytoma (PC12), sympathetic neurons, and fetal nigral neurons. These models have in vivo relevance, since apoptotic death of nigral dopamine neurons during development may be due to insufficient trophic support from striatal target cells; this mechanism has been suggested as a causal cell death factor in Parkinson's disease. Tetrahydrobiopterin (BH4) is an essential regulatory cofactor for tyrosine hydroxylase and nitric oxide (NO) synthase in the synthesis of catecholamines and NO, which will not occur if BH4 is lacking. Catecholamine cells contain among the highest concentrations of BH4. The metabolism of BH4, catecholamines, and NO can generate damaging reactive oxygen species (ROS). Our preliminary data shows that apoptotic death of differentiated neuron-like PC12 cells during nerve growth factor withdrawal is directly proportional to the intracellular level of BH4. Thus, we hypothesize that the endogenous level of BH4 supports catecholamine cell functions under normal conditions and promotes apoptotic death when trophic support is withdrawn. Our working hypothesis and specific aim is: Intracellular BH4 mediates apoptosis and death of catecholamine cells deprived of trophic support. While the complex processes of apoptosis occur in many cell types, we will focus on catecholamine cells and the direct and indirect interactions of BH4 with pivotal mediators of apoptosis of these cells during insufficient trophic support. These mediators include oxidative stress, oncogenes that can initiate fatal reentry into the cell cycle, and critical cysteine proteases (caspases) mediating apoptosis. Our studies will identify the mechanism of BH4 involvement in apoptosis by testing for: 1) elevation of ROS and the source (BH4, catecholamines, or NO); 2) altered expression of the apoptotic-mediating oncogenes, pS3, c-myc, and the bc1-2 family (bax, bak, bc1-2, bcl-xl), and 3) activation of caspases 2,3, and 9. Apoptosis will be monitored by: a) number of living and dead cells; and b) fluorescent quantitation of cells at different stages of apoptosis. These studies may will reveal novel apoptotic regulatory mechanisms and provide new avenues for therapeutic approaches to promote neuronal survival and prevent debilitating neurological diseases, such as Parkinson's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARDIAC SIGNIFICANCE
MYOCYTE
APOPTOSIS--MECHANISM
AND
Principal Investigator & Institution: Kitsis, Richard N.; Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: Numerous studies have demonstrated myocyte apoptosis during myocardial infarction, ischemia-reperfusion injury, and chronic heart failure. Despite these observations, the two most critical questions in the field remain unexplored: 1) What is the precise molecular mechanism of apoptosis in cardiac myocytes? 2) To what extent does myocyte apoptosis contribute to myocardial dysfunction in these disease states? The research program described herein addresses both of these interrelated questions. To facilitate a molecular genetic analysis, models of myocardial infarction and ischemiareperfusion injury have been developed and characterized in the mouse. Using genetically altered mice, we have tested the necessity of proteins that mediate apoptosis in non-cardiac contexts for apoptosis during myocardial infarction. These studies have shown that one such protein, p53, while present in ischemic cardiac myocytes and
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sufficient to induce apoptosis in these cells, is not required for myocyte apoptosis. This result suggests that the apoptotic program in complex pathophysiologic states can be activated by multiple, redundant signaling pathways. In contrast, the caspases, a family of cysteine proteases, are components of the final common pathway for apoptosis in all metazoan cells from worm to mammal. Indeed we have shown that pharmacologic blockade of these enzymes markedly inhibits myocyte apoptosis during myocardial infarction in vivo. The potential significance of this result is two-fold: First, caspase inhibition may provide a direct means to determine the contribution of myocyte apoptosis to myocardial dysfunction. Second, caspase inhibition may provide a new therapeutic approach to ischemic heart disease and heart failure. We now propose to deepen our understanding of the mechanism and significance of cardiac myocyte apoptosis through the following specific aims: 1. To determine which caspases are expressed in adult cardiac myocytes and undergo proteolytic activation during myocardial infarction and ischemia-reperfusion injury. 2. To block myocyte apoptosis in these ischemic syndromes using caspase inhibition. Complementary pharmacologic (peptide pseudosubstrates) and transgenic (overexpression of a dominant caspase inhibitor) approaches will be employed. 3. To determine the contribution of apoptosis to changes in myocardial structure and function during and after infarction and ischemiareperfusion injury. Using caspase inhibition, the contribution of myocyte apoptosis to infarct size, ventricular remodeling, and contractile dysfunction will be determined. These studies will increase our understanding of the mechanism of cardiac myocyte apoptosis and its role in the pathogenesis of ischemic heart disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARDIAC NA+ CHANNEL:MOLECULAR BASIS OF PERMEATION Principal Investigator & Institution: Tomaselli, Gordon F.; Associate Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-JUL-1994; Project End 31-MAR-2008 Summary: (provided by applicant): The Na channel is an integral membrane protein central to signaling in the heart and other excitable tissues. The pores of ion channels are principal determinants of ion selectivity, drug binding and gating. The determination of the crystal structure of an inwardly rectifying K channel was an important advance that provided a framework for testing hypotheses concerning the pore structure of related channels. Nevertheless, as such crystal structures have the important limitation that movement, a feature of the pore that is vitally important to channel function, is imperceptible. Thus, this proposal will emphasizes vital approaches to structurefunction analysis of the permeation pathway with an emphasis on understanding the role of the pore in fundamental mechanisms of channel gating. This proposal builds on the work from the prior period of support and will test the hypotheses that: 1. Motion in the outerpore mouth underlies slow forms of inactivation of the channel. We will use the complementary approaches of measuring the state-dependence of spontaneous and induced disulfide bond formation and fluorescence resonance energy transfer (FRET) in channels with paired cysteine substitutions in the outer pore. 2. The structure of the outer pore can be further refined by studying the blocking characteristics of muconotoxins. Paired mutations in the channel protein and toxin and the analytic techniques of mutant cycle analysis and electrostatic compliance will be used to estimate molecular distances between toxin and channel residues. 3. The cytoplasmic portions of the S6 segments of the channels form a part of the activation gate. Cysteine mutations in the S6 segments of all channel domains will be expressed on an inactivation-deficient channel background to determine the state-dependent accessibility to thiol-specific
12
Cysteine
modifying reagents, block by the group II metal ions, Cd 2+ and Zn 2+ and state dependent block by quarternary ammonium derivatives of local anesthetic antiarrhythmic drugs. 4. Calcium/calmodulin signaling regulates Na channel gating in a physiologically significant, isoform-specific manner. Using electrophysiological, biochemical and fluorescence measurements we will test the hypothesis that CaM is constitutively tethered to the channel has direct and indirect (through CaCaMKinase) effects on Na channel isoforms that modulate inactivation gating. Given the central role of the Na channel in normal physiology and disease (arrhythmias, myotonia and epilepsy) this proposal promises to further our understanding of permeation and gating, pathophysiological mechanisms of diseases of excitability and the mechanism of action of clinically useful drugs (antiarrhythmic percent local anesthetic percent and anticonvulsants). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CASPASE ACTIVATION IN APOPTOSIS Principal Investigator & Institution: Joshua-Tor, Leemor; Associate Professor; Cold Spring Harbor Laboratory 1 Bungtown Road Cold Spring Harbor, Ny 11724 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2007 Summary: (provided by applicant) Programmed cell death, or apoptosis, plays a crucial role throughout the life of all multicellular organisms. This mechanism allows for the controlled removal of cells during development in sculpturing the body, maintaining body structure and tissue size, and is also used for eliminating damaged or infected cells. Apoptosis has to be a tightly regulated process or else various abnormalities and diseases may arise from either too much or too little cell death. These include various developmental defects, neurodegenerative diseases, autoimmune diseases and cancer. Central to this process are a family of cysteine proteases called caspases. Their activation leads to the typical morphological changes that occur during apoptosis and thus their regulation is key for proper control of apoptosis. The objectives of this proposal is to provide the structural framework which will enable us to understand the mechanism by which caspases are activated from their inactive, zymogen form to a fully active enzyme, and how these relate to enzymatic activity and ultimately to cellular function. We will focus specifically on caspase-9 activation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMMUNITY
CATHEPSINS
IN
ANTIGEN
PRESENTATION
AND
LUNG
Principal Investigator & Institution: Riese, Richard J.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The immune response within the lung is critically dependent on antigen presentation by the major histocompatibility complex (MHC) class II and CD1 molecules. These antigen presentation pathways are critical effector mechanisms in asthma and host defense against infection. Endosomal cysteine proteases, including cathepsin S, play important roles in trafficking of both MHC class II and CD1d. Antigen presenting cells (APC) devoid of cathepsin activity do not degrade class II-associated invariant chain (Ii) resulting in accumulation of endosomal class II-Ii complexes. Interestingly, APC from cathepsin S-deficient mice also exhibit abnormal endosomal trafficking of CD1ld molecules, resulting in defective selection of NK1.1+T cells. These data implicate an interaction between the MHC class II and CD1d antigen
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presentation pathways, and suggest that cysteine proteases regulate components of both innate and adaptive immunity. The central hypothesis of the proposed studies is that regulation of cathepsin activity, particularly cathepsins S, L, and F, will control MHC class II- and CD1-restricted antigen presentation, T cell activation, and lung inflammation. To study this hypothesis three specific aims are advanced. The first aim addresses the hypothesis that different cysteine proteases control Ii proteolysis and MHC class II function in different APC. This hypothesis will be tested by analyzing Ii processing and class II-dependent antigen presentation in cathepsin-deficient APC, derived from a variety of tissues including the lung. The second aim will focus on examining the molecular basis for class II-CD1d interactions in cathepsin-deficient APC. We will address whether there is a direct class II-CD1d molecular association, or whether these interactions are solely the result of a generalized endosomal trafficking defect. The third aim is based on the premise that alteration of cathepsin activity can modulate lung immunity via effects on class II and CD1d function. These studies will use a mouse model of asthma, based on ovalbumin-induced pulmonary inflammation (Th2-type), and a mouse model of mycobacterium tuberculosis pulmonary infection (Th1-type). Together, these studies will probe the basic mechanisms by which cysteine proteases regulate immunity, and will determine whether inhibition of these enzymes can affect MHC class II- and CD1-dependent inflammatory responses within the lung. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTROL MODULATION
OF
RETROVIRUS
CNS
DISEASE
BY
REDOX
Principal Investigator & Institution: Wong, Paul K.; Professor; Carcinogenesis; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 18-JUN-2002; Project End 31-MAY-2006 Summary: The retrovirus tsl, a mutant of Moloney murine leukemia virus, like HIV infection in human, causes a progressive neuroimmunodegenerative (NID) syndrome in mice. Infection in the central nervous system by tsl results in neuronal loss with gliosis and spongiform lesions. Since glial cells but not neurons are infected with the virus, the neuropathogenic mechanism of tsl, like those of HIV, are most likely indirect. We previously demonstrated that accumulation of tsl precursor envelope proteins occurs in the endoplasmic reticulum (ER) of tsl infected astrocytes. This accumulation is accompanied by cell death in tsl-infected astrocytes. We also observed intracellular calcium accumulation and activation of NFkappaB in both astrocytes and neurons m the area of lesions in the CNS of tsl- infected mice. We therefore hypothesize that the excessive accumulation of tsl precursor envelope proteins in the astrocytic ER activates ER overload response resulting in excessive Ca2+ release that uncouples mitochondria causing release of toxic reactive oxygen species (ROS). In the CNS of tsl-infected mice there is a significant reduction of cysteine levels. A consequence of cysteine deficiency is the decrease in intracellular glutathione, which provides the major antioxidant defense in cells. This together with our recent finding that tsl decreases catalase levels in infected astrocytes and CNS suggests that the defense against oxidative stress in astrocytes and in the CNS is deficient. The oxidative damaged astrocytes may fail to support the developing neurons, and the release of ROS from astrocytes may also result in damage to neuronal membrane. Both of these effects could in turn result in neuronal death. Glutathione precursor N-acetyl cysteine, or peroxisome proliferator that activate production of catalase, have been shown to ameliorate both the tsl-induced astrocytic death in vitro and to prolong the latency period of tsl-induced neurodegeneration in vivo. Based on these preliminary observations we therefore propose here to: 1)
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Cysteine
Determine whether tsl induces thiol deficiency and oxidative damage in astrocytes in culture and in the CNS, 2) Elucidate the mechanisms underlying tsl-mediated thiol deficiency and redox stress in astrocytes and neurons in culture and in the CNS, and 3) Determine whether (a) NAC, (b) alpha-lipoic acid/dihydrolipoic acid, (c) peroxisome proliferators, such as PBA, that generate catalase, and (d) other antioxidants, e.g. Oxothiazolidine-4-carboxylate (OTC), either alone or in combination, can prevent or ameliorate tsl-induced astrocyte damage and neurodegeneration in the CNS. This project is focused on a well-characterized animal model. It addresses questions critical to our understanding of thiol deficiency and oxidative stress in retroviral-induced encephalopathy. It also provides a therapeutic rationale for controlling retroviralinduced neurodegeneration Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--CHEMICAL AND ANALYTICAL Principal Investigator & Institution: Ball, Louise M.; Professor and Director; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: The Chemistry and Analytical Core will provide support for the individual research projects. The Core consists of two components: the Synthesis Laboratory and the Mass Spectrometry Facility. The Synthesis Laboratory will be responsible for providing, on a continuing basis, specific compounds for which need has been established by the Program Projects. Compounds synthesized by the Core will be used as standards in quantitation, for in vitro formation of DNA and protein adducts for in vivo dosing protocols. The availability of standards multiply labeled with stable isotopes from the Synthesis Laboratory will crucial to the development of isotope dilution methods for ultra-trace analysis of metabolites and DNA and protein adducts by the Mass Spectrometry Facility. Specific classes of compounds for which synthetic needs have been established are: Project 1, tricyclic nucleobases, deoxynucleosides and deoxynucleotides; protein adducts of malondialdehyde and 4-hydroxynon-2-enal; cysteine contual basis for dosing protocols; Projects 3 and 8, S-phenyl-d5-cysteine and mercapturic acid; Project 4, fungal metabolites of PAH and Project 5, 13C-labeled PAH phenoles. Synthesis Laboratory will also be available for consultation on questions involving structural characterizations, and application of spectroscopic techniques to problems of quantitation and characterization. Other areas where Core expertise may be useful to Program Projects are in the application of structure-activity relationships to direct efforts in isolation and characterization of products of metabolism or nonenzymatic decay. The Core has access to 500 and 500 MHz NMR spectrometers with multinuclear and variable temperature capability. Core personnel are trained operators, proficient in all aspects of data acquisition, work-up and interpretation, and will fill the NMR needs of program projects. Additional techniques of physical characterization accessible through the Core are circular dichroism X-ray crystallography, EPR and FTIR. The Mass Spectrometry Facility will provide support for Program Projects when mass spectrometry requirements are beyond the capacity of equipment belonging to Program Projects or when extensive methods development is necessary. The Mass Spectrometry Facility performs characterization and ultra-trace analysis on a routine basis by a variety of mass spectrometric techniques, and is also involved in developmental work. Major objectives of the Mass Spectrometry Facility will be to develop on-line sample clean-up and analyte pre-concentration procedures and to apply HPLC/MS/MS techniques to characterization of DNA adducts, protein adducts and PAH metabolites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CYSTEINE DEVELOPMENT
PROTEASES
&
INHIBITORS
IN
15
NEMATODE
Principal Investigator & Institution: Lustigman, Sara; Member, Head of Laboratory; New York Blood Center 310 E 67Th St New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: (provided by the applicant): Onchocerciasis, or river blindness, is a major filarial disease and is the fifth most common cause of blindness in the world. Limitations of control programs and the possible emergence of ivermectin-resistant strains suggest the need for alternative strategies for treatment and control of Onchocerciasis. Currently, few suitable targets for chemotherapy have been precisely identified in filarial and other parasitic nematodes, due in part to a lack of understanding of the basic biology and biochemistry of these parasites. We propose to explore cysteine proteases as potential targets for chemotherapy. In our previous studies we identified a cysteine protease inhibitor, onchocystatin, and a cathepsin Z-like cysteine protease, and proposed that they are essential for molting, growth and remodeling of the cuticle in larvae and adult worms, and the development of microfilariae. Recently, a cathepsin LIike enzyme and another member of the cystatin family were cloned, suggesting that the role of cysteine proteases and their endogenous inhibitors is more elaborate than initially thought. However, these proteins cannot be easily studied in 0. volvulus in vivo as we lack a system for observing gene expression during the development of the parasite, particularly in its adult stages and in the gravid female worms. As many of the essential genes for nematode development are conserved in free-living and parasitic nematodes, we will take advantage of the existence of homologous proteins in C. elegansto understand the cellular processes by which the 0. volvuluscysteine proteases participate in the development of the 0. volvulusparasite in humans. The integrated approach of using genetic, molecular, biochemical and anatomical studies in this proposal, combined with a well-defined organism, will result in understanding how regulation of three distinct cysteine proteases is critical for the development and survival of C. elegansand 0. volvulus. The proposed project has three specific objectives: 1. To establish the distinct physiological roles for each cathepsin Z and cathepsin L-like cysteine protease during C. elegans development and then verify that the proposed 0. volvulushomologues will perform similar functions in 0. volvulus. 2. To compare and contrast the developmental regulation and tissue specificity of 0. volvulusand C. elegans cystatins. 3. To determine the substrate specificity of each 0. volvulusand C. elegans cysteine protease and identify their specific inhibitors in vitro. We will also determine which low molecular weight inhibitors could, eventually, be tested for their in vivoeffects on adult worm survival and microfilariae development. This will provide the basis for developing effective drugs, targeting cysteine proteases, to control onchocerciasis and filariasis in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CYSTEINE STRING PROTEINS: CELLULAR & MOLECULAR FUNCTION Principal Investigator & Institution: Umbach, Joy A.; Associate Professor; Molecular & Med Pharmacology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 27-JUL-1993; Project End 31-JUL-2005 Summary: This application has two long-range goals. The first is to advance our understanding of cellular and molecular functions of cysteine string proteins (csps).
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Cysteine
Csps are a family of proteins associated with secretory organelles in nerve cells and elsewhere. The second is to pursue recent findings which indicate that lithium (Li) ions modulate csp gene expression in vitro and in vivo. While the first goal entails basic investigations of the role of csps in secretion, the latter goal is likely to have moreimmediate clinical relevance. This is because Li, which is used in the management of bipolar-affective disorders, remains a mechanistic enigma. Thus, further study of the LIcsp link may afford insights into the therapeutic role of Li, as well as into the cause and improved treatment of bipolar syndromes. To approach these long-term goals, the current proposal has three specific aims: First, we will study regulatory, and functional/anatomical correlates of Li's effect on csp gene expression. These investigations will illuminate the signaling pathways that mediate this effect of Li, and also suggest whether Li is likely to modify the secretory behavior of discrete populations of neurons in the brain. Second, we propose to characterize further the secretory functions of a unique relative of csp. It is our hypothesis that this protein substitutes for csp in csp null mutant fruit flies. Using genetic, biochemical and physiological strategies, we plan to evaluate the role of this "csp substitute" in wild type and csp mutant Drosophila, as well as in vertebrates. Finally, we plan to exhibit calciumion independent regulated secretion of cortical granules. Perturbation of csp function in this system will afford insight into molecular contributions of csps to regulated secretion. Taken together, these aims constitute substantial progress toward resolving the role of csps in normal and pathological circumstances. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOPAMINE TRANSPORTER STRUCTURE-FUNCTION STUDIES Principal Investigator & Institution: Surratt, Christopher K.; Pharmacology and Toxicology; Duquesne University 600 Forbes Avenue Pittsburgh, Pa 15282 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): Cocaine initiates its euphoric effects in the brain by binding to the dopamine transporter (DAT), blocking uptake of synaptic dopamine. No specific DAT-ligand contacts have been identified to date, but it is widely held (owing to a previous report) that the DAT transmembrane (TM) 1 aspartic acid residue (D79) forms an ionic interaction with charged nitrogen atoms in both dopamine and cocaine that governs recognition of the ligand. Alternatively, the D79 residue may contribute to a ligand aromatic binding pocket, an ion permeation pore that influences ligand binding, or may simply form intramolecular contacts that retain DAT infrastructure. Toward the goal of elaborating on the nature of DAT substrate and inhibtor binding sites, it is critical to determine whether the "ion pair" model for DAT-ligand interactions is credible. The objective of this proposal is to address the validity of the ion pair model, while also assessing alternative potential contributions of the D79 residue to DAT structure and function. D79 DAT mutants that modify side chain size, charge or hydrogen bonding potential will be pharmacologically characterized with a diverse collection of DAT substrates and inhibitors. Other, cysteine-substituted, DAT mutants will test the accessibility of a given position in the DAT polypeptide to cysteine-specific alkylating agents, and whether such alkylation events influence DAT function. By measuring accessibility of an introduced DAT TM 1 (or vicinity) cysteine residue (variably located) in the presence and absence of substrates or inhibitors, the spatial relationship between D79 and DAT substrates and inhibitors will be explored. Because the TM 1 aspartate has been implicated as a contributor to the substrate permeation pore, the substituted cysteine accessibility method will also be used to elaborate on the secondary structure and cell membrane orientation of TM 1 in the vicinity of D79, for
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which there are multiple models. The proposed experiments should significantly enhance understanding of the TM 1 aspartate residue role in DAT function, as well as advance structure-function studies on the plasma membrane norepinephrine and serotonin transporters which share this residue. Clarification of the role of this residue in recognition of dopamine and cocaine may forward rational design of therapeutics that block cocaine action without significantly interfering with dopamine uptake. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOPAMINE TRANSPORTER--SUBSTRATE & COCAINE BINDING SITES Principal Investigator & Institution: Javitch, Jonathan A.; Associate Professor of Psychiatry and Ph; Psychiatry; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 20-FEB-1998; Project End 31-MAR-2003 Summary: (Applicant's Abstract): Dopamine reuptake at the plasma membrane by the dopamine transporter (DAT) is a major mechanism for terminating dopaminergic synaptic transmission. DAT and the related sodium- and chloride-coupled neurotransmitter transporters combine functional aspects of both G-protein-coupledreceptors and ion channels: namely binding sites for substrate, inhibitors, and ions, and a gated channel or transport pathway through which substrate and ions move. Binding of substrate, sodium and chloride mediates a conformational change which exposes the substrate and ions to the intracellular environment where they are released. Therefore, a water-accessible transport pathway must be formed among the membrane-spanning segments. This pathway should be accessible to hydrophilic reagents applied extracellularly. Although they may not be identical, the binding sites for substrate, ions and inhibitors, such as cocaine, likely lie, at least in part, within this transport pathway. We have developed an approach, the substituted-cysteine-accessibility method, to obtain information about the structure of binding sites and channels by systematically identifying the residues which line the site or channel. Our approach combines: sitedirected mutagenesis to replace putative membrane-spanning segment residues, one at a time, with cysteine; heterologous expression of the mutant; and probing the aqueous surface accessibility of the engineered cysteine residue by its ability to react with small, charged, hydrophilic, lipophobic, sulfhydryl-specific reagents. The long-term goals of this project are to determine the structural bases of the transport of substrate by DAT and its inhibition by drugs such as cocaine. The specific aims are: l) To identify the amino acid residues forming the surface of the cocaine binding site, the dopamine binding site, and the transport pathway in DAT. 2) To determine the secondary structure of the membrane-spanning segments containing these residues. 3) To identify conformational changes of the membrane-spanning segments associated with transport. The approach outlined in this proposal will enable us to create a low resolution structural model of DAT, thereby laying a foundation for understanding, at the molecular level, the binding and transport of dopamine and its inhibition by cocaine. This approach might lead to a differentiation of the binding sites for cocaine and for dopamine and thereby facilitate the development of cocaine antagonists which do not inhibit dopamine transport. Furthermore, the approach will provide insights into structure-function relationships for other members of the neurotransmitter transporter family, such as the serotonin transporter and norepinephrine transporter, which are targets for a wide variety of antidepressant drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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•
Cysteine
Project Title: EFFECT OF APOLIPOPROTEIN STRUCTURAL ADAPTABILITY Principal Investigator & Institution: Ryan, Robert O.; Research Scientist; Children's Hospital & Res Ctr at Oakland Research Center at Oakland Oakland, Ca 946091809 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: The long terms goal of this research is to elucidate the metabolic significance of exchangeable apolipoprotein structural alterations. Studies will focus on a key member of this protein class, human apolipoprotein E (apoE). While structural information is available for this protein in the absence of lipid, it is recognized that exchangeable apolipoproteins exert their biological effects only in a lipid-associated state. Evidence suggests these proteins undergo significant conformational changes) upon lipid binding. The N-terminal domain of apoE is organized as a bundle of elongated amphipathic alpha-helices. Models have been proposed which predict the helix bundle can open about a putative hinge domain located in the loop between helices. Such a conformational change would result in exposure of hydrophobic residues, making them available for interaction with lipoprotein surfaces. It is proposed that this conformational change is reversible and that helix boundaries present in the lipid-free conformation are maintained in the lipid associated state. The precise nature of lipid binding-induced conformational adaptations of apoE N-terminal domain will be determined. Structural information will be used to select candidate amino acid residues for site directed mutagenesis. Disulfide bond engineering and fluorescence resonance energy transfer will be performed to evaluate lipid binding-induced helix repositioning. Mutant proteins containing a single tryptophan and a single cysteine will be expressed in bacteria. Modification of cysteine with an appropriate chromophore provides an energy acceptor from excited tryptophan for distance measurements. Through judicious placement of energy donor/acceptor pairs in the molecule, it will be possible to construct a map of helix movements upon lipid binding. It is hypothesized that conformational opening of the N-terminal domain of human apoE represents a physiologically important mechanism for regulation of its receptor binding activity. Studies will be performed to characterize the correlation between lipid-associated full length apoE interactions with the low density lipoprotein receptor on cultured human skin fibroblasts and the conformational status of its N-terminal domain. The results obtained will provide new information about the physiological relevance of the conformational adaptability of exchangeable apolipoproteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FUNCTIONAL ANALYSIS OF AN RNA STRUCTURAL MOTIF Principal Investigator & Institution: Hou, Ya-Ming; Professor; Biochem & Molecular Pharmacol; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2006 Summary: (provided by applicant): Aminoacy-tRNA synthetases establish the genetic code through aminoacylation reactions that link specific amino acids to tRNAs that bear triplet anticodon sequences. The universal distribution of these enzymes across the phylogenetic tree suggests that they are among the oldest proteins to have developed specificity towards amino acids and tRNAs. The specificity of cysteinyl-tRNA synthetase (CysRS) is extraordinary- even the simple replacement of the thiol of the substrate cysteine with the hydroxyl of serine, or a single substitution in tRNA cys can cause reduction in activity of a million-fold or more. Although recent studies have provided major insights into the substrate specificity of CysRS, this is not sufficient to
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understand specificity in broader evolutionary terms. For example, recent studies have identified a CysRS embedded within the sequence framework of a prolyltRNA synthetase (ProRS) that has the ability to activate both proline and cysteine and catalyze aminoacylation of tRNA with proline and with cysteine. The dual-specificity ProRS has challenged the view of one synthetase for one amino acid and raised many fundamental questions about synthetase specificity. In addition, recognition of tRNAcys through indirect readout of structural features has been established for bacterial, but not eucaryotic, CysRS. Such an indirect readout can have major impact on our understanding of specificity well beyond that obtained from analysis of direct contacts in tRNA-synthetase interactions. The difference between the bacterial and eucaryotic recognition also provides the basis for developing species-specific inhibitors of aminoacylation. Further, emerging crystal structures of E. coli CysRS have now offered a novel opportunity to address the outstanding question of how this enzyme recognizes cysteine and discriminates against the closely similar serine without an editing mechanism. This investigation is timely and promises new insight into molecular medicine that targets disorders in amino acid metabolism. Three specific aims are proposed: (1) to study recognition of tRNAcys by the dual-specificity ProRS of the halophilic archaeon Halobacteriurn halobium, (2) to study the thermodynamic and structural contribution of indirect readout of tRNA structural motifs in aminoacylation, and (3) to study the molecular basis of the exquisite specificity of E. coli CysRS for its ability to distinguish cysteine from serine. These studies shall shed new light on the molecular interactions responsible for the accurate translation of the genetic code. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC MANIPULATION OF ENTAMOEBA VIRULENCE Principal Investigator & Institution: Reed, Sharon L.; Professor; Pathology; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-MAY-2006 Summary: (from the applicant's abstract): Cysteine proteinases are key virulence factors of E. histolytica and play a central role in tissue invasion and disruption of host defenses. We have shown that purified cysteine proteinases of E. histolytica degrade components of the extracellular matrix and cleave IgG, IgA, the C3 and C5 components of complement, and the anaphylatoxins, C3a and C5a, limiting the host response to amebic infection. E. histolytica and E. dispar are morphologically identical with highly homologous genomes including cysteine proteinase genes, but only E. histolytica can invade the host. We propose to test the hypothesis that surface and extracellular cysteine proteinases are critical for amebic invasion with the following Specific Aims: Aim 1: We will test the hypothesis that the cysteine proteinases, which are critical to invasion, differ in their location, release, or specificity for substrates. These studies will identify the major extracellular proteinases, express active, recombinant cysteine proteinases, and identify differences in specificity against peptide and physiological substrates. Aim 2: We will test the hypothesis that inhibition of the key cysteine proteinases will block invasion. These studies will compare the effect of specific peptide inhibitors, antisense constructs, and insertional proteinase mutants on invasion. Aim 3: We will test the hypothesis that complementation of cysteine proteinase expression in proteinase-deficient strains will restore virulence. We will use selectable expression vectors to over express specific cysteine proteinases in E. dispar and L6 to evaluate the effect on invasion. These studies should further our understanding of an important virulence factor of E. histolytica and establish the key cysteine proteinases, which are linked to invasion and could be targets of novel drug therapy in the future.
20
Cysteine
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GINGIPAIN R1 PEPTIDES FOR ORAL IMMUNIZATION Principal Investigator & Institution: Genco, Caroline A.; Professor; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Porphyromonas gingivalis is a well-established oral pathogen that produces substantial quantities of cysteine proteinase activity. These enzymes are essential for the growth and survival of P. gingivalis by providing a source of nutrients, interrupting host- defense mechanisms, and participating in the penetration and destruction of host connective tissue. The cysteine proteinases with specificity for arginine and lysinecontaining peptide bonds (gingipain R and gingipain K, respectively) have the potential to contribute directly to the inflammatory disease process through direct complement activation, C5a generation, and bradykinin release. We have demonstrated that the generation of a systemic immune response to gingipain R1 or a peptide derived from the N- terminus of the catalytic domain is effective in limiting both colonization and invasion of P. gingivalis in the mouse chamber model. In this study, we will examine the ability of peptides derived from gingipain R1 to generate a protective response in the mouse periodontitis model and we will evaluate the feasibility of using avirulent Salmonella typhimurium strains expressing these peptides to stimulate mucosal and systemic immune responses and to protect against periodontal destruction in this model. In Aim 1, we will examine the immunogenic potential of peptides derived from the catalytic and adhesin domains of gingipain R1 in the mouse periodontitis model. In Aim 2, we will examine the systemic and mucosal immune responses in mice orally immunized with avirulent S. typhimurium expressing gingipain R1 derived peptides fused to protein carriers. Responses obtained following oral immunization will be compared to responses obtained in mice immunized systemically with S. typhimurium expressing the same gingipain R1 derived peptide fusions. In Aim 3, we will examine the protection against P. gingivalis infection in the mouse periodontitis model following immunization with S. typhimurium expressing gingipain RI derived peptide fusions. The results of these studies will enable us to demonstrate the feasibility of using attenuated Salmonella strains as carriers of gingipain R1 derived peptide fusions for subsequent evaluation of the role of the systemic and mucosal immune response against P. gingivalis induced periodontal destruction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GLUTAMATE-L-CYSTEINE LIGASE EXPRESSION AND LIVER INJURY Principal Investigator & Institution: Kavanagh, Terrance J.; Environmental and Occupational Health Studies; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Oxidative stress is involved the pathophysiology of a large number of diseases. This stress originates not only from normal aerobic metabolism, but also from the metabolism of foreign compounds, and as a direct result of the release of reactive oxygen species by certain cell types. Organisms have evolved antioxidant defenses against oxidative insults, which include antioxidant enzymes and through the consumption of antioxidant compounds. A very important enzyme involved in antioxidant defense is glutamate-cysteine ligase (GCL), the rate limiting
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enzyme for the synthesis of the cellular antioxidant glutathione (GSH). The primary goal of this project will be to investigate the role of GCL in defense against substances and conditions which induce oxidative damage to the liver. We propose to characterize a transgenic mouse model of GCL overexpression, and to assess the effects of modulating GCL expression on susceptibility to oxidant-induced damage to the liver. We propose to use three agents known to cause oxidative liver injury, namely acetaminophen, carbon tetrachioride, and tumor necrosis factor-alpha. Transgenic and wild-type (normal) littermates will be exposed to non-lethal doses of these agents, and sacrificed from 6 to 48 hours later. Liver tissue will be excised and examined for signs of oxidative damage, cellular necrosis and apoptosis, and biochemical and cellular measures of cell viability and function will be made. Such information will be useful in determining the functional significance of GCL in defense against reactive oxygen species and xenobiotics which induce oxidative stress, and lead to a better understanding of the significance of variable GCL expression in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GLUTATHIONE, ATHEROSCLEROSIS
MACROPHAGES
AND
UNSTABLE
Principal Investigator & Institution: Rosenfeld, Michael E.; Professor; Pathobiology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): The death of macrophages within an atherosclerotic plaque may play a fundamental role in conversion of the plaque to an unstable plaque, one that is vulnerable to rupture and hemorrhage. It is currently unknown precisely what kills macrophages within the plaque. One likely possibility is accumulation of oxidized lipids and free cholesterol derived from lipoproteins that have been trapped and retained by the extra-cellular matrix. Accumulation of oxidized LDL by macrophages in vitro is accompanied by depletion of glutathione, the major endogenous antioxidant for most cell types. Pharmacological stimulation of glutathione synthesis protects macrophages from the cytotoxic effects of oxidized LDL. Our preliminary data suggests that overexpression of the catalytic subunit of glutamate cysteine ligase, the rate-limiting enzyme for glutathione synthesis also protects macrophages from death due to oxidized LDL, oxidized lipid moieties and other prooxidants. Oxidized LDL is also a potent inducer of the expression of both the catalytic and regulatory subunits of glutamate cysteine ligase. Thus, we hypothesize that increased stable expression of glutamate cysteine ligase in macrophages will protect the cells from pro-oxidant induced death and increase the stability of atherosclerotic plaques. To test this hypothesis and to further investigate how oxidized lipid moieties contribute to the regulation of expression of the glutamate cysteine ligase genes in macrophages, we propose the following three specific aims. 1.To determine the role of oxidized lipid components of oxidized LDL in the regulation of macrophage expression of the glutamate cysteine ligase subunit genes. 2.To determine whether ad how increased expression of GCL-c by RAW cells inhibits pro-oxidant and free cholesterol induced death. 3.To determine the effects of bone marrow transplantation of cells overexpressing GCL-c (increased capacity to make glutathione) or deficient in GCL-m (decreased capacity to make glutathione) on macrophage death and atherosclerosis in older apo E-l- mice with established lesions. Strategies such as those included in the present proposal that are designed to prevent macrophage death have a high probability of successfully stabilizing atherosclerotic plaques and should help reduce plaque rupture, occlusive thrombosis, myocardial infarction and stroke.
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Cysteine
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GROWTH HORMONE RECEPTOR DIMERIZATION/DISULFIDE LINKAGE Principal Investigator & Institution: Frank, Stuart J.; Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: (provided by applicant) Growth hormone (GH) is a potent growth-promoting and metabolic hormone. GH receptor (GHR) is a member of the cytokine receptor superfamily. GHR binds GH in its extracellular domain and signals via its cytoplasmic domain's regulated interaction with molecules including the tyrosine kinase, JAK2. GH promotes homodimerization of GHRs such that a 1:2 GH:GHR complex is believed to constitute the activated GHR assemblage. Relatively little is known about GHR dimerization as it occurs in cells and about influence of GHR dimerization on its association with signaling molecules. We previously described GH-induced GHR disulfide linkage that results in a covalently linked GHR dimer form. The role(s) of GHR disulfide linkage has been enigmatic, but a large fraction of activated GHRs undergo this linkage and GHRs rendered detergent-insoluble by GH are progressively accounted for by the disulfide-linked form. We recently found that cysteine-241 (an unpaired extracellular cysteine) is critical for GHR disulfide linkage and GUR detergent insolubility. In addition, this linkage is a biochemical proxy for GHR dimerization. Using this proxy, along with our new dimerization-sensitive anti-GHR extracellular domain antibody, anti-GHRext our data suggest that GH-induced dimerization augments association of GHR with JAK2. We hypothesize: 1) GH-induced GHR dimerization and/or conformational change pursuant to dimerization results in signal initiation by enhancing GHR-JAK2 interaction; 2) though noncovalent GHR dimerization is essential for signal initiation, other important aspects of GH-induced GHR function, such as its capacity for sustained signaling, its intracellular itinerary, and its degradation are influenced by GHR disulfide-linkage and detergent insolubility. To test these hypotheses, our specific aims are: 1. Systematically examine the relationships between GH-induced GHR dimerization, GHR disulfide linkage, and anti-GHRext reactivity by: using cells that express either normal GHR or GHRs mutated in the GHR dimerization interface; comparing normal GH (22K) to the 20K GH variant; and mapping the anti-GHRext epitope(s) accounting for the antibody's dimerization sensitivity. 2. Determine the influence of the GHR cytoplasmic domain on GHR dimerization and the basis for GH-induced enhancement of association between GHR and JAK2. 3. Determine roles of GH-induced GHR disulfide linkage and GHR detergent insolubility in OH-induced signaling, cell proliferation, and subcellular OHR routing, using cells that stably express wild-type vs. cysteine-241 mutant GHRs. Results will significantly impact knowledge of GH-induced GHR activation and cytokine receptor signaling. Longer-term goals made possible by these studies may include; mechanistic evaluation of drugs that activate or inhibit OH signaling; crystallographic structural analysis of the GHR-JAK2 complex; and evaluation of functions of GHR disulfide linkage in intact animals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HUMAN INFLAMMATION
PHAGOCYTES,
OXYGEN
METABOLITES
23
AND
Principal Investigator & Institution: Weiss, Stephen J.; Upjohn Professor of Medicine, Chief; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JUL-1984; Project End 31-MAR-2004 Summary: In chronic inflammatory disease states ranging from rheumatoid arthritis to ulcerative colitis, blood monocytes infiltrate affected tissues and differentiate into tissuedestructive populations of macrophages. Unlike neutrophils or eosinophils which predominantly rely on their ability to generate halogenated oxidants and release serine proteinases to mediate tissue damage, the destructive systems mobilized by human macrophages remain undefined. In order to identify and characterize the mechanisms by which macrophages mediate tissue-destructive effects in chronic inflammatory disease states, human monocytes will be cultured in vitro and induced to mature into a macrophage population capable of expressing an extracellular matrix-degrading phenotype hundreds of times greater than that of any other leukocyte population described previously. Based on preliminary data, the macrophage's unique destructive activity is mediated by the exocytosis/secretion of active cysteine proteinases, a class of acid proteases normally categorized as intracellular, lysosomal catabolic enzymes. To date, little is known with regard to the function of these enzymes in human macrophages since many members of this proteinase family have only recently been identified and few molecular or biochemical tools have been developed for their analysis in intact cell systems. Furthermore, the mechanisms by which lysosomal enzymes could be routed to an extracellular compartment in which conditions permissive for cysteine proteinase activity could be generated and maintained remain unknown. Thus, in an attempt to identify a novel role for cysteine proteinases in macrophage effector functions, the following five aims will be addressed. First, to characterize the intracellular and extracellular expression of the cysteine proteinases, cathepsins B, L and S, as well as the cysteine proteinase inhibitor, cystatin C, in monocyte-derived macrophages. Second, to determine the role of the mannose-6phosphate receptor recognition systems in directing cysteine proteinase traffic from the lysosomal to the extracellular compartment. Third, to characterize the role of the macrophage vacuolar-type H+-ATPase and L-cystine transport systems in generating an acidic and reducing extracellular environment permissive for cysteine proteinase activity. Fourth, to assess the role of the cysteine proteinase system in the macrophagemediated degradation of the extracellular matrix via the selective "knockout" of individual cathepsins, the vacuolar-type H+-- ATPase or the L-cystine transport system. Fifth, and finally, to determine the response and function of the macrophage cysteine proteinase system during chemotactic factor-induced tissue invasion. The characterization of the cysteine proteinase system mobilized by human macrophages at inflamed sites should not only provide new insights into the pathogenesis and treatment of chronic inflammatory disease states, but also into the regulation of the tissue-invasive phenotype in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOPROTEOMICS Principal Investigator & Institution: Boyle, Michael D.; Professor; Biology; Juniata College 1700 Moore St Huntingdon, Pa 16652 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2005
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Cysteine
Summary: (provided by applicant): The proposed studies are designed to evaluate new methods using a mass spectral readout to provide sensitive, detection of selected proteins, as well as methods to monitor post-translational modification events of targeted antigens. The proposed assay involves an antigen capture step mediated by immobilized antibody (immuno) and an analytical step involving mass spectral analysis of bound antigen (proteomics). The goal of the project is to develop rapid sensitive methods of antigen capture from complex mixtures of unrelated proteins in a maimer that permits the subsequent precise molecular weight determination of the bound antigen using time of flight mass spectrometry. The ability to distinguish subtle variation in the size of a targeted antigen will allow analysis of post-translational modification events for any targeted antigen to be achieved. In addition, the ability to obtain semi-quantitative data based on the area under a specific molecular weight peak on the mass spectral read-out will be critically evaluated. The proof of concept studies will focus on a number of properties of the secreted streptococcal cysteine protease SpeB which is known to post-translationally modify the surface anti-phagocytic M protein, and degrade the secreted bacterial plasminogen activator SK. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHIBITION OF TUBERCULAR MYCOTHIOL PATHWAYS Principal Investigator & Institution: Knapp, Spencer A.; Chemistry and Chemical Biology; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Drug-resistant tuberculosis now threatens a large portion of the earth's population, and the development of new treatments for tuberculosis infection has become a national and international priority. Mycobacterium tuberculosis depends on a low molecular weight thiol, "mycothiol," to maintain a reducing intracellular environment and to remove exogenous electrophilic agents. Disruption of the enzymatic pathways of mycothiol biosynthesis and/or mycothiolbased detoxification could leave M. tuberculosis vulnerable to drugs, oxygen, and other stress factors, and constitutes a new tactic for the control of tuberculosis. The objective of this project is to develop inhibitors of the mycothiol-related enzymes of M. tuberculosis, and eventually to design new and successful treatments for tuberculosis. Three enzymes will be targeted initially: mycothione reductase, mycothiol S-conjugate amidase, and inosityl GIcNAc deacetylase, although others, including a cysteine ligase and a cysteine transacetylase, could be added. This work will be guided by enzymatic assays conducted by collaborators using existing screens, and by preliminary results that already indicate that substantial structural simplification in designing mycothiol analogues is possible. First, the minimum substrate requirements for the M. tuberculosis enzymes will be defined. Then, inhibitors based on these minimum structures will be synthesized and evaluated. New methods for the synthesis of mycothiol-analogous compounds will be developed, and new ideas for enzyme inhibitor design will be explored. The most active compounds will be taken as leads for further analogue development and for increasing the potency, specificity, bioavailability, and metabolic stability in M. tuberculosis itself. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: LISTERIA PHOSPHOLIPASE ACTIVATION & CELL-TO-CELL SPREAD Principal Investigator & Institution: Marquis, Helene; Microbiology and Immunology; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853
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Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2003 Summary: Listeria monocytogenes is a facultative intracellular bacterial pathogen that causes serious illness in pregnant women, neonates, elderly, and immunocompromised individuals. Listeriosis is among the leading causes of death from contaminated food products in US. In the last decade, L.monocytogenes has served as an excellent model system for exploring the interactions that take place between an intracellular parasite and its host. The overall goal of this proposal is to define the mechanisms by which L.monocytogenes is capable of spreading from cell to cell without exposure to the extracellular environment. In previous studies, a broad-range bacterial phospholipase C (PC-PLC) was shown to be necessary for efficient bacterial cell-to-cell spread. PC-PLC is secreted as an inactive precursor (proPC-PLC), and proteolytic cleavage at its Nterminus generates the active form of the enzyme. Recently, we obtained genetic and biochemical evidence that the intracellular activation of pro PC-PLC is mediated by a bacterial metalloprotease (Mpl), which is also active in broth culture, and a cysteine protease, whose activity can only be detected during intracellular infection. The activity of PC-PLC generated by either protease is essentially the same, although there is a small shift in substrate preference. Furthermore, proPC-PLC activation by either pathway is dependent on bacterial localization to a vacuole, and on vacuolar acidification. These observations support a model of bacterial escape from double membrane vacuoles formed during cell-to-cell spread that is dependent on host and bacterial determinants. In this proposal, a multidisciplinary approach will be used to test this model of bacterial cell-to-cell spread. Intravacuolar activation of proPC-PLC will serve as a probe to define the host and bacterial requirements for efficient and rapid lysis of double membrane vacuoles. More specifically, this proposal will define (I) the vacuolar compartment in which proPC-PLC activation occurs, (II) the influence of other bacterial virulence determinants on vacuolar maturation and proPC-PLC activation, (III) the origin and identity of the intracellular-specific proPC-PLC activating cysteine protease, and (IV) the relative importance of the two activating proteases. The long term objective of this research is to define the mechanism by which L.monocytogenes spreads from cell to cell. This may provide a novel target for development of drugs to treat or prevent intracellular microbial infections in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MAST CELL CYSTEINE PROTEASES IN LUNG INFLAMMATION Principal Investigator & Institution: Wolters, Paul J.; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 04-AUG-1999; Project End 31-JUL-2004 Summary: Mast cell cysteine, metalloprotease, and serine proteases may play a significant role in the pathogenesis of inflammatory lung diseases. The long-term objective of this proposal is to identify the cysteine proteases present in mast cells, and to characterize their roles in mast cell dependent inflammation. We hypothesize that tissue mast cells are a major source of dipeptidyl peptidase I (DPPI) and a newly identified 60-kDa cysteine protease and that these proteases participate in inflammation by hydrolyzing extracellular proteins. Specific aims are : 1. To explore structure-function relationships of DPPI; 2. To identify cells expressing DPPI in normal and inflamed lung tissues; 3. To characterize substrate specificity of DPPI, and 4. To characterize a nove1 60 kDa cysteine protease found in mast cells. To achieve these goals: 1. Proteolytic processing of proDPPI will be studied in recombinantly expressed DPPI. 2. DPPI's expressed with mutated propeptides will be assayed for their dipeptidyl peptidase and endoprotease activity, 3. Expression of DPPI by specific cell types in normal and
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Cysteine
inflamed dog lungs will be determined by immunohistochemistry and in situ hybridization. 4. DPPI will be studied for its ability to hydrolyze extracellular peptides and proteins. 5. Mast cell functional characteristics and proteolytic activities will be studied in DPPI knockout mice. 6. A novel mast cell cysteine protease will be purified and characterized. Dr. Wolters has completed training in internal medicine and pulmonary and critical care medicine. He has demonstrated a firm commitment to a career in academic medicine and an interest in studying the pathophysiology of lung diseases. The research training plan includes: an intensive laboratory experience, didactic coursework, weekly seminars, and journal clubs. The research training will be overseen by an advisory committee including the sponsor (Dr. Caughey) and experts on cysteine proteases (Dr. McKerrow), immunohistopathology (Dr. McDonald), and pulmonary diseases (Dr. Matthay), who will guide the candidates development into an independent investigator in pulmonary research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF ALVEOLAR EPITHELIAL APOPTOSIS DURING INJURY Principal Investigator & Institution: Chandel, Navdeep S.; Assistant Professor of Medicine; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAY-2008 Summary: Patients develop acute lung injury upon exposure to an injurious stimulus. Acute lung injury is a clinical syndrome characterized by airspace flooding with the development of an intrapulmonary shunt resulting in hypoxemic respiratory failure. The alveolar epithelium is the primary barrier preventing the formation of edema and intrapulmonary shunt. Recent studies have indicated that apoptosis may be an important mechanism underlying the pathogenesis of acute lung injury. A commonly used laboratory model of lung injury is hyperoxia (95%-100% O2). Hyperoxia causes alveolar epithelial cell death, edema, inflammation and death of the animal within 3 days. The apoptotic pathway is executed by caspases, a family of cysteine proteases. Alveolar epithelial cells can undergo activate caspases through either a mitochondrial or a receptor dependent pathway. However, it is not known whether either apoptotic pathway is important in the development of acute lung injury. Furthermore, it is unclear whether caspase inhibition following the initiation of apoptosis through either a death receptor or mitochondrial dependent pathway can prevent cell death and preserve the function of alveolar epithelial cells. We hypothesize that the loss of alveolar epithelial cells due to apoptosis is an initiating event in the pathology associated with hyperoxia. The focus of this application is to determine whether mitochondrial or receptor dependent pathways regulate hyperoxia induced lung injury. In addition we will examine the efficacy of genetic strategies to inhibit caspase activation in preventing lung injury and preserving epithelial function during hyperoxia. Collectively these studies will provide important insight into the mechanisms underlying acute lung injury and may lead to the development of novel therapeutic strategies both for patients with established ARDS and those at risk for developing ARDS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM OF DIOXYGEN REDUCTION BY HEME-COPPER OXIDASES Principal Investigator & Institution: Einarsdottir, Olof; Associate Professor; Chemistry and Biochemistry; University of California Santa Cruz 1156 High St Santa Cruz, Ca 95064
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Timing: Fiscal Year 2002; Project Start 01-FEB-1997; Project End 31-MAR-2005 Summary: The primary objective of this research is to elucidate the mechanism of electron and proton transfer during the reduction of dioxygen to water by heme-copper oxidases. Our specific aims will focus on four problems: 1. The mechanism of the reduction of dioxygen to water by bacterial heme-copper oxidases will be studied by the CO flow-flash method. Time-resolved multichannel optical absorption spectroscopy, in conjunction with singular value decomposition (SVD) and global exponential fitting analysis, will be used to follow the kinetics of electron and proton transfer and to deduce the UV-Vis spectra of the transient intermediates. These studies should provide new insight into the mechanism of the dioxygen reduction reaction by heme-copper oxidases. 2. We will investigate the reaction of dioxygen with bovine heart and bacterial oxidases in different oxidation states using dioxygen which is produced in situ by photodissociating synthetic dioxygen carriers. We will also extend this approach to rapid dioxygen binding and activation in ribonucleotide reductase (RNR), in which the reactions occur too rapidly to be monitored by conventional stopped-flow methods. 3. The intramolecular electron transfer in the bacterial oxidases, bo3 from E. coil, aa3 from Rhodobacter sphaeroides and ba3 from Thermus thermophilus will be investigated using a photoactivatable dye, thiouredopyrene-trisulfonate (TUPS), covalently linked to single reactive cysteine residues on the oxidases. Time-resolved optical absorption spectroscopy, in conjunction with SVD and global exponential fitting, will be used to determine the spectra of the intermediates present and the rate constants of individual electron transfer steps. By varying the distance between the labeled cysteine and the initial electron acceptor and by introducing breaks into presumed electron transfer pathways by site-directed mutagenesis, detailed information regarding intramolecular electron transfer pathways in heme-copper oxidases will be obtained. 4. We propose to make chemical analogs of the active site of cytochrome oxidase, including the His-Tyr cross-linked dipeptide and the cyclic pentapeptide (His-Pro-Glu-Val-Tyr) with and without Cu-ligands incorporated. The analogs will be studied using a multispectroscopic approach, including steady-state and time-resolved UV-Vis spectroscopy, FTIR and ESR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF GLUTATHIONE CONJUGATE DEPENDENT TOXICITY Principal Investigator & Institution: Cooper, Arthur J.; Research Professor of Biochemistry; Winifred Masterson Burke Med Res Inst Medical Research Institute White Plains, Ny 10605 Timing: Fiscal Year 2003; Project Start 01-AUG-1997; Project End 31-JUL-2008 Summary: (provided by applicant): A significant portion of the US population is exposed to toxic, halogenated alkenes (e.g., trichloroethylene, tetrachloroethylene and tetrafluoroethylene) in the workplace and environment. These compounds are metabolized in part to halogenated cysteine S-conjugates, which are thought to be the major toxicants. S-(1,1,2,2-Tetrafluoroethyl)-L-cysteine (TFEC), the cysteine S-conjugate of tetrafluoroethylene, is chosen here as a representative toxic, halogenated cysteine Sconjugate. Toxic, halogenated cysteine S-conjugates are converted to pyruvate, ammonia and a reactive (thioacylating) fragment by cysteine S-conjugate ?-lyases. In vivo, the kidney and, to some extent, liver and brain, are susceptible. Previously, we showed that (i) a high-Mr cysteine S-conjugate ?-lyase in rat kidney co-purifies with mitochondrial HSP70 and protein disulfide isomerase, and contains mitochondrial aspartate aminotransferase (mitAspAT) (ii) several aminotransferases [mitochondrial
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Cysteine
branched-chain aminotransferase (BCATm), cytosolic branched-chain aminotransferase, alanine-glyoxylate aminotransferase II, mitAspAT] possess cysteine S-conjugate ?-lyase activity, but are themselves inactivated during turnover (syncatalytic inactivation), and (iii) exposure of PC12 cells and astrocytes in culture to TFEC causes selective loss of key mitochondrial enzymes of energy metabolism, including mitAspAT and ?-ketoglutarate dehydrogenase complex (KGDHC). Others have shown that KGDHC and branchedchain keto acid dehydrogenase complex (BCKAD) are targets of TFEC in rat kidney cells in vivo, and that halogenated cysteine S-conjugates are metabolic poisons of isolated kidney and liver mitochondria. The PI and coworkers have suggested that KGDHC and BCKAD are sensitive to inactivation due to toxicant channeling involving mitAspAT and BCATm, respectively. The overall goal of the present proposal is to determine the mechanism by which mitochondrial metabolism is poisoned by TFEC/TFEC thioacylating fragment. Accordingly, our aims are to determine: a) the effects of TFEC on respiration, Ca 2+ homeostasis, membrane potential and swelling in isolated rat liver, brain and kidney mitochondria, and correlate such pathological changes with loss of key mitochondrial enzyme activities, b) the mechanism whereby mitAspAT and BCATm are syncatalytically inactivated by TFEC, and c) the mechanism of toxicant (TFEC thioacylating fragment) transfer (channeling) from mitAspAT to KGDHC and from BCATm to BCKAD. The findings should elucidate the link between exposure to certain halogenated xenobiotics and impaired energy metabolism, and may suggest a means to minimize the toxic effects in heavily exposed individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISMS OF METHYLMERCURY INDUCED NEURONAL TOXICITY Principal Investigator & Institution: Aschner, Michael; Professor; Physiology and Pharmacology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from the Investigator's Abstract) Methylmercury (MeHg) is a significant environmental contaminant that continues to pose a great risk to human health. Considerable attention in the scientific and health policy fora is focused on the question of whether MeHg intake from a diet high in fish is associated with aberrant CNS function. A number of recent studies (Kjellstrom et al., 1986, 1989; McKeon-Eyssen et al., 1983; Grandjean et al., 1997) suggest that fetal exposure at levels attained by mothers eating fish regularly during pregnancy are associated with neurological deficits in their offspring. Astrocytes play a key role in MeHg-induced excitotoxicity. [1] MeHg preferentially accumulates in astrocytes. [2] MeHg potently and specifically inhibits glutamate uptake in astrocytes. [3] Neuronal function is secondary to disturbances in astrocytes. [4] co-application of nontoxic concentrations of mercury and glutamate leads to the typical appearance of neuronal lesions associated with excitotoxic stimulation. [5] MeHg induces swelling in astrocytes. These observations are fully consistent with MeHg-induced dysregulation of excitatory amino acid homeostasis, and indicate that a glutamate-mediated excitotoxic mechanism is involved. The working hypotheses of the proposal outline a number of critical target sites for MeHg-induced neurotoxicity. In Specific Aim 1.0 we will test the hypothesis that activation of the astrocyte-specific enzyme, cytosolic phospholipase A2 (cPLA2) and the ensuing hydrolysis and release of arachidonic acid (AA) are mediators of glutamate release upon exposure to MeHg. We will investigate the lipase(s) involved, and determine the relationship between cPLA2 activation, regulatory volume decrease (RVD), and glutamate release. In specific Aim 2.0, we will test the hypothesis that MeHg-induced increased extracellular glutamate
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concentrations will competitively inhibit cystine transport into astrocytes, leading to diminished supply of cysteine for neuronal glutathione (GSH) synthesis. In Specific Aim 3.0, we will test the hypothesis that modification of cysteine residues by MeHg is associated with altered glutamate transport, and that it is regulated by the chemical redox-state of reactive cysteine residues in the astrocyte-specific glutamate transporters, GLAST and GLT1. The studies will be carried out in rat primary cultures of neurons and astrocytes, as well as Chinese hamster ovary (CHO-K1) cells (where transporters can be over expressed in cells that lack the endogenous glutamate transporter). Our approach will encompass a broad array of methods, including molecular biology, electrophysiology, radiolabel trans-membrane fluxes, and electrical impedance measurements of cell volume. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR MECHANISMS OF INTESTINAL TRANSPORT Principal Investigator & Institution: Wright, Ernest M.; Professor; Physiology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-DEC-1976; Project End 31-MAR-2008 Summary: (provided by applicant): The goal of this project is to understand how sodium, glucose and water are transported across the brush border membrane of the small intestine by the Na+/glucose cotransporter (hSGLT1). This membrane transport protein is responsible for the absorption of 180 g of glucose and galactose and more than 4 liters of fluid per day. Oral Rehydration Therapy, credited with saving thousands of infants a day from infectious diarrhea, is based on the coupling of glucose, salt and water transport by SGLT1. It is postulated that hSGLT1 couples Na+ transport to glucose and water transport by a series of ordered ligand induced conformational changes. Evidence suggests that sodium binding produces a reorganization of four transmemembranes helices near the C-terminus of the protein that permits sugar binding and transport. In order to accommodate the large glycosides that are transported (20 x 12 x 7 Angstroms) and the 300 water molecules that are also transported during one turnover of the transporter, we predict extensive changes in transmembrane helical packing during the transport cycle. To test this hypothesis we will use cysteine scanning mutagenesis along with thiol reactive fluorescent probes to identify which helices move, the order in which they move, and the distances they move during partial reactions of the transport cycle. This will be accomplished by expressing the cysteine mutant transporters in Xenopus laevis oocytes, and the cysteine residues will be labeled with fluorescent thiol reagents. The oocytes will be placed on the stage of an epifluorescence microscope and voltage clamped. Simultaneous recordings of charge movement and fluorescence will be obtained as a function of membrane voltage and the ligand concentrations. We will also use double cysteine mutants and fluorescence and luminescence energy transfer (FRET & LRET) to measure the distance between the probes on the two cysteines and how far they move as the transporter is moved from one conformation to another. This information will enable us to map the changes in helical packing, including the order, time course and magnitude of the helical motion during the transport cycle, and determine if they account for the transport of glucose and water. The impact of the work ranges from a molecular understanding of oral rehydration therapy to how large class of membrane transport proteins work. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Cysteine
Project Title: MOLECULAR MECHANISMS OF MECHANOSENSITIVE CHANNEL GATING Principal Investigator & Institution: Blount, Paul L.; Physiology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: Bacterial mechanosensitive channels are emerging as molecular paradigms for investigation of the mechanosensory transduction that occurs in physiological processes such as touch, proprioception, cardiovascular regulation, hearing and balance. The use of the MscL channel of Escherichia coli has advanced the field considerably by allowing molecular genetic analysis to be combined with electrophysiology and transport assays in the study of a protein with a well-defined physiological role. Hence, MscL serves as a good model for determining the molecular mechanisms of mechanosensitive channel gating as well as the general principles of how proteins detect and respond to membrane tension. Purification of the MscL channel protein led to the identification of the structural gene and ultimately to a 3.5 angstrom X-ray crystallographic structure of the Mycobacterium tuberculosis MscL. This is a closed structure, which unfortunately provides few clues to the process of channel gating or to the structure of the open channel. Because a large pore of 30 to 40 angstrom diameter is generated upon gating, a large conformational change must occur and several residues normally embedded in protein or lipid environments must contribute to the lining of the open pore. The residue interations that are strongest and of greatest importance for keeping the channel closed, the movements of residues and domains that take place upon gating, and the residues that contribute to the lining of the open pore are currently all unknown. The experiments in this application are designed to use molecular analyses based on the solved structure to determine these functional and structural properties of the channel. The approaches include: 1) Cysteine scanning to determine which interactions within the transmembrane domains are of most importance in MS channel gating. 2) Utilizing the "Substituted Cysteine Accessibility Method" (SCAM) to identify the residues that move into an aqueous environment upon channel opening, and thus are likely candidates for lining the open-channel pore. 3) Isolating and characterizing suppressor mutations of gain-of-function MscL mutants to identify pairs of residues that potentially interact in the closed, transition or open states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOLECULAR TOXICOLOGY IN HUMAN KIDNEY CELLS Principal Investigator & Institution: Lash, Lawrence H.; Professor; Pharmacology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2004; Project Start 15-SEP-1999; Project End 31-MAR-2008 Summary: (provided by applicant): Trichloroethylene (TRI) is a major environmental contaminant, is an established animal carcinogen, and is considered a "probably human carcinogen" by the National Toxicology Program and the International Agency for Research on Cancer. The kidneys are one target organ for TRI and its nephrotoxic and nephrocarcinogenic effects are mediated by metabolites derived from conjugation with glutathione (GSH). Subsequent metabolism to the cysteine conjugate S- (1,2dichlorovinyl)-L-cysteine (DCVC) generates the penultimate toxic metabolite. It is metabolism of DCVC by either the cysteine conjugate a-Iyase or the flavin-containing monooxygenase that generates the ultimate reactive and toxic species. Most of the previous research that has delineated the metabolism and potential modes of action for TRI and DCVC has been performed in rodents or with tissue from rodents. While these
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studies, some of which have been done by the PI, have provided much useful insight, there are problems in using data obtained from rodents for human health risk assessment. This is particularly true for halogenated solvents such as TRI, because of marked species differences in metabolism, transport, and overall sensitivity to toxicity. Previous studies of ours showed that DCVC can cause both apoptosis or necrosis in primary cultures of human proximal tubular (hPT) cells, depending on concentration and time of exposure. Findings also suggested effects of DCVC on expression of proteins related to stress response and regulation of cell growth. This application uses primary cultures of hPT cells as the experimental model and will investigate the ability of hPT cells exposed to moderately toxic concentrations of DCVC to undergo repair and regeneration, the potential for DCVC to induce cell proliferation by non-genotoxic mechanisms, and the requirement for mitochondrial toxicity in the course of events leading from exposure to toxicity. The application comprises three Specific Aims. Specific Aim 1 addresses the question of whether hPT cells exposed to moderately toxic concentrations of DCVC undergo repair and regeneration. Several markers of repair will be assessed and precise conditions and potential mechanisms by which the repair and regeneration response are induced will be investigated. Specific Aim 2 will address the question of whether DCVC can stimulate uncontrolled proliferation of hPT cells. Effects on cell cycle and cell cycle signaling molecules under various conditions of DCVC exposure will be studied. Finally, Specific Aim 3 will address the question of whether mitochondrial toxicity is sufficient and necessary for DCVC-induced toxicity in hPT cells. Although previous work has shown that mitochondria are early and potently affected intracellular targets of DCVC, it is not known whether mitochondrial toxicity is an obligatory step in the progression of events that occur after DCVC exposure or whether other pathways that are independent of mitochondria can mediate renal cell injury. Achievement of these aims should build on our previous work in human kidney cells and extend it to provide a much more complete understanding of the various and complex ways in which DCVC affects the human kidney Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NA/K PUMP CURRENT IN ISOLATED HEART CELLS Principal Investigator & Institution: Gadsby, David C.; Professor; Lab/Cardiac/Membrane Physiol; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2002; Project Start 01-APR-1987; Project End 31-MAR-2006 Summary: (provided by applicant): The long term goal remains a detailed understanding of how the Na/K pump works and how it may be modulated. The Na/K pump plays the vital role of maintaining the electrochemical gradients for Na and K ions that underlie electrical signaling, essential coupled transport, and cell pH and volume regulation; the Na/K pump is also the receptor for the still widely prescribed cardiotonic steroid, and pump inhibitor, digoxin. Charge translocation is a fundamental feature of the ion pumping cycle, and of individual partial reactions. It provides a readily accessible, reproducible, and sensitive signal for assaying turnover rates and rates of conformational transitions, and sheds light on the molecular mechanism of ion transport, now viewed in light of the new high-resolution crystal structure of the related SR Ca pump. Specific aim (1) is to further investigate the ion transport mechanism, using two approaches. In one, we will continue characterizing the charge translocating steps by quantitative analysis of the dependence on membrane potential, external and internal ion and nucleotide concentrations, and temperature, of steady- and pre-steadystate pump currents in internally dialyzed guinea-pig ventricular myocytes and squid giant axons (in which technical advances now permit ultra high-speed measurements of
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pump-mediated charge movements, resolving relaxation rates as fast as 10 to the 5th power per s, some 3 orders of magnitude faster than the Na/K pump's maximum turnover rate. In the other, the lethal coral toxin, palytoxin, is used to transform the Na/K pump into a gated ion channel. We will express in HEK293 cells mutant ouabainresistant Na/K pumps with cysteine residues introduced at strategic locations, and then use sulfhydrl-specific reagents to investigate structure of the gates and mechanisms of gating, which should provide information on ion occlusion/deocclusion mechanisms during normal Na/K pumping. Specific aim (2) is to see whether, under what conditions, and by which mechanisms, Na/K pump activity in myocytes may be acutely modulated by cellular regulatory processes like kinase-mediated phosphorylation of the pump (or associated regulatory molecule), or interactions with cytoplasmic Ca ions. We will directly apply regulatory molecules, such as purified kinases or phosphatases, to the pump's cytoplasmic surface in giant inside-out patches of membrane, excised from myocytes. Explicit kinetic models of the Na/K transport mechanism will be developed to account for experimental observations, and will be refined by fits to the data. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MEMBRANES
NITRIC
OXIDE
MEDIATED
OXIDATION/NITRATION
IN
Principal Investigator & Institution: Kalyanaraman, Balaraman; Professor/Director; Biophysics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 31-JUL-2003 Summary: (Adapted from the Investigator's Abstract) Increased levels of nitrotyrosine and nitrated proteins have been detected in a variety of pulmonary and cardiovascular diseases, and in neurodegenerative and chronic inflammatory disorders. The overall objective of this R01 application is to obtain new mechanistic insight into how the hydrophobic interior of biological membranes facilitates oxidation and nitration reactions of reactive nitrogen species (RNS), such as peroxynitrite (ONOO or ONOOH) or nitrogen dioxide radical (NO2). This proposal is based on the following recent discoveries: 1) peroxynitrite can cross lipid membranes through anion transport channels or passive diffusion at rates significantly faster than their reaction with any other target molecule in the aqueous phase. 2) The reaction between NO and O2 is significantly faster in the membrane interior. 3) Peroxynitrite and NO2 cause extensive nitration of alpha-tocopherol in membranes under conditions where tyrosine nitration in the aqueous phase was negligible. The investigators hypothesize that nitration of phenols and nitrosation of thiols by RNS in biological systems is increased in a hydrophobic environment. To investigate the nitration and nitrosation reactions in membranes, they will synthesize tyrosylated lipid and tyrosine- or cysteine-containing peptides that are anchored at defined locations in the lipid bilayer. The investigators will use HPLC, stop-flow spectrophotometry, mass spectrometry, and spin trapping to investigate nitration and nitrosation reactions in membranes. Specifically, the PI will: 1) compare the yields of formation of nitro-gama-tocopherol in membranes and nitrotyrosine in the aqueous phase; 2) detect and characterize nitration products of tyrosylated lipid; 3) determine the mechanism of nitration and nitrosation of tyrosineand cysteine-containing peptides in membranes; and 4) use nitro-gama-tocopherol or nitrated transmembrane peptide as a marker product to detect peroxynitrite formation from nitric oxide synthase enzymes. This comprehensive study of RNS reactions in simple well-defined model membrane system may provide new mechanistic insight for understanding oxidative and nitrosative stress in pulmonary cardiovascular, neurodegenerative, and inflammatory diseases.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITRIC OXIDE REGULATION OF SMOOTH MUSCLE TONE Principal Investigator & Institution: Jones, Keith A.; Associate Professor of Anesthesiology; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2004; Project Start 01-APR-1996; Project End 31-MAR-2008 Summary: (provided by applicant): Reactive oxidant species (ROS), such as nitric oxide (NO) and hydrogen peroxide (H2O2), play an important physiologic role in living tissue, and a pathophysiologic role in diseases, particularly those involving inflammation. Although cyclic nucleotides are key mediators of ROS-induced cellular processes, cyclic nucleotide-independent mechanisms are also important. In the previous grant cycle, we obtained data showing that the cyclic nucleotide-independent inhibition of smooth muscle contraction by ROS is due to novel mechanisms that inhibit Ca2+ sensitivity. This effect is spontaneously reversible in intact tissue and due to inhibition of the actomyosin ATPase activity of myosin II and the activities of myosin light chain kinase (MLCK) and heterotrimeric G-proteins. The overall goal of the current proposal is elucidate the biochemical mechanisms for redox regulation of these proteins by ROS. Aim A will test the hypotheses that ROS inhibit actomyosin ATPase activity by inhibiting nucleotide binding at the catalytic site and by stabilizing the myosin structure, thereby preventing F-actin binding. Both of these mechanisms are due to reversible oxidation of cysteine (Cys) residues on myosin. Aim B will test hypotheses related to ROS-induced inhibition of phosphorylation of the regulatory light chain of myosin (rMLC). Our preliminary data indicate that MLCK activity and GDP-GTP exchange at the Galpha subunit of heterotrimeric G-proteins are inhibited by ROS; both of these effects would inhibit rMLC phosphorylation. A permeabilized preparation is used for in situ biochemical studies, thereby demonstrating the physiologic relevance of the proposed mechanisms. Soluble proteolytic fragments of isolated myosin II and sitedirected mutagenesis of candidate Cys on myosin are used to explore specific biochemical mechanisms for ROS effects on actomyosin ATPase activity. Purified MLCK holoenzyme and a constituitively active, proteolytic subfragment of the catalytic domain of MLCK are used to investigate biochemical mechanisms on MLCK. Finally, a crude membrane preparation and recombinant Gprotein subunits are used to elucidate novel redox effects on GDP-GTP exchange at Galpha. Elucidation of these mechanisms is of importance in understanding the role of ROS as key mediators of physiologic effects in both health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NITROSYLATION OF CYTOCHROME C DURING APOPTOSIS Principal Investigator & Institution: Mannick, Joan B.; Assistant Professor; Medicine; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Apoptosis is a tightly regulated form of cell death that removes excess or unwanted cells from organisms. Cytochrome c plays a critical role in many apoptotic cascades. When mitochondria receive an apoptotic signal, cytochrome c is released from the mitochondrial intermembrane space into the cytoplasm. Cytoplasmic cytochrome c forms a complex with Apaf-1 and caspase-9 leading to the activation of downstream caspases and subsequent apoptotic cell death.
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The mechanisms regulating cytochrome c function during apoptosis are poorly understood. In our preliminary studies we investigated the role of nitric oxide (NO) in cytochrome c regulation. NO is an endogenously produced gas that regulates protein function by binding to transition metals or cysteine residues on proteins, a process called nitrosylation. Our preliminary data suggests that cytochrome c is endogenously nitrosylated during Fas-induced apoptosis. Our studies also suggest that cytochrome c nitrosylation increases caspase activation. This is the first demonstration of an endogenous posttranslational modification of cytochrome c during apoptosis. The preliminary findings raise the possibility that cytochrome c nitrosylation is a novel mechanism of apoptosis regulation. This hypothesis will be tested in the proposed studies. In Specific Aim 1 we will determine if cytochrome c is nitrosylated in mitochondria or in the cytoplasm. In Specific Aim 2 we will determine if cytochrome c is nitrosylated on a heme or a cysteine residue. In Specific Aim 3 we will analyze the function of nitrosylated cytochrome c during apoptosis. In Specific Aim 4 we will determine if cytochrome c nitrosylation is a generalized mechanism regulating mitochondria-dependent forms of apoptosis. The results of these studies will determine if cytochrome c nitrosylation is a novel mechanism regulating apoptotic signaling. Ultimately the findings may lead to the development of rational NO-based therapies for diseases associated with dysregulated apoptosis including cancer, autoimmune disease and neurodegeneration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NMDA EFFICACY/TRANSDUCTION
RECEPTOR--AGONIST
AFFINITY,
Principal Investigator & Institution: Vandongen, Antonius M.; Associate Professor; Pharmacology and Cancer Biology; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: The long term goal of this project is to define the molecular basis of agonist affinity and efficacy in the NMDA receptor, a ligand-gated ion channel that belongs to the glutamate receptor family. Activation of NMDA receptors requires binding of two co-agonists, glycine and L-glutamate, to receptor domains in the in the NR1 and NR2 subunits. Occupancy by both agonists initiates a series of molecular events that culminates in opening of the associated ion channel. The objective of this proposal is to identify specific molecular determinants of the interaction of agonists with the NMDA receptor. The recently published crystal structure of the ligand binding domains of a related glutamate receptor (GluR2) predicts which amino acids are in direct contact with the agonists. Preliminary data from our lab suggest the existence of transduction elements in the glycine binding pocket and a highly conserved region in the M3 transmembrane segment. Therefore, the following specific aims are proposed: (1) To identify amino acid residues that determine agonsist affinity and efficacy. Site-directed mutagenesis has identified many amino acid residues whose mutation caused shifts in the agonist dose-response curves. However, such shifts in agonist sensitivity cannot be interpreted unambiguously. A new approach will therefore be used which can distinguish between mutations that affect agonist affinity or efficacy. By using of cysteine-substitution mutagenesis and thiol-specific modifying reagents, the same population of channels can be studied before and after modification. Full and partial agonists will be employed to unequivocally interpret alterations in efficacy and affinity. Parallel experiments using the GluR2 receptor will be used to confirm the structural assignments. (2) To test the hypothesis that the M3 segment is a transduction segment coupling ligand binding to channel opening. The M3 transmembrane segment of
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glutamate receptors contains a strictly conserved amino acid sequence. Cysteine substitutions in this region identified a residue for which thiol modification results in constitutively active NMDA receptors. Since this modification requires the presence of agonists, it was hypothesized that M3 undergoes a conformational change upon receptor activation and that thiol modification locks the receptor in the active state. These studies will result in a detailed molecular picture of the dynamic change in structure that accompany activation of the NMDA receptor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NO-MEDIATED MODIFICATION OF NMDA RECEPTOR DURING HYPOXIA Principal Investigator & Institution: Mishra, Om P.; Research Professor; Pediatrics; Drexel University College of Medicine 245 N 15Th St Philadelphia, Pa 19102 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAR-2007 Summary: (provided by applicant): The proposed studies will investigate nitric oxide (NO)-mediated phosphorylation mechanisms that result in hypoxic neuronal death by transcription-independent and transcription-dependent pathways in the newborn. We propose that NO produced during hypoxia leads to increased phosphorylation of the cell death repressor protein Bcl-2 and cyclic AMP-response element binding (CREB) protein. Phosphorylation of Bcl-2 and CREB proteins will correlate with the severity of cerebral tissue hypoxia. We propose that NO free radicals generated during hypoxia lead to inactivation of protein tyrosine phosphatase (PIP) and mitogen-activated kinase phosphatase1 (MKP-1) and MKP-3. Inactivation of these phosphatases results in increased phosphorylation of BcI-2, a NO-mediated transcription-independent mechanism of hypoxic neuronal death. Furthermore, we propose that NO generated during hypoxia increases intranuclear Ca++-influx in neuronal nuclei leading to activation of nuclear CaM-kinase resulting in increased phosphorylation of CREB protein and increased expression of the cell death promoter protein Bax, a NO-mediated transcription-dependent mechanism of neuronal death following hypoxia. The degree of brain hypoxia in vivo will be monitored by continuous measurement of high energy phosphate compounds with 31P-nuclear magnetic resonance spectroscopy and confirmed biochemically. Experimental protocols will be carried out on newborn piglets investigating: (1) the relationship of quantitative tissue hypoxia to phosphorylation of Bcl-2 and CREB proteins, (2) the effect of hypoxia on: (a) the activity and expression of SH-PTP-1, MKP-1 and MKP-3, (b) the activation and activity of MAP kinases ERK and JNK; (3) the effect of hypoxia on nitrosylation of cysteine residues in SH-PTP-1, MKP-1 and MKP-3; (4) the relationship of NO-mediated nitrosylation of cysteine residues in vitro to inhibition of the activity of protein tyrosine phosphatase and MAP kinase phosphatases MKP-1 and MKP-3; (5) the effect of NO donors on Ca++-influx in neuronal nuclei; (6) the effect of hypoxia on the activity of neuronal nuclear CaM-kinase and subsequent expression of cell death promoter protein Bax; and (7) the effect of administration of nitric oxide synthase (NOS) inhibitors during hypoxia on activity of phosphatases, phosphorylation of Bcl-2 and CREB, expression of Bax and immunocytochemical and morphological indices of neuronal death. These studies will provide a novel mechanism of NO-mediated phosphorylation of specific proteins resulting in hypoxic neuronal death by transcription-independent and transcriptiondependent pathways. The elucidation of molecular mechanisms of NO-mediated phosphorylation of the cell death repressor protein Bcl-2 and expression of the cell death promoter protein Bax in response to hypoxia will aid in the development of novel preventive strategies for hypoxia-induced brain dysfunction in the newborn.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL RECEPTORS OF VITAMIN A IN THE CYTOPLASM Principal Investigator & Institution: Hammerling, Ulrich G.; Member; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: During a century of vitamin A research in nutrition much detailed knowledge on the mechanism of action has accrued. Yet several aspects of nutritional vitamin A deficiency remain unexplained by the reigning paradigm of transcription control via retinoic acid. In particular, the regulation of cytoplasmic events by vitamin A and metabolites, postulated by many, has remained elusive. We have identified a family of likely receptors by showing that retinol and the metabolite, 14-hydroxy-retro-retinol (14HRR), bind the cysteine-rich, zinc-finger subdomains of the regulatory domains of several PKC isoforms and other serine/threonine kinases. Our hypothesis is that the retinoid/zinc-finger complex functions as reversible switch during redox activation of the kinase. The primary event is oxidation of selected cysteine residues tagged by a retinoid bound nearby. The retinoid acts as catalyst to facilitate oxidation. Release of zinc from cysteines and loss of coordination of an otherwise rigid structure leads to the changed conformational state in PKC that ushers in its activation. Thus, a zinccoordinated structure with its bound retinoid could serve as a sensor and actuator, directly linked to the redox state of the cytoplasm, allowing cells to maintain a steadystate level of active PKC as well as to respond quickly to oxidative stress. It is proposed to determine the influence of retinol on the redox potential and the reversibility of redox activation of PKC alpha (Aim #1); to study the chemistry of the zinc finger with respect to redox changes that cause Zn2+ release/binding (Aim # 2); to investigate the finetuning of redox potential by different retinoids bound to the zinc-finger (Aim # 3); to verify by imaging techniques the binding of retinoids to PKC in vivo (Aim # 4). The study will move the field of vitamin A forward. Furthermore, a new paradigm would be created how redox regulation, an every-day requirement for cells, connects to the general signalling apparatus and on to the actuators of metabolism and transcription. These fundamental insights, will impact on inflammatory processes and contribute to understand how reactive oxygen promotes cancer progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NUTRITIONAL REGULATION OF CYSTEIN DIOXYGENASE Principal Investigator & Institution: Stipanuk, Martha H.; Div/Nutritional Sciences; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2004; Project Start 01-MAR-2000; Project End 31-MAR-2009 Summary: (provided by applicant): Maintenance of a low cellular cysteine level is essential for cellular integrity, but having a sufficiently high cellular cysteine level to ensure adequate rates of synthesis of glutathione, coenzyme A, and proteins is also critical. Hepatic cysteine dioxygenase (CDO) activity plays a central role in regulating the partitioning of cysteine to meet various metabolic demands while at the same time maintaining low cysteine levels in the body by disposing of excess cysteine. Hepatic CDO activity increases more than 30-fold within hours after rats are switched from a 10% protein diet to a 40% protein diet, while hepatic cysteine levels remain less than 0.1 mmol/g. This upregulation of CDO is largely due to decreased ubiquitination and degradation of CDO by the 26S proteasome. The inhibition of CDO polyubiquitination can be effected by cysteamine, as well as cysteine, in cultured hepatocyte systems,
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suggesting cysteine itself may be the regulatory molecule. Evidence of abnormal or deficient CDO activity, including elevated cysteine and low sulfate concentrations, has been reported in individuals with a variety of diseases, both non-neurological and neurological, suggesting heterogeneity in CDO expression in the human population and a role of CDO activity in the etiology of several chronic diseases associated with aging. The major goal of this project is to further elucidate the molecular mechanisms involved in the marked changes in CDO levels that occur in response to dietary protein or SAAs. The specific aims for the proposed work are: (a.) To further characterize the two isoforms of CDO, the processes involved in their formation, and their relative enzymatic activity. (b.) To determine the physical structure of CDO and to elucidate the catalytic mechanism and details of the active site structure as well as sites and conformations involved in the action of cysteine in protecting CDO from rapid degradation. (c.) To evaluate the role of protein degradation, in particular the ubiquitin-proteasome pathway, in the regulation of the level of expressed CDO and to elucidate the role of cysteine in the regulation of CDO degradation. (d.) To evaluate the physiological significance of CDO in the regulation of cellular cysteine (and gtutathione) level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ORAL EPITHELIAL CELLS: INNATE IMMUNE "GATEKEEPER" OF HIV Principal Investigator & Institution: Herzberg, Mark C.; Professor; Oral Sciences; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAY-2007 Summary: (provided by applicant): The oral mucosa is directly challenged with Human Immunodeficiency Virus (HIV) by exposure of infants to HIV-carrying vaginal fluids at birth and to breast milk postnatally, and with passive oral sex among men. Exposures commonly include both X4 and R5 HIV, yet R5 viruses account for most primary systemic infections. When exposed to HIV and Porphyromas gingivalis cysteine proteases, we hypothesize that oral keratinocytes up-regulate expression of innate immune molecules, including alpha- and beta-defensins and other associated genes, to enhance HIV R5 transcytosis and intracellular resistance to HIV infection. To test this hypothesis, we will: 1. show that expression of CXCR4 and CCR5 by oral keratinocytes contribute to coreceptor-specific transcytosis of X4 and R5 HIV isolates; 2. determine if exposure to HIV regulates expression of the innate immune molecules calprotectin and alpha- and beta-defensins directly or in association with PAR signaling mediated by specific P. gingivalis protease mutants; 3. identify and profile oral keratinocyte innate immune-associated gene expression patterns, including known plausible HIV coreceptors and other innate immune molecules, which are regulated by HIV in the presence and absence of P. gingivalis proteases; and 4 show how innate immune molecules modulate transcytosis, translocation by paracellular routes, and anti-HIV resistance in oral keratinocytes in vitro. This project will show that oral keratinocytes express innate immune molecules to resist intracellular infection by X4 and R5 HIV. In the presence of cysteine proteases, innate immune molecules and genes required for transcytosis of R5 HIV expression will be up-regulated, increasing intracellular anit-HIV resistance and facilitating transfer R5 HIV-1 to initiate systemic infection. Innate immune factor-related genes may prove to be novel targets to prevent mucosal HIV. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Cysteine
Project Title: OXIDATIVE MECHANISMS IN CHROMIUM CARCINOGENESIS Principal Investigator & Institution: Sugden, Kent D.; Assistant Professor; Anthropology; University of Montana University Hall 202 Missoula, Mt 598124104 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Chromium(VI) compounds pose a serious health risk to occupationally and environmentally exposed human populations. Exposure to Cr(VI) produces lung carcinomas in humans and laboratory animals. The overall objective of this research project is to elucidate the mechanism by which chromium(VI) compounds act as carcinogens. The hypotheses to be tested in this research project are: (1) that high valent +5 and +4 oxidation states of chromium are the primary intermediates that lead to oxidative DNA damage via direct DNA-metal interactions; (2) that reduction of Cr(VI) by intracellularly important reductants such as glutathione, ascorbate and cysteine form ligand-based radicals leading to oxidative DNA lesions but are of a lesser significance than oxidation by high valent chromium; (3) that these oxidative lesions are manifested in repair-deficient prokaryotic cell systems which are selectively sensitive to the DNA lesions detected in the in vitro studies. The specific aims of the proposed research are: (1) The mechanism of direct- or metal-centered oxidation of DNA by high valent chromium will be measured using model high valent Cr(V) compounds. Oxidation products arising from H-atom abstraction at the C1', C3', C4' and C5' of deoxyribose will be determined by HPLC and GC/MS using the model dinucleotide sugar oxidation substrate, 5',3'-di-O-Acetyl- d(TpT). Formation of guanine and cytosine base oxidation products will be determined using model dinucleotide substrates of d(GpG) and d(CpC). Base- and sequence-specificity of reactions with oligonucleotides will be determined by gel electrophoresis for formation of frank strand breaks and alkali-labile sites. The effect of aerobic vs anaerobic atmospheres will be determined on the above reactions. (2) The role of ligand-based radicals of glutathione, ascorbate and cysteine in the formation of DNA oxidation products will be probed by the specific (nonchromium) generation of these radical species and through their in situ formation by reduction with Cr(VI). The formation and fate of the radicals will be monitored by EPR. Measurement of sugar and base oxidation products as well as the formation of frank strand breaks and alkali-labile sites will be carried out as described in specific aim 1. (3) Selective lethality of Cr(VI) in DNA repair-deficient strains of E. coli will be determined. The synergistic effects of added ascorbate or modulation of intracellular glutathione levels will be determined. Transformation of a plasmid into the sensitive E. coli strains will be carried out for later extraction and measurement of base and sugar oxidation products and mutations. The proposed studies should give insight into the mechanisms of chromium(Vl)-induced DNA damage critical to the formation of cancer. Understanding these mechanisms may allow reduction of risk to exposed human populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: POSTTRANSLATIONAL REGULATION OF HSF ACTIVITY Principal Investigator & Institution: Bonner, James J.; Associate Professor; Biology; Indiana University Bloomington P.O. Box 1847 Bloomington, in 47402 Timing: Fiscal Year 2002; Project Start 01-MAY-1996; Project End 31-MAR-2004 Summary: (provided by applicant): In eukaryotes, the regulation of stress-induced genes is dependent upon the Heat Shock Transcription Factor, HSF. Recent reports show that HSF is activated by superoxide anion, O2-. O2- is produced nonenzymatically during heat shock, and by mitochondrial activity during hypoxia or recovery from anoxia. The
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response to O2- shows that HSF is an immediate cellular defense against reperfusion injury, incurred subsequent to ischemic stresses such as stroke. This proposal seeks to understand the mechanism of the HSF conformational change and regulation of transcriptional activation. How does HSF recognize 02-? Are specific amino acid residues modified by superoxide-and if so, which ones? How is the change in cooperativity, which involves the DNA binding domain, transmitted to the trimerization domain, and to the transcriptional activation domains to change the biological function of the protein?. These problems will be addressed through genetic manipulations and biochemical analyses. Specific mutations will be induced in the yeast HSF protein, and their effects will be determined on the superoxide-induced conformational change, and on the biological activity of HSF in vivo. Two regions within the DNA binding domain will be targeted to examine the role of these regions in the conformational change. The trimerization domain will be targeted to examine its role in the regulation of transcriptional activity, and to determine how it collaborates with the DNA binding domain to activate HSF. To move the genetic analysis onto a stronger biochemical foundation, unique cysteine residues will be put into HSF, and used to introduce probes for fluorescence resonance energy transfer. To expand the understanding of the heat shock system beyond the detailed mechanism of HSF regulation, synthetic lethal interactions will be exploited. These will identify those cellular systems that require HSF activity in the absence of stress, and thus reveal why HSF is an essential gene in yeast. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEIN NEURODEGENERATION
STRUCTURE
IN
APOE4-ASSOCIATED
Principal Investigator & Institution: Weisgraber, Karl; Deputy Director/Senior Investigator; J. David Gladstone Institutes Box 419100, 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: Apolipoprotein E (apoE) displays critical isoform-specific effects in neurodegeneration and in the normal maintenance and repair of neurons. Unlike the other major human isoforms, apoE3 and apoE2, apoE4 is an established risk factor for Alzheimer's disease (AD). However, the basis underlying this isoform-specific effect is unknown and, most importantly, has not been explored systematically in terms of the effect of structure on function. A basic paradigm of protein chemistry is that the structure and biophysical properties of a protein determine whether it functions normally or abnormally. Thus, analyzing the structural and biophysical differences among the isoforms can provide important clues regarding the apoE isoform-specific mechanisms and basis for the association of apoE4 with AD. Previous studies fi'om the Project Leader's laboratory identified three major characteristics that distinguish apoE4 from apoE3 and apoE2: (1) the amino-terminal domain of apoE4 is the least resistant to chemical or thermal unfolding and forms a stable folding intermediate, which we determined is a molten globule state; (2) apoE4 lacks cysteine and does not form a disulfide-linked homodimer, whereas apoE3 and apoE2 contain cysteine at position 112 and form dimers; and (3) apoE4 domain interaction, an interaction of the amino- and carboxyl-terminal domains that is unique to apoE4. Our central hypothesis is that one or more of these structural or biophysical differences plays a major role in the association of apoE4 with neurodegeneration or deficits in neuronal repair. Our experimental approach is to alter the mouse Apoe gene by gene targeting to "humanize" mouse apoE with respect to each of the human isoform structural differences by introducing mutations that engineer in these structural differences individually and selectively.
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Using mouse models expressing mutant apoE displaying selected structural and biophysical features of human apoE4, we will examine the relative contribution of each of the human isoform structural differences to apoE4 behavior. As proof of principle, we have generated a mouse model of apoE4 domain interaction by gene targeting and are characterizing its phenotype. In this proposal, we will extend this structure-based approach with three specific aims that will test the hypothesis that the propensity of apoE4 to form a molten globule state and its lack of cysteine also contribute to the apoE4-specific effects. The identification of the key apoE4 structural and biophysical differences responsible for neurodegeneration holds the potential to provide new opportunities for novel therapeutic strategies designed to interfere with or diminish the pathological impact of these differences. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEIN-PROTEIN INTERACTIONS OF PLASMODIAL MSP-1 Principal Investigator & Institution: Bergman, Lawrence W.; Professor; Microbiology and Immunology; Drexel University College of Medicine 245 N 15Th St Philadelphia, Pa 19102 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 31-MAY-2005 Summary: Of the numerous blood-stage malaria antigens that have been identified in both infected humans and in animal models of this disease, the clearest rationale for a vaccine candidate exists for the merozoite surface protein-1 (MSP-1). This protein is synthesized as a large precursor during schizogony and is processed after merozoite egress from the erythrocyte into a series of proteolytic fragments. Despite the studies available on the MSP-1 protein, we have little definitive information on its role or roles in the functioning of plasmodium species. Its presence on all species of plasmodia examined to date, its regions of conservation such as the cysteine-rich C-terminal portion of the molecule, its resistance to being disrupted by gene knock-out, and its complex and specific processing all support the biological importance of MSP-1 to the parasite. A number of functions have been proposed for MSP-1 protein including participation in the initial binding of the merozoite to the red cell, involvement in signaling the parasite that it is now within the red cell to promote growth or playing a role in the egress of merozoites from the erythrocyte. Our current hypothesis is that MSP-1 is a multi-domain protein composed of a number of modular regions with different functions and that many, if not all, of these functions are mediated via proteinprotein interactions either with MSP-1 itself or other plasmodial or host molecules. We have chosen to utilize and our preliminary observations support the potential of the yeast two-hybrid system for examining protein-protein interactions of MSP-1. We will address the following specific aims in this proposal: (1) Define the intramolecular interactions of the MSP-1 protein. Preliminary experiments have demonstrated an interaction between two different regions of MSP-1. We propose to construct a detailed map of each of the interacting regions on the MSP-1 molecule and investigate the biological significance of this interaction. (2) Define the intermolecular interactions of the MSP-1 protein. Preliminary experiments have identified two previously undefined proteins that may interact with the N- terminal fragment of MSP-1. Experiments are proposed to investigate the nature of these molecules at the molecular level and characterize their interaction with MSP-1. Additional experiments are proposed to conduct similar two-hybrid studies for the other fragments of MSP-1 and to investigate additional relevant interactions through the construction of a bone marrow- derived cDNA library to explore potential parasite-host interactions. (3) Conduct a molecular analysis of the C-terminal 19 kDa fragment of MSP-1. Due to the cysteine-rich nature of
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this region, it has presented obstacles in using the two-hybrid approach. We propose alternative approaches to investigating the protein-protein interactions of this region. Finally, we describe a combinatorial chemistry approach to isolate small molecules that interfere with critical functions associated with this domain of MSP-1. We anticipate that this detailed analysis of the functioning of MSP-1 may lead to identification of new targets for immunologic or chemotherapeutic intervention, in addition to aiding our understanding of the biology of this key parasite molecule. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEOMICS OF COMPLEX 1 INHIBITION IN GSH-DEPLETED CELLS Principal Investigator & Institution: Gibson, Bradford Wayne.; Professor and Director; Buck Institute for Age Research Novato, Ca 94945 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Oxidative stress appears to play an important role in degeneration of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD). The SN of early PD patients have dramatically decreased levels of the thiol tripeptide glutathione (GSH). GSH plays multiple roles in the nervous system both as an antioxidant and a redox modulator. Recently, we generated dopaminergic cell lines in which levels of GSH can be inducibly down-regulated via doxycycline (dox) induction of antisense messages against both the heavy and light subunits of gamma glutamyl cysteine synthetase (gamma-GCS), the rate-limiting enzyme in glutathione synthesis. Down-regulation of GCS results in reduction in mitochondrial GSH levels, increased oxidative stress, and decreased mitochondrial function. Interestingly, decreases in mitochondrial activities in GSH-depleted PC12 cells appears to be due to a selective inhibition of complex I activity similar to that observed in PD. This loss in enzymatic activity appears to be a result of cysteine oxidation which is reversible by the thiol-reducing agent dithiothreitol. These results suggest that early observed GSH losses in PD may be directly responsible for the noted decreases in complex I activity and the subsequent mitochondrial dysfunction which ultimately leads to dopaminergic cell death associated with the disease. The hypothesis we will examine in this proposal is that oxidation of specific cysteines within the protein subunits of mitochondrial complex I are responsible for the selective inhibition of its activity following GSH depletion. To accomplish this goal, we will employ a series of sulfhydryl-specific probes to assess the redox states of cysteine thiol groups in complex I proteins. We will use highly sensitive mass spectrometry-based proteomics methods to identify the cysteine residue(s) that are responsible for this reversible loss of mitochondrial complex I activity. We will also examine complex I proteins for other types of oxidative damage (both reversible and irreversible) that may contribute to this loss of activity. These data should provide valuable insight into the effect of oxidative stress on mitochondrial physiology as it relates to PD, particularly the structural basis for alterations in mitochondrial function. Knowledge of the molecular details of complex I dysfunction and the identification specific subunit(s) that are involved may point us towards novel therapeutic targets for the disease and provide key data on whether thiol replacement therapy is a viable option for treatment of the disease. Once identified, presence of these alterations will be assessed in future years in both an antiGSH transgenic mouse model of Parkinson disease as well as in Parkinsonian brains. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REACTIVE METABOLITES AND DRUG TOXICITY Principal Investigator & Institution: Hanzlik, Robert P.; Professor; Medicinal Chemistry; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2002; Project Start 01-AUG-1978; Project End 31-MAR-2004 Summary: Many simple organic molecules containing phenyl substituents or benzene rings become cytotoxic upon biotransformation to reactive electrophilic metabolites. Prime examples include halothane, acetaminophen and bromobenzene (BB). Their hepatotoxicity is correlated with covalent binding of reactive metabolites to cellular proteins. As a start toward elucidating the biochemical mechanism(s) of their cytotoxicity we identified the structures of ten adducts of BB metabolites to protein-SH groups; most arose via quinone metabolites, but we also found that BB-3,4-oxide (BBO), thought to be the primary "toxic" metabolite of BB, alkylates histidine and lysine as well as cysteine residues of rat liver proteins. Key questions concerning the mechanism of cell injury by reactive metabolites include the identity of the proteins they target and the functional consequences of their covalent modification. We recently identified several rat liver proteins targeted by BB metabolites. One was a nonspecific esterase also known to be a target for metabolites of halothane and molinate. Another, surprisingly, was epoxide hydrolase, which is supposed to detoxify BBO. To address the mechanism of BB-induced cytotoxicity it is essential to expand this list by identifying other liver proteins targeted by BB metabolites. In doing so we will emphasize mitochondrial proteins but will continue to explore cytosolic and microsomal proteins. To facilitate recognition of BBO adducts, we raised antibodies to p-bromophenyl-cysteine and demonstrated their utility for western blotting; we will now develop antibodies to pbromophenyl-histidine and p-bromophenyl-lysine as well. These antibodies, coupled with [C14]-BB, will give us a broad and powerful means for finding and identifying those proteins of greatest toxicological interest. Very little is known about the chemistry and consequences of protein adduction by reactive metabolites. Thus we will elucidate in detail the specific site(s), metabolite(s) and linkage(s) involved in adduct formation for select BB target proteins. For those target proteins which are enzymes, we will evaluate the effect of adduction on catalytic activity to assess its potential contribution to cell injury. Comparing the proteins modified by bromobenzene to those modified by other small bioactivated toxins may reveal the existence, or the lack of, a "common pathway" for chemically-induced cytotoxic responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF CYSTATIN S GENE EXPRESSION Principal Investigator & Institution: Shaw, Phyllis A.; Assistant Professor; Anatomy/Functional Morphology; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-MAY-1987; Project End 31-MAR-2004 Summary: Mammalian salivary glands produce secretions that initiate digestion and bathe and protect the oral cavity. Salivary cystatins, proteins secreted by the submandibular and parotid glands, are believed to play a major role in this protection. Cystatins are evolutionarily conserved, naturally occurring cysteine proteinase inhibitors that regulate proteolysis by endogenous cysteine proteinases, as well as by proteinases of microbial pathogens and of some viruses. Although cystatins inhibit cysteine proteinases in vitro, their in vivo functions have not been delineated in detail. Since our long-term goal is to understand the role of cystatins in growth, differentiation, morphogenesis, and function of salivary glands, we propose to examine mechanisms
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governing expression of the cystatin S gene, which is expressed in rat salivary glands. This proposal will elaborate upon our previous findings that the cystatin S gene is unique in that it is cell type-and salivary gland-specific, it is expressed at a specific stage of posnatal development of the submandibular gland, it is turned off in adult animals, and it can be induced in adult rats by beta-receptor mediated mechanisms. In addition, its 5' flanking sequence has three sequence elements (I, II, and III) that are common to salivary gland-specific genes, and inserted between conserved elements II and III is a GT rich region (GT rich regions are thought to either inhibit or increase transcriptional activity of specific genes). Two major or hypotheses to be tested are that: 1) the conserved sequence elements present in all salivary gland-specific genes are the genetic elements that dictate salivary gland-specific phenotype, and 2) these conserved sequence elements somehow participate in the beta-adrenergic modulation of expression of a salivary gland-specific gene, cystatin S. Our specific aims are to: 1. determine the role of the conserved salivary gland-specific DNA sequence elements in cells in culture 2. identify and delineate potential regulatory elements In the cystatin S promoter that mediate IPR-induced cystatin S gene expression 3. verify that the cisacting conserved salivary gland-specific regulatory elements, and the regulatory elements that mediate IPR-induced cystatin S gene expression, that were identified in tissue culture act in vivo using transgenic mice 4. determine whether there are changes in trans-acting factors that accompany changes in expression of the cystatin S gene Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF ION CHANNELS BY METHIONINE OXIDATION Principal Investigator & Institution: Hoshi, Toshinori; Physiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 01-MAY-1998; Project End 31-JUL-2007 Summary: (provided by applicant): Many physiological and pathophysiological phenomena, including aging, ischemia/hypoxia, diabetes and some neurodegenerative diseases, promote oxidation of cellular constituents. Methionine and cysteine residues in proteins are readily oxidized; often inducing marked changes in protein function. It is hypothesized that reversible oxidation of cysteine and methionine serves as a physiological modulatory mechanism to regulate protein function. To test this hypothesis, the research program proposed here will examine how oxidation of cysteine and methionine alters gating behavior of human large-conductance calcium-dependent potassium channels (hSIo channels) using electrophysiological assays in combination with molecular mutagenesis. The proposed project will examine how hSIo channel gating is altered by methionine and cysteine oxidation. The biophysical and molecular targets of cysteine and methionine oxidation will be identified. The research program will also study regulation of the hSIo channel by heme, nitric oxide and hypoxia. It is hypothesized that these physiologically relevant variables alter the hSIo channel function in part by cysteine and/or methionine oxidation. Many of the experiments will be conducted in heterologous expression systems so that potential confounding variables, such as the channel subunit composition, are better controlled. These results will be confirmed by using native channels in hippocampal and cortical neurons. The electrophysiological results are quantitatively analyzed to elucidate which specific gating transitions are altered by oxidation of cysteine/methionine and by application of heme/nitric oxide. Previous studies using native calcium-dependent potassium channels often produced conflicting results. The results expected from this research program will clarify many of the important issues raised and provide molecular and biophysical insights into oxidative regulation of ion channels.
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Cysteine
Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF STREPTOCOCCUS PYOGENES EXOPROTEINS Principal Investigator & Institution: Chaussee, Michael S.; Basic Biomedical Sciences; University of South Dakota 414 E Clark St Vermillion, Sd 57069 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Streptococcus pyogenes secretes several proteins to the extracellular environment that directly influence host-pathogen interactions and contribute to virulence. Many secreted proteins have been studied in detail; however, the functions of several others are unknown. The locus-designated rgg is required for the expression of streptococcal pyrogenic exotoxin B (SPE B), a secreted cysteine protease that contributes to virulence. Inactivation of rgg also altered the expression of additional secreted proteins. Results obtained from genetic and physiological analyses of the rgg mutant strain have led to the hypothesis that the composition of available catabolic substrates influences exoprotein expression in an Rgg-dependent manner. To test the hypothesis, the following aims are proposed: Specific Aim 1. Determine if the availability of nitrogen-containing catabolic substrates influences Rgg dependent expression of virulence-associated exoproteins. Quantitative RT-PCR will be used to identify changes in mf-1 and speB expression in response to the availability of catabolic substrates. Proteomics and metabolite analysis will be used to assess the influence of catabolic substrates on exoprotein expression. Specific Aim 2. Identify Rgg-regulated proteins. Differences in protein expression between wild-type strain NZ131 and an isogenic rgg mutant will be detected with two-dimensional gel electrophoresis and differentially expressed proteins identified with mass spectrometry. Specific Aim 3. Distinguish between Rgg-regulated proteins and changes in expression due to perturbations of other regulatory circuits. Changes in protein expression will be identified with proteomics following induction of rgg expression by using a nisininducible promoter. Specific Aim 4. Determine if Rgg binds to promoter regions of genes encoding exoproteins to control expression. Electrophoretic mobility-shift assays will be used to determine if Rgg binds to the promoter regions of mf-1 and speB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF THE PAX-5 PROTO-ONCOGENE Principal Investigator & Institution: Hagman, James R.; Assistant Faculty Member; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): The Pax family of DNA-binding proteins includes essential regulators of tissue-specific gene expression in humans and other higher eukaryotes. Pax proteins are essential for the formation of differentiated cells and tissues, however, increasing levels of DNA binding activity results in neoplastic transformation and tumorigenesis. For example, chromosomal abnormalities and gene rearrangements resulting in overexpression of Pax-5 are associated with B lineage lymphomas in humans. Mechanisms contributing to Pax-5-mediated lymphomagenesis are not understood, but multiple lines of evidence suggest that the dosage of Pax-5 is exquisitely regulated in normal B cells by transcriptional and post-translational mechanisms. As one mechanism contributing to post-translational regulation of Pax-5, we propose that Pax- 5 DNA binding is regulated, in part, by the redox status of highly conserved cysteine residues in its paired DNA-binding domain. Thus, DNA binding by Pax-5 (and other Pax family members) may be reduced in response to oxidative stress.
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To date, this hypothesis has only been tested using limited in vitro model systems that do not adequately reflect the complexity of homeostatic mechanisms governing transcriptional activity in vivo. Moreover, it has not been determined whether Sthiolation (glutathionylation) of Pax-5 is an important mechanism for controlling its activity in vivo. In this application, we propose a genetic approach that bypasses previously encountered deficiencies associated with transfection assays and other in vitro experimental protocols. Our experiments will address a relatively unexplored area of molecular biology with profound implications for understanding how cells maintain precise levels of key regulatory factors. Our studies will eventually aid in devising new therapeutics for treating Pax-related cancers (lymphoma, astrocytoma, and rhabdomyosarcoma). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF UROTHELIAL CELL BEHAVIOR BY SPARC Principal Investigator & Institution: Bassuk, James A.; Research Scientist; Children's Hospital and Reg Medical Ctr Box 5371, 4800 Sand Point Way Ne, Ms 6D-1 Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 10-APR-2002; Project End 31-MAR-2007 Summary: Understanding how the urothelium grows and differentiates is central to understanding a number of bladder diseases. Being able to modulate these processes would allow us to improve how we repair urinary tract abnormalities in children. Preliminary evidence in our laboratory suggests that Secreted Protein Acidic and Rich in Cysteine (SPARC) plays an important role in regulating DNA synthesis and shape change of urothelial cells, which are two crucial processes involved in control of growth and differentiation of the urothelium. Other processes include a complex network of crosstalk communication between the urothelium and the mesenchyme. We propose to attack the SPARC part of this process because a) nothing is known about the biology of SPARC in the bladder and b) an understanding of how SPARC works in conjunction with these other processes will allow us to develop new and innovative methods to strengthen our translational approach to the problem of bladder and urinary tract disease. In order to achieve these goals, we have established specific aims for this period of support to better understand how SPARC functions in the context of a dynamic steady-state interrelationship that suppresses the progression of the urothelial cell cycle and mediates the attachment of urothelial cells to its underlying basement membrane. A dual role for SPARC in regulating these process is hypothesized to depend on whether SPARC is secreted or whether it remains inside the cell or nucleus. We propose that abundant levels of intracellular SPARC define the normal urothlelial phenotype - that of quiescence. During the proliferative phase, SPARC is no longer sequestered within cells, but instead is secreted into the extracellular space where it contributes to changes in cell shape that accompany the dismantling of focal adhesions, spreading, and a formation of the invasive phenotype. Information gained from this research will provide us with a basic descriptive understanding of SPARC function that we will use to design SPARC implants that will be tested clinically or in animal models by which SPARC modulates urothelial function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF CASPASE-9 IN HEART Principal Investigator & Institution: Kang, Peter M.; Assistant Professor of Medicine; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215
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Timing: Fiscal Year 2002; Project Start 23-JUL-2001; Project End 31-MAR-2006 Summary: (provided by applicant) The long-term goal of this research project is to characterize the roles of caspase-9 in heart. Apoptosis is a regulated cell deletion process that has been implicated in various cardiovascular diseases. Therefore, specific therapies targeted toward attenuating cardiac apoptosis most likely will have potential therapeutic benefit. Caspase-9, a member of a family of cysteine proteases, plays a critical role in the regulation of apoptosis. In our preliminary study, we showed thatreoxygenation is a strong inducer of apoptosis in adult cardiomyocytes, and reoxygenation-induced apoptosis involves the mitochondria-mediated pathway associated with the activation of caspase-9. This result suggests that caspase-9 is an important regulartor of apoptosis, and that the inhibition of caspase-9 could effectively inhibit cardiomyocyte apoptosis. However, the molecular mechanism of apoptosis in cardiomyocyte is poorly understood. Furthermore, we observed high caspase-9 protein expression in the adult cardiomyocytes, suggesting a possible important role of caspase9 in adult heart. Yet, very little is known about the role of caspase-9 in heart and the mechanism involved in its activation. Our hypothesis is that caspase-9 is an important reoxygenation-induced apoptosis in adult cardiomvocytes, and the inhibition of caspase-9 will be an effective strategy to attenuate cardiac apoptosis in vitro and in vivo. To test this hypothesis, in Specific Aim 1, we will investigate the role of caspase-9 and its interactions during the induction of cardiac apoptosis. We will study reoxygenationinduced apoptosis in adult cardiomyocytes as our model of cardiac apoptosis. To study the effect of caspase-9 and modulation of its interaction, we will generate and analyze recombinant adenoviruses to overexpress caspase-9 and various mutant forms of caspase-9 in adult cardiomyocytes. In Specific Aim 2, we will examine several strategies to inhibit caspase-9 activity including, pharmacological caspase-9 inhibition, overexpression of the dominant negative form of caspase-9, overexpression of endogenous caspase-9 inhibitor, and overexpression of anti-apoptotic Akt. Finally, in Specific Aim 3, we will define the role of caspase-9 in heart in vivo by generating cardiac-specific caspase-9 knockout mice. Since caspase-9 knock-out by homologous recombination results in perinatal lethality, the effect of caspase-9 in adult tissue can not be studied. Thus, the cardiac specific knockout of caspase-9 using Cre-loxP technology allows us to examine the tissue-specific role of capase-9 in adult animal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF CYSTEINE PROTEASES IN ATHEROSCLEROSIS & ANEURYSM Principal Investigator & Institution: Shi, Guo-Ping P.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2004; Project Start 10-JUN-1999; Project End 31-MAR-2008 Summary: (provided by applicant): One of the key steps during the pathogenesis of atherosclerosis and abdominal aortic aneurysm (AAA) is the vessel wall remodeling, which involves extensive extracellular elastin and collagen degradation. Our laboratory has demonstrated that elastolytic cathepsins (Cat) S, K, and L are highly expressed during the progression of these diseases. Deficiency of Cat S results in significantly attenuated atherogenesis. However, it remains uncertain if other elastolytic cathepsins (e.g. K and L) are playing a similar role in atherogenesis and/or AAA, although their expression profiles in these lesions suggest this potential. To examine these possibilities, we proposed two specific aims to test our central hypothesis that the cysteine proteases Cat S, K, and L play critical roles in atherosclerosis and AAA and the regulation of their expression directly affects the pathogenesis of these diseases. We will first examine how
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and by which inflammatory cytokine(s) Cat K and L are regulated in primary cultured human and mouse vascular cells followed by directly examining their roles in mouse atherosclerosis and AAA models. Our preliminary data demonstrated that cysteine protease inhibitor cystatin C is deficient in lesions from human atheroma and AAA. By contrast, the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) is highly expressed in these lesions as well as in sera from patients with AAA. A role for MIF in cultured endothelial cells and macrophages is implicated in regulating cysteine protease expression. We will thus examine if deficiency of MIF or cystatin C will affect atherosclerosis and AAA in mice and study how MIF regulates cysteine protease expressison. The availability of animal models of atherosclerosis and AAA and different gene deficient mice of cysteine proteases and their regulators in the P.l.'s laboratory and the promising observations from the Cat S null mice completed by this group make this proposal practical, crucial, and unique. Data from these specific aims will not only delineate a molecular/cellular mechanism for these elastolytic cathepsins involving in atherosclerosis and AAA, but also lead to the discoveries of novel drug targets against these life threatening diseases as potent and selective small molecule cathepsin inhibitors are readily available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF ELASTOLYTIC CATHEPSINS IN EMPHYSEMA Principal Investigator & Institution: Chapman, Harold A.; Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2006 Summary: (Applicant's Abstract): Although excessive proteolysis is a key element in the pathogenesis of emphysema, pathways of protease dysregulation in this disorder remain uncertain. New studies implicate lymphocyte-derived cytokines in emphysema. Interferon-y acts on macrophages as well as non-inflammatory cells such as smooth muscle cells to promote expression and secretion of the active cysteine protease cathepsin S, a potent elastase stable at neutral pH. Transgenic mice expressing either IL13 or interferon-y on airway surfaces develop cysteine protease-dependent emphysematous changes. Further, a significant correlation was recently found between serum levels of cystatin C, the major cysteine protease inhibitor, and severe reductions in FEV1 (<20 percent predicted) in a cohort of 30 patients with early-onset emphysema compared to controls with normal FEV1 and comparable smoking history. These studies invite the hypothesis that pro-inflammatory cytokines and possibly cigarette smoke stimulate mesenchymal lung cells and macrophages to secrete elastolytic cysteine proteases and downregulate their cystatin C release. This imbalance creates an accelerated process of collagen and elastin degradation important to the development of emphysema and COPD. The research plan is centered on the question of whether dysregulation of elastolytic cathepsins is important to the pathogenesis of emphysema. Parallel tracks of animal and human experiments are proposed: Mouse cathepsin S/L and cystatin C "knockouts" are used in Aims 1 and 2 to answer the question of whether excess elastolytic cathepsin activity exacerbates the development of interferon-yinduced emphysema and whether mesenchymal cells in the lung are a source of these enzymes. Aim 3 is designed to determine if low levels of cystatin C and/or polymorphic markers in or near the major genes regulating cystatin C (and elastolytic cathepsins) are associated with increased risk of COPD. Together, these studies should determine if some patients with early-onset COPD can be grouped, based on either phenotypic (cystatin C) or genetic markers, into a functional subset defined by a common pathogenic pathway involving dysregulation of elastolytic cathepsins.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF GLUTAREDOXIN IN METABOLIC OXIDATIVE STRESS Principal Investigator & Institution: Lee, Yong J.; Pharmacology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 05-FEB-2004; Project End 31-JAN-2008 Summary: (provided by applicant): The long-term goal of the proposed research project is to understand the molecular mechanisms of cellular responses to the unique tumor microenvironment (low glucose concentration, chronic hypoxia, and low extracellular pH). We previously observed that glucose deprivation increases the intracellular concentration of hydroperoxide. It also activates the SAPK (stress activated protein kinase) signal transduction pathway. In this grant proposal, we postulate that glutaredoxin (GRX), a redox-regulatory protein, recognizes the metabolic oxidative stress and triggers the ASK1-MEK-MAPK signal transduction pathway. The guiding hypothesis is that glucose deprivation raises the intracellular level of reactive oxygen species (ROSs) and increases the level of oxidized glutathione. GRX, which contains two redox-active half-cystine residues (Cys-Pro-Tyr-Cys) in an active center, recognizes metabolic oxidative stress through catalysis of thiol-disulfide interchange reactions with oxidized molecules such as oxidized glutathione. The oxidized GRX dissociates from ASK1 (apoptosis signal regulating kinase 1). The dissociation of GRX from ASK1 results in the activation of ASK1 and subsequently activates the ASK1-MEK-MAPK signal transduction pathway. The specific aims of this project are to examine (1) how GRX recognizes the metabolic oxidative stress, (2) the role of GRX in the ASK1-MEK-MAPK signal transduction pathway, (3) cooperation between GRX and thioredoxin (TRX) to regulate ASKI activation during glucose deprivation. The proposed studies for the first aim employ site-directed mutagenesis to create a point mutant at the redox-active site as well as at other cysteine residues. These studies will illustrate how half-cystine residues are involved in the recognition of metabolic oxidative stress. The second aim will employ molecular genetics and biochemical techniques to elucidate the involvement of GRX in the ASK1-MEK-MAPK signal transduction pathway. The third aim will use the immune complex kinase assay to assess the effect of intracellular glutathione deprivation, extracellular oxidized glutathione treatment, inhibition of GRX or TRX gene expression on ASK1 activation. We believe that investigating the mechanisms of metabolic oxidative stress responses in tumor cells will provide insight into how tumor cells recognize metabolic oxidative stress and initiate signal transduction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF PROTEASES IN CHEMOTHERAPY INDUCED APOPTOSIS Principal Investigator & Institution: Kaufmann, Scott H.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-1995; Project End 31-MAR-2006 Summary: (PROVIDED BY APPLICANT): Apoptosis, a morphologically distinct form of cell death observed during development, after withdrawal of trophic hormones, and after treatment with ionizing radiation or chemotherapeutic agents, is characterized by active participation of endogenous cellular enzymes in the disassembly of the cell. The present proposal seeks funds for collaborative studies by two laboratories with a longstanding interest in testing the central hypothesis that protease activation and activity plays an important role in the apoptotic process triggered by anticancer agents. Previous studies from these laboratories have demonstrated that 1) topoisomerase-directed drugs
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and other clinically useful antineoplastic agents trigger apoptosis in a variety of cell types; 2) the morphological changes of apoptosis are accompanied by the early, quantitative cleavage of a number of nuclear polypeptides; 3) this cleavage is mediated by multiple aspartate-directed cysteine proteases (caspases) with differing substrate preferences; 4) the pathways leading to activation of the caspases after treatment with etopside, topotecan, paclitaxel or ionizing radiation are distinguishable from the pathways of activation after death receptor ligation; 5) activation of protein kinase C by phorbol 12-myristate 13-acetatae (PMA) has no effect on drug-induced apoptosis but inhibits death receptor-induced apoptosis, at least in part, by preventing recruitment of the adaptor molecule FADD to ligated death receptors; 6) several of the procaspases are phosphoproteins; and 7) one key enzyme activated by caspase-3 is CAD, a unique caspase-activated deoxyribonuclease that cooperates with DNA topoisomerase II in playing an important role in nuclear disassembly downstream of caspases during druginduced apoptosis. We now propose to 1) more fully characterize the nature and physiological significance of posttranslational modifications detected in procaspses and active caspases; 2) identify the protein kinase C isoform responsible for PMA-induced inhibition of death receptor signaling and examine the signal transduction pathway leading to this inhibition; 3) evaluate the roles of survivin and a novel lymphomaassociated cIAP2/MALT fusion protein in caspase activation and apoptosis; and 4) perform a series of pilot experiments to determine whether disruption of the ICAD/CAD complex will result in CAD activation and cell death independent of prior caspase activation. These studies, which are designed to provide improved understanding of the biochemistry of chemotherapy-induced apoptosis, should be helpful in designing more effective cancer chemotherapeutic treatments in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF RED CELL MEMBRANE IN MALARIA PARASITE RELEASE Principal Investigator & Institution: Hanspal, Manjit; Assistant Professor; St. Elizabeth's Medical Center of Boston 736 Cambridge St Boston, Ma 02135 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JAN-2007 Summary: Plasmodium falciparum causes the most severe form of human malaria. During its 48-hour life cycle inside human red blood cells (RBCs) the parasite replicates into infective merozoites, which must then exit the host cell to invade new erythrocytes. Mounting evidence suggests that proteases are involved in host cell rupture and parasite release, although the molecular mechanisms underlying this process remain largely uncharacterized. Recently, we identified a novel P. falciparum cysteine protease named falcipain-2 (FP-2) that cleaves host erythrocyte membrane ankyrin, protein 4.1, adducin, and dematin with maximum proteolytic activity at late stages of parasite development. Based on our findings we propose that FP-2 mediates the cleavage of erythrocyte membrane skeletal proteins that are vital to the stability of red cell membrane, thus modulating the parasite release in vivo. The aim of this proposal is to define the functional role of FP-2 in vivo. Specifically, the following issues will be addressed: (1) What are the FP-2-mediated cleavage sites of erythrocyte ankyrin, adducin, and dematin? We have recently identified the site of protein 4.1 cleavage by FP-2, and have isolated an inhibitory peptide (Pi) that blocks all known functions of FP2 in vitro. Similar strategy will be used to determine the precise sequence of the cleavage sites of ankyrin, adducin, and dematin. Also, we will determine the specificity of FP-2 by using a series of peptides derived from Pi in which critical residues are varied based on substrate specificities of other papain family enzymes. The potent peptide(s) will be selected to determine it's (their) effect on the intraerythrocytic growth and ultimate
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release of P. falciparum parasite. (2) Is parasite-derived cytosolic falcipain-2 accessible to the erythrocyte membrane skeleton in vivo? This will be achieved by immunodetection of FP-2 within parasite- infected erythrocytes, and in subcellular fractions, and by studying biosynthesis and maturation of FP-2. Furthermore, we will use a cellpermeable cysteine protease inhibitor in P. falciparum cultures as well as in the mouse in vivo model to elucidate the role of cysteine proteases in parasite release. (3) What is the role of falcipain-2 in th intraerythrocytic life cycle of P. falciparum? To directly confirm the function of FP-2 in vivo and to determine whether FP-2 alone is sufficient for parasite release, a model will be developed by disrupting the FP- 2 gene using gene targeting technology. Together, the proposed studies on FP-2 may begin to reveal molecular mechanisms underlying the release of malaria parasite from the host erythrocyte. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SELENIUM-THIOREDOXIN SEMISYNTHESIS
REDUCTASE
STUDIED
BY
Principal Investigator & Institution: Hondal, Robert J.; Biochemistry; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Mammalian thioredoxin reductases are pyridine nucleotide-disulfide oxidoreductases that contain the unusual amino acid selenocysteine. In vivo, selenocysteine is coded in the mRNA by a UGA codon (normally a stop codon). This makes expression of these proteins in heterologous systems difficult. A second remarkable feature of the enzyme is that it utilizes a Se-S bond between adjacent residues in the catalytic cycle. Formation of this bond results in an 8-membered ring structure, and requires that the intervening peptide bond between neighboring cysteine and selenocysteine residues adopt a cis configuration. It is the major hypothesis of this proposal that the enzyme uses the catalytic power of adjacent cysteine and selenocysteine residues in a cis configuration to catalyze reduction of target disulfides. The cis configuration is expected to be more reducing because of the high local concentration of thiol this geometry imposes on the active-site. This proposal utilizes a semisynthetic system for studying the enzyme mechanism. This system divides the protein into two modules, one protein module, and a synthetic peptide containing selenocysteine. This semisynthetic approach to studying thioredoxin reductase and other selenocysteine-containing proteins is novel and unique. This semisynthetic system can be used to generate the wild-type protein and to insert peptide bond isosteres that restrict the geometry of the peptide bond. These isosteres allow for the study of the enzyme mechanism in great detail. The semisynthetic system also permits structure-function studies to be explored by using the method of peptide complementation. Model disulfide compounds that form an 8-membered ring will be synthesized. The redox potentials of these model compounds will be correlated to their backbone geometry. The redox potential of the catalytic disulfide bond of TR (S replaces Se) will be measured and correlated to the model compounds to determine the geometry of the peptide bond in the enzyme active-site. The importance of the thioredoxin system in disease processes such as cancer, arthritis, and malaria gives impetus to the study of the enzyme mechanism for the development of potential therapeutic inhibitors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SITE DIRECTED SPIN LABELING OF FEPA Principal Investigator & Institution: Feix, Jimmy B.; Associate Professor; Biophysics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 31-MAY-2004 Summary: (Adapted from abstract): FepA is an 81 kDa outer membrane protein responsible for iron uptake in E. coli and many other gram-negative bacteria via the binding and transport of its cognate ligand, ferric enterobactin (FeEnt). Since the ability of microorganisms to compete effectively for limited supplies of iron in the host is a key factor in the development of pathogenicity, a detailed understanding of the components and mechanisms involved in iron uptake is of significant medical importance. Electron spin resonance (ESR) spectroscopy is able to provide information on the structure and dynamics of large membrane proteins such as FepA that is not accessible by other techniques. In particular, site-direct spin labeling ESR has emerged as a powerful technique for mapping protein structure and investigating functional dynamics. Based on previous observations of conformation changes in FepA upon ligand binding, highly cooperative unfolding of the ligand-binding surface loop, and spin-label mapping of an entire transmembrane beta- strand, the investigators hypothesize that FepA functions as a ligand-gated porin with surface loops that bind the ligand and regulate access to an underlying transmembrane channel and that interactions between surface loops and residues in the transmembrane domain play an important role in the structural organization of the receptor. To test this hypothesis, the investigators will 1) evaluate the proposal that FepA is a ligand- gated beta-barrel receptor utilizing cysteine-scanning mutagenesis and site-direct spin labeling, 2) analyze pairs of spin-labeled cysteine residues to characterize loop-channel interactions and determine strand proximity in the beta-barrel domain, 3) employ time-domain ESR methods to measure distances between an array of spin-labeled sites and bound FeEnt, 4) identify ligand-induced conformational changes in purified, reconstituted FepA, and 5) selectively label FepA in live bacteria and examine conformational changes that occur upon FeEnt binding and transport. This research will provide insights into the structure and location of the ligand-binding site in FepA, the structure of the transmembrane beta-barrel, and the conformational changes that accompany ligand binding. These studies may significantly advance understanding of the structure and dynamics of ligand-gated bacterial outer membrane receptors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURAL BASIS OF ION SELECTIVITY IN CALCIUMN CHANNELS Principal Investigator & Institution: Sather, William A.; Associate Professor; Pharmacology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-JUN-1996; Project End 31-MAR-2006 Summary: Voltage-gated Ca2+ channels are the principal link between electrical signals in nerve cells and intracellular Ca2+ signaling pathways that allow nerve cells to, for example, release neurotransmitter or alter their gene expression. To accomplish these tasks, voltage-gated Ca2+ channels open in response to an action potential and allow exclusively Ca2+ to travel through the channel's highly selective pore into the cellular interior. Malfunction of neuronal voltage-gated Ca2+ channels has serious health consequences for humans, including the genetic diseases spinocerebellar ataxia type 6, familial hemiplegic migraine, and episodic ataxia type-2. The goal of the proposed
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research is to understand the structural basis of selective ion flux through Ca2+ channels. In pursuit of this broad goal, we plan to carry out three Specific Aims: (1) determine the topography of the pore in an L-type Ca2+ channel; (2) localize Ca2+ channel gate(s) by testing for state-dependent accessibility of sulfhydryl-modifiers; and (3) measure the electrostatic potential profile in the pore of an L-type Ca2+ channel. In all of these studies we will measure the accessibility to sulfhydryl-modifying agents of cysteine-substituted mutant forms of the a1c L-type Ca2+ channel. If the sulfhydrylbearing side chain of a substituted cysteine residue is exposed in the lumen of the pore, then covalent attachment of a sulfhydryl-modifying reagent may result in obstruction of permeant ion flow through the pore. Using the resulting persistent block as an index, we will determine which residues of putative pore-lining sequences (S5, P-loop, S6 segment) in fact line the pore. We will determine the dimensions of several parts of the ion-conducting pore (external and internal vestibules, ion selectivity filter) using sulfhydryl-modifiers of various sizes. We will use open/closed/inactivated statedependent accessibility to localize the gate(s) of the Ca2+ channel. An important parameter of selective ion transport is the intrinsic electrostatic potential in the pore, and this will be determined from measurements of modification rate for differently charged sulfhydryl modifiers. In all experiments, block of current will be measured for voltageclamped, heterologously expressed Ca2+ channels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STRUCTURAL/FUNCTION B CELL DIFFERENTIATION ANTIGENS Principal Investigator & Institution: Clark, Edward A.; Professor; Microbiology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2004; Project Start 01-DEC-1986; Project End 31-MAR-2008 Summary: (provided by applicant): In this grant the major goal is to investigate mechanisms regulating quiescent B cells either poised in the GO stage of the cell cycle (GO B cells) or leaving GO to enter the cell cycle. We have found that caspases- a family of cysteine proteases involved in programmed death of B cells- also regulates B cell entry into the cell cycle. The caspase-6 inhibitor VEID blocks proliferation of GO B cells. However, caspase inhibitors do not block induction of inhibitors of apoptosis (lAPs). Our data suggest caspases are required for a pathway common to all modes of inducing B cells into the cell cycle. Our Aims are: Aim 1: To define the requirements for caspase activation in B cells, i.e., the signaling pathways upstream of caspase activation in B cells. We will test whether or not different receptors activate the same or distinct sets of caspases in GO B cells. We will test the hypothesis that T cell dependent (TD) vs. T cell independent (TI) signaling receptors activate similar or distinct caspase pathways in GO B cells. We will define the upstream pathways required for activating caspase-6 and -8 in B cells. Using a dominant negative (DN) form of FADD or caspase-6 and B cells from caspase-6 knockout mice, we will test if activation of caspase-6 is required for activation of caspase-8 or vice versa. We will also test if clAPs, when activated via CD40, contribute to the selective activation of caspases -6 and -8 and ceil cycle entry. Aim 2. We will test the hypothesis that caspase-6 cleaves a functional set of substrates in GO B cells as they enter the cell cycle and activate a survival program. First, we will characterize the cell cycle block observed upon inhibition of caspase-6. Second, we will define substrates for caspase-6 and assess their roles in B cells. We will define where caspase-6 goes in B cells after they are activated and how the caspase-6 substrate, SATB1, is regulated by caspase-6 in B cells. Aim 3. We will characterize the B cell defects in caspase-6 -/- mice and compare the survival of B cell subsets in wildtype vs. CD40 -/- or caspase-6 -/- mice. We predict that caspase-6 and CD40 are required for optimal B cell
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survival. We will also test if caspases selectively regulate homeostasis and expansion of B cell subsets. These studies will provide new insights into the mechanisms, which regulate the survival of normal B cells, malignant B cells and B cells contributing to autoimmune diseases Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STRUCTURE AND FUNCTION OF MEMBRANE PROTEINS Principal Investigator & Institution: Dowhan, William; Professor, & Holder of the Johns S. Dunn; Biochem and Molecular Biology; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-JUN-1976; Project End 31-MAR-2005 Summary: (Adapted from the Investigator's abstract): Several members or the Major Facilitator Supertamily (MFS) are detective in active solute transport when expressed in mutants of Escherichia co/i lacking phosphatidylethanolamine (PE). The molecular basis for dysfunction in lactose permease (LacY) was established to be a requirement for PE as a molecular chaperone in the conformational maturation of LacY after membrane insertion. A large cytoplasmic domain in the middle of LacY when assembled in PElacking cells is topologically mis-assembled and exposed to the periplasm. A major aim of this proposal is to establish the molecular determinants within polytopic membrane proteins that in cooperation with membrane lipid composition and the protein assembly machinery dictate the topological organization of membrane proteins. The primary molecular probe will be accessibility of single cysteine replacements within a cysteinelacking derivative of LacY. The topological organization of LacY and its interaction with PE will be studied using both in vivo and in vitro assembly of LacY in the presence and absence of PE. The structural and functional properties of LacY will be studied in proteoliposomes reconstituted from defined lipid components. Interaction between lipids and LacY will be studied in detergent-lipid mixed micelles. Site directed mutagenesis aimed at putative topogenic signals within LacY will be used to define elements within LacY that determine its topology. Second site suppressors of dysfunction of LacY will be isolated to identify elements of LacY and other components that determine protein topology. The phenylalanine permease and the aromatic amino acid permease are dysfunctional in PE-lacking cells. The same approaches will be used to study the molecular basis for the dysfunction of these transporters and to establish the generality of the involvement of PE in assembly of members of the MFS. The development of strains lacking FE has provided versatile biological reagents to probe the role of lipids in cell function. To broaden the scope of reagents available to study the role of lipids, E. co/i strains will be developed that either contain or replace native lipids with lipids (monoglucosyl diacylglycerol, phosphatidylcholine, phosphatidylinositol) found in other organisms. The proposed experiments are expected to define at the molecular level the role of PE and other lipids in the assembly, organization, and function of polytopic membrane proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURE OF ADENOSINE RECEPTORS Principal Investigator & Institution: Wells, Jack N.; Pharmacology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Adenosine is a hormone with localized effects in most, if not all, organ systems. It is released under stress of low energy levels in a cell, resulting in decreased
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oxygen demand and increased oxygen delivery. The receptors for adenosine(AR) are members of the G protein-coupled receptor (GPCR) superfamily, but little firm biochemical information is available concerning the amino acids that comprise the ligand-binding pocket of the four subtypes of AR, and it is anticipated the the unique structure of adenosine will require a binding pocket distinct from that for monoamines. The widespread effects of adenosine agonists and antagonists serve to illustrate the potential importance of developing subtype-specific agonists and antagonists of AR. The goal of this program is to generate firm biochemical data that can be utilized to develop reliable molecular models of the AR which will facilitate receptor-based design of subtype specific agonists and antagonists of AR. The present studies aim to establish, by the Substituted Cysteine Accessibility Methods (SCAM), which amino acids of the transmembrane spans (TM) of the A1AR are accessible to the aqueous-milieu and, therefore, are positioned within the ligand-binding crevice of the A1AR. This strategy entails substituting cysteines for individual amino acids and determining the reactivity of the cysteines with hydrophilic, lipophobic, cysteine-specific reagents. If the cysteinespecific reagents irreversibly inhibit ligand binding and the presence of agonists and/or antagonists retard the rate of inactivation of the receptor, the cysteine must be positioned within the ligand binding pocket. The periodicity of reactive cysteines will provide insights concerning the structural nature of the TM. Similar methodology will be employed to determine if agonists and xanthine-type antagonists occupy the same binding site, and determine the relative orientations of adenosine and xanthines within the binding site. In a third phase of this program, studies are designed to delineate the three-dimensional arrangement of the TM of the A1AR by determining some of the contact points between the seven TM by combining expression of non-overlapping fragments of the A1AR and cysteine-scanning mutagenesis with disulfide crosslinking to reveal these contact points. These studies should provide insights concerning the mechanism of signal transduction through the receptor protein and in conjunction with data generated from the SCAM studies will allow discrimination between clockwise and counterclockwise bundling of the seven TM. Thus, these studies should provide data that will test currently available computational models of GPCR and allow the molecular modeling of the A1AR based on firm biochemical data that establishes the gross three-dimensional arrangement of the membrane spanning portions of the receptor and the amino acids accessible from the aqueous environment of the ligand binding pocket. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STRUCTURE, MECHANISM AND REGULATION OF THE VATPASES Principal Investigator & Institution: Forgac, Michael D.; Professor; Physiology; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 30-AUG-1985; Project End 31-JUL-2006 Summary: The long term objectives of this proposal are to determine the structure, mechanism and regulation of the vacuolar (H+)-ATPases (or V- ATPases). The VATPases are responsible for acidification of intracellular compartments in eukaryotic cells and serve an important function in a variety of cellular processes, including receptor-mediated endocytosis, intracellular membrane traffic, protein processing and degradation and coupled transport of small molecules. V-ATPases in the plasma membrane of specialized cells also function in renal acidification, pH homeostasis, bone resorption and tumor metastasis. Understanding how V-ATPases are regulated is thus crucial to understanding many disease processes, including viral entry, osteoporosis and
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metastasis. The V-ATPases are organized into two functional domains: a peripheral V1 domain responsible for ATP hydrolysis and a integral V0 domain responsible for proton translocation. Electron microscopic images of the V-ATPase complex reveal multiple connections between the V1 and V0 domains. To determine the arrangement of subunits within the V-ATPase complex, unique cysteine residues will be introduced into the B subunit and used as sites of attachment of a photoactivated crosslinker. In addition, electron microscopy of complexes decorated with subunit- specific antibodies will be performed. The function of a unique domain of the catalytic A subunit will be addressed by deletion and random mutagenesis. The structure of the 100 kDa a subunit and its interactions with the proteolipid subunits of the V0 domain will be determined using cysteine mutagenesis, chemical labeling and disulfide bond formation. Finally, the in vivo dissociation of the V-ATPase complex, which has been proposed to be an important regulatory mechanism, will be investigated. Dissociation in response to glucose depletion will be compared in V-ATPases located in different intracellular compartments and mutants defective in dissociation will be selected and analyzed. These studies should provide further insight into the structure and regulation of this important family of (H+)-ATPases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SULFATE ADENYLATION -- BIOCHEMISTRY & ENZYMOLOGY Principal Investigator & Institution: Leyh, Thomas S.; Professor; Biochemistry; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2004; Project Start 02-SEP-1995; Project End 31-MAR-2008 Summary: (provided by applicant): The entry of sulfate into metabolism requires that it be chemically activated. The only known metabolic means of activating sulfate is the formation of the very high-energy phosphoric-sulfuric acid anhydride bond (?Go= -19 kcal/mole). This bond is the chemical hallmark of activated sulfate (APS or PAPS), and it is from this high-energy environment that the sulfuryl-moiety (-SO3) passes quickly and favorably into its subsequent metabolic biochemistry. The activated bond is formed in a transfer reaction, catalyzed by ATP sulfurylase, in which the adenylyl-moiety (AMP~) of ATP is transferred to sulfate. In mammals, sulfuryl-group transfer to proteins and small molecule metabolites regulates a wide-variety of metabolic processes including neuropeptide- and steroid-hormone action, growth-factor recognition, and lymph cell circulation. This proposal outlines structurally-based mechanistic inquires designed to address central issues regarding the function and evolution of the mammalian class of ATP sulfurylases. Bacterial ATP sulfurylases harbor a GTPase subunit (discovered in this laboratory) that is an evolutionary descendant of elongation factor Tu. The conformational changes that this subunit undergoes as a consequence of GTP hydrolysis accelerate turnover of the adenylyl-transferase subunit, and couple the chemical potentials of GTP hydrolysis and APS synthesis. We have recently discovered that ATP sulfurylase forms a complex with another enzyme in the cysteine biosynthetic pathway (O-acetly-l-serine sulfhydrylase), and that their interactions produce "new" catalytic function - the hydrolysis of ATP. These enzymes organize into a metabolic pump, each stroke of which delivers one molecule of APS into the pathway. The mechanism of the pump will be explored in this grant. Working with an as yet uncharacterized and novel ATP sulfurylase from Mycobacterium tuberculosis, our preliminary data extends these finding to include five of the seven enzymes in the pathway. We will define and study the cysteine metabolon with the goal of understanding the hierarchical functions that emerge from the self-organization of this pathway.
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Project Title: SULFUR-CENTERED CRYSTALLIN MODIFICATIONS & LENS OPACITY Principal Investigator & Institution: Pande, Jayanti; Research Associate; Physics; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 01-JUN-1994; Project End 31-MAY-2003 Summary: Sulfur-centered post-transitional modifications of the crystallins are a recurring feature in many cataractous lenses. This is especially true of maturity-onset human nuclear cataract, in which the cysteine and methionine residues of the beta and gamma crystallins are found to be chemically modified. It is generally assumed that all such modifications are cataractogenic, despite the vast chemical differences between them. In this proposal a strategy is presented to identify the general chemical determinants of cataractogenicity in a variety of crystallin modifications at the cysteine and methionine residues. This strategy is based on the hypothesis that: polar or charged modifications decrease the net attraction between proteins, and are therefore "cataractinhibiting". Conversely, marginally polar and hydrophobic modifications increase the net attraction between proteins and are therefore "cataractogenic." The following Specific Aims are proposed to test this hypothesis. 1. Introduce in vitro, oxidative modifications normally found in the lens, at the sulfur centers of the beta and gamma crystallins individually and in mixtures, and measure the "cataractogenic" or "cataractinhibiting" properties of the modified proteins, as defined above. 2. Examine the influence of charge, hydrophilicity and stearic effects on the cataractogenic or cataractinhibiting tendency of the gamma crystallins and beta-gamma crystallin mixtures modified at the cysteine or methionine residues, using selected chemical modifiers. 3. Evaluate the role of alpha-crystallin and its subunits alpha-A and alpha-B in inhibiting protein aggregation due to sulfur-centered modifications of the gamma crystallins and beta gamma crystallin mixtures. 4. Determine the role of individual cysteine and methionine residues in cataractogenesis by introducing point mutations at these residues using site-directed mutagenesis. The long-term objectives are to devise strategies to prevent cataractogenic modifications in vivo. The proposed studies in Aim 2 are expected to eventually guide the development of anticataract drug candidates. Changes in the net attraction between lens crystallins will be determined by measuring Tph, the phase separation temperature and protein aggregation. SDS-PAGE, size exclusion HPLC, quasielastic light scattering and protein clouding measurements to determine Tph. Ion-exchange HPLC, low pressure chromatography, isoelectricfocusing, Raman and mass spectroscopies will be used as analytical methods for protein characterization. Molecular modeling studies will guide the selection of reagents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE CRES GENE IN REPRODUCTION Principal Investigator & Institution: Cornwall, Gail A.; Cell Biology and Biochemistry; Texas Tech University Health Scis Center Health Sciences Center Lubbock, Tx 79430 Timing: Fiscal Year 2002; Project Start 01-APR-1995; Project End 31-MAR-2006 Summary: The long-range objective of our studies is to determine the role of the CRES (cystatin-related epididymal spermatogenic) protein in reproductive function. Gene and protein structure studies show that the CRES protein is a new member of the family 2 cystatins of the cystatin superfamily of cysteine protease inhibitors. However, several lines of evidence suggest that CRES may not function as a classic cystatin. Firstly, CRES
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protein lacks two of three consensus sites important for inhibition of cysteine proteases. Secondly, our in vitro enzyme assays show that, in contrast to cystatin C, CRES protein does not inhibit the cysteine proteases papain, cathepsin B, legumain, or caspase. Finally, unlike the ubiquitous expression of the family 2 cystatins, CRES protein expression is unique and is restricted to sites of high proteolytic activity within specific reproductive tissues including the proximal caput epididymis, anterior pituitary gonadotropes, and sperm acrosomes. Besides being localized to sites of high proteolytic activity, very strong evidence that CRES protein is a protease inhibitor is our recent in vitro enzyme assays showing that CRES protein is inhibitory against members of a family of highly substrate specific serine proteases known as the prohormone convertases. This recently discovered family of proteins play critical roles in prohormone and proprotein processing in a variety of organ systems including the neuroendocrine and reproductive systems. Taken together, our preliminary studies provide strong evidence that CRES protein is a potential inhibitor of an important family of proteases with widespread biological significance and therefore further studies on CRES protein are warranted. Because the epididymis and sperm acrosome are active sites where precursor proteins are processed to their mature forms and in vitro, CRES inhibits proteases with confirmed biological roles in protein processing, we hypothesize that CRES protein is a novel prohormone convertase inhibitor which regulates proteolytic processing events in the sperm acrosome and epididymis and thus is important for fertilization and sperm maturation. We will test our hypothesis in the following specific aims: 1) examine CRES protein as a convertase inhibitor by in vitro enzyme assays and co- immunoprecipitation experiments. Functional analyses of CRES as a convertase inhibitor will be initiated by examining potential targets of convertases; 2) examine acrosomal CRES protein in mouse sperm function; and 3) examine the biological function of CRES protein in vivo by gene knock-out studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE MOLECULAR BASIS OF LOCAL ANESTHESIA Principal Investigator & Institution: Balser, Jeffrey R.; Professor; Anesthesiology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-1997; Project End 31-JUL-2005 Summary: (Verbatim from the applicant's abstract) Sodium (Na) channels, the principle target of local anesthetic agents, change their conformational state in response to membrane potential. Depolarization increases the intensity of the drug-receptor interaction nearly 100-fold. While this phenomenon imderlies the broad therapeutic efficacy of local anesthetics, these voltage-dependent interactions also provoke lifethreatening side effects (arrhythmias, seizures). Clarifying this dynamic modulation of the drug-receptor interaction will complement new data identifying local anesthetic binding domains, and will improve the design of these compounds. A number of distinct Na channel loci that mediate intrinsic conformational changes (fast and slow inactivation) also modulate local anesthetic action, consistent with the original proposal (the Modulated Receptor Hypothesis) that local anesthetic binding affinity is governed by conformational state. A corollary prediction is that local anesthetics, when bound, should induce the Na channel to occupy higher-affinity conformational state(s). Recent work reveals that intrinsic Na channel conformational changes involve sizeable molecular motions that modify the architecture of the pore. We propose that local anesthetics function as allosteric effectors to induce intrinsic conformational changes in the pore, analogous to ligand effects on allosteric enzymes. Our studies will examine the gating conformational properties of heterologously-expressed Na channels containing
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engineered cysteine residues using patch-clamp methods. Using methanethiosulfonate reagents, we will examine how slow inactivation changes the sulfhydryl accessibility of amino acid residues in the outer pore region in response to local anesthetic binding. In addition, we will examine the linkage between the earliest phase of depolarizationinduced block and motion of the charged S4 segments, with a view to linking motion of these segments to conformational changes in the outer pore. Finally, we will utilize a disulfide trapping approach to constrain the interdomain distance changes induced by local anesthetic block, and will interpret these using a new molecular model of the Na channel pore. Our studies will illuminate the dynamic structure of the Na channel pore, and will facilitate the design of more targeted and less toxic local anesthetic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THERAPEUTIC/MECHANISTIC ROLE OF APE1 IN GERM CELL TUMORS Principal Investigator & Institution: Kelley, Mark R.; Associate Director; Pediatrics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2003; Project Start 05-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Therapy for disseminated germ cell tumors (GCT) has been successful with 70-80% of patients being cured with front line chemotherapy. However, for those 20-30% of patients with extra-gonadal primaries or refractory disease, the response to therapy is poor with only 3-30% surviving disease-free after second line agents. One approach to treating resistant disease is the development of strategies to augment the chemotherapeutic agents that have been so successful in the majority of GCT patients. Little is known about the role of DNA repair systems in GCT's except that efficient repair appears to make tumor cells resistant to therapy. We have observed that GCT's express high levels of Ape1/ref-1 compared to normal tissues. Ape1/ref-1 is a multifunctional protein with DNA base excision repair (BER) activity and redox activity required for activation of specific transcription factors including Fos, Jun, NFkappaB, HIF-1alpha (hypoxia inducible factor), p53, and PAX5. This novel combination of functions links Ape1/ref-1 with resistance to many of the therapeutic agents (bleomycin, cisplatin, radiation, and VP-16) used to treat GCT's by acting as direct substrates for BER or indirectly by altering signaling through transcription factors regulated by Ape1/ref-l. Based on this information, we hypothesize: High level expression of Ape1/ref-1 in GCT's is a functional marker of disease which 1) is predictive of high risk disease and 2) can be manipulated to gain a therapeutic advantage. The major thrust of this proposal is to characterize the molecular biology of Ape1/ref-1 in GCT's as it relates to the clinical course of patients and the response of GCT cells to therapeutic agents. To approach this goal, we have developed four Specific Aims: Specific Aim1: Determine the relative expression of, Ape1/ref-1in good prognosis and high-risk GCT's. This takes advantage of the wealth of clinical GCT material available at Indiana University. Specific Aim 2: What is the role of Ape1/ref-1 in GCT progression and development, including cell growth, apoptosis, cell cycle, and differentiation? That is how does the high level expression of Ape1/ref-1, including over-expression of repair, redox, and nuclear localization domain mutants independently affect the ability of GCT cells to grow as cancer cells. Specific Aim 3: How do changes in the redox status of Ape1/ref-1 affect repair function? Using site-specific mutants, determine which cysteine residues specifically control repair function of Ape1/ref-l? Specific Aim 4: How do alterations in the repair and redox functioning of Ape1/ref-1 affect the response of GCT cells to therapeutic agents? Using what we learn
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in Aims 2 & 3, how can we alter the resistance of GCT cells to therapeutic agents. Through these analyses, we hope to determine the underlying mechanisms by which Ape1/ref-1 function is linked to the progression of testicular cancer. If any mutants are shown to sensitize the GCT cell lines to chemo-/IR agents, as expected, this will set the stage for future gene therapy approaches to sensitize GCT's to therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSGENIC STUDIES OF AMYOTROPHIC LATERAL SCLEROSIS Principal Investigator & Institution: Deng, Han-Xiang; Neurology; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Adapted from applicant's abstract): The goal of this project is to investigate the pathogenic mechanisms underlying the neurodegeneration of amyotrophic lateral sclerosis (ALS) using transgenic mouse models. Our application has two immediate Aims: The first one is to replace the two free cysteine residues in mutant human SOD 1 protein to test the role of free -SH groups in the formation of intracellular aggregates noted in ALS. The second aim is to define the smallest fragment of SOD 1 that would still cause ALS in transgenic mice. AIM 1: About 20 percent of the familial ALS cases are caused by mutations in Cu/Zn superoxide dismutase gene (SOD 1). Transgenic mice that over express mutant SOD 1 develop an ALS-like phenotype and motor neuron degeneration. A common feature in the pathology of both human SOD1-linked ALS and the ALS (SOD1) mouse models is the presence of the SOD 1-inimunoreactive inclusions or aggregates in neurons of the brain and spinal cord. These inclusions/aggregates are thought to be important elements in motor neuron death in ALS. To test the hypothesis that these inclusions/aggregates may be formed by disulfide bonds through interaction of free -SH groups of one or both free cysteines in SOD 1, we propose to develop new transgenic mouse model that over expresses a mutated SOD 1 (C6A/C1 1 1S/G93A). In this transgenic mouse model, two free cysteines in human SOD1 are replaced by an alanine and a serine. Absence of inclusions/aggregates will indicate a role for free cysteines; Absence of disease as well as inclusions/aggregates may indicate a causative role of the free cysteines (-SH groups). AIM 2: We recently made a new transgenic mouse model that over expresses a truncation mutation in SOD 1 (L126Z). These mice developed a typical ALS-like phenotype and pathology. These results provide the experimental evidence that only a part of the SOD1 polypeptide, rather than entire SOD1 protein, is sufficient to produce the neuronal toxicity and cause motor neuron degeneration. We plan to define the minimum fragment of SOD 1 essential for toxicity so that further studies into the pathogenesis of ALS may be facilitated. To achieve this goal we propose to develop additional transgenic mouse lines that over express successively smaller fragments of SOD 1 polypeptide to determine the smallest segment of SOD 1 that causes ALS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: VARIOLA VIRUS G1L:AN ANTIVIRAL DRUG TARGET Principal Investigator & Institution: Hruby, Dennis E.; Chief Scientific Officer; Microbiology; Oregon State University Corvallis, or 973391086 Timing: Fiscal Year 2004; Project Start 15-JUN-2004; Project End 31-MAY-2006 Summary: (provided by applicant): Variola virus (Smallpox) is a Category A pathogen considered to be one of the most significant threats for use as a bioterrorism agent. Due to complications from vaccination, mass immunization of the populace is contra-
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indicated. Our current research seeks to develop effective anti-orthopoxvirus drug(s), which is designated as a high priority biodefense project. Using vaccinia virus (VV) as a model system, the goal of our previous research was to determine if the l7L cysteine proteinase or the G1L metalloproteinase encoded by W is the poxvirus core protein proteinase (vCPP), and to use this information to develop vCPP inhibitors as candidate antiviral drugs. We have recently demonstrated that the l7L cysteine proteinase is the vCPP and are proceeding with drug development efforts on this target. But what about G1L? This represents an unexpected opportunity that should be investigated. We believe that the W G1L metalloproteinase represents a unique and distinct orthopoxvirus antiviral target. The purpose of the experiments outlined in this application are to: 1) Produce a G1L conditional-lethal mutant to assess the phenotype of the null mutant; 2) Elucidate the biological role of G1L during viral replication and/or assembly; and 3) Demonstrate and characterize the enzymatic activity of the G1L gene product. Successful completion of these experiments should allow the development of G1L metalloproteinase inhibitors as antiviral drugs to be initiated. There are several important reasons to exploit the G1L target in addition to l7L: Not all enzymes are equally "drug-able" and G1L inhibitors may have superior activity/specificity profiles; When exposed to selective pressure, viruses rapidly acquire resistance so having multiple antiviral drugs available is essential; and using a cocktail approach with multiple inhibitors may be more effective than using a single drug. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VOLTAGE-GATING IN BACTERIAL ION CHANNELS Principal Investigator & Institution: Correa, Ana M.; Anesthesiology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Voltage-gated ion channels (VGC) are proteins found in the membranes of practically all cells, that through opening and closing (gating) events let ions flow through between the internal and external milieu of the cells acting as very fast signaling entities. The most characteristic and intriguing aspect of VGC is that their function is modulated by voltage. That means that the protein senses changes in the electrical field and responds by opening, possibly through a sequence of conformational changes. With the advent of high resolution electrical recording techniques combined with the molecular cloning and engineering of ion channel proteins, it has been possible to identify parts of VGC that would serve as voltage-sensors, which has led to proposal of several mechanistic models on how the voltage-sensing event is translated into channel opening. Yet, the molecular and physical natures of the events that take place during voltage-gating are not resolved. It is the long-term goal of this proposal to contribute a physical molecular model of how VGC gate by studying intramolecular distances at rest and while channels are open, using optical tools along with functional recordings. The recent cloning of a bacterial sodium channel, NaChBac, which can be produced in large quantities, purified and reconstituted into lipid membranes, provides a unique opportunity to address these questions in great molecular detail. The specific aims are: 1) Search for regions and residues that undergo distances changes associated with the voltage sensor and between the sensor and the gate region using lanthanide-based resonance energy transfer (LRET) in the reconstituted protein in different conformational states induced by voltage changes in proteoliposomes; 2) Measurement of distances in tandem proteins, purified and reconstituted, bearing a single donor acceptor pair using the same technique as in aim 1; and 3) Functional analysis of voltage sensing and gating using electrophysiology
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and site directed fluorescence and its correlation to structure and structural changes studied in aims 1 and 2. To measure distances, cysteines are introduced in different parts of the protein and a special sequence, an EF-hand motif that binds lanthanides, is introduced in another part of the same protein. Fluorescent probes are then used to label the cysteine group and are prompted to emit upon excitation of the lanthanide with light. Because groups will be placed in areas suspected to participate in voltage gating, these measurements are expected to contribute real molecular distances and information on molecular rearrangements occurring during voltage gating. VGC are particularly important in nerve and muscle cells because they determine cell excitability and participate in cell-to-cell communication. The results from this work should help in our understanding of a large number of VGC that are crucial in health and in drawing strategies to 1'ameliorate or perhaps eventually cure some illnesses that involve the dysfunction of this important family of channels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “cysteine” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for cysteine in the PubMed Central database: •
A 21-amino acid peptide from the cysteine cluster II of the family D DNA polymerase from Pyrococcus horikoshii stimulates its nuclease activity which is Mre11-like and prefers manganese ion as the cofactor. by Shen Y, Tang XF, Yokoyama H, Matsui E, Matsui I.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=373266
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A Novel Family in Medicago truncatula Consisting of More Than 300 NoduleSpecific Genes Coding for Small, Secreted Polypeptides with Conserved Cysteine Motifs. by Mergaert P, Nikovics K, Kelemen Z, Maunoury N, Vaubert D, Kondorosi A, Kondorosi E.; 2003 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166962
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A Proline-rich Region and Nearby Cysteine Residues Target XL[alpha]s to the Golgi Complex Region. by Ugur O, Jones TL.; 2000 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14856
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Alteration of Sendai Virus Morphogenesis and Nucleocapsid Incorporation due to Mutation of Cysteine Residues of the Matrix Protein. by Sakaguchi T, Uchiyama T, Huang C, Fukuhara N, Kiyotani K, Nagai Y, Yoshida T.; 2002 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=135885
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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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Bactericidal effect of cysteine exposed to atmospheric oxygen. by Carlsson J, Granberg GP, Nyberg GK, Edlund MB.; 1979 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=243226
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C terminus of the small GTP-binding protein smg p25A contains two geranylgeranylated cysteine residues and a methyl ester. by Farnsworth CC, Kawata M, Yoshida Y, Takai Y, Gelb MH, Glomset JA.; 1991 Jul 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52049
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Characterization of two highly diverged but developmentally co-regulated cysteine proteinase genes in Dictyostelium discoideum. by Pears CJ, Mahbubani HM, Williams JG.; 1985 Dec 20; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=318956
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Conversion of cysteine to formylglycine: A protein modification in the endoplasmic reticulum. by Dierks T, Schmidt B, von Figura K.; 1997 Oct 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23670
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Crystal structure of the cystine C-S lyase from Synechocystis: Stabilization of cysteine persulfide for FeS cluster biosynthesis. by Clausen T, Kaiser JT, Steegborn C, Huber R, Kessler D.; 2000 Apr 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18106
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cysQ, a gene needed for cysteine synthesis in Escherichia coli K-12 only during aerobic growth. by Neuwald AF, Krishnan BR, Brikun I, Kulakauskas S, Suziedelis K, Tomcsanyi T, Leyh TS, Berg DE.; 1992 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=205732
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Dimerization of thiol-specific antioxidant and the essential role of cysteine 47. by Chae HZ, Uhm TB, Rhee SG.; 1994 Jul 19; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=44330
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Disruption of a rhodaneselike gene results in cysteine auxotrophy in Saccharopolyspora erythraea. by Donadio S, Shafiee A, Hutchinson CR.; 1990 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=208439
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Distinct Cysteine Residues in Keap1 Are Required for Keap1-Dependent Ubiquitination of Nrf2 and for Stabilization of Nrf2 by Chemopreventive Agents and Oxidative Stress. by Zhang DD, Hannink M.; 2003 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=262403
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Dsb-insensitive expression of CcrA, a metallo-beta-lactamase from Bacteroides fragilis, in Escherichia coli after amino acid substitution at two cysteine residues within CcrA. by Elksne LE, Rasmussen BA.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=178192
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Dual Role of Cysteine 172 in Redox Regulation of Ribulose 1,5-Bisphosphate Carboxylase/Oxygenase Activity and Degradation. by Marcus Y, Altman-Gueta H, Finkler A, Gurevitz M.; 2003 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148051
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Editing function of Escherichia coli cysteinyl-tRNA synthetase: cyclization of cysteine to cysteine thiolactone. by Jakubowski H.; 1994 Apr 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=307951
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Excretion of cysteine and gamma-glutamylcysteine moieties in human and experimental animal gamma-glutamyl transpeptidase deficiency. by Griffith OW, Meister A.; 1980 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=349620
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Functional Characterization of Cysteine Residues in GlpT, the Glycerol 3-Phosphate Transporter of Escherichia coli. by Fann MC, Busch A, Maloney PC.; 2003 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161592
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Herpes Simplex Virus Type 1 Glycoprotein B Requires a Cysteine Residue at Position 633 for Folding, Processing, and Incorporation into Mature Infectious Virus Particles. by Laquerre S, Anderson DB, Argnani R, Glorioso JC.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110055
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High Levels of Intracellular Cysteine Promote Oxidative DNA Damage by Driving the Fenton Reaction. by Park S, Imlay JA.; 2003 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150142
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Identification and Characterization of a Shared TNFR-Related Receptor for Subgroup B, D, and E Avian Leukosis Viruses Reveal Cysteine Residues Required Specifically for Subgroup E Viral Entry. by Adkins HB, Brojatsch J, Young JA.; 2000 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111866
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Identification of cysteine and arginine residues essential for the phosphotransacetylase from Methanosarcina thermophila. by Rasche ME, Smith KS, Ferry JG.; 1997 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179733
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Increased Cysteine Biosynthesis Capacity of Transgenic Tobacco Overexpressing an O-Acetylserine(thiol) Lyase Modifies Plant Responses to Oxidative Stress. by Youssefian S, Nakamura M, Orudgev E, Kondo N.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116457
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Inhibition of Trypsin-Like Cysteine Proteinases (Gingipains) from Porphyromonas gingivalis by Tetracycline and Its Analogues. by Imamura T, Matsushita K, Travis J, Potempa J.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90745
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Isolation of a lambdadcys transducing bacteriophage and its use in determining the regulation of cysteine messenger ribonucleic acid synthesis in Escherichia coli K-12. by Fimmel AL, Loughlin RE.; 1977 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=235575
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Landmark mapping: a general method for localizing cysteine residues within a protein. by Nefsky B, Bretscher A.; 1989 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=287175
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Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. by Kudo N, Matsumori N, Taoka H, Fujiwara D, Schreiner EP, Wolff B, Yoshida M, Horinouchi S.; 1999 Aug 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17741
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m5C RNA and m5C DNA methyl transferases use different cysteine residues as catalysts. by Liu Y, Santi DV.; 2000 Jul 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26935
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Mammalian thioredoxin reductase: Oxidation of the C-terminal cysteine /selenocysteine active site forms a thioselenide, and replacement of selenium with sulfur markedly reduces catalytic activity. by Lee SR, Bar-Noy S, Kwon J, Levine RL, Stadtman TC, Rhee SG.; 2000 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15961
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Measles Virus Fusion Protein Is Palmitoylated on Transmembrane-Intracytoplasmic Cysteine Residues Which Participate in Cell Fusion. by Caballero M, Carabana J, Ortego J, Fernandez-Munoz R, Celma ML.; 1998 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110167
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Metabolic activation and detoxication of nephrotoxic cysteine and homocysteine Sconjugates. by Elfarra AA, Lash LH, Anders MW.; 1986 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=323360
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Modulation of cysteine biosynthesis in chloroplasts of transgenic tobacco overexpressing cysteine synthase [O-acetylserine(thiol)-lyase]. by Saito K, Kurosawa M, Tatsuguchi K, Takagi Y, Murakoshi I.; 1994 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=159611
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Mutation of Neuraminidase Cysteine Residues Yields Temperature-Sensitive Influenza Viruses. by Basler CF, Garcia-Sastre A, Palese P.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112825
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Mutations Affecting Conserved Cysteine Residues within the Extracellular Domain of Neu Promote Receptor Dimerization and Activation. by Siegel PM, Muller WJ.; 1996 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38562
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Neutral thiol as a proximal ligand to ferrous heme iron: Implications for heme proteins that lose cysteine thiolate ligation on reduction. by Perera R, Sono M, Sigman JA, Pfister TD, Lu Y, Dawson JH.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152975
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Oxidative folding intermediates with nonnative disulfide bridges between adjacent cysteine residues. by Cemazar M, Zahariev S, Lopez JJ, Carugo O, Jones JA, Hore PJ, Pongor S.; 2003 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156273
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Palmitylation of an amino-terminal cysteine motif of protein tyrosine kinases p56lck and p59fyn mediates interaction with glycosyl-phosphatidylinositol-anchored proteins. by Shenoy-Scaria AM, Gauen LK, Kwong J, Shaw AS, Lublin DM.; 1993 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=364697
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Redox state of tumor suppressor p53 regulates its sequence-specific DNA binding in DNA-damaged cells by cysteine 277. by Buzek J, Latonen L, Kurki S, Peltonen K, Laiho M.; 2002 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117181
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Reduction of Adenosine-5[prime prime or minute]-Phosphosulfate Instead of 3[prime prime or minute]-Phosphoadenosine-5[prime prime or minute]-Phosphosulfate in Cysteine Biosynthesis by Rhizobium meliloti and Other Members of the Family Rhizobiaceae. by Abola AP, Willits MG, Wang RC, Long SR.; 1999 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94033
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Regulatory mutants and control of cysteine biosynthetic enzymes in Salmonella typhimurium. by Borum PR, Monty KJ.; 1976 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=233339
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RhoB prenylation is driven by the three carboxyl-terminal amino acids of the protein: Evidenced in vivo by an anti-farnesyl cysteine antibody. by Baron R, Fourcade E, Lajoie-Mazenc I, Allal C, Couderc B, Barbaras R, Favre G, Faye JC, Pradines A.; 2000 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17251
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rlk/TXK Encodes Two Forms of a Novel Cysteine String Tyrosine Kinase Activated by Src Family Kinases. by Debnath J, Chamorro M, Czar MJ, Schaeffer EM, Lenardo MJ, Varmus HE, Schwartzberg PL.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116078
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Role of cysteine amino acid residues on the RNA binding activity of human thymidylate synthase. by Lin X, Liu J, Maley F, Chu E.; 2003 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=169953
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Role of cysteine in regulating morphogenesis and mitochondrial activity in the dimorphic fungus Histoplasma capsulatum. by Maresca B, Lambowitz AM, Kumar VB, Grant GA, Kobayashi GS, Medoff G.; 1981 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=319840
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Roles of cysteine sulfinate and transaminase on in vitro dark reversion of urocanase in Pseudomonas putida. by Hug DH, Hunter JK.; 1982 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=220330
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Site-Specific Mutational Analysis of a Novel Cysteine Motif Proposed To Ligate the 4Fe-4S Cluster in the Iron-Sulfur Flavoprotein of the Thermophilic Methanoarchaeon Methanosarcina thermophila. by Leartsakulpanich U, Antonkine ML, Ferry JG.; 2000 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110971
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Study of growth requirements other than cysteine of naturally occurring Escherichia coli and Klebsiella spp. auxotrophic for cysteine. by McIver CJ, Tapsall JW.; 1993 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=266017
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Substitution of cysteine 192 in a highly conserved Streptococcus pyogenes extracellular cysteine protease (interleukin 1beta convertase) alters proteolytic activity and ablates zymogen processing. by Musser JM, Stockbauer K, Kapur V, Rudgers GW.; 1996 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174016
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Substitutions of a cysteine conserved among DNA cytosine methylases result in a variety of phenotypes. by Wyszynski MW, Gabbara S, Bhagwat AS.; 1992 Jan 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=310373
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The sac Mutants of Chlamydomonas reinhardtii Reveal Transcriptional and Posttranscriptional Control of Cysteine Biosynthesis. by Ravina CG, Chang CI, Tsakraklides GP, McDermott JP, Vega JM, Leustek T, Gotor C, Davies JP.; 2002 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166719
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The structural basis of cysteine aminoacylation of tRNAPro by prolyl-tRNA synthetases. by Kamtekar S, Kennedy WD, Wang J, Stathopoulos C, Soll D, Steitz TA.; 2003 Feb 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149891
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Toxins, Butyric Acid, and Other Short-Chain Fatty Acids Are Coordinately Expressed and Down-Regulated by Cysteine in Clostridium difficile. by Karlsson S, Lindberg A, Norin E, Burman LG, Akerlund T.; 2000 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101550
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Transcription Factor FnrP from Paracoccus denitrificans Contains an Iron-Sulfur Cluster and Is Activated by Anoxia: Identification of Essential Cysteine Residues. by Hutchings MI, Crack JC, Shearer N, Thompson BJ, Thomson AJ, Spiro S.; 2002 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139558
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Truncated Forms of Glycoprotein D of Herpes Simplex Virus 1 Capable of Blocking Apoptosis and of Low-Efficiency Entry into Cells Form a Heterodimer Dependent on the Presence of a Cysteine Located in the Shared Transmembrane Domains. by Zhou G, Roizman B.; 2002 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=136777
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals.
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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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To generate your own bibliography of studies dealing with cysteine, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “cysteine” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for cysteine (hyperlinks lead to article summaries): •
A brain-specific isoform of small glutamine-rich tetratricopeptide repeat-containing protein binds to Hsc70 and the cysteine string protein. Author(s): Tobaben S, Varoqueaux F, Brose N, Stahl B, Meyer G. Source: The Journal of Biological Chemistry. 2003 October 3; 278(40): 38376-83. Epub 2003 July 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12878599
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A cysteine protease from Taenia solium metacestodes induce apoptosis in human CD4+ T-cells. Author(s): Tato P, Fernandez AM, Solano S, Borgonio V, Garrido E, Sepulveda J, Molinari JL. Source: Parasitology Research. 2004 February; 92(3): 197-204. Epub 2003 December 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14652742
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A cysteine scan of the inner vestibule of cyclic nucleotide-gated channels reveals architecture and rearrangement of the pore. Author(s): Flynn GE, Zagotta WN. Source: The Journal of General Physiology. 2003 June; 121(6): 563-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12771192
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A novel cysteine cluster in human metal-responsive transcription factor 1 is required for heavy metal-induced transcriptional activation in vivo. Author(s): Chen X, Zhang B, Harmon PM, Schaffner W, Peterson DO, Giedroc DP. Source: The Journal of Biological Chemistry. 2004 February 6; 279(6): 4515-22. Epub 2003 November 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14610091
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A novel form of the plasminogen activator inhibitor created by cysteine mutations extends its half-life: relevance to cancer and angiogenesis. Author(s): Chorostowska-Wynimko J, Swiercz R, Skrzypczak-Jankun E, Wojtowicz A, Selman SH, Jankun J. Source: Molecular Cancer Therapeutics. 2003 January; 2(1): 19-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12533669
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A prospective study of plasma total cysteine and risk of breast cancer. Author(s): Zhang SM, Willett WC, Selhub J, Manson JE, Colditz GA, Hankinson SE. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 November; 12(11 Pt 1): 1188-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14652279
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A surface amebic cysteine proteinase inactivates interleukin-18. Author(s): Que X, Kim SH, Sajid M, Eckmann L, Dinarello CA, McKerrow JH, Reed SL. Source: Infection and Immunity. 2003 March; 71(3): 1274-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595442
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Activation of human acid sphingomyelinase through modification or deletion of Cterminal cysteine. Author(s): Qiu H, Edmunds T, Baker-Malcolm J, Karey KP, Estes S, Schwarz C, Hughes H, Van Patten SM. Source: The Journal of Biological Chemistry. 2003 August 29; 278(35): 32744-52. Epub 2003 June 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801930
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ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. Author(s): Soejima K, Matsumoto M, Kokame K, Yagi H, Ishizashi H, Maeda H, Nozaki C, Miyata T, Fujimura Y, Nakagaki T. Source: Blood. 2003 November 1; 102(9): 3232-7. Epub 2003 July 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12869506
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Akt1 protects against inflammatory microglial activation through maintenance of membrane asymmetry and modulation of cysteine protease activity. Author(s): Kang JQ, Chong ZZ, Maiese K. Source: Journal of Neuroscience Research. 2003 October 1; 74(1): 37-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13130504
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Analysis of antibody reactivity against cysteine sulfinic acid decarboxylase, a pyridoxal phosphate-dependent enzyme, in endocrine autoimmune disease. Author(s): Skoldberg F, Rorsman F, Perheentupa J, Landin-Olsson M, Husebye ES, Gustafsson J, Kampe O. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 April; 89(4): 163640. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15070923
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Analysis of proteins with caseinolytic activity in a human stratum corneum extract revealed a yet unidentified cysteine protease and identified the so-called "stratum corneum thiol protease" as cathepsin l2. Author(s): Bernard D, Mehul B, Thomas-Collignon A, Simonetti L, Remy V, Bernard MA, Schmidt R. Source: The Journal of Investigative Dermatology. 2003 April; 120(4): 592-600. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12648222
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Analysis of the membrane topology for transmembrane domains 7-12 of the human reduced folate carrier by scanning cysteine accessibility methods. Author(s): Cao W, Matherly LH. Source: The Biochemical Journal. 2004 February 15; 378(Pt 1): 201-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14602046
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Analysis of transmembrane segment 7 of the dipeptide transporter hPepT1 by cysteine-scanning mutagenesis. Author(s): Kulkarni AA, Haworth IS, Uchiyama T, Lee VH. Source: The Journal of Biological Chemistry. 2003 December 19; 278(51): 51833-40. Epub 2003 October 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14532279
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Analysis of transmembrane segment 8 of the GLUT1 glucose transporter by cysteinescanning mutagenesis and substituted cysteine accessibility. Author(s): Mueckler M, Makepeace C. Source: The Journal of Biological Chemistry. 2004 March 12; 279(11): 10494-9. Epub 2003 December 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14688257
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Antigen genes for molecular epidemiology of leishmaniasis: polymorphism of cysteine proteinase B and surface metalloprotease glycoprotein 63 in the Leishmania donovani complex. Author(s): Tintaya KW, Ying X, Dedet JP, Rijal S, De Bolle X, Dujardin JC. Source: The Journal of Infectious Diseases. 2004 March 15; 189(6): 1035-43. Epub 2004 Mar 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14999607
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Antiproliferative and phenotype-transforming antitumor agents derived from cysteine. Author(s): Glenn MP, Kahnberg P, Boyle GM, Hansford KA, Hans D, Martyn AC, Parsons PG, Fairlie DP. Source: Journal of Medicinal Chemistry. 2004 June 3; 47(12): 2984-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15163181
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Arylaminoethyl amides as inhibitors of the cysteine protease cathepsin Kinvestigating P1' substituents. Author(s): Altmann E, Green J, Tintelnot-Blomley M. Source: Bioorganic & Medicinal Chemistry Letters. 2003 June 16; 13(12): 1997-2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12781182
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Cysteine
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Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction. Author(s): Koide S, Kugiyama K, Sugiyama S, Nakamura S, Fukushima H, Honda O, Yoshimura M, Ogawa H. Source: Journal of the American College of Cardiology. 2003 February 19; 41(4): 539-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12598062
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Autosomal dominant hypocalcemia: a novel activating mutation (E604K) in the cysteine-rich domain of the calcium-sensing receptor. Author(s): Tan YM, Cardinal J, Franks AH, Mun HC, Lewis N, Harris LB, Prins JB, Conigrave AD. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 February; 88(2): 605-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12574188
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Bait region involvement in the dimer-dimer interface of human alpha 2macroglobulin and in mediating gross conformational change. Evidence from cysteine variants that form interdimer disulfides. Author(s): Bowen ME, Gettins PG. Source: The Journal of Biological Chemistry. 1998 January 16; 273(3): 1825-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9430734
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Bax-alpha promotes apoptosis induced by cancer chemotherapy and accelerates the activation of caspase 3-like cysteine proteases in p53 double mutant B lymphoma Namalwa cells. Author(s): Schmitt E, Steyaert A, Cimoli G, Bertrand R. Source: Cell Death and Differentiation. 1998 June; 5(6): 506-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10200502
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Bcl-2 regulates the levels of the cysteine proteases ICH and CPP32/Yama in human neuronal precursor cells. Author(s): Korhonen L, Hamner S, Olsson PA, Lindholm D. Source: The European Journal of Neuroscience. 1997 November; 9(11): 2489-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9464943
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Bcl-2 relieves the trans-repressive function of the glucocorticoid receptor and inhibits the activation of CPP32-like cysteine proteases. Author(s): Miyashita T, Mami U, Inoue T, Reed JC, Yamada M. Source: Biochemical and Biophysical Research Communications. 1997 April 28; 233(3): 781-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9168933
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71
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Binding of fatty acids facilitates oxidation of cysteine-34 and converts copperalbumin complexes from antioxidants to prooxidants. Author(s): Gryzunov YA, Arroyo A, Vigne JL, Zhao Q, Tyurin VA, Hubel CA, Gandley RE, Vladimirov YA, Taylor RN, Kagan VE. Source: Archives of Biochemistry and Biophysics. 2003 May 1; 413(1): 53-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12706341
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Biological monitoring of workers exposed to N,N-dimethylformamide by determination of the urinary metabolites, N-methylformamide and N-acetyl-S-(Nmethylcarbamoyl) cysteine. Author(s): Sakai T, Kageyama H, Araki T, Yosida T, Kuribayashi T, Masuyama Y. Source: International Archives of Occupational and Environmental Health. 1995; 67(2): 125-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7672856
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Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. Author(s): Ito S, Iwashita T, Asai N, Murakami H, Iwata Y, Sobue G, Takahashi M. Source: Cancer Research. 1997 July 15; 57(14): 2870-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9230192
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Biosynthesis of surfactant protein C: characterization of aggresome formation by EGFP chimeras containing propeptide mutants lacking conserved cysteine residues. Author(s): Kabore AF, Wang WJ, Russo SJ, Beers MF. Source: Journal of Cell Science. 2001 January; 114(Pt 2): 293-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11148131
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Biotin-labelled peptidyl diazomethane inhibitors derived from the substrate-like sequence of cystatin: targeting of the active site of cruzipain, the major cysteine proteinase of Trypanosoma cruzi. Author(s): Lalmanach G, Mayer R, Serveau C, Scharfstein J, Gauthier F. Source: The Biochemical Journal. 1996 September 1; 318 ( Pt 2): 395-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8809025
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Biotransformation of L-cysteine S-conjugates and N-acetyl-L-cysteine S-conjugates of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1(trifluoromethyl)vinyl ether (compound A) in human kidney in vitro: interindividual variability in N-acetylation, N-deacetylation, and beta-lyase-catalyzed metabolism. Author(s): Gul Altuntas T, Kharasch ED. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2002 February; 30(2): 148-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11792683
72
Cysteine
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Biotransformation of perchloroethene: dose-dependent excretion of trichloroacetic acid, dichloroacetic acid, and N-acetyl-S-(trichlorovinyl)-L-cysteine in rats and humans after inhalation. Author(s): Volkel W, Friedewald M, Lederer E, Pahler A, Parker J, Dekant W. Source: Toxicology and Applied Pharmacology. 1998 November; 153(1): 20-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9875296
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Blood glutathione and cysteine changes in cardiovascular disease. Author(s): Mills BJ, Weiss MM, Lang CA, Liu MC, Ziegler C. Source: The Journal of Laboratory and Clinical Medicine. 2000 May; 135(5): 396-401. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10811054
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Blood glutathione and cysteine concentrations in twin children. Author(s): Lang CA, Matheny AP Jr, Mastropaolo W, Liu MC. Source: Experimental Biology and Medicine (Maywood, N.J.). 2001 April; 226(4): 349-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11368428
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Buthionine sulfoximine induction of gamma-L-glutamyl-L-cysteine synthetase gene expression, kinetics of glutathione depletion and resynthesis, and modulation of carmustine-induced DNA-DNA cross-linking and cytotoxicity in human glioma cells. Author(s): Ali-Osman F, Antoun G, Wang H, Rajagopal S, Gagucas E. Source: Molecular Pharmacology. 1996 June; 49(6): 1012-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8649339
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Carboxydipeptidase activities of recombinant cysteine peptidases. Cruzain of Trypanosoma cruzi and CPB of Leishmania mexicana. Author(s): Judice WA, Puzer L, Cotrin SS, Carmona AK, Coombs GH, Juliano L, Juliano MA. Source: European Journal of Biochemistry / Febs. 2004 March; 271(5): 1046-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15009216
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Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Author(s): Joyce JA, Baruch A, Chehade K, Meyer-Morse N, Giraudo E, Tsai FY, Greenbaum DC, Hager JH, Bogyo M, Hanahan D. Source: Cancer Cell. 2004 May; 5(5): 443-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15144952
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Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. Author(s): Levonen AL, Landar A, Ramachandran A, Ceaser EK, Dickinson DA, Zanoni G, Morrow JD, Darley-Usmar VM. Source: The Biochemical Journal. 2004 March 1; 378(Pt 2): 373-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14616092
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Characterization of a cysteine-less human reduced folate carrier: localization of a substrate-binding domain by cysteine-scanning mutagenesis and cysteine accessibility methods. Author(s): Cao W, Matherly LH. Source: The Biochemical Journal. 2003 August 15; 374(Pt 1): 27-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12749765
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Characterization of the cysteine-rich calcium-binding S100A3 protein from human hair cuticles. Author(s): Kizawa K, Troxler H, Kleinert P, Inoue T, Toyoda M, Morohashi M, Heizmann CW. Source: Biochemical and Biophysical Research Communications. 2002 December 20; 299(5): 857-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12470658
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Comparison of adult somatic and cysteine proteinase antigens of Fasciola gigantica in enzyme linked immunosorbent assay for serodiagnosis of human fasciolosis. Author(s): Rokni MB, Massoud J, Hanilo A. Source: Acta Tropica. 2003 September; 88(1): 69-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943979
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Concerted stimulation and deactivation of pertussis toxin-sensitive G proteins by chimeric G protein-coupled receptor-regulator of G protein signaling 4 fusion proteins: analysis of the contribution of palmitoylated cysteine residues to the GAP activity of RGS4. Author(s): Bahia DS, Sartania N, Ward RJ, Cavalli A, Jones TL, Druey KM, Milligan G. Source: Journal of Neurochemistry. 2003 June; 85(5): 1289-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12753087
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Conserved cysteine-rich domain of paramyxovirus simian virus 5 V protein plays an important role in blocking apoptosis. Author(s): Sun M, Rothermel TA, Shuman L, Aligo JA, Xu S, Lin Y, Lamb RA, He B. Source: Journal of Virology. 2004 May; 78(10): 5068-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15113888
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Contribution of cytosolic cysteine residues to the gating properties of the Kir2.1 inward rectifier. Author(s): Garneau L, Klein H, Parent L, Sauve R. Source: Biophysical Journal. 2003 June; 84(6): 3717-29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12770878
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Critical cysteine residues for regulation of integrin alphaIIbbeta3 are clustered in the epidermal growth factor domains of the beta3 subunit. Author(s): Kamata T, Ambo H, Puzon-McLaughlin W, Tieu KK, Handa M, Ikeda Y, Takada Y. Source: The Biochemical Journal. 2004 March 15; 378(Pt 3): 1079-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14690453
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Crystal structure of IscS, a cysteine desulfurase from Escherichia coli. Author(s): Cupp-Vickery JR, Urbina H, Vickery LE. Source: Journal of Molecular Biology. 2003 July 25; 330(5): 1049-59. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12860127
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Cysteine 10 is a key residue in amyloidogenesis of human transthyretin Val30Met. Author(s): Takaoka Y, Ohta M, Miyakawa K, Nakamura O, Suzuki M, Takahashi K, Yamamura K, Sakaki Y. Source: American Journal of Pathology. 2004 January; 164(1): 337-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14695346
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Cysteine cathepsins (proteases)--on the main stage of cancer? Author(s): Turk V, Kos J, Turk B. Source: Cancer Cell. 2004 May; 5(5): 409-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15144947
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Cysteine protease inhibitors containing small rings. Author(s): Schirmeister T, Klockow A. Source: Mini Reviews in Medicinal Chemistry. 2003 September; 3(6): 585-96. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871161
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Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis. Author(s): Strojan P, Oblak I, Svetic B, Smid L, Kos J. Source: British Journal of Cancer. 2004 May 17; 90(10): 1961-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15138478
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Cysteine string protein (CSP) inhibition of N-type calcium channels is blocked by mutant huntingtin. Author(s): Miller LC, Swayne LA, Chen L, Feng ZP, Wacker JL, Muchowski PJ, Zamponi GW, Braun JE. Source: The Journal of Biological Chemistry. 2003 December 26; 278(52): 53072-81. Epub 2003 October 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14570907
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Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxidemediated oxidation in vivo in human umbilical vein endothelial cells. Author(s): Kinumi T, Kimata J, Taira T, Ariga H, Niki E. Source: Biochemical and Biophysical Research Communications. 2004 May 7; 317(3): 722-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15081400
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Cysteine-rich fibroblast growth factor receptor 1, a new marker for precancerous epithelial lesions defined by the human monoclonal antibody PAM-1. Author(s): Brandlein S, Beyer I, Eck M, Bernhardt W, Hensel F, Muller-Hermelink HK, Vollmers HP. Source: Cancer Research. 2003 May 1; 63(9): 2052-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727819
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Cysteine-scanning mutagenesis of transmembrane segment 1 of glucose transporter GLUT1: extracellular accessibility of helix positions. Author(s): Heinze M, Monden I, Keller K. Source: Biochemistry. 2004 February 3; 43(4): 931-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14744136
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Decreased levels of cystatin C, an inhibitor of the elastolytic enzyme cysteine protease, in acute and subacute phases of kawasaki disease. Author(s): Gupta-Malhotra M, Levine DM, Cooper RS, Zabriskie JB. Source: Cardiology. 2003; 99(3): 121-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12824719
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Deficiency of the cysteine protease cathepsin S impairs microvessel growth. Author(s): Shi GP, Sukhova GK, Kuzuya M, Ye Q, Du J, Zhang Y, Pan JH, Lu ML, Cheng XW, Iguchi A, Perrey S, Lee AM, Chapman HA, Libby P. Source: Circulation Research. 2003 March 21; 92(5): 493-500. Epub 2003 February 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12600886
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Degradation of host heme proteins by lysine- and arginine-specific cysteine proteinases (gingipains) of Porphyromonas gingivalis. Author(s): Sroka A, Sztukowska M, Potempa J, Travis J, Genco CA. Source: Journal of Bacteriology. 2001 October; 183(19): 5609-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11544223
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Degradation to sulphate of S-methyl-L-cysteine sulphoxide and S-carboxymethyl-Lcysteine sulphoxide in man. Author(s): Waring RH, Harris RM, Steventon GB, Mitchell SC. Source: Drug Metabol Drug Interact. 2003; 19(4): 241-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14768973
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Design of potent, selective, and orally bioavailable inhibitors of cysteine protease cathepsin k. Author(s): Tavares FX, Boncek V, Deaton DN, Hassell AM, Long ST, Miller AB, Payne AA, Miller LR, Shewchuk LM, Wells-Knecht K, Willard DH Jr, Wright LL, Zhou HQ. Source: Journal of Medicinal Chemistry. 2004 January 29; 47(3): 588-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14736240
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Detection of high titers of antibody against Helicobacter cysteine-rich proteins A, B, C, and E in Helicobacter pylori-infected individuals. Author(s): Mittl PR, Luthy L, Reinhardt C, Joller H. Source: Clinical and Diagnostic Laboratory Immunology. 2003 July; 10(4): 542-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12853383
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Determinants of NPC1 expression and action: key promoter regions, posttranscriptional control, and the importance of a "cysteine-rich" loop. Author(s): Watari H, Blanchette-Mackie EJ, Dwyer NK, Watari M, Burd CG, Patel S, Pentchev PG, Strauss JF 3rd. Source: Experimental Cell Research. 2000 August 25; 259(1): 247-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10942596
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Determination by liquid chromatography of free and total cysteine in human urine in the form of its S-quinolinium derivative. Author(s): Bald E, Glowacki R, Drzewoski J. Source: J Chromatogr A. 2001 April 13; 913(1-2): 319-29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11355829
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Determination of L-cysteine in amino acid mixture and human urine by flowinjection analysis with a biamperometric detector. Author(s): Zhao C, Zhang J, Song J. Source: Analytical Biochemistry. 2001 October 15; 297(2): 170-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11673884
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Determination of N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) in the general population using gas chromatography-mass spectrometry. Author(s): Kafferlein HU, Angerer J. Source: Journal of Environmental Monitoring : Jem. 1999 October; 1(5): 465-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11529165
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Development of a sensitive assay to detect reversibly oxidized protein cysteine sulfhydryl groups. Author(s): Makmura L, Hamann M, Areopagita A, Furuta S, Munoz A, Momand J. Source: Antioxidants & Redox Signalling. 2001 December; 3(6): 1105-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11813984
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Development of an in vitro model for cysteine dioxygenase expression in the brain. Author(s): Qusti S, Parsons RB, Abouglila KD, Waring RH, Williams AC, Ramsden DB. Source: Cell Biology and Toxicology. 2000; 16(4): 243-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11101006
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Differential activation of cysteine-substitution mutants of fibroblast growth factor receptor 3 is determined by cysteine localization. Author(s): Adar R, Monsonego-Ornan E, David P, Yayon A. Source: Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. 2002 May; 17(5): 860-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12009017
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Differential expression of the 27 kDa cathepsin L-like cysteine protease in developmental stages of Spirometra erinacei. Author(s): Kong Y, Yun DH, Cho SY, Sohn WM, Chung YB, Kang SY. Source: The Korean Journal of Parasitology. 2000 September; 38(3): 195-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11002659
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Differential regulation of NO availability from macrophages and endothelial cells by the garlic component S-allyl cysteine. Author(s): Kim KM, Chun SB, Koo MS, Choi WJ, Kim TW, Kwon YG, Chung HT, Billiar TR, Kim YM. Source: Free Radical Biology & Medicine. 2001 April 1; 30(7): 747-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11275474
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Discovery of a new inhibitor lead of adenovirus proteinase: steps toward selective, irreversible inhibitors of cysteine proteinases. Author(s): Pang YP, Xu K, Kollmeyer TM, Perola E, McGrath WJ, Green DT, Mangel WF. Source: Febs Letters. 2001 August 3; 502(3): 93-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11583118
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Distribution and pharmacology of alanine-serine-cysteine transporter 1 (asc-1) in rodent brain. Author(s): Helboe L, Egebjerg J, Moller M, Thomsen C. Source: The European Journal of Neuroscience. 2003 October; 18(8): 2227-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14622183
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Domain II of m-calpain is a Ca(2+)-dependent cysteine protease. Author(s): Hata S, Sorimachi H, Nakagawa K, Maeda T, Abe K, Suzuki K. Source: Febs Letters. 2001 July 20; 501(2-3): 111-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11470267
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Domain shuffling as a tool for investigation of protein function: substitution of the cysteine-rich region of Raf kinase and PKC eta for that of yeast Pkc1p. Author(s): Schmitz HP, Jockel J, Block C, Heinisch JJ. Source: Journal of Molecular Biology. 2001 August 3; 311(1): 1-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11469853
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Double-stranded RNA-mediated gene silencing of cysteine proteases (falcipain-1 and -2) of Plasmodium falciparum. Author(s): Malhotra P, Dasaradhi PV, Kumar A, Mohmmed A, Agrawal N, Bhatnagar RK, Chauhan VS. Source: Molecular Microbiology. 2002 September; 45(5): 1245-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12207693
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Ectodomain shedding of furin: kinetics and role of the cysteine-rich region. Author(s): Denault J, Bissonnette L, Longpre J, Charest G, Lavigne P, Leduc R. Source: Febs Letters. 2002 September 11; 527(1-3): 309-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12220680
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Effect of folic acid on fenofibrate-induced elevation of homocysteine and cysteine. Author(s): Melenovsky V, Stulc T, Kozich V, Grauova B, Krijt J, Wichterle D, Haas T, Malik J, Hradec J, Ceska R. Source: American Heart Journal. 2003 July; 146(1): 110. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12851616
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Effect of N-acetyl-L-cysteine on peroxynitrite and superoxide anion production of lung alveolar macrophages in systemic sclerosis. Author(s): Failli P, Palmieri L, D'Alfonso C, Giovannelli L, Generini S, Rosso AD, Pignone A, Stanflin N, Orsi S, Zilletti L, Matucci-Cerinic M. Source: Nitric Oxide : Biology and Chemistry / Official Journal of the Nitric Oxide Society. 2002 December; 7(4): 277-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12446176
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Effects of combined in vivo treatment of transplantable solid mammary carcinoma in wistar rats using vitamin E and cysteine peptidase inhibitors from human placenta. Author(s): Saleh Y, Siewinski M, Sebzda T, Grybos M, Pawelec M, Janocha A. Source: Journal of Experimental Therapeutics & Oncology. 2003 March-April; 3(2): 95102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12822515
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Effects of cysteine on the cytotoxicity of arsenic compounds. Author(s): Zhou X, Yoshida K, Kuroda K, Endo Y, Endo G. Source: Archives of Environmental Contamination and Toxicology. 2003 October; 45(3): 324-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14674584
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Effects of N-acetyl-L-cysteine and glutathione on antioxidant status of human serum and 3T3 fibroblasts. Author(s): Hong SY, Yang JO, Lee EY, Lee ZW. Source: Journal of Korean Medical Science. 2003 October; 18(5): 649-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14555815
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Electron transfer in flavocytochrome P450 BM3: kinetics of flavin reduction and oxidation, the role of cysteine 999, and relationships with mammalian cytochrome P450 reductase. Author(s): Roitel O, Scrutton NS, Munro AW. Source: Biochemistry. 2003 September 16; 42(36): 10809-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962506
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Engineering of cysteine and methionine biosynthesis in potato. Author(s): Nikiforova V, Kempa S, Zeh M, Maimann S, Kreft O, Casazza AP, Riedel K, Tauberger E, Hoefgen R, Hesse H. Source: Amino Acids. 2002; 22(3): 259-78. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12083069
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Entamoeba histolytica cysteine proteinases disrupt the polymeric structure of colonic mucin and alter its protective function. Author(s): Moncada D, Keller K, Chadee K. Source: Infection and Immunity. 2003 February; 71(2): 838-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12540564
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Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells. Author(s): Zipper LM, Mulcahy RT. Source: Toxicological Sciences : an Official Journal of the Society of Toxicology. 2003 May; 73(1): 124-34. Epub 2003 March 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12657749
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Essential cysteine-alkylation strategies to monitor structurally altered estrogen receptor as found in oxidant-stressed breast cancers. Author(s): Meza JE, Scott GK, Benz CC, Baldwin MA. Source: Analytical Biochemistry. 2003 September 1; 320(1): 21-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12895466
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Evaluation of an IgG cystatin capture enzyme-linked immunosorbent assay for the detection of anti-cysteine proteinase antibodies in asymptomatic trichomoniasis patients. Author(s): Tawfeek GM, Oteifa NM, el-Gozamy BR. Source: J Egypt Soc Parasitol. 2003 April; 33(1): 67-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12739802
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Evidence for specific tetraspanin homodimers: inhibition of palmitoylation makes cysteine residues available for cross-linking. Author(s): Kovalenko OV, Yang X, Kolesnikova TV, Hemler ME. Source: The Biochemical Journal. 2004 January 15; 377(Pt 2): 407-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14556650
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Evolutionary relationships of conserved cysteine-rich motifs in adhesive molecules of malaria parasites. Author(s): Michon P, Stevens JR, Kaneko O, Adams JH. Source: Molecular Biology and Evolution. 2002 July; 19(7): 1128-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12082132
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Expression and structure-function analysis of de, a sperm cysteine-rich secretory protein that mediates gamete fusion. Author(s): Ellerman DA, Da Ros VG, Cohen DJ, Busso D, Morgenfeld MM, Cuasnicu PS. Source: Biology of Reproduction. 2002 October; 67(4): 1225-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12297540
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Expression of cysteine dioxygenase (EC 1.13.11.20) and sulfite oxidase in the human lung: a potential role for sulfate production in the protection from airborne xenobiotica. Author(s): Millard J, Parsons RB, Waring RH, Williams AC, Ramsden DB. Source: Molecular Pathology : Mp. 2003 October; 56(5): 270-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14514920
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Expression of cysteine peptidase cathepsin L and its inhibitors stefins A and B in relation to tumorigenicity of breast cancer cell lines. Author(s): Zajc I, Sever N, Bervar A, Lah TT. Source: Cancer Letters. 2002 December 10; 187(1-2): 185-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12359367
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Expression of cysteine proteinase of Clonorchis sinensis and its use in serodiagnosis of clonorchiasis. Author(s): Na BK, Lee HJ, Cho SH, Lee HW, Cho JH, Kho WG, Lee JS, Lee JS, Song KJ, Park PH, Song CY, Kim TS. Source: J Parasitol. 2002 October; 88(5): 1000-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12435144
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Expression of cysteine proteinase type I and II of Leishmania infantum and their recognition by sera during canine and human visceral leishmaniasis. Author(s): Rafati S, Nakhaee A, Taheri T, Ghashghaii A, Salmanian AH, Jimenez M, Mohebali M, Masina S, Fasel N. Source: Experimental Parasitology. 2003 March-April; 103(3-4): 143-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12880591
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Expression of high molecular weight cysteine proteinase inhibitor in ovarian cancer tissues: regulation of cathepsin B expression by placental CPI. Author(s): Siewinski M, Saleh Y, Popiela A, Ziolkowski P, Jelen M, Grybos M. Source: Biological Chemistry. 2003 July; 384(7): 1103-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12956427
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Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of jagged 1. Author(s): Le Caignec C, Lefevre M, Schott JJ, Chaventre A, Gayet M, Calais C, Moisan JP. Source: American Journal of Human Genetics. 2002 July; 71(1): 180-6. Epub 2002 May 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12022040
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Family C1 cysteine proteases: biological diversity or redundancy? Author(s): Nagler DK, Menard R. Source: Biological Chemistry. 2003 June; 384(6): 837-43. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12887050
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Fibrinogen cleavage by the Streptococcus pyogenes extracellular cysteine protease and generation of antibodies that inhibit enzyme proteolytic activity. Author(s): Matsuka YV, Pillai S, Gubba S, Musser JM, Olmsted SB. Source: Infection and Immunity. 1999 September; 67(9): 4326-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10456870
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Five families with arginine 519-cysteine mutation in COL2A1: evidence for three distinct founders. Author(s): Bleasel JF, Holderbaum D, Brancolini V, Moskowitz RW, Considine EL, Prockop DJ, Devoto M, Williams CJ. Source: Human Mutation. 1998; 12(3): 172-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9711874
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FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. Author(s): Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ, Frantz GD, Tumas DB, Peale FV Jr, Shelton DL, Hebert CC. Source: The Embo Journal. 2000 August 1; 19(15): 4046-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10921885
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Flow cytometric determination of cysteine and serine proteinase activities in living cells with rhodamine 110 substrates. Author(s): Klingel S, Rothe G, Kellermann W, Valet G. Source: Methods Cell Biol. 1994; 41: 449-59. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7861975
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Flow injection chemiluminescence determination of L-cysteine in amino acid mixture and human urine with the BrO3--quinine system. Author(s): Li B, Zhang Z, Liu M, Xu C. Source: Analytical and Bioanalytical Chemistry. 2003 December; 377(7-8): 1212-6. Epub 2003 September 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14647935
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Folding incompetence of cathepsin L-like cysteine proteases may be compensated by the highly conserved, domain-building N-terminal extension of the proregion. Author(s): Schilling K, Pietschmann S, Fehn M, Wenz I, Wiederanders B. Source: Biological Chemistry. 2001 May; 382(5): 859-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11517942
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Formation and fate of nephrotoxic and cytotoxic glutathione S-conjugates: cysteine conjugate beta-lyase pathway. Author(s): Dekant W, Vamvakas S, Anders MW. Source: Adv Pharmacol. 1994; 27: 115-62. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8068551
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Free cysteine is increased in plasma from hemodialysis patients. Author(s): Nakanishi T, Hasuike Y, Otaki Y, Hama Y, Nanami M, Miyagawa K, Moriguchi R, Nishikage H, Izumi M, Takamitsu Y. Source: Kidney International. 2003 March; 63(3): 1137-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12631098
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Full-length cDNA of human cathepsin F predicts the presence of a cystatin domain at the N-terminus of the cysteine protease zymogen. Author(s): Nagler DK, Sulea T, Menard R. Source: Biochemical and Biophysical Research Communications. 1999 April 13; 257(2): 313-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10198209
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Fully automated assay for total homocysteine, cysteine, cysteinylglycine, glutathione, cysteamine, and 2-mercaptopropionylglycine in plasma and urine. Author(s): Pastore A, Massoud R, Motti C, Lo Russo A, Fucci G, Cortese C, Federici G. Source: Clinical Chemistry. 1998 April; 44(4): 825-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9554495
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Functional analysis of tumour necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL): cysteine-230 plays a critical role in the homotrimerization and biological activity of this novel tumoricidal cytokine. Author(s): Trabzuni D, Famulski KS, Ahmad M. Source: The Biochemical Journal. 2000 September 1; 350 Pt 2: 505-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10947965
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Functional characterization and regulation of the taurine transporter and cysteine dioxygenase in human hepatoblastoma HepG2 cells. Author(s): Satsu H, Terasawa E, Hosokawa Y, Shimizu M. Source: The Biochemical Journal. 2003 October 15; 375(Pt 2): 441-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871209
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Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Author(s): Leesnitzer LM, Parks DJ, Bledsoe RK, Cobb JE, Collins JL, Consler TG, Davis RG, Hull-Ryde EA, Lenhard JM, Patel L, Plunket KD, Shenk JL, Stimmel JB, Therapontos C, Willson TM, Blanchard SG. Source: Biochemistry. 2002 May 28; 41(21): 6640-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12022867
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Functional cysteine-less subunits of the transporter associated with antigen processing (TAP1 and TAP2) by de novo gene assembly. Author(s): Heintke S, Chen M, Ritz U, Lankat-Buttgereit B, Koch J, Abele R, Seliger B, Tampe R. Source: Febs Letters. 2003 January 2; 533(1-3): 42-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12505156
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Functional effects of the inhibition of the cysteine protease activity of the major house dust mite allergen Der p 1 by a novel peptide-based inhibitor. Author(s): John RJ, Rusznak C, Ramjee M, Lamont AG, Abrahamson M, Hewitt EL. Source: Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2000 June; 30(6): 784-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10848897
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Functional role of cysteine residues in the Na+/H+ exchanger effects of mutation of cysteine residues on targeting and activity of the Na+/H+ exchanger. Author(s): Wang H, Singh D, Fliegel L. Source: Archives of Biochemistry and Biophysics. 1998 October 1; 358(1): 116-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9750172
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Functions of propeptide parts in cysteine proteases. Author(s): Wiederanders B, Kaulmann G, Schilling K. Source: Current Protein & Peptide Science. 2003 October; 4(5): 309-26. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14529526
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Gamma-glutamyl cysteine synthetase up-regulates glutathione and multidrug resistance-associated protein in patients with chemoresistant epithelial ovarian cancer. Author(s): Kigawa J, Minagawa Y, Cheng X, Terakawa N. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1998 July; 4(7): 1737-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9676849
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gamma-Glutamyl transpeptidase and l-cysteine regulate methylmercury uptake by HepG2 cells, a human hepatoma cell line. Author(s): Wang W, Clarkson TW, Ballatori N. Source: Toxicology and Applied Pharmacology. 2000 October 1; 168(1): 72-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11000102
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Gas chromatographic-mass spectrometric analysis of stable isotopes of cysteine and glutathione in biological samples. Author(s): Capitan P, Malmezat T, Breuille D, Obled C. Source: J Chromatogr B Biomed Sci Appl. 1999 September 10; 732(1): 127-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10517229
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Gas chromatographic-mass spectrometric detection of S-nitroso-cysteine and Snitroso-glutathione. Author(s): Tsikas D, Sandmann J, Rossa S, Gutzki FM, Frolich JC. Source: Analytical Biochemistry. 1999 August 1; 272(2): 117-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10415079
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Gastrointestinal safety of nitric oxide-derived aspirin is related to inhibition of ICElike cysteine proteases in rats. Author(s): Fiorucci S, Antonelli E, Santucci L, Morelli O, Miglietti M, Federici B, Mannucci R, Del Soldato P, Morelli A. Source: Gastroenterology. 1999 May; 116(5): 1089-106. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10220501
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Gene activation by Varicella-zoster virus IE4 protein requires its dimerization and involves both the arginine-rich sequence, the central part, and the carboxyl-terminal cysteine-rich region. Author(s): Baudoux L, Defechereux P, Rentier B, Piette J. Source: The Journal of Biological Chemistry. 2000 October 20; 275(42): 32822-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10889190
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Gene expression of mouse S100A3, a cysteine-rich calcium-binding protein, in developing hair follicle. Author(s): Kizawa K, Tsuchimoto S, Hashimoto K, Uchiwa H. Source: The Journal of Investigative Dermatology. 1998 November; 111(5): 879-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9804353
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Gene transfer via reversible plasmid condensation with cysteine-flanked, internally spaced arginine-rich peptides. Author(s): Siprashvili Z, Scholl FA, Oliver SF, Adams A, Contag CH, Wender PA, Khavari PA. Source: Human Gene Therapy. 2003 September 1; 14(13): 1225-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952594
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General solid-phase method to prepare novel cyclic ketone inhibitors of the cysteine protease cruzain. Author(s): Huang L, Ellman JA. Source: Bioorganic & Medicinal Chemistry Letters. 2002 October 21; 12(20): 2993-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12270191
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Generation of a mature streptococcal cysteine proteinase is dependent on cell wallanchored M1 protein. Author(s): Collin M, Olsen A. Source: Molecular Microbiology. 2000 June; 36(6): 1306-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10931281
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Genetic approach to the role of cysteine proteases in the expansion of abdominal aortic aneurysms. Author(s): Eriksson P, Jones KG, Brown LC, Greenhalgh RM, Hamsten A, Powell JT. Source: The British Journal of Surgery. 2004 January; 91(1): 86-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14716800
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Genetic inactivation of the extracellular cysteine protease enhances in vitro internalization of group A streptococci by human epithelial and endothelial cells. Author(s): Burns EH Jr, Lukomski S, Rurangirwa J, Podbielski A, Musser JM. Source: Microbial Pathogenesis. 1998 June; 24(6): 333-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9632537
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Genetic variation of Porphyromonas gingivalis genes encoding gingipains, cysteine proteinases with arginine or lysine specificity. Author(s): Mikolajczyk-Pawlinska J, Kordula T, Pavloff N, Pemberton PA, Chen WC, Travis J, Potempa J. Source: Biological Chemistry. 1998 February; 379(2): 205-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9524073
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Genomic organization and chromosomal localization of the human CD163 (M130) gene: a member of the scavenger receptor cysteine-rich superfamily. Author(s): Ritter M, Buechler C, Langmann T, Schmitz G. Source: Biochemical and Biophysical Research Communications. 1999 July 5; 260(2): 46674. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10403791
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Genomic structure and genetic mapping of the human neutral cysteine protease bleomycin hydrolase. Author(s): Montoya SE, Ferrell RE, Lazo JS. Source: Cancer Research. 1997 October 1; 57(19): 4191-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9331073
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Glutamate-cysteine ligase modulatory subunit in BAL alveolar macrophages of healthy smokers. Author(s): Neurohr C, Lenz AG, Ding I, Leuchte H, Kolbe T, Behr J. Source: The European Respiratory Journal : Official Journal of the European Society for Clinical Respiratory Physiology. 2003 July; 22(1): 82-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12882455
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Glutamyl substrate-induced exposure of a free cysteine residue in the vitamin Kdependent gamma-glutamyl carboxylase is critical for vitamin K epoxidation. Author(s): Bouchard BA, Furie B, Furie BC. Source: Biochemistry. 1999 July 20; 38(29): 9517-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10413529
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Glutathione and cysteine in HIV-infected hemophiliacs. Author(s): Lopez Galera RM, Juarez Gimenez JC, Montoro Ronsano JB, Segura Cardona RM, Arbos Via MA, Altisent Roca C, Tusell Puigbert JM. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1996 October 15; 254(1): 63-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8894310
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Glutathione content but not gamma glutamyl cysteine synthetase mRNA expression predicts cisplatin resistance in head and neck cancer cell lines. Author(s): Newkirk K, Heffern J, Sloman-Moll E, Sessions RB, Rasmussen AA, Andrews PA, Cullen KJ. Source: Cancer Chemotherapy and Pharmacology. 1997; 40(1): 75-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9137534
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Grafting of features of cystatins C or B into the N-terminal region or second binding loop of cystatin A (stefin A) substantially enhances inhibition of cysteine proteinases. Author(s): Pavlova A, Bjork I. Source: Biochemistry. 2003 September 30; 42(38): 11326-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503883
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High cysteine levels in renal transplant recipients: relationship with hyperhomocysteinemia and 5,10-MTHFR polymorphism. Author(s): Marcucci R, Fedi S, Brunelli T, Pepe G, Prisco D, Rosati A, Zanazzi M, Bertoni E, Abbate R, Salvadori M. Source: Transplantation. 2001 March 27; 71(6): 746-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11330536
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High resistance of human parainfluenza type 2 virus protein-expressing cells to the antiviral and anti-cell proliferative activities of alpha/beta interferons: cysteine-rich V-specific domain is required for high resistance to the interferons. Author(s): Nishio M, Tsurudome M, Ito M, Kawano M, Komada H, Ito Y. Source: Journal of Virology. 2001 October; 75(19): 9165-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11533180
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Highly reactive cysteine residues in rodent hemoglobins. Author(s): Miranda JJ. Source: Biochemical and Biophysical Research Communications. 2000 August 28; 275(2): 517-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10964696
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High-performance liquid chromatographic method to quantify total cysteine excretion in urine. Author(s): Fermo I, Arcelloni C, Paroni R. Source: Analytical Biochemistry. 2002 August 1; 307(1): 181-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12137797
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Homocysteine and cysteine - albumin binding in homocystinuria: assessment of cysteine status and implications for glutathione synthesis? Author(s): Hargreaves IP, Lee PJ, Briddon A. Source: Amino Acids. 2002; 22(2): 109-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12395179
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Homocysteine strongly enhances metal-catalyzed LDL oxidation in the presence of cystine and cysteine. Author(s): Pfanzagl B, Tribl F, Koller E, Moslinger T. Source: Atherosclerosis. 2003 May; 168(1): 39-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12732385
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Homocysteine, cysteine, and B vitamins as predictors of kidney disease progression. Author(s): Sarnak MJ, Wang SR, Beck GJ, Kusek JW, Selhub J, Greene T, Levey AS. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2002 November; 40(5): 932-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12407637
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Homocysteine, cysteine, and glutathione in human colonic mucosa: elevated levels of homocysteine in patients with inflammatory bowel disease. Author(s): Morgenstern I, Raijmakers MT, Peters WH, Hoensch H, Kirch W. Source: Digestive Diseases and Sciences. 2003 October; 48(10): 2083-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627359
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House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. Author(s): Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, Stewart GA. Source: Journal of Immunology (Baltimore, Md. : 1950). 2002 October 15; 169(8): 4572-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12370395
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How the sequestration of a protein interferes with its mechanism of action: example of a new family of proteins characterized by a particular cysteine-rich carboxyterminal domain involved in gene expression regulation. Author(s): Thebault S, Mesnard JM. Source: Current Protein & Peptide Science. 2001 June; 2(2): 155-67. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12370022
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Human alpha 1,3/4 fucosyltransferases. Characterization of highly conserved cysteine residues and N-linked glycosylation sites. Author(s): Holmes EH, Yen TY, Thomas S, Joshi R, Nguyen A, Long T, Gallet F, Maftah A, Julien R, Macher BA. Source: The Journal of Biological Chemistry. 2000 August 11; 275(32): 24237-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10816554
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Human and parasitic papain-like cysteine proteases: their role in physiology and pathology and recent developments in inhibitor design. Author(s): Lecaille F, Kaleta J, Bromme D. Source: Chemical Reviews. 2002 December; 102(12): 4459-88. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12475197
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Human autophagins, a family of cysteine proteinases potentially implicated in cell degradation by autophagy. Author(s): Marino G, Uria JA, Puente XS, Quesada V, Bordallo J, Lopez-Otin C. Source: The Journal of Biological Chemistry. 2003 February 7; 278(6): 3671-8. Epub 2002 November 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12446702
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Human cathepsin W, a cysteine protease predominantly expressed in NK cells, is mainly localized in the endoplasmic reticulum. Author(s): Wex T, Buhling F, Wex H, Gunther D, Malfertheiner P, Weber E, Bromme D. Source: Journal of Immunology (Baltimore, Md. : 1950). 2001 August 15; 167(4): 2172-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11490002
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Human cathepsin X. A novel cysteine protease with unique specificity. Author(s): Menard R, Nagler DK, Zhang R, Tam W, Sulea T, Purisima EO. Source: Advances in Experimental Medicine and Biology. 2000; 477: 317-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10849759
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Human cathepsins W and F form a new subgroup of cathepsins that is evolutionary separated from the cathepsin B- and L-like cysteine proteases. Author(s): Wex T, Levy B, Wex H, Bromme D. Source: Advances in Experimental Medicine and Biology. 2000; 477: 271-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10849754
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Human eosinophils are activated by cysteine proteases and release inflammatory mediators. Author(s): Miike S, Kita H. Source: The Journal of Allergy and Clinical Immunology. 2003 April; 111(4): 704-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12704347
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Human proteoglycan testican-1 inhibits the lysosomal cysteine protease cathepsin L. Author(s): Bocock JP, Edgell CJ, Marr HS, Erickson AH. Source: European Journal of Biochemistry / Febs. 2003 October; 270(19): 4008-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14511383
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Human salivary MUC7 mucin peptides: effect of size, charge and cysteine residues on antifungal activity. Author(s): Situ H, Wei G, Smith CJ, Mashhoon S, Bobek LA. Source: The Biochemical Journal. 2003 October 1; 375(Pt 1): 175-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12812519
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Hydrolysis of interleukin-12 by Porphyromonas gingivalis major cysteine proteinases may affect local gamma interferon accumulation and the Th1 or Th2 T-cell phenotype in periodontitis. Author(s): Yun PL, Decarlo AA, Collyer C, Hunter N. Source: Infection and Immunity. 2001 September; 69(9): 5650-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11500441
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Identification of a novel maturation mechanism and restricted substrate specificity for the SspB cysteine protease of Staphylococcus aureus. Author(s): Massimi I, Park E, Rice K, Muller-Esterl W, Sauder D, McGavin MJ. Source: The Journal of Biological Chemistry. 2002 November 1; 277(44): 41770-7. Epub 2002 August 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12207024
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Identification of a variant antioxidant response element in the promoter of the human glutamate-cysteine ligase modifier subunit gene. Revision of the ARE consensus sequence. Author(s): Erickson AM, Nevarea Z, Gipp JJ, Mulcahy RT. Source: The Journal of Biological Chemistry. 2002 August 23; 277(34): 30730-7. Epub 2002 June 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12070177
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Identification of human cysteine-rich secretory protein 3 (CRISP-3) as a matrix protein in a subset of peroxidase-negative granules of neutrophils and in the granules of eosinophils. Author(s): Udby L, Calafat J, Sorensen OE, Borregaard N, Kjeldsen L. Source: Journal of Leukocyte Biology. 2002 September; 72(3): 462-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12223513
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Identification of the binding sites of the SR49059 nonpeptide antagonist into the V1a vasopressin receptor using sulfydryl-reactive ligands and cysteine mutants as chemical sensors. Author(s): Tahtaoui C, Balestre MN, Klotz P, Rognan D, Barberis C, Mouillac B, Hibert M. Source: The Journal of Biological Chemistry. 2003 October 10; 278(41): 40010-9. Epub 2003 July 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12869559
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Identification of the carboxyl-terminal membrane-anchoring region of HPC1/syntaxin 1A with the substituted-cysteine-accessibility method and monoclonal antibodies. Author(s): Suga K, Yamamori T, Akagawa K. Source: Journal of Biochemistry. 2003 March; 133(3): 325-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12761168
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Identification of two cysteine residues involved in the binding of UDP-GalNAc to UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 1 (GalNAc-T1). Author(s): Tenno M, Toba S, Kezdy FJ, Elhammer AP, Kurosaka A. Source: European Journal of Biochemistry / Febs. 2002 September; 269(17): 4308-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12199709
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Inactivation of human peroxiredoxin I during catalysis as the result of the oxidation of the catalytic site cysteine to cysteine-sulfinic acid. Author(s): Yang KS, Kang SW, Woo HA, Hwang SC, Chae HZ, Kim K, Rhee SG. Source: The Journal of Biological Chemistry. 2002 October 11; 277(41): 38029-36. Epub 2002 August 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12161445
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Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Author(s): Ding Z, Kim S, Dorsam RT, Jin J, Kunapuli SP. Source: Blood. 2003 May 15; 101(10): 3908-14. Epub 2003 January 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12560222
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Increased cell density decreases cysteine proteinase inhibitor activity and increases invasive ability of two prostate tumor cell lines. Author(s): Colella R, Goodwyn E, Gopal P. Source: Cancer Letters. 2002 November 28; 185(2): 163-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12169390
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In-gel derivatization of proteins for cysteine-specific cleavages and their analysis by mass spectrometry. Author(s): Thevis M, Ogorzalek Loo RR, Loo JA. Source: Journal of Proteome Research. 2003 March-April; 2(2): 163-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716130
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Inhibition of cysteine protease activity by NO-donors. Author(s): Ascenzi P, Salvati L, Bolognesi M, Colasanti M, Polticelli F, Venturini G. Source: Current Protein & Peptide Science. 2001 June; 2(2): 137-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12370021
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Inhibition of cysteine proteinases by autolytic digestion is mediated by CBP2/Hsp47. Author(s): Siavash H, Lopes M, Norris K, Hebert C, Nikitakis N, Sauk JJ. Source: Connective Tissue Research. 2002; 43(4): 589-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12685865
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Inhibition of papain-like cysteine proteases and legumain by caspase-specific inhibitors: when reaction mechanism is more important than specificity. Author(s): Rozman-Pungercar J, Kopitar-Jerala N, Bogyo M, Turk D, Vasiljeva O, Stefe I, Vandenabeele P, Bromme D, Puizdar V, Fonovic M, Trstenjak-Prebanda M, Dolenc I, Turk V, Turk B. Source: Cell Death and Differentiation. 2003 August; 10(8): 881-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867995
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Interaction of cysteine conjugates with human and rabbit organic anion transporter 1. Author(s): Groves CE, Munoz L, Bahn A, Burckhardt G, Wright SH. Source: The Journal of Pharmacology and Experimental Therapeutics. 2003 February; 304(2): 560-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12538807
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Intracellular thiol concentration modulating inflammatory response: influence on the regulation of cell functions through cysteine prodrug approach. Author(s): Santangelo F. Source: Current Medicinal Chemistry. 2003 December; 10(23): 2599-610. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14529474
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Invasion of melanoma cells into dermal connective tissue in vitro: evidence for an important role of cysteine proteases. Author(s): Dennhofer R, Kurschat P, Zigrino P, Klose A, Bosserhoff A, van Muijen G, Krieg T, Mauch C, Hunzelmann N. Source: International Journal of Cancer. Journal International Du Cancer. 2003 September 1; 106(3): 316-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12845667
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Invasiveness of transformed human breast epithelial cell lines is related to cathepsin B and inhibited by cysteine proteinase inhibitors. Author(s): Bervar A, Zajc I, Sever N, Katunuma N, Sloane BF, Lah TT. Source: Biological Chemistry. 2003 March; 384(3): 447-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12715895
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Involvement of lysosomal cysteine proteases in hydrogen peroxide-induced apoptosis in HL-60 cells. Author(s): Ishisaka R, Utsumi K, Utsumi T. Source: Bioscience, Biotechnology, and Biochemistry. 2002 September; 66(9): 1865-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12400685
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Iron regulatory protein 2 as iron sensor. Iron-dependent oxidative modification of cysteine. Author(s): Kang DK, Jeong J, Drake SK, Wehr NB, Rouault TA, Levine RL. Source: The Journal of Biological Chemistry. 2003 April 25; 278(17): 14857-64. Epub 2003 February 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591920
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KIM127, an antibody that promotes adhesion, maps to a region of CD18 that includes cysteine-rich repeats. Author(s): Stephens P, Romer JT, Spitali M, Shock A, Ortlepp S, Figdor CG, Robinson MK. Source: Cell Adhes Commun. 1995 December; 3(5): 375-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8640375
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Kinetic analysis of covalent binding between N-acetyl-L-cysteine and albumin through the formation of mixed disulfides in human and rat serum in vitro. Author(s): Harada D, Naito S, Otagiri M. Source: Pharmaceutical Research. 2002 November; 19(11): 1648-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12458670
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Kinetic characterization of native and cysteine 112-modified glutathione S-transferase A1-1: reassessment of nonsubstrate ligand binding. Author(s): Lyon RP, Atkins WM. Source: Biochemistry. 2002 September 10; 41(36): 10920-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12206662
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Kinetics and equilibria of S-nitrosothiol-thiol exchange between glutathione, cysteine, penicillamines and serum albumin. Author(s): Meyer DJ, Kramer H, Ozer N, Coles B, Ketterer B. Source: Febs Letters. 1994 May 30; 345(2-3): 177-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8200453
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Lack of correlation between the observed stability and pharmacological properties of S-nitroso derivatives of glutathione and cysteine-related peptides. Author(s): Tullett JM, Rees DD, Shuker DE, Gescher A. Source: Biochemical Pharmacology. 2001 November 1; 62(9): 1239-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11705457
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lcd from Streptococcus anginosus encodes a C-S lyase with alpha,beta-elimination activity that degrades L-cysteine. Author(s): Yoshida Y, Nakano Y, Amano A, Yoshimura M, Fukamachi H, Oho T, Koga T. Source: Microbiology (Reading, England). 2002 December; 148(Pt 12): 3961-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12480900
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L-cysteine increases glucose uptake in mouse soleus muscle and SH-SY5Y cells. Author(s): Gazit V, Ben-Abraham R, Vofsi O, Katz Y. Source: Metabolic Brain Disease. 2003 September; 18(3): 221-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14567472
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L-cysteine prevents oxidation-induced block of the cardiac Na+ channel via interaction with heart-specific cysteinyl residues in the P-loop region. Author(s): Yatsuhashi T, Hisatome I, Kurata Y, Sasaki N, Ogura K, Kato M, Kinugasa R, Matsubara K, Yamawaki M, Yamamoto Y, Tanaka Y, Ogino K, Igawa O, Makita N, Shigemasa C. Source: Circulation Journal : Official Journal of the Japanese Circulation Society. 2002 September; 66(9): 846-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12224824
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Lead phthalocyanine as a selective carrier for preparation of a cysteine-selective electrode. Author(s): Shahrokhian S. Source: Analytical Chemistry. 2001 December 15; 73(24): 5972-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11791568
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Lecithin retinol acyltransferase contains cysteine residues essential for catalysis. Author(s): Mondal MS, Ruiz A, Bok D, Rando RR. Source: Biochemistry. 2000 May 2; 39(17): 5215-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10819989
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Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. Author(s): Kudo N, Matsumori N, Taoka H, Fujiwara D, Schreiner EP, Wolff B, Yoshida M, Horinouchi S. Source: Proceedings of the National Academy of Sciences of the United States of America. 1999 August 3; 96(16): 9112-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10430904
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Lifestyle and cardiovascular disease risk factors as determinants of total cysteine in plasma: the Hordaland Homocysteine Study. Author(s): El-Khairy L, Ueland PM, Nygard O, Refsum H, Vollset SE. Source: The American Journal of Clinical Nutrition. 1999 December; 70(6): 1016-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10584046
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Ligand binding properties and structural studies of recombinant and chemically modified hemoglobins altered at beta 93 cysteine. Author(s): Cheng Y, Shen TJ, Simplaceanu V, Ho C. Source: Biochemistry. 2002 October 1; 41(39): 11901-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12269835
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Ligand recognition of serine-cysteine amino acid exchanges in transmembrane domain 5 of alpha2-adrenergic receptors by UK 14,304. Author(s): Cockcroft V, Frang H, Pihlavisto M, Marjamaki A, Scheinin M. Source: Journal of Neurochemistry. 2000 April; 74(4): 1705-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10737629
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LIM-domain protein cysteine- and glycine-rich protein 2 (CRP2) is a novel marker of hepatic stellate cells and binding partner of the protein inhibitor of activated STAT1. Author(s): Weiskirchen R, Moser M, Weiskirchen S, Erdel M, Dahmen S, Buettner R, Gressner AM. Source: The Biochemical Journal. 2001 November 1; 359(Pt 3): 485-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11672422
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L-n-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity. Author(s): Feghali JG, Liu W, Van De Water TR. Source: The Laryngoscope. 2001 July; 111(7): 1147-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11568534
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Local movement in the S2 region of the voltage-gated potassium channel hKv2.1 studied using cysteine mutagenesis. Author(s): Milligan CJ, Wray D. Source: Biophysical Journal. 2000 April; 78(4): 1852-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10733965
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Localization of the IGF binding domain and evaluation of the role of cysteine residues in IGF binding in IGF binding protein-4. Author(s): Byun D, Mohan S, Baylink DJ, Qin X. Source: The Journal of Endocrinology. 2001 April; 169(1): 135-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11250654
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Long-term treatment of erythropoietic protoporphyria with cysteine. Author(s): Mathews-Roth MM, Rosner B. Source: Photodermatology, Photoimmunology & Photomedicine. 2002 December; 18(6): 307-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12535027
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Lymphopain, a cytotoxic T and natural killer cell-associated cysteine proteinase. Author(s): Brown J, Matutes E, Singleton A, Price C, Molgaard H, Buttle D, Enver T. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1998 November; 12(11): 1771-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9823953
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Lysosomal cysteine proteases (cathepsins): promising drug targets. Author(s): Turk D, Guncar G. Source: Acta Crystallographica. Section D, Biological Crystallography. 2003 February; 59(Pt 2): 203-13. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12554931
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Lysosomal cysteine proteases regulate antigen presentation. Author(s): Honey K, Rudensky AY. Source: Nature Reviews. Immunology. 2003 June; 3(6): 472-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12776207
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Lysosomal cysteine proteases: facts and opportunities. Author(s): Turk V, Turk B, Turk D. Source: The Embo Journal. 2001 September 3; 20(17): 4629-33. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11532926
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Lysosomal cysteine proteases: more than scavengers. Author(s): Turk B, Turk D, Turk V. Source: Biochimica Et Biophysica Acta. 2000 March 7; 1477(1-2): 98-111. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10708852
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MANSC: a seven-cysteine-containing domain present in animal membrane and extracellular proteins. Author(s): Guo J, Chen S, Huang C, Chen L, Studholme DJ, Zhao S, Yu L. Source: Trends in Biochemical Sciences. 2004 April; 29(4): 172-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15124631
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Matrix metalloproteinase inhibitor reversion-inducing cysteine-rich protein with Kazal motifs: a prognostic marker for good clinical outcome in human breast carcinoma. Author(s): Span PN, Sweep CG, Manders P, Beex LV, Leppert D, Lindberg RL. Source: Cancer. 2003 June 1; 97(11): 2710-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12767082
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Measurement of S-nitrosoalbumin by gas chromatography--mass spectrometry. III. Quantitative determination in human plasma after specific conversion of the Snitroso group to nitrite by cysteine and Cu(2+) via intermediate formation of Snitrosocysteine and nitric oxide. Author(s): Tsikas D, Sandmann J, Frolich JC. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2002 June 5; 772(2): 335-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12007779
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Mechanisms by which cysteine can inhibit or promote the oxidation of low density lipoprotein by copper. Author(s): Patterson RA, Lamb DJ, Leake DS. Source: Atherosclerosis. 2003 July; 169(1): 87-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12860254
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Mechanistic aspects of on-line electrochemical tagging of free L-cysteine residues during electrospray ionisation for mass spectrometry in protein analysis. Author(s): Roussel C, Rohner TC, Jensen H, Girault HH. Source: Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry. 2003 February 17; 4(2): 200-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12619420
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Medical significance of cysteine protease inhibitors in mammalian secretory fluids. Author(s): Katunuma N, Shiota H, Le QT. Source: J Med Invest. 2003 August; 50(3-4): 154-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13678384
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MERTK arginine-844-cysteine in a patient with severe rod-cone dystrophy: loss of mutant protein function in transfected cells. Author(s): McHenry CL, Liu Y, Feng W, Nair AR, Feathers KL, Ding X, Gal A, Vollrath D, Sieving PA, Thompson DA. Source: Investigative Ophthalmology & Visual Science. 2004 May; 45(5): 1456-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15111602
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Methanethiosulfonate-modification alters local anesthetic block in rNav1.4 cysteinesubstituted mutants S1276C and L1280C. Author(s): O'Reilly JP, Wang SY, Wang GK. Source: The Journal of Membrane Biology. 2003 May 1; 193(1): 47-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879165
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MGC29506 gene, frequently down-regulated in intestinal-type gastric cancer, encodes secreted-type protein with conserved cysteine residues. Author(s): Katoh M, Katoh M. Source: International Journal of Oncology. 2003 July; 23(1): 235-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12792799
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MMP-28, a new human matrix metalloproteinase with an unusual cysteine-switch sequence is widely expressed in tumors. Author(s): Marchenko GN, Strongin AY. Source: Gene. 2001 March 7; 265(1-2): 87-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11255011
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Modification of human serum albumin by acrylamide at cysteine-34: a basis for a rapid biomonitoring procedure. Author(s): Noort D, Fidder A, Hulst AG. Source: Archives of Toxicology. 2003 September; 77(9): 543-5. Epub 2003 June 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12819856
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Modulation of an interleukin-12 and gamma interferon synergistic feedback regulatory cycle of T-cell and monocyte cocultures by Porphyromonas gingivalis lipopolysaccharide in the absence or presence of cysteine proteinases. Author(s): Yun PL, DeCarlo AA, Collyer C, Hunter N. Source: Infection and Immunity. 2002 October; 70(10): 5695-705. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12228299
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Molecular and biochemical analysis of the enzymes of cysteine biosynthesis in the plant Arabidopsis thaliana. Author(s): Hell R, Jost R, Berkowitz O, Wirtz M. Source: Amino Acids. 2002; 22(3): 245-57. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12083068
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Molecular cloning and characterization of the mouse CD163 homologue, a highly glucocorticoid-inducible member of the scavenger receptor cysteine-rich family. Author(s): Schaer DJ, Boretti FS, Hongegger A, Poehler D, Linnscheid P, Staege H, Muller C, Schoedon G, Schaffner A. Source: Immunogenetics. 2001 March; 53(2): 170-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11345593
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Molecular cloning and functional characterization of crustapain: a distinct cysteine proteinase with unique substrate specificity from northern shrimp Pandalus borealis. Author(s): Aoki H, Ahsan MN, Watabe S. Source: Journal of Biochemistry. 2003 June; 133(6): 799-810. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12869537
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Molecular cloning, expression and modelling of cat allergen, cystatin (Fel d 3), a cysteine protease inhibitor. Author(s): Ichikawa K, Vailes LD, Pomes A, Chapman MD. Source: Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2001 August; 31(8): 1279-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11529899
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Molecular mechanism of hypoxia-inducible factor 1alpha -p300 interaction. A leucine-rich interface regulated by a single cysteine. Author(s): Gu J, Milligan J, Huang LE. Source: The Journal of Biological Chemistry. 2001 February 2; 276(5): 3550-4. Epub 2000 November 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11063749
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Molecular modeling in cysteine protease inhibitor design. Author(s): Lindvall MK. Source: Current Pharmaceutical Design. 2002; 8(18): 1673-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12132998
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Mutational analysis of roles for extracellular cysteine residues in the assembly and function of human alpha 7-nicotinic acetylcholine receptors. Author(s): Dunckley T, Wu J, Zhao L, Lukas RJ. Source: Biochemistry. 2003 February 4; 42(4): 870-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12549904
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101
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Mutations in congenital myasthenic syndromes reveal an epsilon subunit C-terminal cysteine, C470, crucial for maturation and surface expression of adult AChR. Author(s): Ealing J, Webster R, Brownlow S, Abdelgany A, Oosterhuis H, Muntoni F, Vaux DJ, Vincent A, Beeson D. Source: Human Molecular Genetics. 2002 November 15; 11(24): 3087-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12417530
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N-acetyl cysteine therapy in acute viral hepatitis. Author(s): Gunduz H, Karabay O, Tamer A, Ozaras R, Mert A, Tabak OF. Source: World Journal of Gastroenterology : Wjg. 2003 December; 9(12): 2698-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14669316
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N-Acetyl-cysteine inhibits phospholipid metabolism, proinflammatory cytokine release, protease activity, and nuclear factor-kappaB deoxyribonucleic acid-binding activity in human fetal membranes in vitro. Author(s): Lappas M, Permezel M, Rice GE. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 April; 88(4): 1723-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679464
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N-acetyl-cysteine promotes angiostatin production and vascular collapse in an orthotopic model of breast cancer. Author(s): Agarwal A, Munoz-Najar U, Klueh U, Shih SC, Claffey KP. Source: American Journal of Pathology. 2004 May; 164(5): 1683-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15111315
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N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome. Author(s): Fulghesu AM, Ciampelli M, Muzj G, Belosi C, Selvaggi L, Ayala GF, Lanzone A. Source: Fertility and Sterility. 2002 June; 77(6): 1128-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12057717
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N-acetyl-L-cysteine does not affect the pharmacokinetics or myelosuppressive effect of busulfan during conditioning prior to allogeneic stem cell transplantation. Author(s): Sjoo F, Aschan J, Barkholt L, Hassan Z, Ringden O, Hassan M. Source: Bone Marrow Transplantation. 2003 August; 32(4): 349-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12900770
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N-acetyl-L-cysteine suppresses constitutive expression of CD11a/LFA-1alpha protein in myeloid lineage. Author(s): Hashizume K, Hatanaka Y, Fukuda I, Sano T, Yamaguchi Y, Tani Y, Danno G, Suzuki K, Ashida H. Source: Leukemia Research. 2002 October; 26(10): 939-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163056
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NEDP1, a highly conserved cysteine protease that deNEDDylates Cullins. Author(s): Mendoza HM, Shen LN, Botting C, Lewis A, Chen J, Ink B, Hay RT. Source: The Journal of Biological Chemistry. 2003 July 11; 278(28): 25637-43. Epub 2003 May 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730221
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New cysteine protease inhibitors in physiological secretory fluids and their medical significance. Author(s): Katunuma N, Ohashi A, Sano E, Murata E, Shiota H, Yamamoto K, Majima E, Le QT. Source: Advances in Enzyme Regulation. 2003; 43: 393-410. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791399
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New functions of lactoferrin and beta-casein in mammalian milk as cysteine protease inhibitors. Author(s): Ohashi A, Murata E, Yamamoto K, Majima E, Sano E, Le QT, Katunuma N. Source: Biochemical and Biophysical Research Communications. 2003 June 20; 306(1): 98-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12788072
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Non-peptidic inhibitors of cysteine proteases. Author(s): Schirmeister T, Kaeppler U. Source: Mini Reviews in Medicinal Chemistry. 2003 June; 3(4): 361-73. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12678829
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On the evolution of programmed cell death: apoptosis of the unicellular eukaryote Leishmania major involves cysteine proteinase activation and mitochondrion permeabilization. Author(s): Arnoult D, Akarid K, Grodet A, Petit PX, Estaquier J, Ameisen JC. Source: Cell Death and Differentiation. 2002 January; 9(1): 65-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11803375
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Overexpression of cruzipain, the major cysteine proteinase of Trypanosoma cruzi, is associated with enhanced metacyclogenesis. Author(s): Tomas AM, Miles MA, Kelly JM. Source: European Journal of Biochemistry / Febs. 1997 March 1; 244(2): 596-603. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9119029
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Overlapping substrate specificities of cytochrome P450 3A and P-glycoprotein for a novel cysteine protease inhibitor. Author(s): Zhang Y, Guo X, Lin ET, Benet LZ. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 1998 April; 26(4): 360-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9531525
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Oxidation of an engineered pore cysteine locks a voltage-gated K+ channel in a nonconducting state. Author(s): Zhang HJ, Liu Y, Zuhlke RD, Joho RH. Source: Biophysical Journal. 1996 December; 71(6): 3083-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8968579
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Oxidation of cysteine residues from alpha-A crystallin during cataractogenesis of the human lens. Author(s): Takemoto LJ. Source: Biochemical and Biophysical Research Communications. 1996 June 14; 223(2): 216-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8670261
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Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments. Author(s): Schweers O, Mandelkow EM, Biernat J, Mandelkow E. Source: Proceedings of the National Academy of Sciences of the United States of America. 1995 August 29; 92(18): 8463-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7667312
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Oxidation of human lens recombinant alphaA-crystallin and cysteine-deficient mutants. Author(s): Chen SJ, Sun TX, Akhtar NJ, Liang JJ. Source: Journal of Molecular Biology. 2001 January 26; 305(4): 969-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11162107
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Oxidation of the glutathione/glutathione disulfide redox state is induced by cysteine deficiency in human colon carcinoma HT29 cells. Author(s): Miller LT, Watson WH, Kirlin WG, Ziegler TR, Jones DP. Source: The Journal of Nutrition. 2002 August; 132(8): 2303-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163679
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Oxidoreductive modification of two cysteine residues in paired domain by Ref-1 regulates DNA-binding activity of Pax-8. Author(s): Cao X, Kambe F, Ohmori S, Seo H. Source: Biochemical and Biophysical Research Communications. 2002 September 20; 297(2): 288-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12237116
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Oxygen-induced seizures and inhibition of human glutamate decarboxylase and porcine cysteine sulfinic acid decarboxylase by oxygen and nitric oxide. Author(s): Davis K, Foos T, Wu JY, Schloss JV. Source: Journal of Biomedical Science. 2001 July-August; 8(4): 359-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11455199
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Palmitoylation regulates regulators of G-protein signaling (RGS) 16 function. I. Mutation of amino-terminal cysteine residues on RGS16 prevents its targeting to lipid rafts and palmitoylation of an internal cysteine residue. Author(s): Hiol A, Davey PC, Osterhout JL, Waheed AA, Fischer ER, Chen CK, Milligan G, Druey KM, Jones TL. Source: The Journal of Biological Chemistry. 2003 May 23; 278(21): 19301-8. Epub 2003 March 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12642593
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Pharmacokinetics and pharmacodynamics of mesna-mediated plasma cysteine depletion. Author(s): Smith PF, Booker BM, Creaven P, Perez R, Pendyala L. Source: Journal of Clinical Pharmacology. 2003 December; 43(12): 1324-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14615468
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Plasma taurine and cysteine levels following an oral methionine load: relationship with coronary heart disease. Author(s): Obeid OA, Johnston K, Emery PW. Source: European Journal of Clinical Nutrition. 2004 January; 58(1): 105-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14679374
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Plasma total cysteine, mortality, and cardiovascular disease hospitalizations: the Hordaland Homocysteine Study. Author(s): El-Khairy L, Vollset SE, Refsum H, Ueland PM. Source: Clinical Chemistry. 2003 June; 49(6 Pt 1): 895-900. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12765985
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Platelet resistance to the antiaggregating effect of N-acetyl-L-cysteine in obese, insulin-resistant subjects. Author(s): Anfossi G, Russo I, Massucco P, Mattiello L, Trovati M. Source: Thrombosis Research. 2003 April 15; 110(1): 39-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12877907
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Polymorphism in glutamate-cysteine ligase modifier subunit gene is associated with impairment of nitric oxide-mediated coronary vasomotor function. Author(s): Nakamura S, Sugiyama S, Fujioka D, Kawabata K, Ogawa H, Kugiyama K. Source: Circulation. 2003 September 23; 108(12): 1425-7. Epub 2003 Sep 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12975258
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Possible identity of IL-8 converting enzyme in human fibroblasts as a cysteine protease. Author(s): Ohashi K, Sano E, Nakaki T, Naruto M. Source: International Immunopharmacology. 2003 April; 3(4): 609-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12689664
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Proteasomal degradation of N-acetyltransferase 1 is prevented by acetylation of the active site cysteine: a mechanism for the slow acetylator phenotype and substratedependent down-regulation. Author(s): Butcher NJ, Arulpragasam A, Minchin RF. Source: The Journal of Biological Chemistry. 2004 May 21; 279(21): 22131-7. Epub 2004 March 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039438
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Protein kinase C inhibition induces DNA fragmentation in COLO 205 cells which is blocked by cysteine protease inhibition but not mediated through caspase-3. Author(s): Lewis AE, Wong BC, Langman MJ, Eggo MC. Source: Experimental Cell Research. 2003 September 10; 289(1): 1-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12941599
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Proteolysis of enteric cell villin by Entamoeba histolytica cysteine proteinases. Author(s): Lauwaet T, Oliveira MJ, Callewaert B, De Bruyne G, Saelens X, Ankri S, Vandenabeele P, Mirelman D, Mareel M, Leroy A. Source: The Journal of Biological Chemistry. 2003 June 20; 278(25): 22650-6. Epub 2003 April 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12690119
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Quantification of kininogens in plasma. A functional method based on the cysteine proteinase inhibitor activity. Author(s): Karlsrud TS, Buo L, Aasen AO, Johansen HT. Source: Thrombosis Research. 1996 May 1; 82(3): 265-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8732630
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Quantification of S-carboxymethyl-(R)-cysteine in human plasma by highperformance ion-exchange liquid chromatography/atmospheric pressure ionization mass spectrometry. Author(s): Anacardio R, Cantalini MG, De Angelis F, Gentile M. Source: Journal of Mass Spectrometry : Jms. 1997 April; 32(4): 388-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9130397
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Quantification of the expression levels of lysosomal cysteine proteinases in purified human osteoclastic cells by competitive RT-PCR. Author(s): Ishibashi O, Inui T, Mori Y, Kurokawa T, Kokubo T, Kumegawa M. Source: Calcified Tissue International. 2001 February; 68(2): 109-16. Erratum In: Calcif Tissue Int 2002 June; 70(6): 514. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11310346
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Quantitation of protein sulfinic and sulfonic acid, irreversibly oxidized protein cysteine sites in cellular proteins. Author(s): Hamann M, Zhang T, Hendrich S, Thomas JA. Source: Methods Enzymol. 2002; 348: 146-56. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11885268
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Regulation of angiogenesis and endothelial cell function by connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61). Author(s): Brigstock DR. Source: Angiogenesis. 2002; 5(3): 153-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12831056
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Renal cysteine conjugate C-S lyase mediated toxicity of halogenated alkenes in primary cultures of human and rat proximal tubular cells. Author(s): McGoldrick TA, Lock EA, Rodilla V, Hawksworth GM. Source: Archives of Toxicology. 2003 July; 77(7): 365-70. Epub 2003 April 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12700887
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Requirement for integrase during reverse transcription of human immunodeficiency virus type 1 and the effect of cysteine mutations of integrase on its interactions with reverse transcriptase. Author(s): Zhu K, Dobard C, Chow SA. Source: Journal of Virology. 2004 May; 78(10): 5045-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15113886
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Reversible oxidation of the active site cysteine of peroxiredoxins to cysteine sulfinic acid. Immunoblot detection with antibodies specific for the hyperoxidized cysteinecontaining sequence. Author(s): Woo HA, Kang SW, Kim HK, Yang KS, Chae HZ, Rhee SG. Source: The Journal of Biological Chemistry. 2003 November 28; 278(48): 47361-4. Epub 2003 October 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14559909
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Reversing the inactivation of peroxiredoxins caused by cysteine sulfinic acid formation. Author(s): Woo HA, Chae HZ, Hwang SC, Yang KS, Kang SW, Kim K, Rhee SG. Source: Science. 2003 April 25; 300(5619): 653-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12714748
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Role of a cysteine synthase in Staphylococcus aureus. Author(s): Lithgow JK, Hayhurst EJ, Cohen G, Aharonowitz Y, Foster SJ. Source: Journal of Bacteriology. 2004 March; 186(6): 1579-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996787
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Role of cysteine amino acid residues on the RNA binding activity of human thymidylate synthase. Author(s): Lin X, Liu J, Maley F, Chu E. Source: Nucleic Acids Research. 2003 August 15; 31(16): 4882-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12907731
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Role of cysteine S-conjugate beta-lyase in the metabolism of cisplatin. Author(s): Zhang L, Hanigan MH. Source: The Journal of Pharmacology and Experimental Therapeutics. 2003 September; 306(3): 988-94. Epub 2003 May 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12750429
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Role of RopB in growth phase expression of the SpeB cysteine protease of Streptococcus pyogenes. Author(s): Neely MN, Lyon WR, Runft DL, Caparon M. Source: Journal of Bacteriology. 2003 September; 185(17): 5166-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12923089
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Selective modulation of superantigen-induced responses by streptococcal cysteine protease. Author(s): Kansal RG, Nizet V, Jeng A, Chuang WJ, Kotb M. Source: The Journal of Infectious Diseases. 2003 February 1; 187(3): 398-407. Epub 2003 January 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12552423
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Simple and effective titrimetric procedure for the determination of sulfide and cysteine in the leather industry effluents. Author(s): Gallina A, Pastore P, Magno F. Source: Ann Chim. 2002 November-December; 92(11-12): 1151-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12556039
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Simple plasma work-up for a fast chromatographic analysis of homocysteine, cysteine, methionine and aromatic amino acids. Author(s): Husek P, Matucha P, Vrankova A, Simek P. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 June 15; 789(2): 311-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742122
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Soluble human core 2 beta6-N-acetylglucosaminyltransferase C2GnT1 requires its conserved cysteine residues for full activity. Author(s): Yang X, Qin W, Lehotay M, Toki D, Dennis P, Schutzbach JS, Brockhausen I. Source: Biochimica Et Biophysica Acta. 2003 May 30; 1648(1-2): 62-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12758148
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Specific cleavage sites on human IgG subclasses by cruzipain, the major cysteine proteinase from Trypanosoma cruzi. Author(s): Berasain P, Carmona C, Frangione B, Cazzulo JJ, Goni F. Source: Molecular and Biochemical Parasitology. 2003 August 11; 130(1): 23-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14550893
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Structural comparison of human monoamine oxidases A and B: mass spectrometry monitoring of cysteine reactivities. Author(s): Hubalek F, Pohl J, Edmondson DE. Source: The Journal of Biological Chemistry. 2003 August 1; 278(31): 28612-8. Epub 2003 May 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777388
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Substitution of arginine for cysteine 643 of the glucocorticoid receptor reduces its steroid-binding affinity and transcriptional activity. Author(s): Nagano M, Nakamura T, Niimi S, Fujino T, Nishimura T, Murayama N, Ishida S, Ozawa S, Saito Y, Sawada J. Source: Cancer Letters. 2002 July 8; 181(1): 109-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12430185
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Substitution of cysteine for selenocysteine in the catalytic center of type III iodothyronine deiodinase reduces catalytic efficiency and alters substrate preference. Author(s): Kuiper GG, Klootwijk W, Visser TJ. Source: Endocrinology. 2003 June; 144(6): 2505-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12746313
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Synthesis and phorbol ester binding of the cysteine-rich domains of diacylglycerol kinase (DGK) isozymes. DGKgamma and DGKbeta are new targets of tumorpromoting phorbol esters. Author(s): Shindo M, Irie K, Masuda A, Ohigashi H, Shirai Y, Miyasaka K, Saito N. Source: The Journal of Biological Chemistry. 2003 May 16; 278(20): 18448-54. Epub 2003 March 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12621060
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Synthesis of N-acetyl-S-(3-coumarinyl)-cysteine methyl ester and HPLC analysis of urinary coumarin metabolites. Author(s): Eisenbrand G, Otteneder M, Tang W. Source: Toxicology. 2003 August 28; 190(3): 249-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12927379
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The function of conserved cysteine residues in the extracellular domain of human receptor-activity-modifying protein. Author(s): Steiner S, Born W, Fischer JA, Muff R. Source: Febs Letters. 2003 December 4; 555(2): 285-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644429
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The human dopamine transporter forms a tetramer in the plasma membrane: crosslinking of a cysteine in the fourth transmembrane segment is sensitive to cocaine analogs. Author(s): Hastrup H, Sen N, Javitch JA. Source: The Journal of Biological Chemistry. 2003 November 14; 278(46): 45045-8. Epub 2003 September 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14519759
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The squamous cell carcinoma antigen 2 inhibits the cysteine proteinase activity of a major mite allergen, Der p 1. Author(s): Sakata Y, Arima K, Takai T, Sakurai W, Masumoto K, Yuyama N, Suminami Y, Kishi F, Yamashita T, Kato T, Ogawa H, Fujimoto K, Matsuo Y, Sugita Y, Izuhara K. Source: The Journal of Biological Chemistry. 2004 February 13; 279(7): 5081-7. Epub 2003 November 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14630915
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The structure of the extracellular region of human hepsin reveals a serine protease domain and a novel scavenger receptor cysteine-rich (SRCR) domain. Author(s): Somoza JR, Ho JD, Luong C, Ghate M, Sprengeler PA, Mortara K, Shrader WD, Sperandio D, Chan H, McGrath ME, Katz BA. Source: Structure (Cambridge, Mass. : 2001). 2003 September; 11(9): 1123-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962630
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The ubiquitin-proteasome system is responsible for cysteine-responsive regulation of cysteine dioxygenase concentration in liver. Author(s): Stipanuk MH, Hirschberger LL, Londono MP, Cresenzi CL, Yu AF. Source: American Journal of Physiology. Endocrinology and Metabolism. 2004 March; 286(3): E439-48. Epub 2003 November 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644768
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Thiol modification of cysteine 327 in the eighth transmembrane domain of the light subunit xCT of the heteromeric cystine/glutamate antiporter suggests close proximity to the substrate binding site/permeation pathway. Author(s): Jimenez-Vidal M, Gasol E, Zorzano A, Nunes V, Palacin M, Chillaron J. Source: The Journal of Biological Chemistry. 2004 March 19; 279(12): 11214-21. Epub 2004 January 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722095
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Treatment of chronic hepatitis B with high-dose intravenous N-acetyl-L-cysteine. Author(s): Weidenbach H, Orth M, Adler G, Mertens T, Schmid RM. Source: Hepatogastroenterology. 2003 November-December; 50(54): 2105-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14696474
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Two Trichomonas vaginalis loci encoding for distinct cysteine proteinases show a genomic linkage with putative inositol hexakisphosphate kinase (IP6K2) or an ABC transporter gene. Author(s): Leon-Sicairos Cdel R, Perez-Martinez I, Alvarez-Sanchez ME, LopezVillasenor I, Arroyo R. Source: The Journal of Eukaryotic Microbiology. 2003; 50 Suppl: 702-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14736227
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Tying everything together: the multiple roles of cysteine string protein (CSP) in regulated exocytosis. Author(s): Evans GJ, Morgan A, Burgoyne RD. Source: Traffic (Copenhagen, Denmark). 2003 October; 4(10): 653-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12956868
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Tyrosine-to-cysteine modification of human alpha-synuclein enhances protein aggregation and cellular toxicity. Author(s): Zhou W, Freed CR. Source: The Journal of Biological Chemistry. 2004 March 12; 279(11): 10128-35. Epub 2003 December 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14699135
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Ultrastructural localization of S100A3, a cysteine-rich, calcium binding protein, in human scalp hair shafts revealed by rapid-freezing immunocytochemistry. Author(s): Takizawa T, Takizawa T, Arai S, Kizawa K, Uchiwa H, Sasaki I, Inoue T. Source: The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society. 1999 April; 47(4): 525-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10082754
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Unclassifiable craniosynostosis phenotypes, FGFR2 Trp290 mutations, acanthosis nigricans, and unpaired cysteine mutations. Author(s): Cohen MM Jr. Source: American Journal of Medical Genetics. 2002 November 15; 113(1): 1-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12400057
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Urinary and plasma homocysteine and cysteine levels during prolonged oral Nacetylcysteine therapy. Author(s): Ventura P, Panini R, Abbati G, Marchetti G, Salvioli G. Source: Pharmacology. 2003 June; 68(2): 105-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12711838
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Urinary determination of N-acetyl- S-( N-methylcarbamoyl)cysteine and Nmethylformamide in workers exposed to N, N-dimethylformamide. Author(s): Imbriani M, Maestri L, Marraccini P, Saretto G, Alessio A, Negri S, Ghittori S. Source: International Archives of Occupational and Environmental Health. 2002 September; 75(7): 445-52. Epub 2002 June 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172890
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Urinary excretion measurement of cysteine and homocysteine in the form of their Spyridinium derivatives by high-performance liquid chromatography with ultraviolet detection. Author(s): Kaniowska E, Chwatko G, Glowacki R, Kubalczyk P, Bald E. Source: J Chromatogr A. 1998 March 6; 798(1-2): 27-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9542124
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Urinary excretion of free cysteine in critically ill neonates. Author(s): Cambonie G, Bellet H, Houdon L, Vallat C, El Younsi M, Vergnes C. Source: Acta Paediatrica (Oslo, Norway : 1992). 2001 December; 90(12): 1405-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11853338
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Use of phage display to select novel cystatins specific for Acanthoscelides obtectus cysteine proteinases. Author(s): Melo FR, Mello MO, Franco OL, Rigden DJ, Mello LV, Genu AM, Silva-Filho MC, Gleddie S, Grossi-de-Sa MF. Source: Biochimica Et Biophysica Acta. 2003 September 23; 1651(1-2): 146-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14499599
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Use of the substituted cysteine accessibility method to study the structure and function of G protein-coupled receptors. Author(s): Javitch JA, Shi L, Liapakis G. Source: Methods Enzymol. 2002; 343: 137-56. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11665562
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Variable regulation of glutamate cysteine ligase subunit proteins affects glutathione biosynthesis in response to oxidative stress. Author(s): Krzywanski DM, Dickinson DA, Iles KE, Wigley AF, Franklin CC, Liu RM, Kavanagh TJ, Forman HJ. Source: Archives of Biochemistry and Biophysics. 2004 March 1; 423(1): 116-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14871475
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Various forms of plasma cysteine and its metabolites in patients undergoing hemodialysis. Author(s): Wlodek PJ, Iciek MB, Milkowski A, Smolenski OB. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2001 February; 304(1-2): 9-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11165194
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Virulence and other phenotypic characteristics of urinary isolates of cysteinerequiring Escherichia coli. Author(s): McIver CJ, Tapsall JW. Source: Journal of Medical Microbiology. 1995 January; 42(1): 39-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7739023
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When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations? Author(s): Niccoli-Sire P, Murat A, Rohmer V, Gibelin H, Chabrier G, Conte-Devolx B, Visset J, Ronceray J, Jaeck D, Henry JF, Proye C, Carnaille B, Kraimps JL; Groupe D'etude Des Tumeurs Endocrines. Source: Surgery. 2003 December; 134(6): 1029-36; Discussion 1036-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14668737
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Whole blood-, plasma- and red blood cell glutathione and cysteine in patients with kidney disease and during hemodialysis. Author(s): Jacobson SH, Moldeus P. Source: Clinical Nephrology. 1994 September; 42(3): 189-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7994938
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Widespread expression of human cysteine string proteins. Author(s): Coppola T, Gundersen C. Source: Febs Letters. 1996 August 12; 391(3): 269-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8764987
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Young stroke and basal plasma and post-methionine load homocysteine and cysteine levels 1 year after the acute event: do plasma folates make the difference? Author(s): Beccia M, Mele MC, Ferrari M, Ranieri M, Barini A, Rasura M. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2004 April; 11(4): 269-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15061829
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Zn2+ binding to cysteine-rich domain of extracellular human immunodeficiency virus type 1 Tat protein is associated with Tat protein-induced apoptosis. Author(s): Misumi S, Takamune N, Ohtsubo Y, Waniguchi K, Shoji S. Source: Aids Research and Human Retroviruses. 2004 March; 20(3): 297-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15117453
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Z-Phe-Gly-NHO-Bz, an inhibitor of cysteine cathepsins, induces apoptosis in human cancer cells. Author(s): Zhu DM, Uckun FM. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 May; 6(5): 2064-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10815933
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CHAPTER 2. NUTRITION AND CYSTEINE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and cysteine.
Finding Nutrition Studies on Cysteine The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail:
[email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “cysteine” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
7
Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following information is typical of that found when using the “Full IBIDS Database” to search for “cysteine” (or a synonym): •
Application of SCAM (substituted cysteine accessibility method) to gap junction intercellular channels. Author(s): Department of Biological Sciences, SUNY at Buffalo, NY 14260, USA. Source: Skerrett, M Kasperek, E Cao, F L Shin, J H Aronowitz, J Ahmed, S Nicholson, B J Cell-Commun-Adhes. 2001; 8(4-6): 179-85 1541-9061
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Counting the number of disulfides and thiol groups in proteins and a novel approach for determining the local pKa for cysteine groups in proteins in vivo. Author(s): Melvin Calvin Laboratory, Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720-5230, USA. Source: Bellacchio, E McFarlane, K L Rompel, A Robblee, J H Cinco, R M Yachandra, V K J-Synchrotron-Radiat. 2001 May 1; 8(3): 1056-8 0909-0495
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Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein-calorie malnutrition. Author(s): College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Kwanak-Gu, Republic of Korea. Source: Kim, Y G Cho, M K Kwon, J W Kim, S G Chung, S J Shim, C K Le Myung, G Biopharm-Drug-Dispos. 2002 April; 23(3): 121-9 0142-2782
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Human kidney flavin-containing monooxygenases and their potential roles in cysteine s-conjugate metabolism and nephrotoxicity. Author(s): Department of Comparative Biosciences and Center for Molecular and Environmental Toxicology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. Source: Krause, R J Lash, L H Elfarra, A A J-Pharmacol-Exp-Ther. 2003 January; 304(1): 185-91 0022-3565
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Inhibition of acetylcholinesterase by physostigmine analogs: conformational mobility of cysteine loop due to the steric effect of the alkyl chain. Author(s): Ist. di Strutturistica Chimica, CNR Montelibretti, Rome, Italy. Source: Gavuzzo, E Pomponi, M J-Biochem-Mol-Toxicol. 2002; 16(2): 64-9 1095-6670
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Leishmania donovani methionine adenosyltransferase. Role of cysteine residues in the recombinant enzyme. Author(s): Departamento de Farmacologia y Toxicologia (INTOXCAL), Universidad de Leon, Leon, Spain. Source: Perez Pertejo, Y Reguera, R M Villa, H Garcia Estrada, C Balana Fouce, R Pajares, M A Ordonez, D Eur-J-Biochem. 2003 January; 270(1): 28-35 0014-2956
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Regulation of cellular alpha-MSH and beta-endorphin during stimulated secretion from intermediate pituitary cells: involvement of aspartyl and cysteine proteases in the control of cellular levels of alpha-MSH and beta-endorphin. Author(s): Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Source: Sei, C Toneff, T Aaron, W Hook, V Y Peptides. 2002 August; 23(8): 1409-18 01969781
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Stage-specific antimalarial activity of cysteine protease inhibitors. Author(s): Department of Medicine, San Francisco General Hospital, University of California, 94143, USA. Source: Shenai, B R SemeNovember, A V Rosenthal, P J Biol-Chem. 2002 May; 383(5): 843-7 1431-6730
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The role of the second binding loop of the cysteine protease inhibitor, cystatin A (stefin A), in stabilizing complexes with target proteases is exerted predominantly by Leu73. Author(s): Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, Uppsala Biomedical Centre, Sweden. Source: Pavlova, A Bjork, I Eur-J-Biochem. 2002 November; 269(22): 5649-58 0014-2956
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Tripodal pseudopeptides with three histidine or cysteine donors: synthesis and zinc complexation. Author(s): Institut fur Anorganische und Analytische Chemie der Universitat Freiburg, Albertstr. 21, D-79104 Freiburg, Germany. Source: Gelinsky, M Vogler, R Vahrenkamp, H Inorg-Chem. 2002 May 6; 41(9): 2560-4 0020-1669
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMD®Health: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
The following is a specific Web list relating to cysteine; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
Vitamins Folic Acid Source: Healthnotes, Inc.; www.healthnotes.com Folic Acid Source: Integrative Medicine Communications; www.drkoop.com Folic Acid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,887,00.html Pyridoxine Source: Integrative Medicine Communications; www.drkoop.com Vitamin B Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10067,00.html Vitamin B12 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B12 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B12 (Cobalamin) Source: Integrative Medicine Communications; www.drkoop.com Vitamin B3 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B6 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B6 Source: Prima Communications, Inc.www.personalhealthzone.com
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Vitamin B6 (Pyridoxine) Source: Integrative Medicine Communications; www.drkoop.com Vitamin B9 (Folic Acid) Alternative names: Folate, Folic Acid Source: Integrative Medicine Communications; www.drkoop.com Vitamin C Source: Healthnotes, Inc.; www.healthnotes.com •
Minerals Betaine Hydrochloride Source: Healthnotes, Inc.; www.healthnotes.com Cisplatin Source: Healthnotes, Inc.; www.healthnotes.com Fluoxetine Source: Healthnotes, Inc.; www.healthnotes.com Folate Source: Integrative Medicine Communications; www.drkoop.com Folate Source: Prima Communications, Inc.www.personalhealthzone.com Gabapentin Source: Healthnotes, Inc.; www.healthnotes.com Lecithin/Phosphatidylcholine/Choline Source: Healthnotes, Inc.; www.healthnotes.com Selenium Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10055,00.html Spironolactone Source: Healthnotes, Inc.; www.healthnotes.com Sulfur Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com
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Food and Diet Artichoke Source: Healthnotes, Inc.; www.healthnotes.com
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Arugula Source: Healthnotes, Inc.; www.healthnotes.com Asparagus Source: Healthnotes, Inc.; www.healthnotes.com Avocado Source: Healthnotes, Inc.; www.healthnotes.com Beets Source: Healthnotes, Inc.; www.healthnotes.com Betaine (Trimethylglycine) Source: Healthnotes, Inc.; www.healthnotes.com Bibb Lettuce Source: Healthnotes, Inc.; www.healthnotes.com Bok Choy Source: Healthnotes, Inc.; www.healthnotes.com Broccoflower Source: Healthnotes, Inc.; www.healthnotes.com Broccoli Source: Healthnotes, Inc.; www.healthnotes.com Brussels Sprouts Source: Healthnotes, Inc.; www.healthnotes.com Cabbage Source: Healthnotes, Inc.; www.healthnotes.com Carrots Source: Healthnotes, Inc.; www.healthnotes.com Cauliflower Source: Healthnotes, Inc.; www.healthnotes.com Chicory Source: Healthnotes, Inc.; www.healthnotes.com Coffee Source: Healthnotes, Inc.; www.healthnotes.com Collards Source: Healthnotes, Inc.; www.healthnotes.com Dandelion Greens Source: Healthnotes, Inc.; www.healthnotes.com
Nutrition
Endive Source: Healthnotes, Inc.; www.healthnotes.com Garlic Alternative names: Allium sativum Source: Healthnotes, Inc.; www.healthnotes.com Garlic Alternative names: Allium sativum Source: Integrative Medicine Communications; www.drkoop.com Jerusalem Artichoke Source: Healthnotes, Inc.; www.healthnotes.com Jicama Source: Healthnotes, Inc.; www.healthnotes.com Kale Source: Healthnotes, Inc.; www.healthnotes.com Kohlrabi Source: Healthnotes, Inc.; www.healthnotes.com Leeks Source: Healthnotes, Inc.; www.healthnotes.com Mustard Greens Source: Healthnotes, Inc.; www.healthnotes.com Okra Source: Healthnotes, Inc.; www.healthnotes.com Onions Source: Healthnotes, Inc.; www.healthnotes.com Parsnips Source: Healthnotes, Inc.; www.healthnotes.com Radishes Source: Healthnotes, Inc.; www.healthnotes.com Romaine Lettuce Source: Healthnotes, Inc.; www.healthnotes.com Rutabagas Source: Healthnotes, Inc.; www.healthnotes.com Saturated Fats Source: Healthnotes, Inc.; www.healthnotes.com Snow Peas Source: Healthnotes, Inc.; www.healthnotes.com
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Spinach Source: Healthnotes, Inc.; www.healthnotes.com Summer Squash Source: Healthnotes, Inc.; www.healthnotes.com Sweet Peppers Source: Healthnotes, Inc.; www.healthnotes.com Sweet Potatoes Source: Healthnotes, Inc.; www.healthnotes.com Tomatoes Source: Healthnotes, Inc.; www.healthnotes.com Trans-Fats Source: Healthnotes, Inc.; www.healthnotes.com Turnips Source: Healthnotes, Inc.; www.healthnotes.com Winter Squash Source: Healthnotes, Inc.; www.healthnotes.com Yams Source: Healthnotes, Inc.; www.healthnotes.com Zucchini Source: Healthnotes, Inc.; www.healthnotes.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND CYSTEINE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to cysteine. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to cysteine and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “cysteine” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to cysteine: •
(R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis. Author(s): Suh JH, Wang H, Liu RM, Liu J, Hagen TM. Source: Archives of Biochemistry and Biophysics. 2004 March 1; 423(1): 126-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14871476
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A comparative study of antioxidants S-allyl cysteine sulfoxide and vitamin E on the damages induced by nicotine in rats. Author(s): Helen A, Krishnakumar K, Vijayammal PL, Augusti KT. Source: Pharmacology. 2003 March; 67(3): 113-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12571405
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A cysteine-rich extracellular protein, LAT52, interacts with the extracellular domain of the pollen receptor kinase LePRK2. Author(s): Tang W, Ezcurra I, Muschietti J, McCormick S.
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Source: The Plant Cell. 2002 September; 14(9): 2277-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12215520 •
A novel extracellular calcium-dependent cysteine proteinase from Crithidia deanei. Author(s): d'Avila-Levy CM, Souza RF, Gomes RC, Vermelho AB, Branquinha MH. Source: Archives of Biochemistry and Biophysics. 2003 December 1; 420(1): 1-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14622969
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Altered cytokeratin expression during chemoprevention of hamster buccal pouch carcinogenesis by S-allylcysteine. Author(s): Balasenthil S, Rao KS, Nagini S. Source: Polish Journal of Pharmacology. 2003 September-October; 55(5): 793-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704476
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Altered kinetic properties of tyrosine-183 to cysteine mutation in glutamine synthetase of anabaena variabilis strain SA1 is responsible for excretion of ammonium ion produced by nitrogenase. Author(s): Healy FG, Latorre C, Albrecht SL, Reddy PM, Shanmugam KT. Source: Current Microbiology. 2003 June; 46(6): 423-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12732949
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Analysis of the non-covalent interaction between metal ions and the cysteine-rich domain of protein kinase C eta by electrospray ionization mass spectrometry. Author(s): Shindo M, Irie K, Fukuda H, Ohigashi H. Source: Bioorganic & Medicinal Chemistry. 2003 November 17; 11(23): 5075-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14604671
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Anti-oxidant properties of N-acetyl-L-cysteine do not improve the immune resistance of mice fed dietary lipids to Listeria monocytogenes infection. Author(s): Puertollano MA, de Pablo MA, Alvarez de Cienfuegos G. Source: Clinical Nutrition (Edinburgh, Lothian). 2003 June; 22(3): 313-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12765672
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Antioxidant S-allylcysteine prevents gentamicin-induced oxidative stress and renal damage. Author(s): Maldonado PD, Barrera D, Rivero I, Mata R, Medina-Campos ON, Hernandez-Pando R, Pedraza-Chaverri J. Source: Free Radical Biology & Medicine. 2003 August 1; 35(3): 317-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12885594
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Antioxidants N-acetylcysteine (NAC) and 2-mercaptoethanol (2-ME) affect the survival and differentiative potential of cholinergic precursors from the embryonic
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septal nuclei and basal forebrain: involvement of ras signaling. Author(s): Ni L, Wen Y, Peng X, Jonakait GM. Source: Brain Research. Developmental Brain Research. 2001 October 24; 130(2): 207-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11675123 •
Apoptosis induction by S-allylcysteine, a garlic constituent, during 7,12dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. Author(s): Balasenthil S, Rao KS, Nagini S. Source: Cell Biochemistry and Function. 2002 September; 20(3): 263-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12125104
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Comparative trial of N-acetyl-cysteine, taurine, and oxerutin on skin and kidney damage in long-term experimental diabetes. Author(s): Odetti P, Pesce C, Traverso N, Menini S, Maineri EP, Cosso L, Valentini S, Patriarca S, Cottalasso D, Marinari UM, Pronzato MA. Source: Diabetes. 2003 February; 52(2): 499-505. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12540627
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Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. Author(s): Dickinson DA, Iles KE, Zhang H, Blank V, Forman HJ. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2003 March; 17(3): 473-5. Epub 2003 January 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12514113
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Cys32 and His105 are the critical residues for the calcium-dependent cysteine proteolytic activity of CvaB, an ATP-binding cassette transporter. Author(s): Wu KH, Tai PC. Source: The Journal of Biological Chemistry. 2004 January 9; 279(2): 901-9. Epub 2003 October 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14570918
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Cysteine supplementation improves the erythrocyte glutathione synthesis rate in children with severe edematous malnutrition. Author(s): Badaloo A, Reid M, Forrester T, Heird WC, Jahoor F. Source: The American Journal of Clinical Nutrition. 2002 September; 76(3): 646-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12198013
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Cysteine supplementation prevents unweighting-induced ubiquitination in association with redox regulation in rat skeletal muscle. Author(s): Ikemoto M, Nikawa T, Kano M, Hirasaka K, Kitano T, Watanabe C, Tanaka R, Yamamoto T, Kamada M, Kishi K.
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Source: Biological Chemistry. 2002 March-April; 383(3-4): 715-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12033461 •
Cysteine-less glycosylphosphatidylinositol-specific phospholipase C is inhibited competitively by a thiol reagent: evidence for glyco-mimicry by pchloromercuriphenylsulphonate. Author(s): Stanton JD, Rashid MB, Mensa-Wilmot K. Source: The Biochemical Journal. 2002 August 15; 366(Pt 1): 281-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12010122
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Detailed characterization of cysteine-less P-glycoprotein reveals subtle pharmacological differences in function from wild-type protein. Author(s): Taylor AM, Storm J, Soceneantu L, Linton KJ, Gabriel M, Martin C, Woodhouse J, Blott E, Higgins CF, Callaghan R. Source: British Journal of Pharmacology. 2001 December; 134(8): 1609-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11739236
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Development of a biosensor specific for cysteine sulfoxides. Author(s): Keusgen M, Junger M, Krest I, Schoning MJ. Source: Biosensors & Bioelectronics. 2003 May; 18(5-6): 805-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12706595
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Dietary N-acetyl-L-cysteine modulates benzo[a]pyrene-induced skin tumors in cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) mice. Author(s): Martin KR, Trempus C, Saulnier M, Kari FW, Barrett JC, French JE. Source: Carcinogenesis. 2001 September; 22(9): 1373-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11532857
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Effect of fraxetin and myricetin on rotenone-induced cytotoxicity in SH-SY5Y cells: comparison with N-acetylcysteine. Author(s): Molina-Jimenez MF, Sanchez-Reus MI, Benedi J. Source: European Journal of Pharmacology. 2003 July 4; 472(1-2): 81-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12860476
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Effect of lipid composition on meat-like model systems containing cysteine, ribose, and polyunsaturated fatty acids. Author(s): Elmore JS, Campo MM, Enser M, Mottram DS. Source: Journal of Agricultural and Food Chemistry. 2002 February 27; 50(5): 1126-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11853493
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Effect of S-(1,2-dicarboxyethyl) glutathione and S-(1,2-dicarboxyethyl) cysteine on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in
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human neutrophils. Author(s): Wang C, Lu H, Chen G, Yamashita K, Manabe M, Kodama H. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 November; 40(11): 1101-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521225 •
Effects of oral N-acetylcysteine on plasma homocysteine and whole blood glutathione levels in healthy, non-pregnant women. Author(s): Roes EM, Raijmakers MT, Peters WH, Steegers EA. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 May; 40(5): 496-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12113295
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Efficiency of a cysteine-taurine-threonine-serine supplemented parenteral nutrition in an experimental model of acute inflammation. Author(s): Osowska S, De Bandt JP, Chaib S, Neveux N, Berard MP, Cynober L. Source: Intensive Care Medicine. 2003 October; 29(10): 1798-801. Epub 2003 July 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879241
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Enhancement of glutathione and g-glutamylcysteine synthetase, the rate limiting enzyme of glutathione synthesis, by chemoprotective plant-derived food and beverage components in the human hepatoma cell line HepG2. Author(s): Scharf G, Prustomersky S, Knasmuller S, Schulte-Hermann R, Huber WW. Source: Nutrition and Cancer. 2003; 45(1): 74-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791507
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Fibrillin-2 defects impair elastic fiber assembly in a homocysteinemic chick model. Author(s): Hill CH, Mecham R, Starcher B. Source: The Journal of Nutrition. 2002 August; 132(8): 2143-50. Erratum In: J Nutr 2002 November; 132(11): 3431. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163653
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Five cysteine-containing compounds have antioxidative activity in Balb/cA mice. Author(s): Hsu CC, Huang CN, Hung YC, Yin MC. Source: The Journal of Nutrition. 2004 January; 134(1): 149-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704308
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Flavonoids increase the intracellular glutathione level by transactivation of the gamma-glutamylcysteine synthetase catalytical subunit promoter. Author(s): Myhrstad MC, Carlsen H, Nordstrom O, Blomhoff R, Moskaug JO. Source: Free Radical Biology & Medicine. 2002 March 1; 32(5): 386-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11864778
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Functional and structural consequences of cysteine substitutions in the NH2 proximal region of the human multidrug resistance protein 1 (MRP1/ABCC1). Author(s): Leslie EM, Letourneau IJ, Deeley RG, Cole SP. Source: Biochemistry. 2003 May 13; 42(18): 5214-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12731862
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Furfural-cysteine model reaction in food grade nonionic oil/water microemulsions for selective flavor formation. Author(s): Yaghmur A, Aserin A, Garti N. Source: Journal of Agricultural and Food Chemistry. 2002 May 8; 50(10): 2878-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11982414
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Increased recovery of brain acetylcholinesterase activity in dichlorvos-intoxicated European eels Anguilla anguilla by bath treatment with N-acetylcysteine. Author(s): Pena-Llopis S, Ferrando MD, Pena JB. Source: Dis Aquat Organ. 2003 August 4; 55(3): 237-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13677510
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Induction of apoptosis by the garlic-derived compound S-allylmercaptocysteine (SAMC) is associated with microtubule depolymerization and c-Jun NH(2)-terminal kinase 1 activation. Author(s): Xiao D, Pinto JT, Soh JW, Deguchi A, Gundersen GG, Palazzo AF, Yoon JT, Shirin H, Weinstein IB. Source: Cancer Research. 2003 October 15; 63(20): 6825-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14583480
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Inhibitory effect of green tea catechins on cysteine proteinases in Porphyromonas gingivalis. Author(s): Okamoto M, Sugimoto A, Leung KP, Nakayama K, Kamaguchi A, Maeda N. Source: Oral Microbiology and Immunology. 2004 April; 19(2): 118-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14871352
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Investigation of sequential behavior of carboxyl protease and cysteine protease activities in virus-infected Sf-9 insect cell culture by inhibition assay. Author(s): Gotoh T, Miyazaki Y, Kikuchi K, Bentley WE. Source: Applied Microbiology and Biotechnology. 2001 September; 56(5-6): 742-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11601624
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Isolation and characterization of a cysteine protease of freesia corms. Author(s): Uchikoba T, Okubo M, Arima K, Yonezawa H. Source: Bioscience, Biotechnology, and Biochemistry. 2002 February; 66(2): 448-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11999426
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Isolation of S-n-butylcysteine sulfoxide and six n-butyl-containing thiosulfinates from Allium siculum. Author(s): Kubec R, Kim S, McKeon DM, Musah RA. Source: Journal of Natural Products. 2002 July; 65(7): 960-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12141853
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Isolation, purification, and properties of cysteine proteinase from Bombyx mori L. eggs. Author(s): Yarygin DV, Klunova SM, Filippovich YB. Source: Biochemistry. Biokhimiia. 2003 January; 68(1): 63-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12693978
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Micellar electrokinetic chromatography estimation of size and composition of procyanidins after thiolysis with cysteine. Author(s): Herrero-Martinez JM, Rafols C, Roses M, Bosch E, Lozano C, Torres JL. Source: Electrophoresis. 2003 May; 24(9): 1404-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12731026
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Modes of membrane interaction of a natural cysteine-rich peptide: viscotoxin A3. Author(s): Coulon A, Berkane E, Sautereau AM, Urech K, Rouge P, Lopez A. Source: Biochimica Et Biophysica Acta. 2002 February 15; 1559(2): 145-59. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11853681
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Molecular cloning and functional expression of cDNA encoding a cysteine proteinase inhibitor, cystatin, from Job's tears (Coix lacryma-jobi L. var. Ma-yuen Stapf). Author(s): Yoza K, Nakamura S, Yaguchi M, Haraguchi K, Ohtsubo K. Source: Bioscience, Biotechnology, and Biochemistry. 2002 October; 66(10): 2287-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12450152
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N-acetyl-L-cysteine enhances chemotherapeutic effect on prostate cancer cells. Author(s): Tozawa K, Okamoto T, Hayashi Y, Sasaki S, Kawai N, Kohri K. Source: Urological Research. 2002 March; 30(1): 53-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11942326
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Neurotoxicity induced by amyloid beta-peptide and ibotenic acid in organotypic hippocampal cultures: protection by S-allyl-L-cysteine, a garlic compound. Author(s): Ito Y, Ito M, Takagi N, Saito H, Ishige K. Source: Brain Research. 2003 September 19; 985(1): 98-107. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12957372
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Nonredundant antioxidant defense by multiple two-cysteine peroxiredoxins in human prostate cancer cells. Author(s): Shen C, Nathan C.
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Source: Molecular Medicine (Cambridge, Mass.). 2002 February; 8(2): 95-102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12080185 •
Novel bicistronic retroviral vector expressing gamma-glutamylcysteine synthetase and the multidrug resistance protein 1 (MRP1) protects cells from MRP1-effluxed drugs and alkylating agents. Author(s): Rappa G, Lorico A, Hildinger M, Fodstad O, Baum C. Source: Human Gene Therapy. 2001 September 20; 12(14): 1785-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11560771
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Physical, chemical, and biological properties of s-allylcysteine, an amino acid derived from garlic. Author(s): Kodera Y, Suzuki A, Imada O, Kasuga S, Sumioka I, Kanezawa A, Taru N, Fujikawa M, Nagae S, Masamoto K, Maeshige K, Ono K. Source: Journal of Agricultural and Food Chemistry. 2002 January 30; 50(3): 622-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11804540
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Protective effect of S-allyl-L-cysteine, a garlic compound, on amyloid beta-proteininduced cell death in nerve growth factor-differentiated PC12 cells. Author(s): Ito Y, Kosuge Y, Sakikubo T, Horie K, Ishikawa N, Obokata N, Yokoyama E, Yamashina K, Yamamoto M, Saito H, Arakawa M, Ishige K. Source: Neuroscience Research. 2003 May; 46(1): 119-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12725918
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Redox balance in patients with Down's syndrome before and after dietary supplementation with alpha-lipoic acid and L-cysteine. Author(s): Gualandri W, Gualandri L, Demartini G, Esposti R, Marthyn P, Volonte S, Stangoni L, Borgonovo M, Fraschini F. Source: Int J Clin Pharmacol Res. 2003; 23(1): 23-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14621070
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S-alk(en)yl cysteines of garlic inhibit cholesterol synthesis by deactivating HMGCoA reductase in cultured rat hepatocytes. Author(s): Liu L, Yeh YY. Source: The Journal of Nutrition. 2002 June; 132(6): 1129-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12042421
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S-allylcysteine inhibits circulatory lipid peroxidation and promotes antioxidants in N-nitrosodiethylamine-induced carcinogenesis. Author(s): Sundaresan S, Subramanian P. Source: Polish Journal of Pharmacology. 2003 January-February; 55(1): 37-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12856824
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S-allylcysteine, a garlic constituent, inhibits 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. Author(s): Balasenthil S, Ramachandran CR, Nagini S. Source: Nutrition and Cancer. 2001; 40(2): 165-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11962252
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S-allyl-L-cysteine selectively protects cultured rat hippocampal neurons from amyloid beta-protein- and tunicamycin-induced neuronal death. Author(s): Kosuge Y, Koen Y, Ishige K, Minami K, Urasawa H, Saito H, Ito Y. Source: Neuroscience. 2003; 122(4): 885-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14643758
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Specific and reversible inactivation of Phycomyces blakesleeanus isocitrate lyase by ascorbate-iron: role of two redox-active cysteines. Author(s): Rua J, Soler J, Busto F, de Arriaga D. Source: Fungal Genetics and Biology : Fg & B. 2002 April; 35(3): 223-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11929212
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S-propyl cysteine reduces the secretion of apolipoprotein B100 and triacylglycerol by HepG2 cells. Author(s): Han SY, Hu Y, Anno T, Yanagita T. Source: Nutrition (Burbank, Los Angeles County, Calif.). 2002 June; 18(6): 505-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12044824
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Structural and functional consequences of mutating cysteine residues in the amino terminus of human multidrug resistance-associated protein 1. Author(s): Yang Y, Chen Q, Zhang JT. Source: The Journal of Biological Chemistry. 2002 November 15; 277(46): 44268-77. Epub 2002 September 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12235150
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Sulfoxides as urinary metabolites of S-allyl-L-cysteine in rats: evidence for the involvement of flavin-containing monooxygenases. Author(s): Krause RJ, Glocke SC, Elfarra AA. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2002 October; 30(10): 1137-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12228191
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Supplementation of N-acetylcysteine normalizes lipopolysaccharide-induced nuclear factor kappaB activation and proinflammatory cytokine production during early rehabilitation of protein malnourished mice. Author(s): Li J, Quan N, Bray TM.
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Source: The Journal of Nutrition. 2002 November; 132(11): 3286-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12421841 •
Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise. Author(s): Childs A, Jacobs C, Kaminski T, Halliwell B, Leeuwenburgh C. Source: Free Radical Biology & Medicine. 2001 September 15; 31(6): 745-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11557312
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The calpain domain of the maize DEK1 protein contains the conserved catalytic triad and functions as a cysteine proteinase. Author(s): Wang C, Barry JK, Min Z, Tordsen G, Rao AG, Olsen OA. Source: The Journal of Biological Chemistry. 2003 September 5; 278(36): 34467-74. Epub 2003 June 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12824178
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The effect of N-acetylcysteine supplementation upon viral load, CD4, CD8, total lymphocyte count and hematocrit in individuals undergoing antiretroviral treatment. Author(s): Spada C, Treitinger A, Reis M, Masokawa IY, Verdi JC, Luiz MC, Silveira MV, Michelon CM, Avila-Junior S, Gil DO, Ostrowskyl S. Source: Clinical Chemistry and Laboratory Medicine : Cclm / Fescc. 2002 May; 40(5): 452-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12113286
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The ferric uptake regulator of Pseudomonas aeruginosa has no essential cysteine residues and does not contain a structural zinc ion. Author(s): Lewin AC, Doughty PA, Flegg L, Moore GR, Spiro S. Source: Microbiology (Reading, England). 2002 August; 148(Pt 8): 2449-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12177338
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The influence of glutathione and cysteine levels on the cytotoxicity of helenanolide type sesquiterpene lactones against KB cells. Author(s): Heilmann J, Wasescha MR, Schmidt TJ. Source: Bioorganic & Medicinal Chemistry. 2001 August; 9(8): 2189-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11504656
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The protective effect of garlic oil on hepatotoxicity induced by acetaminophen in mice and comparison with N-acetylcysteine. Author(s): Kalantari H, Salehi M. Source: Saudi Med J. 2001 December; 22(12): 1080-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11802181
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Therapeutic effect of S-allylmercaptocysteine on acetaminophen-induced liver injury in mice. Author(s): Sumioka I, Matsura T, Yamada K. Source: European Journal of Pharmacology. 2001 December 21; 433(2-3): 177-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11755151
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Timing of supplementation with the antioxidant N-acetyl-L-cysteine reduces tumor multiplicity in novel, cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) transgenic mice but has no impact on malignant progression. Author(s): Martin KR, Saulnier MJ, Kari FW, Barrett JC, French JE. Source: Nutrition and Cancer. 2002; 43(1): 59-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12467136
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Topical N-acetyl cysteine and genistein prevent ultraviolet-light-induced signaling that leads to photoaging in human skin in vivo. Author(s): Kang S, Chung JH, Lee JH, Fisher GJ, Wan YS, Duell EA, Voorhees JJ. Source: The Journal of Investigative Dermatology. 2003 May; 120(5): 835-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12713590
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Two new cysteine endopeptidases obtained from the latex of Araujia hortorum fruits. Author(s): Obregon WD, Arribere MC, del Valle SM, Liggieri C, Caffini N, Priolo N. Source: Journal of Protein Chemistry. 2001 May; 20(4): 317-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11594466
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Unconventional activation mechanisms of MMP-26, a human matrix metalloproteinase with a unique PHCGXXD cysteine-switch motif. Author(s): Marchenko ND, Marchenko GN, Strongin AY. Source: The Journal of Biological Chemistry. 2002 May 24; 277(21): 18967-72. Epub 2002 March 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11889136
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Up-regulation of interferon-gamma production by reduced glutathione, anthocyane and L-cysteine treatment in children with allergic asthma and recurrent respiratory diseases. Author(s): Chernyshov VP, Omelchenko LI, Treusch G, Vodyanik MA, Pochinok TV, Gumenyuk ME, Zelinsky GM. Source: Russ J Immunol. 2002 April; 7(1): 48-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12687266
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Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMD®Health: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to cysteine; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview Acetaminophen Poisoning Source: Integrative Medicine Communications; www.drkoop.com AIDS and HIV Source: Integrative Medicine Communications; www.drkoop.com Allergic Rhinitis Source: Integrative Medicine Communications; www.drkoop.com Alzheimer's Disease Source: Healthnotes, Inc.; www.healthnotes.com Alzheimer's Disease Source: Integrative Medicine Communications; www.drkoop.com Angina Source: Healthnotes, Inc.; www.healthnotes.com
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Arteriosclerosis Source: Integrative Medicine Communications; www.drkoop.com Asthma Source: Integrative Medicine Communications; www.drkoop.com Atherosclerosis Source: Healthnotes, Inc.; www.healthnotes.com Atherosclerosis Source: Integrative Medicine Communications; www.drkoop.com Atherosclerosis and Heart Disease Prevention Source: Prima Communications, Inc.www.personalhealthzone.com Autoimmune Conditions Source: Integrative Medicine Communications; www.drkoop.com Bone Cancer Source: Integrative Medicine Communications; www.drkoop.com Bone Loss Source: Integrative Medicine Communications; www.drkoop.com Bronchitis Source: Healthnotes, Inc.; www.healthnotes.com Bronchitis Source: Integrative Medicine Communications; www.drkoop.com Cardiovascular Disease Overview Source: Healthnotes, Inc.; www.healthnotes.com Cataracts (prevention) Source: Prima Communications, Inc.www.personalhealthzone.com Cervical Dysplasia Source: Integrative Medicine Communications; www.drkoop.com Chronic Obstructive Pulmonary Disease Source: Healthnotes, Inc.; www.healthnotes.com Chronic Obstructive Pulmonary Disease Source: Integrative Medicine Communications; www.drkoop.com Colon Cancer Source: Healthnotes, Inc.; www.healthnotes.com Congestive Heart Failure Source: Integrative Medicine Communications; www.drkoop.com
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Connective Tissue Diseases Source: Integrative Medicine Communications; www.drkoop.com Coronary Artery Disease Source: Integrative Medicine Communications; www.drkoop.com Cough Source: Healthnotes, Inc.; www.healthnotes.com Cystic Fibrosis Source: Integrative Medicine Communications; www.drkoop.com Depression Source: Integrative Medicine Communications; www.drkoop.com Depression (Mild to Moderate) Source: Prima Communications, Inc.www.personalhealthzone.com Diabetes Source: Healthnotes, Inc.; www.healthnotes.com Emphysema Source: Integrative Medicine Communications; www.drkoop.com Eye Disorders Source: Integrative Medicine Communications; www.drkoop.com Gastritis Source: Healthnotes, Inc.; www.healthnotes.com Gastritis Source: Integrative Medicine Communications; www.drkoop.com Hay Fever Source: Integrative Medicine Communications; www.drkoop.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com High Homocysteine Source: Healthnotes, Inc.; www.healthnotes.com Histoplasmosis Source: Integrative Medicine Communications; www.drkoop.com
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HIV and AIDS Source: Integrative Medicine Communications; www.drkoop.com HIV and AIDS Support Source: Healthnotes, Inc.; www.healthnotes.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com Immune System Disorders Source: Integrative Medicine Communications; www.drkoop.com Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Lung Cancer Source: Healthnotes, Inc.; www.healthnotes.com Lung Cancer Source: Integrative Medicine Communications; www.drkoop.com Meningitis Source: Integrative Medicine Communications; www.drkoop.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Miscarriage Source: Integrative Medicine Communications; www.drkoop.com Muscular Dystrophy Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Healthnotes, Inc.; www.healthnotes.com Osteoporosis Source: Integrative Medicine Communications; www.drkoop.com Parkinson's Disease Source: Healthnotes, Inc.; www.healthnotes.com Peptic Ulcer Source: Integrative Medicine Communications; www.drkoop.com Peripheral Vascular Disease Source: Healthnotes, Inc.; www.healthnotes.com Preeclampsia Source: Healthnotes, Inc.; www.healthnotes.com
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Pregnancy and Postpartum Support Source: Healthnotes, Inc.; www.healthnotes.com Respiratory Ailments Source: Integrative Medicine Communications; www.drkoop.com Scleroderma Source: Integrative Medicine Communications; www.drkoop.com Shock Source: Integrative Medicine Communications; www.drkoop.com Sickle Cell Anemia Source: Healthnotes, Inc.; www.healthnotes.com Sjögren's Syndrome Source: Integrative Medicine Communications; www.drkoop.com Spontaneous Abortion Source: Integrative Medicine Communications; www.drkoop.com Stomach Inflammation Source: Integrative Medicine Communications; www.drkoop.com Stroke Source: Healthnotes, Inc.; www.healthnotes.com TIAs Source: Integrative Medicine Communications; www.drkoop.com Transient Ischemic Attacks Source: Integrative Medicine Communications; www.drkoop.com •
Herbs and Supplements Acetaminophen Source: Healthnotes, Inc.; www.healthnotes.com Allium Sativum Source: Integrative Medicine Communications; www.drkoop.com Amiloride Source: Healthnotes, Inc.; www.healthnotes.com Amino Acids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10003,00.html Amino Acids Overview Source: Healthnotes, Inc.; www.healthnotes.com
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Anticonvulsants Source: Healthnotes, Inc.; www.healthnotes.com Antioxidants Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10004,00.html Antioxidants and Free Radicals Source: Healthnotes, Inc.; www.healthnotes.com Arnica Alternative names: Arnica montana L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Astragalus Sp Alternative names: Vetch, Rattlepod, Locoweed; Astragalus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org AZT Source: Healthnotes, Inc.; www.healthnotes.com Betaine Alternative names: Trimethylglycine Source: Integrative Medicine Communications; www.drkoop.com Biguanides Source: Integrative Medicine Communications; www.drkoop.com Cephalosporins Source: Integrative Medicine Communications; www.drkoop.com Chemotherapy Source: Healthnotes, Inc.; www.healthnotes.com Clozapine Source: Healthnotes, Inc.; www.healthnotes.com Cobalamin Source: Integrative Medicine Communications; www.drkoop.com Crataegus Alternative names: Hawthorn; Crataegus oxyacantha L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Cyclophosphamide Source: Healthnotes, Inc.; www.healthnotes.com Cyclosporine Source: Healthnotes, Inc.; www.healthnotes.com
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Cysteine Source: Healthnotes, Inc.; www.healthnotes.com Cysteine Source: Integrative Medicine Communications; www.drkoop.com Diuretics Source: Healthnotes, Inc.; www.healthnotes.com Docetaxel Source: Healthnotes, Inc.; www.healthnotes.com Doxorubicin Source: Healthnotes, Inc.; www.healthnotes.com Equisetum Alternative names: Horsetail; Equisetum arvense L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Fennel Source: Healthnotes, Inc.; www.healthnotes.com Fenofibrate Source: Healthnotes, Inc.; www.healthnotes.com Fluorouracil Source: Healthnotes, Inc.; www.healthnotes.com Flurbiprofen Source: Healthnotes, Inc.; www.healthnotes.com Ginkgo Biloba Source: Integrative Medicine Communications; www.drkoop.com Glutamine Source: Healthnotes, Inc.; www.healthnotes.com Glutathione Source: Healthnotes, Inc.; www.healthnotes.com Glutathione Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,854,00.html Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Hydantoin Derivatives Source: Integrative Medicine Communications; www.drkoop.com
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Interferon Source: Healthnotes, Inc.; www.healthnotes.com Isosorbide Dinitrate Source: Healthnotes, Inc.; www.healthnotes.com Isosorbide Mononitrate Source: Healthnotes, Inc.; www.healthnotes.com Lavandula Alternative names: Lavender; Lavandula sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Levodopa/Carbidopa Alternative names: Sinemet Source: Prima Communications, Inc.www.personalhealthzone.com Loop Diuretics Source: Healthnotes, Inc.; www.healthnotes.com Maidenhair Tree Source: Integrative Medicine Communications; www.drkoop.com Mentha Alternative names: Pennyroyal; Mentha/Hedeoma pulegium Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Metformin Source: Healthnotes, Inc.; www.healthnotes.com Methionine Source: Healthnotes, Inc.; www.healthnotes.com Methionine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10084,00.html Methotrexate Source: Healthnotes, Inc.; www.healthnotes.com Metoclopramide Source: Healthnotes, Inc.; www.healthnotes.com NAC (N-Acetyl Cysteine) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,809,00.html N-Acetyl Cysteine Source: Healthnotes, Inc.; www.healthnotes.com
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N-Acetyl Cysteine (NAC) Source: Prima Communications, Inc.www.personalhealthzone.com Nitroglycerin Source: Healthnotes, Inc.; www.healthnotes.com Nitroglycerin Alternative names: Deponit, Minitran, Nitrek, Nitro-Bid, Nitro-Derm, Nitro-Dur, Nitro-Time, Nitrocine, Nitrodisc, Nitrogard, Nitroglyn, Nitrol, Nitrolingual, Nitrong, NitroQuick, Nitrostat, Transderm-Nitro Source: Prima Communications, Inc.www.personalhealthzone.com Nitrous Oxide Source: Healthnotes, Inc.; www.healthnotes.com Nitrous Oxide Source: Prima Communications, Inc.www.personalhealthzone.com Nonsteroidal Anti-Inflammatory Drugs Source: Prima Communications, Inc.www.personalhealthzone.com Oral Contraceptives Source: Prima Communications, Inc.www.personalhealthzone.com Oral Corticosteroids Source: Healthnotes, Inc.; www.healthnotes.com Paclitaxel Source: Healthnotes, Inc.; www.healthnotes.com Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Phenobarbital Source: Healthnotes, Inc.; www.healthnotes.com Phenytoin Alternative names: Dilantin Infatab, Dilantin-125 Oral Suspension Source: Prima Communications, Inc.www.personalhealthzone.com Phytolacca Alternative names: Poke root, Endod; Phytolacca dodecandra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org S-Adenosylmethionine (SAMe) Source: Integrative Medicine Communications; www.drkoop.com SAMe Source: Healthnotes, Inc.; www.healthnotes.com
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SAMe Source: Integrative Medicine Communications; www.drkoop.com SAMe (S-Adenosylmethionine) Source: Prima Communications, Inc.www.personalhealthzone.com SAMe (S-Adenosylmethionine) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,818,00.html Taurine Source: Healthnotes, Inc.; www.healthnotes.com Taurine Source: Prima Communications, Inc.www.personalhealthzone.com Taurine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10059,00.html Thiazide Diuretics Source: Healthnotes, Inc.; www.healthnotes.com Tmg (trimethylglycine) Source: Prima Communications, Inc.www.personalhealthzone.com Triamterene Source: Healthnotes, Inc.; www.healthnotes.com Trimethylglycine Source: Integrative Medicine Communications; www.drkoop.com Valproic Acid Source: Healthnotes, Inc.; www.healthnotes.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON CYSTEINE Overview In this chapter, we will give you a bibliography on recent dissertations relating to cysteine. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “cysteine” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cysteine, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Cysteine ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to cysteine. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
A magnetic resonance study of radical recombination in irradiated cysteine hydrochloride monohydrate by Ramsbottom, Jeffrey V; ADVDEG from UNIVERSITY OF WATERLOO (CANADA), 1971 http://wwwlib.umi.com/dissertations/fullcit/NK07982
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Association of polymorphisms in the glutamate cysteine ligase catalytic subunit gene and glutathione-S-transferase genes with fibrotic lung diseases by Shao, Jing , PhD from UNIVERSITY OF WASHINGTON, 2003, 126 pages http://wwwlib.umi.com/dissertations/fullcit/3102715
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Design and synthesis of inhibitors for serine and cysteine proteases by Rukamp, Karrie Eileen Adlington, PhD from GEORGIA INSTITUTE OF TECHNOLOGY, 2003, 123 pages http://wwwlib.umi.com/dissertations/fullcit/3110447
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Design and synthesis of mechanism-based cysteine protease inhibitors and proapoptotic 1,4-benzodiazepines by Emal, Cory Dene, PhD from UNIVERSITY OF MICHIGAN, 2003, 163 pages http://wwwlib.umi.com/dissertations/fullcit/3106052
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Design, synthesis, and evaluation of novel thiobenzyl ester substrates and azapeptide inhibitors for serine and cysteine proteases by Rukamp, Brian John, PhD from GEORGIA INSTITUTE OF TECHNOLOGY, 2003, 155 pages http://wwwlib.umi.com/dissertations/fullcit/3110446
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Determination of beta-mercaptopyruvic acid in cysteine transamination mixture by titration with omicron-hydroxymercuribenzoic acid using dithiofluorescein as an indicator. Catalytic determination of iodine in serum at nanogram levels using the arsenic(III by Ke, P. J; PhD from UNIVERSITY OF WINDSOR (CANADA), 1972 http://wwwlib.umi.com/dissertations/fullcit/NK14748
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Distal heme pocket interactions and analysis of cysteine sites in hemoglobins cyanide complexes from Lucina pectinata by Ramos Lorenzo, Johanna, MS from UNIVERSITY OF PUERTO RICO, MAYAGUEZ (PUERTO RICO), 2003, 53 pages http://wwwlib.umi.com/dissertations/fullcit/1416295
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Identification of a novel family of cysteine proteases and their functions in bacterial pathogenesis by Shao, Feng , PhD from UNIVERSITY OF MICHIGAN, 2003, 164 pages http://wwwlib.umi.com/dissertations/fullcit/3096196
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Mechanism of action of mammalian cystatins. Studies of inhibition of cysteine endoand exopeptidases by cystatins A and C by Pavlova, Alona, Fildr from SVERIGES LANTBRUKSUNIVERSITET (SWEDEN), 2003, 63 pages http://wwwlib.umi.com/dissertations/fullcit/f173361
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Radiolysis of penicillamine and cysteine solutions by Goyal, Greesh Chand; PhD from UNIVERSITY OF CALGARY (CANADA), 1974 http://wwwlib.umi.com/dissertations/fullcit/NK23741
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Studies on the mechanism of sulfur transfer by the cysteine desulfurase IscS from Escherichia coli by Urbina, Hugo D., PhD from UNIVERSITY OF CALIFORNIA, IRVINE, 2004, 73 pages http://wwwlib.umi.com/dissertations/fullcit/3119751
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The neuromodulatory roles of glutathione, S-nitrosoglutathione and cysteine in the central nervous system: Neurotransmitter characteristics of glutathione by Hermann, Andras, PhD from TAMPEREEN YLIOPISTO (FINLAND), 2003, 87 pages http://wwwlib.umi.com/dissertations/fullcit/f168593
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The role of cysteine proteases in MHC class II antigen processing and presentation by Beers, Courtney, PhD from UNIVERSITY OF WASHINGTON, 2004, 110 pages http://wwwlib.umi.com/dissertations/fullcit/3118837
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The role of cysteine string proteins at the neuromuscular junction in Drosophila by Dawson-Scully, Kenneth Donald, PhD from UNIVERSITY OF TORONTO (CANADA), 2003, 207 pages http://wwwlib.umi.com/dissertations/fullcit/NQ84839
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Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. PATENTS ON CYSTEINE Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “cysteine” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cysteine, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Cysteine By performing a patent search focusing on cysteine, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We
8Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on cysteine: •
Antibodies to vertebrate serrate proteins and fragments Inventor(s): Artavanis-Tsakonas; Spyridon (Hamden, CT), Fleming; Robert J. (Rochester, NY), Gray; Grace E. (New Haven, CT), Henrique; Domingos Manuel Pinto (Oxford, GB), Ish-Horowicz; David (Oxford, GB), Lewis; Julian Hart (Oxford, GB), Mann; Robert S. (Hamden, CT), Myat; Anna Mary (Oxford, GB) Assignee(s): Imperial Cancer Research Technology, Ltd. (London, GB), Yale University (New Haven, CT) Patent Number: 6,703,489 Date filed: November 19, 1998 Abstract: The present invention relates to nucleotide sequences of Serrate genes, and amino acid sequences of their encoded proteins, as well as derivatives (e.g., fragments) and analogs thereof. In a specific embodiment, the Serrate protein is a human protein. The invention further relates to fragments (and derivatives and analogs thereof) of Serrate which comprise one or more domains of the Serrate protein, including but not limited to the intracellular domain, extracellular domain, DSL domain, cysteine rich domain, transmembrane region, membrane-associated region, or one or more EGF-like repeats of a Serrate protein, or any combination of the foregoing. Antibodies to Serrate, its derivatives and analogs, are additionally provided. Methods of production of the Serrate proteins, derivatives and analogs, e.g., by recombinant means, are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are provided. In specific examples, isolated Serrate genes, from Drosophila, chick, mouse, Xenopus and human, are provided. Excerpt(s): The present invention relates to Serrate genes and their encoded protein products, as well as derivatives and analogs thereof. Production of Serrate proteins, derivatives, and antibodies is also provided. The invention further relates to therapeutic compositions and methods of diagnosis and therapy. Genetic analyses in Drosophila have been extremely useful in dissecting the complexity of developmental pathways and identifying interacting loci. However, understanding the precise nature of the processes that underlie genetic interactions requires a knowledge of the protein products of the genes in question. Embryological, genetic and molecular evidence indicates that the early steps of ectodermal differentiation in Drosophila depend on cell interactions (Doe and Goodman, 1985, Dev. Biol. 111:206-219; Technau and CamposOrtega, 1986, Dev. Biol. 195:445-454; Vassin et al., 1985, J. Neurogenet. 2:291-308; de la Concha et al., 1988, Genetics 118:499-508; Xu et al., 1990, Genes Dev. 4:464-475; Artavanis-Tsakonas, 1988, Trends Genet. 4:95-100). Mutational analyses reveal a small group of zygotically-acting genes, the so called neurogenic loci, which affect the choice of ectodermal cells between epidermal and neural pathways (Poulson, 1937, Proc. Natl. Acad. Sci. 23:133-137; Lehmann et al., 1983, Wilhelm Roux's Arch. Dev. Biol. 192:62-74; Jurgens et al., 1984, Wilhelm Roux's Arch. Dev. Biol. 193:283-295; Wieschaus et al., 1984, Wilhelm Roux's Arch. Dev. Biol. 193:296-307; Nusslein-Volhard et al., 1984, Wilhelm Roux's Arch. Dev. Biol. 193:267-282). Null mutations in any one of the zygotic neurogenic loci--Notch (N), Delta (D1), mastermind (mam), Enhancer of Split (E(spl), neuralized (neu), and big brain (bib)--result in hypertrophy of the nervous system at the expense of ventral and lateral epidermal structures. This effect is due to the misrouting of epidermal precursor cells into a neuronal pathway, and implies that neurogenic gene
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function is necessary to divert cells within the neurogenic region from a neuronal fate to an epithelial fate. Serrate has been identified as a genetic unit capable of interacting with the Notch locus (Xu et al., 1990, Genes Dev. 4:464-475). These genetic and developmental observations have led to the hypothesis that the protein products of the neurogenic loci function as components of a cellular interaction mechanism necessary for proper epidermal development (Artavanis-Tsakonas, S., 1988, Trends Genet. 4:95-100). Web site: http://www.delphion.com/details?pn=US06703489__ •
Composition for inhibition of metal corrosion Inventor(s): Fan; Joseph C. (Lake Zurich, IL), Fan; Lai-Duien Grace (Lake Zurich, IL), Mazo; Jacob (Wilmette, IL) Assignee(s): Donlar Corporation (Bedford Park, IL) Patent Number: 6,620,338 Date filed: September 9, 2002 Abstract: Novel corrosion inhibiting compositions comprising a combination of amino thiol or amino disulfide compounds with acidic amino acid polymers inhibit carbon dioxide induced corrosion of ferrous metals in aqueous systems. Particularly effective inhibitor compositions are the natural amino acids cysteine and cystine and their decarboxylated analogues cysteamine and cystamine in combination with polyaspartic acid. The inhibitor compositions are particularly useful for preventing corrosion and scale formation in oil production applications. Excerpt(s): This invention relates to a composition for inhibiting the corrosion of metals in carbon dioxide containing aqueous systems. More particularly, this invention relates to the use of compositions containing amino thiol or amino disulfide compounds and acidic amino acid polymers as corrosion inhibitors in carbon dioxide containing aqueous systems. Oil bearing geologic formations generally contain mixtures of crude oil and mineral laden waters, hereinafter referred to as formation waters. Oil wells produce a mixture of crude oil and formation water. As wells age, the natural pressures within the formation decrease, thus leading to decreased production of oil. Wells can be artificially pressurized to force the oil and formation water out of the well, however. In offshore oil platforms, sea water is pumped into the wells to displace the oil from the formation. The mixture of sea water and formation water that results from this process is referred to as "produced water." In many cases, the oil bearing formations have very low levels of dissolved oxygen (anaerobic). Often, the formation waters are saturated with dissolved carbon dioxide (known as sweet wells) with or without dissolved hydrogen sulfide (sour wells), which both result in an acidic pH environment, wherein the pH can range from about 3 to about 6. The acidic, highly mineral laden waters produces an environment that is highly corrosive to metals, particularly to mild steel, which is the most common material of construction for well pipe lines and equipment, due to cost considerations. Carbon dioxide induced corrosion differs from oxygen induced corrosion in that iron carbonates and other iron salts are the main corrosion products, as opposed to iron oxide formation (rust) in aerobic systems. Mineral scale formation, caused by temperature and pressure changes in the mineral laden formation and especially in produced waters can either stimulate or inhibit corrosion, depending on the type and physical form of the scale and the pH, temperature and other factors. The expense of cleaning and replacing miles of corrosion and scale damaged pipelines and other equipment on remote oil platforms, and the loss in revenues from diminished oil production can be enormous.
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Web site: http://www.delphion.com/details?pn=US06620338__ •
Compositions and kits for fluorescence polarization assay of large molecules Inventor(s): Herron; James N. (Salt Lake City, UT), Wei; Ai-Ping (Salt Lake City, UT) Assignee(s): University of Utah Research Foundation (Salt Lake City, UT) Patent Number: 6,632,613 Date filed: June 7, 1995 Abstract: An improved oligopeptide composition for use in a fluorescent polarization immunoassay for a high molecular weight analyte is disclosed, along with a kit and a method using the composition. The composition comprises an oligopeptide selected by a screening procedure in which a plurality of different oligopeptides having respective amino acid sequences that represent sequential overlapping segments of the analyte amino acid sequence, and a fluorescent label bound thereto. In a preferred embodiment, the oligopeptide has an amino acid sequence which does not form internal disulfide bridges. Such a preferred oligopeptide will generally have no more than one cysteine residue. In a further preferred embodiment, the fluorescent label is tetramethylrhodamine or a cyanine dye. The kit may be packaged with instructions directing a user to prepare an assay solution containing the monoclonal antibody and the oligopeptide in certain respective concentrations. The composition, method and kit are preferably constructed to detect nanomolar concentrations of the analyte. Excerpt(s): The present invention relates to a fluorogenic homogeneous assay procedure for determination of high molecular weight molecules in solution. A fluorescent molecule is one which, in response to absorption of light in a characteristic frequency range, emits a photon of longer wavelength. When polarized light is used to stimulate the fluorescence, the light emitted by a plurality of such excited fluorescent molecules is often at least partially polarized, since the emitted photons are emitted at a 90.degree. angle with respect to the incident exciting light. This phenomenon is generally termed fluorescence polarization, and can be exploited for quantitation of free vs. analytebound fluorescent molecules. The extent of polarization is a function of several factors including temperature, the rotational mobility of the molecules and solution viscosity. In general, small molecules that rotate rapidly emit light which is less polarized because the emitted light is partially depolarized by the rapid rotation. Very large molecules, however, have limited rotation, which results in a greater degree of polarization. Web site: http://www.delphion.com/details?pn=US06632613__
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Compositions comprising bioactive peptides prepared without formation of native disulfide bonds Inventor(s): Mundschenk; David D. (Dania, FL), Smith; Leonard A. (Clarksburg, MD) Assignee(s): BioTherapeutics, Inc. (Plantation, FL) Patent Number: 6,670,148 Date filed: August 5, 1999 Abstract: A method of preparing a bioactive polypeptide in a stable, inactivated form, the method comprising the step of treating the polypeptide with ozonated water in order to oxidize and/or stabilize the cysteine residues, and in turn, prevent the
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formation of disulfide bridges necessary for bioactivity. The method can involve the use of ozonated water to both oxidize the disulfide bridges in a bioactive polypeptide, and to then stabilize the resultant cysteine residues. Optionally, and preferably, the method can involve the use of ozonated water to stabilize the cysteine residues, and thereby prevent the formation of disulfide bridges, in a polypeptide produced by recombinant means in a manner that allows the polypeptide to be recovered with the disulfide bridges unformed. Excerpt(s): In one aspect, the present invention relates to methods for preparing bioactive polypeptides in an inactive form. In another aspect, the present invention relates to bioactive polypeptides such as neurotoxins, and to methods for the preparation of such neurotoxins. In yet another aspect, the invention relates to the use of inactivated neurotoxin compositions for the study and treatment of viral and neurological diseases. Bioactive polypeptides are typically obtained by either the recovery and purification of natural products, or by synthesis using its genetic counterpart. Typically, the polypeptides, whether purified from natural sources or synthesized using recombinant technology, are ultimately provided in a form having the intended bioactivity. Occasionally, however, it is desirable to prepare otherwise bioactive polypeptides in their inactive form, in which they can be used for other in vivo purposes, such as the preparation of vaccines. In other situations, the bioactivity of the polypeptide itself may be a particularly toxic one, so as to make the recovery of the active polypeptide either unnecessary, or unduly difficult and dangerous. Web site: http://www.delphion.com/details?pn=US06670148__ •
Comprehensive pharmacologic therapy for treatment of obesity including cysteine Inventor(s): Hinz; Martin C. (1150 88th Ave. W., Duluth, MN 55808) Assignee(s): none reported Patent Number: 6,759,437 Date filed: September 6, 2001 Abstract: The comprehensive pharmacologic therapy for treatment of obesity including Cysteine is a procedure which involves the administration of a desired therapeutic range of Diethylpropion and/or Phentermine in combination with a SSRI medication and nutritional supplementation for brief and long durations which may be 12 months or more. The preferred procedure involves the administration of drugs in combination which are identified as: Citalopram (Celexa) and Phentermine; Citalopram (Celexa) and Diethylpropion; Citalopram (Celexa), Phentermine, and Diethylpropion. In addition nutritional supplementation such as a multivitamin, 5-Hydroxytryptophan, Cysteine, vitamin B6, vitamin C, Tyrosine, Calcium, and Lysine may be used to enhance the performance of the weight loss treatment program. Excerpt(s): The medications stop working during therapy where at least 40% to 50% of patients quit losing weight (plateau) on an average of 3.3 months into therapy; and 5% to 8% of patients who receive drug therapy for weight problems experience the complication where the medications fail to assist in appetite suppression where the patient therefore does not lose significant weight. In the past long term treatment, defined as treatment longer than 3 months to many years, with medications, has raised safety issues including, medication intolerability by the patient, medication side effects and most important ineffectiveness of the drugs or the cessation of benefit of the drugs which in turn causes the patient to fall out of appetite suppression and terminate weight
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loss. A weight loss procedure using SSRI medication is disclosed in U.S. Pat. No. 5,795,895. The potential for patients to obtain goal weight loss under the process of U.S. Pat. No. 5,795,895 is low, and the failure of the drugs to provide a desired level of performance is at the heart of the problem. Web site: http://www.delphion.com/details?pn=US06759437__ •
Crustacean antimicrobial peptides Inventor(s): Bachere; Evelyne (Clapiers, FR), Bulet; Philippe (Vendenheim, FR), Destoumieux; Delphine (Montpellier, FR) Assignee(s): Centre National de la Recherche Scientifique (Paris, FR), Institut Francais de Recherche pour l'Exploitation de la Mer (Issy les Moulineaux, FR) Patent Number: 6,642,203 Date filed: April 12, 2000 Abstract: The invention concerns antimicrobial peptides obtained from penaeid prawns having the following characteristics: a molecular mass of about 5 to 7 kDa; a pHi not less than 9; an N-terminal portion comprising a region (A) of about 15 to 25 amino acids rich in proline; and a C-terminal portion comprising a region (B) of about 20 to 30 amino acids and containing 6 cysteine residues forming three intramolecular disulfide bonds. The invention also concerns the nucleic acid sequences coding for said peptides and enabling their production by genetic engineering. Excerpt(s): This application is a 371 of PCT/FR98/01583, filed Jul. 20, 1998. The invention relates to new antimicrobial peptides produced by penaeid prawns. Peptides endowed with antimicrobial properties are produced by a wide variety of (animal or plant) species in which they participitate in nonspecific mechanisms of defence against infections. These peptides are the subject of increasing interest, in particular because they generally possess a broad activity spectrum and a low cytotoxicity for eukaryotic cells. Web site: http://www.delphion.com/details?pn=US06642203__
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Cysteine derivatives Inventor(s): Iwasaki; Keiji (Kawasaki, JP), Kitazawa; Manabu (Kawasaki, JP), Sakamoto; Kazutami (Kawasaki, JP), Shiojiri; Eiji (Kawasaki, JP) Assignee(s): Ajinomoto Co., Inc. (Tokyo, JP) Patent Number: 6,703,031 Date filed: June 14, 2001 Abstract: Objects of the present invention are to provide an oxidative stress inhibitor which is capable of suppressing the expression of a cytotoxic protein and the activation of a gene transcriptional regulatory factor taking part such expression of a cytotoxic protein and exhibits good feeling upon use and safety; to provide a method for preventing, retarding, alleviating or treating a skin change due to aging or an undesirable aesthetic skin change, both caused or promoted by an oxidative stress; and to provide a cosmetic composition or dermatologic preparation for external use comprising the oxidative stress inhibitor as an effective ingredient, and for those purposes are employed an oxidative stress inhibiting agent which comprises, as an
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effective ingredient, at least one selected from cysteine or cystine derivatives and the salts thereof. Excerpt(s): This application is a 371 of PCT/JP99/05584, filed on Oct. 8, 1999. The present invention relates to an oxidative stress inhibitor useful for prevention, retardation, alleviation or treatment of diseases or dermal injuries or diseases caused by an oxidative stress; a method for inhibiting an oxidative stress by using such an oxidative stress inhibitor; and a cosmetic composition or dermatologic preparation for external use which comprises such an oxidative stress inhibitor as an effective ingredient. In recent years, causes of diseases or dermal injuries or diseases brought about by an oxidative stress such as ultraviolet rays, active oxygen, free radicals or the like have been searched briskly. For example, it is known that cytotoxic cytokines such as IL-1.alpha., TNF-.alpha. and the like or extracellular matrix proteases such as collagenase and the like are closely related to aging, canceration or malignant alteration, edema, pigmentation or the like as its cause (for example, "Oxidative Stress in Dermatology", Marcel Dekker, Inc., pp. 187-205, 1993). Expression of a gene coding for such a protein is mainly controlled at the level of genetic transcription, whereas, regarding cytotoxic proteins such as cytotoxic cytokines and extracellular matrix proteases, it is controlled by a transcriptional regulatory factor such as NF-.kappa.B or AP-1 (for example, "Active oxygen and Signal transmission", Kodansha Scientific, pp. 37-46, 1996). In practice, NF-.kappa.B and AP-1 are known to be activated by an oxidative stress and promote the expression of cytotoxic protein (for example, "Active oxygen and Signal transmission", Kodansha Scientific, pp. 1-20, 1996). Diseases or dermal injuries or diseases caused by an oxidative stress are therefore expected to be prevented, retarded, alleviated or treated if it becomes possible to suppress the activation of NF-.kappa.B or AP-1 due to an oxidative stress. Web site: http://www.delphion.com/details?pn=US06703031__ •
Cysteine/glycine rich peptides Inventor(s): L. Boumans; Johannes Wilhelmus (Ouderker Aan de Amstel, NL), Mallee; Leon Franciscus (Utrecht, NL), Nimmagudda; Ram (Oneonta, NY) Assignee(s): Campina Melkunie B.V. (Zaltbommel, NL) Patent Number: 6,620,778 Date filed: October 23, 2001 Abstract: Described is a method for the preparation of a mixture of peptides having a cysteine content between 7-20 w/w % from a protein source, comprising cysteine containing proteins, comprising the steps of:a) cleaving the proteins of the protein source into peptides;b) digesting the peptides obtained in step a) by an exopeptidase, the action of which is at least attenuated at the position of a cysteine in the peptide, therewith forming digested peptides having a terminal cysteine;c) purifying the digested peptides,and the use of the preparation as active component in a medicament, especially for the treatment of conditions mediated by oxidative damage and for the elevation of cellular glutathion levels in the human or animal body. Excerpt(s): The invention relates to a method for the preparation of a mixture of peptides having a cysteine- or cysteine/glycine content between 7-20 w/w %, to preparations comprising said peptides and to the use of such preparations as active compound in a medicament. Peptides are herein defined as amino acid chains, derived from a protein; the molecular weight of the peptides is preferably between 200D and
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8000D, more preferably between 1000D and 5000D. In the art, there is a great demand for cysteine and cysteine/glycine comprising compounds for effective administration of said amino acids to the human or animal body. The availability of especially cysteine and to a lesser extent glycine, is a limiting factor in the syntheses of glutathion. Proper administration of cysteine, but also of glycine is therefore demanded in cases where an elevation of cellular glutathion levels in the human or animal body are needed. Web site: http://www.delphion.com/details?pn=US06620778__ •
Dosage form of N-acetyl cysteine Inventor(s): Guo; Jian-Hwa (Hudson, OH), Wilber; William Robert (Avon Lake, OH) Assignee(s): Noveon IP Holdings Corp. (Cleveland, OH) Patent Number: 6,623,754 Date filed: May 21, 2001 Abstract: A directly-compressed, controlled release tablet contains N-acetyl cysteine as the active ingredient. Excerpt(s): Commonly-assigned application Ser. No. 09/329,471, filed Jun. 10, 1999, describes certain rheology modifying polymers derived from acrylic acid, methacrylic acid or analogues which exhibit enhanced controlled release properties when in granulated form. Commonly-assigned application Ser. No. 09/559,687, filed Apr. 27, 2000, teaches that these granulated rheology modifying polymers are particularly well suited for making solid dosage tablets and other articles by direct compression--i.e., by directly compressing a mixture of the tablet ingredients without granulating the mixture first. It has now been found that the above technology is particularly well-suited for making tablets and other solid dosage pharmaceuticals in which N-acetyl cysteine is the active ingredient. Thus, the present invention provides a directly-compressed, controlled release tablet or other article containing N-acetyl cysteine as the active ingredient. More particularly, the present invention provides a directly-compressed, controlled release tablet or other article containing about 25 to 80 wt. % N-acetyl cysteine, about 5 to 50 wt. % of a granulated, rheology modifying, release-controlling, slightly cross-linked polymer of acrylic acid, methacrylic acid or analogue, and optionally about 0 to 40 wt. % of an additional excipient, which preferably is a directly compressible binder. Web site: http://www.delphion.com/details?pn=US06623754__
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Hair coloring compositions Inventor(s): Bhagyalakshmi; Krithivasan (Karnataka, IN), Mani; Indu (Karnataka, IN), Raman; Govindarajan (Maharashtra, NL) Assignee(s): Unilever Home & Personal Care USA, division of Conopco, Inc. (Chicago, IL) Patent Number: 6,706,077 Date filed: March 5, 2002 Abstract: A coloring system for hair and/or skin comprises at least three separately packaged components:a) a thio compound capable of breaking the S--S bond between
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cysteine residues, and an alkaline reagent;b) a material and/or extract obtainable from the mucuna plant; andc) an oxidizing agent. Excerpt(s): The present invention relates to compositions for changing the colour of keratinic fibers especially human hair. The composition can also be used to darken human skin. Melanin is a naturally occurring pigment present in hair and skin and it is synthesised in melanocytes in the presence of the enzyme tyrosinase. Two different melanins are found in human hair, eumelanin and pheomelanin. While brown and black hair contain eumelanin, pheomelanin is found in red hair. The enzyme tyrosinase catalyses the hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA) and its subsequent oxidation to dopachrome. Dopachrome further undergoes a series of complex reactions to form eumelanins and pheomelanins (often collectively termed melanin). Web site: http://www.delphion.com/details?pn=US06706077__ •
Immunotoxins comprising ribosome-inactivating proteins Inventor(s): Better; Marc D. (Los Angeles, CA), Carroll; Stephen F. (Walnut Creek, CA), Studnicka; Gary M. (Santa Monica, CA) Assignee(s): XOMA Technology Ltd. (BE) Patent Number: 6,649,742 Date filed: November 13, 2000 Abstract: The present invention provides purified and isolated polynucleotides encoding Type I ribosome-inactivating proteins (RIPs) and analogs of the RIPs having a cysteine available for disulfide bonding to targeting molecules. Vectors comprising the polynucleotides and host cells transformed with the vectors are also provided. The RIPs and RIP analogs are particularly suited for use as components of cytotoxic therapeutic agents of the invention which include gene fusion products and immunoconjugates. Cytotoxic therapeutic agents or immunotoxins according to the present invention may be used to selectively eliminate any cell type to which the RIP component is targeted by the specific binding capacity of the second component of the agent, and are suited for treatment of diseases where the elimination of a particular cell type is a goal, such as autoimmune disease, cancer and graft-versus-host disease. Excerpt(s): The present invention generally relates to materials useful as components of cytotoxic therapeutic agents. More particularly, the invention relates to ribosomeinactivating proteins, to analogs of ribosome-inactivating proteins, to polynucleotides encoding such proteins and analogs, some of which are specifically modified for conjugation to targeting molecules, and to gene fusions of polynucleotides encoding ribosome-inactivating proteins to polynucleotides encoding targeting molecules. Ribosome-inactivating proteins (RIPs) comprise a class of proteins which is ubiquitous in higher plants. However, such proteins have also been isolated from bacteria. RIPs are potent inhibitors of eukaryotic protein synthesis. The N-glycosidic bond of a specific adenine base is hydrolytically cleaved by RIPs in a highly conserved loop region of the 28S rRNA of eukaryotic ribosomes thereby inactivating translation. Plant RIPs have been divided into two types. Stirpe et al., FEBS Lett., 195(1,2):1-8 (1986). Type I proteins each consist of a single peptide chain having ribosome-inactivating activity, while Type II proteins each consist of an A-chain, essentially equivalent to a Type I protein, disulfide-linked to a B-chain having cell-binding properties. Gelonin, dodecandrin, tricosanthin, tricokirin, bryodin, Mirabilis antiviral protein (MAP), barley ribosome-
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inactivating protein (BRIP), pokeweed antiviral proteins (PAPs), saporins, luffins, and momordins are examples of Type I RIPs; whereas Ricin and abrin are examples of Type II RIPs. Web site: http://www.delphion.com/details?pn=US06649742__ •
Isolated cathepsin L type cysteine proteases and reducing intercorneocyte cohesion/promoting desquamation therewith Inventor(s): Bernard; Dominique (Paris, FR), Bernard-Bourboulon; Marie-Alix (Noisy le Sec, FR), Kermici; Michel (Paris, FR) Assignee(s): Societe l'Oreal S.A. (Paris, FR) Patent Number: 6,737,055 Date filed: June 21, 2001 Abstract: Isolated, substantially pure natural or synthetic polypeptides comprising cathepsin L type cysteine proteases, or polypeptide fragments or polypeptide admixtures obtained via proteolysis thereof, are useful for reducing intercorneocyte cohesion and, thus, for promoting desquamation. Excerpt(s): The present invention relates to certain isolated polypeptides, to mixtures of polypeptides derived from proteolysis of said isolated polypeptides, to compositions comprised thereof and to cosmetic treatments for reducing intercorneocyte cohesion, and, therefore, for promoting desquamation. The skin constitutes a physical barrier between the body and its surroundings. It consists of two tissues: the epidermis and the dermis. The dermis provides the epidermis with a solid support. It is also its feeder component. It consists principally of fibroblasts and an extracellular matrix itself principally composed of collagen, elastin and a substance deemed "ground substance," these components being synthesized by the fibroblast. Leucocytes, mastocytes or tissue macrophages are also found therein. It also comprises blood vessels and nerve fibers. Web site: http://www.delphion.com/details?pn=US06737055__
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Method for producing a cyanide-free solution of a gold compound that is suitable for galvanic gold baths Inventor(s): Franz; Renate (Gelnhausen, DE), Hoffacker; Gerhard (Aldorf, DE), Reitz; Ramona (Nidderau, DE), Walter; Richard (Alzenau, DE) Assignee(s): W. C. Heraeus GmbH & Co. KG (DE) Patent Number: 6,733,651 Date filed: December 19, 2001 Abstract: A method for producing a cyanide-free solution of a gold compound that is suitable for gold electrodeposition baths. The method includes the steps of reacting at least one of a cysteine and a cysteinate with at least one of tetrachloroauric acid and a tetrachloroaurate in a first aqueous medium, separating a resulting precipitate from the first aqueous medium, and dissolving the precipitate in a second aqueous medium with elevation of the pH to 12.0-14.0. Excerpt(s): The invention concerns a method for producing a cyanide-free solution of a gold compound that is suitable for gold electrodeposition baths, a gold compound
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solution produced by this method, and its uses. The use of cyanide-containing solutions of gold compounds as baths for the electrodeposition of gold on objects has long been known. Due to the high toxicity of the cyanide ions that are used and of the hydrocyanic acid that is liberated under certain conditions, the use of this well-known process is associated with considerable safety problems. Furthermore, solutions or gold compounds for electrodeposition baths are known from the state of the art, but they have the disadvantage of decomposing after a certain amount of time. A solution of ammonium disulfitoaurate is cited as a typical example of this. Web site: http://www.delphion.com/details?pn=US06733651__ •
Methods for increasing vascularization and promoting wound healing Inventor(s): Usala; Anton-Lewis (Winterville, NC) Assignee(s): Encelle, Inc. (Greenville, NC) Patent Number: 6,713,079 Date filed: January 19, 2001 Abstract: The present invention provides a method of stimulating vascularization at a site in a mammal, said method comprising contacting said site with a matrix comprising gelatin and a nitric oxide inhibitor. The gelatin is preferably denatured collagen. The nitric oxide inhibitor may be a sulfonated moiety. The inhibitor may be an L-arginine analog, such as aminoguanidine, N-monoethyl L-arginine, N-nitro-L-arginine and Darginine. The matrix may further comprise a nitric oxide scavenger, such as dextran, heparin, cysteine and cystine. Excerpt(s): The invention is drawn to methods and compositions for improving vascularization in mammals. Additionally, the compositions find use in wound healing. Blood vessels are assembled by two processes known as vasculogenesis and angiogenesis. In vasculogenesis, a primitive vascular network is established during embryonic development from endothelial cell precursors called angioblasts. Angiogenesis involves preexisting vessels sending out capillary buds or sprouts to produce new vessels. Angiogenesis is an important process critical to chronic inflammation and fibrosis, to tumor cell growth, and to the formation of collateral circulation. Angiogenesis is involved in the normal process of tissue repair. Tissue destruction, with damage to both parenchymal cells and stromal framework, occurs in inflammation. Repair to the tissue cannot be accomplished solely by regeneration of parenchymal cells, even in organs whose cells are able to regenerate. Attempts at repairing tissue damage occur by replacement of non-regenerated cells by connective tissue, which in time produces fibrosis and scarring. Web site: http://www.delphion.com/details?pn=US06713079__
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Methods for making proteins containing free cysteine residues Inventor(s): Cox; George N. (Louisville, CO), Doherty; Daniel H. (Boulder, CO), Rosendahl; Mary S. (Broomfield, CO) Assignee(s): Bolder Biotechnology, Inc. (Louisville, CO) Patent Number: 6,753,165 Date filed: September 6, 2001
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Abstract: The present invention relates to novel methods of making soluble proteins having free cysteines in which a host cell is exposed to a cysteine blocking agent. The soluble proteins produced by the methods can then be modified to increase their effectiveness. Such modifications include attaching a PEG moiety to form pegylated proteins. Excerpt(s): The present invention relates generally to methods of making proteins and more specifically to recombinant proteins containing a "free" cysteine residue that does not form a disulfide bond. There is considerable interest on the part of patients and healthcare providers in the development of low cost, long-acting, "user-friendly" protein therapeutics. Proteins are expensive to manufacture and unlike conventional small molecule drugs, are usually not readily absorbed by the body. Moreover they are digested if taken orally. Therefore, proteins must typically be administered by injection. After injection most proteins are cleared rapidly from the body, necessitating frequent, often daily, injections. Patients dislike injections, which leads to reduced compliance and reduced drug efficacy. Some proteins such as erythropoietin (EPO) are effective when administered less often (three times per week for EPO) but this is due to the fact that the proteins are glycosylated. Glycosylation requires that the recombinant proteins be manufactured using mammalian cell expression systems, which is expensive and increase the cost of protein pharmaceuticals. Thus, there is a strong need to develop protein delivery technologies that lower the costs of protein therapeutics to patients and healthcare providers. One solution to this problem is the development of methods to prolong the circulating half-lives of protein therapeutics in the body so that the proteins do not have to be injected frequently. This solution also satisfies the needs and desires of patients for protein therapeutics that are "user-friend", i.e., protein therapeutics that do not require frequent injections. Web site: http://www.delphion.com/details?pn=US06753165__ •
Nitric monoxide metabolite-polyoxyalkylene-hemoglobin complex Inventor(s): Kitabatake; Akira (Hokkaido, JP), Nakai; Kunihiko (Miyagi, JP), Sakuma; Ichiro (Hokkaido, JP), Yasukohchi; Tohru (Kanagawa, JP) Assignee(s): Hokkaido University (Hokkaido, JP), NOF Corporation (Tokyo, JP) Patent Number: 6,667,292 Date filed: February 8, 2000 Abstract: Disclosed is a nitric monoxide metabolite-polyoxyalkylene-hemoglobin complex having a molecular weight of from 100,000 to 2,000,000 daltons, in which a polyoxyalkylene derivative is bound to from 10 to 30% in total of bindable amino groups in hemoglobin and a nitric monoxide metabolite is bound to from 10 to 100% in total of thiol groups of cysteine residues. Excerpt(s): This invention relates to a nitric monoxide metabolite-polyoxyalkylenehemoglobin complex which is useful in blood substitutes and organ perfusion solutions, a method for the production of said complex and an oxygen carrier solution which contains said complex, more particularly to a cell-free hemoglobin-based oxygen carrier which has high safety in blood and does not cause problems such as hypertension (blood pressure increase) at the time of injection into the living body. Currently, attempts are made positively to use cell-free hemoglobin extracted from human or bovine erythrocytes as an oxygen carrier substitute of erythrocyte blood transfusion. It is necessary to solve various problems in order to use cell-free hemoglobin directly as an
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oxygen carrier substitute for erythrocyte blood transfusion. Firstly, stroma as a membrane fragment remains in erythrocyte hemolysate and causes blood coagulation. In this field, Rabiner et al. have established in 1967 a method for the production of stroma-free hemoglobin in which stroma is removed from a hemoglobin solution (Rabiner S. F. et al., Evaluation of a stroma-free hemoglobin solution for use as a plasma expander, J. Exp. Med., 126, 1127-1142, 1967), which solved the problem of disseminated intravascular coagulation (DIC) almost completely. Next, hemoglobin molecules are leaked from the renal glomerulus and exert toxicity upon the renal tube. The problem of renal toxicity has also been solved almost completely based on the finding by Bunn et al. in 1969 that excretion of hemoglobin from the glomerulus can be avoided by introducing intramolecular crosslinking into hemoglobin (Bunn F. et al., The renal handling of hemoglobin, J. Exp. Med., 129, 909-924, 1969) and the subsequent finding that excretion of hemoglobin into urine can be prevented and its intravascular half life can be prolonged by increasing molecular weight of hemoglobin through its chemical modification with polyethylene glycol (e.g., JP-B-5-64128 and JP-B-6-76333; the term "JPB" as used herein means an "examined Japanese patent publication"). Based on these technical improvement, studies on the cell-free hemoglobin as an erythrocyte substitution oxygen carrier have been advanced, and several products are already entering into clinical tests in the United States. Web site: http://www.delphion.com/details?pn=US06667292__ •
Nucleic acids encoding nitric oxide synthase variants Inventor(s): Adak; Subrata (Cleveland, OH), Stuehr; Dennis J. (Broadview Heights, OH) Assignee(s): The Cleveland Clinic Foundation (Cleveland, OH) Patent Number: 6,620,616 Date filed: September 13, 2000 Abstract: Isolated polynucleotides which encode a variant of a mammalian nitric oxide synthase protein or polypeptide are provided. The variant nitric oxide synthase protein and polypeptides are substitution mutants, wherein the tryptophan that is normally located on the alpha 3 helix, six residues upstream from the cysteine which binds heme in the corresponding non-variant nitric oxide synthase protein or peptide is replaced with one of the other 19 naturally-occurring amino acid residues. The present invention also relates to vectors and recombinant cells comprising a nucleic acid which encodes a variant of a mammalian nitric oxide synthase protein. The present invention also relates to the nitric oxide synthase variant proteins and polypeptides. Excerpt(s): The free radical nitric oxide (NO) is a chemical messenger that is involved in regulating blood pressure, homeostasis, platelet aggregation, immuno-integrity and neurotransmission. NO is produced in many cell types, including endothelial cells, neurons, airway epithelial cells and macrophages. In blood vessels, NO mediates endothelium-dependent vasodilation. NO is also involved in maintaining basal vascular tone and regulating regional blood flow. In the nervous system NO plays a role in neurotransmission, synaptic plasticity, peristalsis, penile erection, neuro-degenerative disease, and excitotoxicity. In the immune system, NO is produced by activated macrophages and neutrophils as a cytotoxic agent against tumor cells and pathogens. Recent studies have shown that in vivo gene transfer of polynucleotides encoding different NOS isoforms may represent a therapeutic strategy for diseases characterized by decreased bioavailability of NO, such as vascular diseases. Specifically, Lloyd-Jones and Bloch have shown that gene therapy employing an nNOS-expressing adenoviral
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vector increased the sensitivity of a normal rabbit's carotid arteries to acetylcholine and also reversed the deficit in endothelium-dependent vascular relaxation in cholesterolfed rabbits. (Lloyd-Jones and Bloch (1996) Annual Rev. Med. 47:365-75.) Quian et. al. showed that in vivo transfer of the nNOS gene into cholesterol-fed rabbits reduced vascular adhesion molecule expression, lipid deposition, and inflammatory cell infiltration in the carotid arteries of such animals. (Qian, et. al. (1999) Circulation 98, 2979-2982.) Von der Leyen et al have shown that in vivo transfer of an eNOS-expressing plasmid to balloon denuded rat carotids significantly limited the subsequent development of neointimal hyperplasia. The eNOS-expressing plasmids were delivered via a liposome-Sendai virus hemagglutinin protein complex. (Von der Leyen, et. al. (1995) PNAS 92:1137-1141.) Kullo et al showed that adenovirus-mediated transfer of the gene for eNOS to the adventitia of rabbit carotid arteries had a favorable effect on vascular reactivity (Kullo, et. al. (1996) Circulation 96:7, 2254-2261.) Shears et al have shown that in vivo transfer of an adenovirus expressing iNOS reduced vasculopathy in rat aortic allografts. (Shears, et. al. (1997) J. Clin. Invest. 100:8, 2035-2042.) Thus, all three major NOS isoforms appear to be reasonable candidates for in vivo applications to achieve or augment NO production. Accordingly, it is desirable to have polynucleotides which encode NOS. It is especially desirable to have polynucleotides which encode NOS proteins or polypeptides that are fully active at all possible intracellular concentrations of O.sub.2. Web site: http://www.delphion.com/details?pn=US06620616__ •
Peptide-containing.alpha.-ketoamide cysteine and serine protease inhibitors Inventor(s): Bihovsky; Ron (Wynnewood, PA), Chatterjee; Sankar (Wynnewood, PA), Mallamo; John P. (Glenmoore, PA), Wells; Gregory J. (West Chester, PA) Assignee(s): Cephalon, Inc. (West Chester, PA) Patent Number: 6,703,368 Date filed: June 12, 2001 Excerpt(s): This invention relates to peptide-containing.alpha.-ketoamide inhibitors of cysteine and serine proteases, methods for making these compounds, and methods for using the same. Numerous cysteine and serine proteases have been identified in human tissues. A "protease" is an enzyme which degrades proteins into smaller components (peptides). The terms "cysteine protease" and "serine protease" refer to proteases which are distinguished by the presence therein of a cysteine or serine residue which plays a critical role in the catalytic process. Mammalian systems, including humans, normally degrade and process proteins via a variety of enzymes including cysteine and serine proteases. However, when present at elevated levels or when abnormally activated, cysteine and serine proteases may be involved in pathophysiological processes. For example, calcium-activated neutral proteases ("calpains") comprise a family of intracellular cysteine proteases which are ubiquitously expressed in mammalian tissues. Two major calpains have been identified; calpain I and calpain II. While calpain II is the predominant form in many tissues, calpain I is thought to be the predominant form in pathological conditions of nerve tissues. The calpain family of cysteine proteases has been implicated in many diseases and disorders, including neurodegeneration, stroke, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, platelet aggregation, cataracts and inflammation. Calpain I has been implicated in excitatory amino-acid induced neurotoxicity disorders including ischemia, hypoglycemia, Huntington's Disease, and epilepsy. The lysosomal
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cysteine protease cathepsin B has been implicated in the following disorders: arthritis, inflammation, myocardial infarction, tumor metastasis, and muscular dystrophy. Other lysosomal cysteine proteases include cathepsins C, H, L and S. Interleukin-1.beta. converting enzyme ("ICE") is a cysteine protease which catalyzes the formation of interleukin-1.beta. Interleukin-1.beta. is an immunoregulatory protein implicated in the following disorders: inflammation, diabetes, septic shock, rheumatoid arthritis, and Alzheimer's disease. ICE has also been linked to apoptotic cell death of neurons, which is implicated in a variety of neurodegenerative disorders including Parkinson's disease, ischemia, and amyotrophic lateral sclerosis (ALS). Web site: http://www.delphion.com/details?pn=US06703368__ •
Plant amino acid biosynthetic enzymes Inventor(s): Allen; Stephen M. (West Chester, PA), Falco; Saverio Carl (Arden, DE) Assignee(s): E. I. du Pont de Nemours and Company (Wilmington, DE) Patent Number: 6,664,445 Date filed: December 2, 1999 Abstract: This invention relates to an isolated nucleic acid fragment encoding a plant enzyme that catalyze steps in the biosynthesis of lysine, threonine, methionine, cysteine and isoleucine from aspartate, the enzyme a member selected from the group consisting of: dihydrodipicolinate reductase, diaminopimelate epimerase, threonine synthase, threonine deaminase and S-adenosylmethionine synthetase. The invention also relates to the construction of a chimeric gene encoding all or a portion of the enzyme, in sense or antisense orientation, wherein expression of the chimeric gene results in production of altered levels of the enzyme in a transformed host cell. Excerpt(s): This invention is in the field of plant molecular biology. More specifically, this invention pertains to nucleic acid fragments encoding enzymes involved in amino acid biosynthesis in plants and seeds. Many vertebrates, including man, lack the ability to manufacture a number of amino acids and therefore require these amino acids preformed in the diet. These are called essential amino acids. Human food and animal feed, derived from many grains, are deficient in essential amino acids, such as lysine, the sulfur amino acids methionine and cysteine, threonine and tryptophan. For example, in corn (Zea mays L.) lysine is the most limiting amino acid for the dietary requirements of many animals. Soybean (Glycine max L.) meal is used as an additive to com-based animal feeds primarily as a lysine supplement. Thus, an increase in the lysine content of either corn or soybean would reduce or eliminate the need to supplement mixed grain feeds with lysine produced via fermentation of microbes. Furthermore, in corn the sulfur amino acids are the third most limiting amino acids, after lysine and tryptophan, for the dietary requirements of many animals. The use of soybean meal, which is rich in lysine and tryptophan, to supplement corn in animal feed is limited by the low sulfur amino acid content of the legume. Thus. an increase in the sulfur amino acid content of either corn or soybean would improve the nutritional quality of the mixtures and reduce the need for further supplementation through addition of more expensive methionine. The organization of the pathway leading to biosynthesis of lysine, threonine, methionine, cysteine and isoleucine indicates that over-expression or reduction of expression of genes encoding, inter alia, threonine synthase, dihydrodipicolinate reductase, diaminopimelate epimerase, threonine deaminase and S-adenosylmethionine synthetase in corn, soybean, wheat and other crop plants could be used to alter levels of these amino acids in human food and animal feed. Accordingly, availability of nucleic
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acid sequences encoding all or a portion of these enzymes would facilitate development of nutritionally improved crop plants. Web site: http://www.delphion.com/details?pn=US06664445__ •
Process for obtaining insulin precursors having correctly bonded cystine bridges Inventor(s): Keller; Reinhold (Bad Soden, DE), Rubroder; Franz-Josef (Vilmar, DE) Assignee(s): Aventis Pharma Deutschland GmbH (Frankfurt am Main, DE) Patent Number: 6,727,346 Date filed: September 7, 2001 Abstract: The present invention relates to an improved process for obtaining a precursor of an insulin or insulin derivative having correctly bonded cystine bridges in the presence of cysteine or cysteine hydrochloride and chaotropic auxiliary. Excerpt(s): The present invention relates to an improved process for obtaining a precursor of insulin or an insulin derivative having correctly bonded cystine bridges in the presence of cysteine or cysteine hydrochloride and a chaotropic auxiliary. The letters A and B represent the respective insulin amino acid chain and the numbers represent the position of the amino acid residue, which is counted from the amino to the carboxyl end of the respective amino acid chain. Disulfide bridges can also be formed between two human insulin molecules such that an incalculable number of different disulfide bridges can easily result. A known process for the preparation of human insulin is based on the use of human proinsulin. Human proinsulin is a protein having a linear amino acid chain of 86 amino acid residues, the A and B chains of the human insulin being bonded to one another via a C peptide having 35 amino acid residues. The formation of the disulfide bridges found in human insulin takes place via an intermediate, the cysteine residues of the human insulin being provided with a sulfur protective group, e.g. an S-sulfonate (--S--SO3--) group (EP 0 037 255). A process for obtaining proinsulin having correctly bonded cystine bridges is additionally known (Biochemistry, 60, (1968), pages 622 to 629), which starts from proinsulin obtained from porcine pancreas, in which the cysteine residues are present as thiol residues (--SH). The term "correctly bonded cystine bridges" is understood as meaning the disulfide bridges which are found in biologically active insulin from mammals. Web site: http://www.delphion.com/details?pn=US06727346__
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Process for producing non-proteinogenic L-amino acids by fermentation Inventor(s): Maier; Thomas (Dachau, DE) Assignee(s): Consortium fur Elektrochemische Industrie GmbH (Munchen, DE) Patent Number: 6,756,216 Date filed: September 21, 2001 Abstract: Process for production of non-protenogenic L-amino acids by direct fermentation of a microorganism strain known per se having a deregulated cysteine metabolism in a manner known per se, which comprises adding, during the fermentation, a nucleophilic compound to the fermentation batch in a manner such that this leads to the production of non-proteinogenic L-amino acids by the microorganism strain.
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Excerpt(s): The present invention relates to a process for producing non-proteinogenic L-amino acids by direct fermentation of microorganisms, and to L-amino acids obtained by the process. Non-proteinogenic amino acids are amino acids which are not used in nature as building blocks for protein biosynthesis and as a result may be clearly differentiated from the 20 proteinogenic amino acids. They are preferably.beta.substituted L-alanine derivatives. Non-proteinogenic amino acids are compounds of interest, for example, for the preparation of pharmaceuticals and agricultural active compounds. They can, as active compound or as a part of an active compound imitate, in a type of molecular mimicry, the structure of natural amino acids and as a result, for example, in receptor interactions cause a modulation of the natural reaction. In addition, they can serve quite generally as synthesis building blocks as chiral compounds in the context of the "chiral pool". Web site: http://www.delphion.com/details?pn=US06756216__ •
Profiling of protease specificity using combinatorial fluorogenic substrate libraries Inventor(s): Backes; Bradley J. (San Diego, CA), Craik; Charles S. (San Francisco, CA), Ellman; Jonathan A. (Oakland, CA), Harris; Jennifer L. (San Diego, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,680,178 Date filed: May 25, 2001 Abstract: A method is presented for the preparation and use of fluorogenic peptide substrates that allows for the configuration of general substrate libraries to rapidly identify the primary and extended specificity of enzymes, such as proteases. The substrates contain a fluorogenic-leaving group, such as 7-amino-4-carbamoylmethylcoumarin (ACC). Substrates incorporating the ACC leaving group show comparable kinetic profiles as those with the traditionally used 7-amino-4-methyl-coumarin (AMC) leaving group. The bifunctional nature of ACC allows for the efficient production of single substrates and substrate libraries using solid-phase synthesis techniques. The approximately 3-fold increased quantum yield of ACC over AMC permits reduction in enzyme and substrate concentrations. As a consequence, a greater number of substrates can be tolerated in a single assay, thus enabling an increase in the diversity space of the library. Soluble positional protease substrate libraries of 137,180 and 6,859 members, possessing amino acid diversity at the P4-P3-P2-P1 and P4-P3-P2 positions, respectively, were constructed. Employing this screening method the substrate specificities of a diverse array of proteases were profiled, including the serine proteases thrombin, plasmin, factor Xa, uPA, tPA, granzyme B, trypsin, chymotrypsin, human neutrophil elastase, and the cysteine proteases papain and cruzain. The resulting profiles create a pharmacophoric portrayal of the proteases allowing for the design of selective substrates and potent inhibitors. Excerpt(s): The ability of an enzyme to discriminate among many potential substrates is an important factor in maintaining the fidelity of most biological functions. While substrate selection can be regulated on many levels in a biological context, such as spatial and temporal localization of enzyme and substrate, concentrations of enzyme and substrate, and requirement of cofactors, the substrate specificity at the enzyme active site is the overriding principle that determines the turnover of a substrate. Characterization of the substrate specificity of an enzyme clearly provides invaluable information for the dissection of complex biological pathways. Definition of substrate specificity also provides the basis for the design of selective substrates and inhibitors to
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study enzyme activity. Of the genomes that have been completely sequenced, 2% of the gene products encode proteases (Barrett, A. J., et al., (1998) Handbook of Proteolytic Enzymes (Academic Press, London)). This family of enzymes is crucial to every aspect of life and death of an organism. With the identification of new proteases, there is a need for the development of rapid and general methods to determine protease substrate specificity. While several biological methods, such as peptides displayed on filamentous phage (Matthews, D. J., et al. (1993) Science 260:1113-7; Ding, L., et al., (1995) Proceedings of the National Academy of Sciences of the United States of America 92:7627-31), and chemical methods, such as support-bound combinatorial libraries (Lam, K. S., et al., (1998) Methods in Molecular Biology, 87:1-6), have been developed to identify proteolytic substrate specificity, few offer the ability to rapidly and continuously monitor proteolytic activity against complex mixtures of substrates in solution. The use of 7-amino-4-methyl coumarin (AMC) fluorogenic peptide substrates is a well-established method for the determination of protease specificity (Zimmerman, M., et al., (1977) Analytical Biochemistry 78:47-51). Specific cleavage of the anilide bond liberates the fluorogenic AMC leaving group allowing for the simple determination of cleavage rates for individual substrates. More recently, arrays (Lee, D., et al., (1999) Bioorganic and Medicinal Chemistry Letters 9:1667-72) and positional-scanning libraries (Rano, T. A., et aL, (1997) Chemistry and Biology 4:149-55) of AMC peptide substrate libraries have been employed to rapidly profile the N-terminal specificity of proteases by sampling a wide range of substrates in a single experiment. Each of these published efforts was designed for profiling caspases, cysteine proteases that require an Asp residue at the P1-position for substrate turnover. This requirement allows for the convenient attachment of the P1-Asp to the solid-support through the carboxylic acid side-chain. Since most proteases do not require P1-Asp/Glu for activity, libraries generated by these methods have limited applicability. Naturally, fluorogenic substrates that contain P1-amino acids that do not possess adequate side-chain functionality for attachment to a solid support in a straightforward manner (Gly, Leu, Val, Ile, Ala, Pro, Phe) will not be amenable to similar synthetic strategies. Web site: http://www.delphion.com/details?pn=US06680178__ •
Protegrins Inventor(s): Chang; Conway C. (San Francisco, CA), Chen; Jie (Belmont, CA), Gu; Chee L. (Saratoga, CA), Harwig; Sylvia S. L. (Woodland Hills, CA), Kokryakov; Vladimir N. (St. Petersburg, RU), Lehrer; Robert I. (Santa Monica, CA), Steinberg; Deborah A. (Saratoga, CA) Assignee(s): IntraBiotics Pharmaceuticals, Inc. (Mountain View, CA) Patent Number: 6,653,442 Date filed: August 30, 1999 Abstract: Peptide-based compounds containing four invariant cysteine residues which have been optionally oxidized to contain two intramolecular disulfide bonds, or modified forms where the cysteines are replaced are useful as preservatives and in preventing, treating, or ameliorating viral or microbial infection in animals and plants, and in inactivating endotoxin. Excerpt(s): The invention relates to the field of antibiotic peptides. In particular, the invention concerns short peptides, some of which are isolated from porcine leukocytes, that have a wide range of antimicrobial activities. One of the defense mechanisms against infection by both animals and plants is the production of peptides that have
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antimicrobial and antiviral activity. Various classes of these peptides have been isolated from tissues both of plants and animals. One well known class of such peptides is the tachyplesins which were first isolated from the hemocytes of the horseshoe crab as described by Nakamura, T. et al. J Biol Chem (1988) 263:16709-16713. This article described the initial tachyplesin isolated, Tachyplesin I, from the Japanese species. Tachyplesin I is a 17-amino acid amidated peptide containing four cysteine residues providing two intramolecular cystine bonds. A later article by this group, Miyata, T. et al. J Biochem (1989) 106:663-668, reports the isolation of a second tachyplesin, Tachyplesin II, consisting of 17 residues amidated at the C-terminus, also containing four cysteine residues and two intramolecular disulfide bonds. Two additional 18-mers, called polyphemusins, highly homologous to Tachyplesin II and containing the same positions for the four cysteine residues, were also isolated from the American horseshoe crab. Polyphemusin I and Polyphemusin II differ from each other only in the replacement of one arginine residue by a lysine. All of the peptides were described as having antifungal and antibacterial activity. A later article by Murakami, T. et al. Chemotherapy (1991) 37:327-334, describes the antiviral activity of the tachyplesins with respect to vesicular stomatitis virus; Herpes Simplex Virus I & II, Adenovirus I, Reovirus II and Poliovirus I were resistant to inactivation by Tachyplesin I. Morimoto, M. et al. Chemotherapy (1991) 37:206-211, found that Tachyplesin I was inhibitory to Human Immunodeficiency Virus. This anti-HIV activity was found also to be possessed by a synthetic analog of Polyphemusin II as described by Nakashima, H. et al. Antimicrobial Agents and Chemotherapy (1992) 1249-1255. Antiviral peptides have also been found in rabbit leukocytes as reported by Lehrer, R. I. et al. J Virol (1985) 54:467472. Other important classes of cysteine-containing antimicrobial peptides include the defensins,.beta.-defensins and insect defensins. The defensins are somewhat longer peptides characterized by six invariant cysteines and three intramolecular cystine disulfide bonds. Defensins were described by Lehrer, R. I. et al. Cell (1991) 64:229-230; Lehrer, R. I. et al. Ann Rev Immunol (1993) 11:105-128. A review of mammalian-derived defensins by Lehrer, R. I. et al. is found in Annual Review Immunol (1993) 11:105-128; three patents have issued on the defensins: U.S. Pat. No. 4,705,777; U.S. Pat. No. 4,659,692; and U.S. Pat. No. 4,543,252. Defensins have been found in the polymorphonucleated neutrophils (PMN) of humans and of several other animals, as well as in rabbit pulmonary alveolar macrophages, and in murine small intestinal epithelial (Paneth) cells and in corresponding cells in humans. Web site: http://www.delphion.com/details?pn=US06653442__ •
Purified stat proteins and methods of purifying thereof Inventor(s): Darnell, Jr.; James E. (Larchmont, NY), Vinkemeier; Uwe (New York, NY) Assignee(s): The Rockefeller University (New York, NY) Patent Number: 6,720,154 Date filed: November 2, 1999 Abstract: The present invention describes methods of producing milligram quantities of three forms of purified Stat1 protein from recombinant DNA constructs. In addition, the Stat proteins may be isolated in their phosphorylated or nonphosphorylated forms (Tyr 701). The proteins can be produced in baculovirus infected insect cells, or E. coli. A compact domain in the amino terminus of Stat1.alpha. was isolated and found to enhance DNA binding due to its ability to interact with a neighboring Stat protein. A relatively protease-resistant recombinant truncated form of the Stat protein was isolated
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in 40-50 mg quantities. Purification of the Stat proteins were performed after modifying specific cysteine residues of the Stat proteins to prevent aggregation. Activated EGFreceptor partially purified from membranes by immunoprecipitation was shown to be capable of in vitro catalysis of the phosphorylation of the tyrosine residue of Stat 1 known to be phosphorylated in vivo. Techniques are enclosed to separate the phosphorylated from the nonphosphorylated Stat proteins. The techniques disclosed are general for Stat proteins and may be used to isolate large quantities of purified Stat 2, 3, 4, 5A, 5B and 6. Methods for using purified Stat proteins, truncated Stat proteins, or Stat N-terminal fragments for drug discovery are also disclosed. Excerpt(s): The present invention relates generally to methods of purifying recombinant Stat proteins, modified Stat proteins and functional fragments thereof. Included in the present invention are the purified proteins and fragments themselves. The present invention also relates to methods of separating phosphorylated species of these proteins and fragments from the nonphosphorylated forms. The present invention also relates to methods for using purified Stat proteins, truncated Stat proteins or N-terminal fragments of Stat proteins for drug discovery. Transcription factors play a major role in cellular function by inducing the transcription of specific mRNAs. Transcription factors, in turn, are controlled by distinct signalling molecules. One particular family of transcription factor consists of the Signal Transducers and Activators of Transcription (Stat) proteins. Presently, there are seven known mammalian Stat family members. The recent discovery of Drosophila and Dictyostelium discoideum Stat proteins suggest that Stat proteins have played an important role in signal transduction-since the early stages of our evolution [Yan R. et al., Cell 84:421-430 (1996); Kawata et al., Cell 89:909 (1997)]. Stat proteins mediate the action of a large group of signalling molecules including the cytokines and growth factors (Darnell et al. WO 95/08629, 1995). One distinctive characteristic of the Stat proteins are their apparent lack of requirement for changes in second messenger, e.g., cAMP or Ca.sup.++, concentrations. Another characteristic is that Stat proteins are activated in the cell cytoplasm by phosphorylation on a single tyrosine (Darnell et al., 1994: Schindler and Darnell, 1995). The responsible kinases are either ligand-activated transmembrane receptors with intrinsic tyrosine kinase activity, such as EGF- or PDGF-receptors, or cytokine receptors that lack intrinsic kinase activity but have associated JAK kinases, such as those for interferons and interleukins (Ihle, 1995). When Stat proteins are phosphorylated, they form homo- or heterodimeric structures in which the phosphotyrosine of one partner binds to the SRC homology domain (SH2) of the other. The newly formed dimer then translocates to the nucleus, binds to a palindromic GAS sequence, thereby activating transcription (Shuai et al., 1994; Qureshi et al., 1995; Leung et al., 1996). Stat proteins serve in the capacity as a direct messengers between the cytokine or growth factor receptor present on the cell surface, and the cell nucleus. However, since each cytokine and growth factor produce a specific cellular effect by activating a distinct set of genes, the means in which such a limited number of Stat proteins mediate this result remains a mystery. Indeed, at least thirty different ligand-receptor complexes signal the nucleus through the seven known mammalian Stat proteins [Darnell et al., Science 277:1630-1635 (1997)]. Web site: http://www.delphion.com/details?pn=US06720154__
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Stabilization of envelope glycoprotein trimers by disulfide bonds introduced into a gp 41 glycoprotein ectodomain Inventor(s): Farzan; Michael (Brookline, MA), Sodroski; Joseph G. (Medford, MA) Assignee(s): Dana-Farber Cancer Institute, Inc. (Boston, MA) Patent Number: 6,716,429 Date filed: October 1, 1998 Abstract: Biochemical and structural studies of fragments of the ectodomain of the human immunodeficiency virus type 1 (HIV-1) gp41 transmembrane envelope glycoprotein have demonstrated that the molecular contacts between alpha helices allow the formation of a trimeric coiled coil. By introducing cysteine residues into specific locations along these alpha helices, the normally labile HIV-1 gp160 envelope glycoprotein was converted into a stable disulfide-linked oligomer. Although proteolytic cleavage into gp120 and gp41 glycoproteins was largely blocked, the disulfide-linked oligomer was efficiently transported to the cell surface and was recognized by a series of conformationally dependent antibodies. The pattern of heterooligomer formation between this construct and an analogous construct lacking portions of the gp120 variable loops and of the gp41 cytoplasmic tail demonstrates that these oligomers are trimers. These results support the relevance of the proposed gp41 structure and intersubunit contacts to the native, complete HIV-1 envelope glycoprotein. Disulfide-mediated stabilization of the labile HIV-1 envelope glycoprotein oligomer, which possesses advantages as an immunogen, will facilitate the development of HIV-1specific immunological reagents. Excerpt(s): Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) are the etiologic agents of acquired immunodeficiency syndrome (AIDS), which results from the profound depletion of CD4-positive lymphocytes in infected individuals (BarreSinoussi, F., Science 1983; Gallo, R. C., et al., Science 1984; Fauci, A. S., et al., Ann Intern Med 1984). The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins. The exterior envelope glycoprotein, gp120, and the transmembrane envelope glycoprotein, gp41, are derived from a gp160 precursor (Earl, P. L., et al., J Virol 1984). The gp160 glycoprotein results from the addition of N-linked, high mannose sugar chains to the approximately 845-870 amino acid primary translation product of the env gene in the rough endoplasmic reticulum (ER) [Ibid.]. Oligomers of gp160 form in the endoplasmic reticulum, but the current data do not unambiguously distinguish whether trimers or tetramers constitute this higher-order complex (Earl, P. L., Proc Natl Acad Sci 1987; Pinter, A., et al., J Virol 1989; Schawaller, M., et al., Virology 1989; Lu, M., et al., Nat Struct Biol 1995). Early results studying cell- or virion-associated HIV-1 envelope glycoproteins suggested the formation of dimers, followed by the assembly of dimers into unstable tetramers (Earl, P. L., Proc Natl Acad Sci 1987; Pinter, A., et al., J Virol 1989). This interpretation was supported by the analysis of soluble forms of gp160 lacking a membrane-spanning region (Schawaller, M., et al., Virology 1989). By contrast, studies of peptide fragments of the gp41 ectodomain, which was shown to be necessary of the oligomerization of soluble forms of gp160, revealed a strong tendency for trimer formation (Lu, M., et al., Nat Struct Biol 1995). More recent structural studies of these gp41 peptides have revealed a trimeric coiled coil (Chan, et al. Cell 899: 263-273 (1997); Weissenhorn et al. Nature 384:184-187 (1997)). Host cell factors in addition to CD4 are necessary for effective HIV-1 envelope glycoprotein-mediated membrane fusion. Some human and animal cells have been shown to be resistant to HIV-1 infection and syncytium formation even when human CD4 was expressed on the cell surface (Maddon et al., 1986; Ashorn et al., 1990; Chesebro et al., 1990; McKnight et al., 1994).
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Experiments with somatic cell hybrids suggested the possibility that a positive factor expressed in cells susceptible to syncytium formation could complement he block to fusion in resistant cell types (Clapham et al., 1991; Dragic et al., 1992; Broder et al., 1993). HIV-1 variants exhibiting distinct differences in the ability to fuse with and to enter particular subsets of CD4-positive cells have been identified (Broder and Berger, 1995). Web site: http://www.delphion.com/details?pn=US06716429__ •
Synthesis of glycodendrimer reagents Inventor(s): Bott; Richard R. (Burlingame, CA), Davis; Benjamin G. (Durham, GB), Jones; John Bryan (Lakefield, CA) Assignee(s): Genencor International, Inc. (Palo Alto, CA) Patent Number: 6,627,744 Date filed: April 2, 2001 Abstract: The present invention relates to a chemically modified mutant protein including a cysteine residue substituted for a residue other than cysteine n a precursor protein, the substituted cysteine residue being subsequently modified by reacting the cysteine residue with a glycosylated thiosulfonate. Also a method of producing the chemically modified mutant protein is provided. The present invention also relates to a glycosylated methanethiosulfonate. Another aspect of the present invention is a method of modifying the functional characteristics of a protein including providing a protein and reacting the protein with a glycosylated methanethiosulfonate reagent under conditions effective to produce a glycoprotein with altered functional characteristics as compared to the protein. In addition, the present invention relates to methods of determining the structure-function relationships of chemically modified mutant proteins. The present invention also relates to synthetic methods for producing thioglycoses, the thio-glycoses so produced, and to methods for producing glycodendrimer reagents. Excerpt(s): The present invention relates to chemically modified mutant proteins having modified glycosylation patterns with respect to a precursor protein from which they are derived. In particular, the present invention relates to a chemically modified mutant protein including a cysteine residue substituted for a residue other than cysteine in a precursor protein, the substituted cysteine residue being subsequently modified by reacting the cysteine residue with a glycosylated thiosulfonate. The present invention also relates to a method of producing the chemically modified mutant proteins and glycosylated methanethiosulfonate reagents. Another aspect of the present invention is a method of modifying the functional characteristics of a protein by reacting the protein with a glycosylated methanethiosulfonate reagent. The present invention also relates to methods of determining the structure-function relationships of chemically modified mutant proteins. Modifying enzyme properties by site-directed mutagenesis has been limited to natural amino acid replacements, although molecular biological strategies for overcoming this restriction have recently been derived (Cornish et al., Angew. Chem., Int. Ed. Engl., 34:621-633 (1995)). However, the latter procedures are difficult to apply in most laboratories. In contrast, controlled chemical modification of enzymes offers broad potential for facile and flexible modification of enzyme structure, thereby opening up extensive possibilities for controlled tailoring of enzyme specificity. Changing enzyme properties by chemical modification has been explored previously, with the first report being in 1966 by the groups of Bender (Polgar, et al., J. Am. Chem. Soc., 88:3153-3154 (1966)) and Koshland meet et al., Proc. Natl. Acad. Sci. USA, 56:1606-1611 (1966)), who
Patents 171
created a thiolsubtilisin by chemical transformation (CH.sub.2 OH.fwdarw.CH.sub.2 SH) of the active site serine residue of subtilisin BPN' to cysteine. Interest in chemically produced artificial enzymes, including some with synthetic potential, was reviewed by Wu (Wu et al., J. Am. Chem. Soc., 111:4514-4515 (1989); Bell et al., Biochemistry, 32:37543762 (1993)) and Peterson (Peterson et al., Biochemistry, 34:6616-6620 (1995)), and more recently, Suckling (Suckling et al., Bioorg. Med. Chem. Lett., 3:531-534 (1993)). Web site: http://www.delphion.com/details?pn=US06627744__ •
Undecapeptides containing cysteinesulfinic and cysteinesulfenic acid Inventor(s): Endo; Isao (Kokubunji, JP), Nakasako; Masayoshi (Wako, JP), Odaka; Masafumi (Wako, JP), Takio; Koji (Wako, JP), Yohda; Masafumi (Wako, JP) Assignee(s): The Institute of Physical and Chemical Research (Wako, JP) Patent Number: 6,617,424 Date filed: March 14, 2001 Abstract: Disclosed are peptides represented by IVC.sub.1 SLC.sub.2 SC.sub.3 TAW and C.sub.1 SLC.sub.2 SC.sub.3 wherein I stands for isoleucine, V for valine, C.sub.1 for cysteine, C.sub.2 for cysteinesulfinic acid, C.sub.3 for cysteinesulfenic acid, S for serine, L for leucine, T for threonine, A for alanine, and W for tryptophan. These peptides can impart photoreactivity to a protein by binding to a non-heme iron. Also disclosed are methods for imparting photoreactivity to cells by introducing the peptide sequences into at least one protein which is involved in a metabolic system and/or energy metabolic system of the cells. There can be provided peptide sequences with a shorter peptide chain capable of imparting photoreactivity, which can be easily introduced into a protein with a little risk in degrading original function of the protein. There are also provided methods enabling control of metabolic reactions by imparting photoreactivity to cells with the peptides. Excerpt(s): The present invention relates to a peptide which can impart photoreactivity to a protein, and a method for controlling metabolism of cells by introducing a sequence of the peptide into at least one protein which functions in a metabolic system so that the protein should acquire photoreactivity, thereby controlling metabolism of cells. Nitrile hydratase (NHase) is an enzyme which is produced in microorganisms and converts a nitrile compound into an amide compound by hydration. It is a soluble metalloprotein containing iron or cobalt atom in its active center. NHase derived from Rhodococcus sp. N-771 strain has a non-heme iron center of mononuclear low-spin six coordinate Fe(III). NHases have been isolated from several kinds of bacterial cells, and all of them consist of two kinds of subunits,.alpha. and.beta. Both of the subunits have a molecular weight of about 23,000. NHases of Rhodococcus sp. N-771, N-774, and R312 are considered to be the same enzyme because their base sequences are identical to each another, and their enzymatic activity varies with light irradiation. Namely, when bacterial cells exhibiting high activity are left in the dark, the enzyme activity is reduced, and the activity is increased again by photo-irradiation. It was recently revealed that photodissociation of nitric oxide (NO) which is bound to the non-heme iron center of inactive form Nhase activates the enzyme (Odaka et al., J. Am. Chem. Soc., 119, 3785-3791 (1997)). However, because the structure of the non-heme iron center which is the photoreactive site was not elucidated yet, the detailed mechanism of the photoreaction remained unclear. Therefore, the present inventors performed structural analysis of the non-heme iron center, and reported the results (for example, see Protein, Nucleic acid, Enzyme, Vol.42, No.2, p38-45 (1997)). That is, the present inventor isolated the.alpha. and.beta. subunits
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from the inactive form enzyme under denaturation condition, and found that the NObinding type non-heme iron center is present on the.alpha. subunit. Therefore, they further performed enzymatic degradation of the.alpha. subunit with trypsin, and purified the resulting peptides by reversed phase chromatography under a neutral condition. As a result, a peptide consisting of 24 residues of.sub.105 N to.sub.128 K binding one iron atom and NO has been isolated. This region was well conserved in various kinds of NHases, and contained a cysteine cluster predicted to be a metalbinding site (.sub.109 C-S-L-.sub.112 C-S-.sub.114 C). Web site: http://www.delphion.com/details?pn=US06617424__ •
Variants of vascular endothelial cell growth factor having antagonistic properties, nucleic acids encoding the same and host cells comprising those nucleic acids Inventor(s): Ferrara; Napoleone (San Francisco, CA), Keyt; Bruce A. (Pacifica, CA), Nguyen; Francis Hung (Daly City, CA) Assignee(s): Genentech, Inc. (South San Francisco, CA) Patent Number: 6,750,044 Date filed: October 17, 1996 Abstract: The present invention involves the preparation of vascular endothelial growth factor (VEGF) antagonist molecules comprising variant VEGF polypeptides which are capable of binding to and occupying cell surface VEGF receptors without inducing a VEGF response, thereby antagonizing the biological activity of the native VEGF protein. Specifically, the variant VEGF polypeptides of the present invention comprise modifications of at least one cysteine residue in the native VEGF sequence, thereby inhibiting the ability of the variant polypeptide to dimerize through the formation of disulfide bonds. The present invention is further directed to methods for preparing such variant VEGF antagonists and to methods, compositions and assays utilizing such variants for producing pharmaceutically active materials having therapeutic and pharmacologic properties that differ from the native VEGF protein. Excerpt(s): The present invention is directed to particular variants of vascular endothelial cell growth factor (hereinafter sometimes referred to as VEGF) which bind to and occupy cell surface VEGF receptors without inducing a VEGF response, thereby antagonizing the biological activity of the native VEGF protein. The present invention is further directed to methods for preparing such variant VEGF antagonists and to methods, compositions and assays utilizing such variants for producing pharmaceutically active materials having therapeutic and pharmacologic properties that differ from the native VEGF protein. The two major cellular components of the mammalian vascular system are the endothelial and smooth muscle cells. Endothelial cells form the lining of the inner surface of all blood vessels in the mammal and constitute a non-thrombogenic interface between blood and tissue. Therefore, the proliferation of endothelial cells is,an important component for the development of new capillaries and blood vessels which, in turn, is a necessary process for the growth and/or regeneration of mammalian tissues. One protein that has been shown to play an extremely important role in promoting endothelial cell proliferation and angiogenesis is vascular endothelial cell growth factor (VEGF). VEGF is a heparin-binding endothelial cell-specific growth factor which was originally identified and purified from media conditioned by bovine pituitary follicular or folliculostellate (FS) cells. Ferrara and Henzel, Biochem. Biophys. Res. Comm. 161:851-858 (1989). Naturally-occurring VEGF is a dimeric protein having an apparent molecular mass of about 46 kDa with each subunit
Patents 173
having an apparent molecular mass of about 23 kDa. Normal dimerization between individual native VEGF monomers occurs through the formation of disulfide bonds between the cysteine residues located at amino acid position 51 of one monomeric unit bonding to the cysteine residue at amino acid position 60 of another monomeric unit and vice versa. Human VEGF is expressed in a variety of tissues as multiple homodimeric forms (121, 165, 189 and 206 amino acids per monomer), wherein each form arises as a result of alternative splicing of a single RNA transcript. For example, VEGF.sub.121 is a soluble mitogen that does not bind heparin whereas the longer forms of VEGF bind heparin with progressively higher affinity. Biochemical analyses have shown that the native VEGF dimer exhibits a strong mitogenic specificity for vascular endothelial cells. For example, media conditioned by cells transfected by human VEGF cDNA promoted the proliferation of capillary endothelial cells, whereas medium conditioned by control cells did not. Leung et al., Science 246:1306 (1989). Thus, the native VEGF dimer is known to promote vascular endothelial cell proliferation and angiogenesis, a process which involves the formation of new blood vessels from preexisting endothelium. As such, the native VEGF may be useful for the therapeutic treatment of numerous conditions in which a growth-promoting activity on the vascular endothelial cells is important, for example, in ulcers, vascular injuries and myocardial infarction. The endothelial cell proliferative activity of the VEGF dimer is known to be mediated by two high affinity tyrosine kinase receptors, fit-1 (FMS-like tyrosine kinase) and KDR (kinase domain region), which exist only on the surface of vascular endothelial cells. DeVries, et al., Science 225:989-991 (1992) and Terman, et al., Oncogene 6:1677-1683 (1991). As cells become depleted in oxygen, because of trauma and the like, VEGF production increases in such cells, wherein the generated VEGF protein subsequently binds to its respective cell surface receptors in order to signal ultimate biological effect. The signal then increases vascular permeability and the cells divide and expand to form new vascular pathways. Thus, native VEGF functions to induce vascular proliferation through the binding to endothelial cell-specific receptors. Web site: http://www.delphion.com/details?pn=US06750044__ •
Zcys6: a member of the cystatin superfamily Inventor(s): Gao; Zeren (Redmond, WA), Presnell; Scott R. (Tacoma, WA) Assignee(s): ZymoGenetics, Inc. (Seattle, WA) Patent Number: 6,703,224 Date filed: June 1, 2001 Abstract: The cystatin superfamily includes inhibitors of cysteine proteinases, which function in a protective role with regard to various pathological actions of endogenous proteinases. Zcys6 is a new member of this superfamily. Excerpt(s): The present invention relates generally to a new polypeptide having diagnostic and therapeutic uses. In particular, the present invention relates to a novel polypeptide, designated "Zcys6," and to nucleic acid molecules encoding Zcys6. The cystatin superfamily is an evolutionarily related group of proteins consisting of at least three families: stefins (type 1), cystatins (type 2), and kininogens (type 3) (see, for example, Barrett, TIBS 12:193 (1987); Brown and Dziegielewska, Prot. Sci. 6:5 (1997)). Generally, stefin family members are unglycosylated proteins consisting of about 100 amino acids that are devoid of disulfide bonds. In contrast, cystatin family members are proteins consisting of about 115 amino acids and are characterized by two disulfide bonds in the carboxy-terminal region of the protein. Kininogens contain three regions
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with two disulfide loops, similar to the carboxy terminal domain found in members of the cystatin family. The cystatin superfamily are inhibitors of cysteine proteinases (also referred to as cysteine proteases) and are believed to function in a protective role with regard to pathological action of endogenous or exogenous cysteine proteinases. Cystatins appear to inhibit the cysteine proteinases by forming equimolar reversible complexes with the enzymes. Cystatin-like proteins have also been identified. One such protein, cystatin-related epididymal specific gene does not contain the conserved sequence motifs necessary for cysteine proteinase inhibitory activity (Cornwell et al., Mol. Endocrinol. 6:1653 (1992); Cornwell and Hann, Mol. Reprod. Dev. 41:37 (1995)). Unlike the ubiquitous expression of many of the cystatins, cystatin-related epididymal specific proteins are restricted to the proximal caput epididymal epithelium and testis. Cystatin-related epididymal specific gene expression is stage-specific during spermatogenesis, and the proteins are found in both round and elongating spermatids suggesting a specialized role during spermatogenesis. Web site: http://www.delphion.com/details?pn=US06703224__
Patent Applications on Cysteine As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to cysteine: •
ANTIMICROBIAL PEPTIDES AND METHODS OF USE THEREOF Inventor(s): Pereira, H. Anne; (Edmond, OK) Correspondence: Dunlap, Codding & Rogers P.C.; PO Box 16370; Oklahoma City; OK; 73113; US Patent Application Number: 20040048792 Date filed: December 20, 2002 Abstract: Novel peptide analogs derived from the native sequences of CAP37 peptides 20-44 and 23-42, and their use as therapeutics against bacterial infections and diseases caused by bacterial infection. The peptide analog includes a serine or threonine substitution at one of the two cysteine residues at positions 26 and 42. Substitutions of the native peptide are also contemplated. Excerpt(s): The present application is a divisional of U.S. Ser. No. 09/619,283, filed Jul. 19, 2000, which is a divisional of U.S. Ser. No. 09/258,934, filed Mar. 1, 1999, now U.S. Pat. No. 6,107,460. Each of the applications above is hereby expressly incorporated by reference herein in its entirety. The present invention is related to antimicrobial peptides and methods of use thereof in vivo, and more particularly to substituted derivatives of peptide 20-44 of CAP37. Antimicrobial therapies have advanced greatly over the years; however, people still die from infections and sepsis. The recent re-emergence of old infections once thought to be on the decline and the rapid evolution of resistant bacterial strains reinforces the critical need for designing and/or discovering new and more effective therapies. The most significant development in antibiotic therapy in the last
9
This has been a common practice outside the United States prior to December 2000.
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decade has been the exploitation of a group of naturally occurring host proteins that are potent antimicrobials, to produce more effective, safer and broader acting drugs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Attenuation of ischemia/reperfusion injury Inventor(s): Singh, Inderjit; (Mount Pleasant, SC) Correspondence: Fulbright & Jaworski L.L.P.; 600 Congress AVE.; Suite 2400; Austin; TX; 78701; US Patent Application Number: 20040072138 Date filed: May 2, 2003 Abstract: This current invention includes compositions and methods of nitric oxide synthase inhibitors to treat or reduce ischemia/reperfusion injury in a patient. More specifically, the invention relates to a combinational therapy of 5-Aminoimidazole-4carboxamide-1-B-D-ribonucleoside (AICAR) and N-acetyl cysteine (NAC) to attenuate ischemia/reperfusion injury to a transplanted organ. Excerpt(s): This application is a continuation-in-part application of co-pending U.S. application Ser. No. 10/273,557 filed Oct. 18, 2002, which is a divisional application of U.S. application Ser. No. 09/579,791 filed May 25, 2000, now issued as U.S. Ser. No. 6,511,800, which is a continuation of prior international Application No. PCT/US98/25360 filed Nov. 25, 1998, which claims priority to U.S. Provisional Application Serial No. 60/066,839, filed Nov. 25, 1997. The entire text of the foregoing applications are specifically incorporated herein by reference without disclaimer. The present invention relates to compositions for and methods of treating or reducing ischemia/reperfusion injury in organs. Ischemia, the lack of oxygen to an organ, rapidly sets into motion a complex series of events that affect the structure and function of virtually every organelle and subcellular system of the affected cells. Ischemia/reperfusion injury leads to production of excessive amounts of reactive oxygen species (ROS) and reactive nitrogen species (RNS) causing oxidative stress which results in alterations in mitochondrial oxidative phosphorylation, depletion of ATP, an increase in intracellular calcium and activation of protein kinases, phosphatases, proteases, lipases and nucleases leading to loss of cellular function/integrity. Many studies show that an inflammatory response induced by ischemia followed by reperfusion is largely responsible for tissue damage (Vedder et al., 1990; Takada et al., 1997). The acute inflammatory response initiated by ischemia/reperfusion is characterized by the induction of a proinflammatory cytokine cascade (Herskowitz et al., 1990). Previous studies have shown that N-acetyl cysteine (NAC) inhibits the induction of pro-inflammatory cytokines and iNOS and production of NO (Pahan et al., 1998) and also blocks the TNF-.alpha. induced apoptotic cell death (Singh et al., 1998). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Aza-peptide epoxides Inventor(s): Asgian, Juliana L.; (Fullerton, CA), James, Karen E.; (Cumming, GA), Li, Zhao-Zhao; (Norcross, GA), Powers, James C.; (Atlanta, GA) Correspondence: Thomas, Kayden, Horstemeyer & Risley, Llp; 100 Galleria Parkway, NW; Ste 1750; Atlanta; GA; 30339-5948; US Patent Application Number: 20040048327 Date filed: June 24, 2003 Abstract: The present invention provides compositions for inhibiting proteases, methods for synthesizing the compositions, and methods of using the disclosed protease inhibitors. Aspects of the invention include aza-peptide epoxide compositions that inhibit proteases, for example cysteine proteases, either in vivo or in vitro. The disclosed compounds, pharmaceutically acceptable salts, pharmaceutically acceptable derivatives, prodrugs, or combinations thereof can be used to treat disease or pathological conditions related to the activity of proteases associated with a specific disease or condition. Such treatable conditions include viral infections, stroke, neurodegenerative disease, and inflammatory disease, among others. Excerpt(s): This application claims benefit of U.S. Provisional Patent Application No. 60/394,221 filed on Jul. 5, 2002, U.S. Provisional Patent Application No. 60/394,023, filed on Jul. 5, 2002, and U.S. Provisional Patent Application No. 60/394,024 filed on Jul. 5, 2002, all of which are incorporated by reference in their entirety. This invention relates generally to protease inhibitors and applications thereof, more specifically to peptide inhibitors of cysteine proteases, even more specifically to aza-peptide epoxides, methods of their use, and methods of their production. Protease inhibitors are important therapeutics in the treatment of a variety of disease conditions including viral infections such as HIV infection. Proteases are enzymes that cleave proteins or peptides and are classified into several groups. For example, cysteine proteases form a group of enzymes involved in numerous disease states, and inhibitors of these enzymes can be used therapeutically for the treatment of diseases involving cysteine proteases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Bicyclic oligopeptides Inventor(s): Mack, Juergen; (Biberach, DE), Maurer, Till; (Oberstadion, DE), Peters, Stefan; (Biberach, DE), Potterat, Olivier; (Mittelbiberach, DE), Streicher, Ruediger; (Biberach, DE), Wagner, Klaus; (Warthausen, DE) Correspondence: Boehringer Ingelheim Corporation; 900 Ridgebury Road; P. O. Box 368; Ridgefield; CT; 06877; US Patent Application Number: 20040072736 Date filed: July 17, 2003 Abstract: The invention relates to a bicyclic oligopeptide or ester thereof having the capability to inhibit the glucagon receptor, comprised of:(a) a first cyclic group, which comprises at least one cysteine group and is formed by an amide bonding of the Nterminal amino acid with the second carboxylate group of a diacid amino acid, and(b) a second cyclic group which is formed by an amide bonding of an amino acid with the.alpha.-carboxylate group of said diacid amino acid, and by a disulfide bonding of the C-terminal cysteine and a cysteine group within the first cyclic group (a); andto the
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use of such bicyclic oligopeptides for the preparation of a medicament for the treatment or prevention of diseases, in which glucagon receptors are involved. Excerpt(s): Benefit of U.S. Provisional Application Serial No. 60/416,797, filed on Oct. 8, 2002 is hereby claimed, and said Application is herein incorporated by reference. The invention relates to bicyclic oligopeptides or esters thereof which have the capability to inhibit the glucagon receptor. The U.S. Pat. No. 5,919,926 discloses bicyclic depsipeptides which are produced by fermentation of a specific marine actinomycete (CNB-091) in saltwater-based media. These bicyclic depsipeptides are taught to be useful as anti-biotic and anti-inflammatory agents. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Compounds useful as reversible inhibitors of cysteine proteases Inventor(s): Bekkali, Younes; (Danbury, CT), Spero, Denice Mary; (West Redding, CT), Sun, Sanxing; (Danbury, CT), Ward, Yancey David; (Sandy Hook, CT) Correspondence: Boehringer Ingelheim Corporation; 900 Ridgebury Road; P O Box 368; Ridgefield; CT; 06877; US Patent Application Number: 20040053921 Date filed: October 24, 2002 Abstract: Disclosed are cathepsin S, K, F, L and B reversible inhibitory compounds of the formulas (Ia) and (Ib) where R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.8 and Y are defined herein. The compounds are useful for treating autoimmune and other diseases. Also disclosed are processes for making such novel compounds. 1 Excerpt(s): This application claims benefit to U.S. provisional application No. 60/340,719, filed Oct. 29, 2001. This invention relates to amidino and guanidino peptidyl compounds active as cysteine protease inhibitors. The compounds are reversible inhibitors of the cysteine protease cathepsin S, K, F, L and B are therefore useful in the treatment of autoimmune and other diseases. The invention also relates to processes for preparing such compounds and pharmaceutical compositions comprising them. Cathepsin S and cathepsin K are members of the papain family, within the papain superfamily of cysteine proteases. The papain family is the largest group of cysteine proteases and includes proteases such as cathepsins B, H, K, L, O and S. (A. J. Barrett et al., 1996, Perspectives in Drug Discovery and Design, 6, 1). The cysteine proteases have important roles in human biology and diseases including atherosclerosis, emphysema, osteoporosis, chronic inflammation and immune disorders (H. A. Chapman et al., 1997, Ann. Rev. Physiol., 59, 63). Cathepsin S plays a key role in regulating antigen presentation and immunity (H. A. Chapman, 1998, Current Opinion in Immunology, 10, 93; R. J. Riese et al., 1998, J. Clin. Invest., 101, 2351; R. J. Riese et al., 1996, Immunity, 4, 357). Cathepsin S deficient mice have impaired invariant chain degradation resulting in decreased antigen presentation and germinal center formation, and diminished susceptibility to collagen-induced arthritis indicating the therapeutic potential for a cathepsin S inhibitor (G. Shi et al., 1999, Immunity, 10, 197; T. Y. Nakagawa et al, 1999, Immunity, 10, 207). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compounds useful as reversible inhibitors of cysteine proteases Inventor(s): Bekkali, Younes; (Danbury, CT), Hickey, Eugene R.; (Danbury, CT), Liu, Weimin; (Sandy Hook, CT), Patel, Usha R.; (Brookfield, CT), Spero, Denice Mary; (West Redding, CT), Sun, Sanxing; (Danbury, CT), Thomson, David S.; (Ridgefield, CT), Ward, Yancey D.; (Sandy Hook, CT), Young, Erick R.R.; (Danbury, CT) Correspondence: Boehringer Ingelheim Corporation; 900 Ridgebury Road; P O Box 368; Ridgefield; CT; 06877; US Patent Application Number: 20040063679 Date filed: September 27, 2002 Abstract: Disclosed are novel cathepsin S, K, F, L and B reversible inhibitory compounds of the formulas (Ia) and (Ib) where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8, R.sub.9 and X are defined herein. The compounds are useful for treating autoimmune and other diseases. Also disclosed are processes for making such novel compounds. 1 Excerpt(s): This application claims benefit to U.S. provisional application serial No. 60/326,538 filed Oct. 2, 2001. This invention relates to amidino and guanidino peptidyl compounds active as cysteine protease inhibitors. The compounds are reversible inhibitors of the cysteine protease cathepsin S, K, F, L and B are therefore useful in the treatment of autoimmune and other diseases. The invention also relates to processes for preparing such compounds and pharmaceutical compositions comprising them. The specificity of the immune response relies on processing of foreign protein and presentation of antigenic peptide at the cell surface. Antigenic peptide is presented bound to MHC Class II, a heterodimeric glycoprotein expressed in certain antigen presenting cells of hematopoietic lineage, such as B cells, macrophages and dendritic cells. Presentation of antigen to effector cells, such as T-cells, is a fundamental step in recognition of non-self and thus initiation of the immune response. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Cyclic 2-carbonylaminoketones as inhibitors of cruzipain and other cysteine proteases Inventor(s): Quibell, Martin; (Cambridge, GB) Correspondence: Hale And Dorr, Llp; 60 State Street; Boston; MA; 02109 Patent Application Number: 20040127549 Date filed: January 8, 2004 Abstract: Compounds of general formula (I), wherein R.sup.1, R.sup.2, R.sup.3, Y, (X).sub.o, (W).sub.n, (V).sub.m, Z and U are as defined in the specification, are inhibitors of cruzipain and other cysteine protease inhibitors and are useful as therapeutic agents, for example in Chagas' disease, or for validating therapeutic target compounds. 1 Excerpt(s): THIS INVENTION relates to compounds which are inhibitors of the protease cruzipain, a gene product of the Trypanosoma cruzi parasite. In particular, the invention provides compounds that are useful for the therapeutic treatment of Trypanosoma cruzi infection, to the use of these compounds, and to pharmaceutical compositions comprising them. Furthermore, this invention relates to compounds which are inhibitors across a broad range of cysteine proteases, to the use of these compounds, and to pharmaceutical compositions comprising them. Such compounds are useful for the
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therapeutic treatment of diseases in which participation of a cysteine protease is implicated. The trypanosomal family of parasites have a substantial worldwide impact on human and animal healthcare (NcKerrow, J. H., et al, Ann. Rev. Microbiol. 4, 821-853, 1993). One parasite of this family, Trypanosoma cruzi, is the causative agent of Chagas' disease, which affects in excess of twenty million people annually in Latin and South America, is the leading cause of heart disease in these regions and results in more than 45,000 deaths per annum (Centers for Disease Control and prevention website). In addition, with the increase in migration of the infected population from rural to urban sites and movements from South and Central America into North America, the infection is spreading via blood transfusions, and at birth. The present treatments of choice for Trypanosoma cruzi infection, nifurtimox and benznidazole (an NADH fumarate reductase inhibitor, Turrens, J F, et al, Mol Biochem Parasitol., 82(1)125-9, 1996) are at best moderately successful, achieving 60% cure during the acute phase of infection (see Docampo, R. Curr. Pharm. Design, 7. 1157-1164, 2001 for a general discussion) whilst not being prescribed at all during the chronic phase where cardiomyopathy associated heart failure often occurs (Kirchhoff, L. V. New Engl. J. Med 329, 639-644, 1993). Additionally, these two drugs have serious adverse toxic effects, requiring close medical supervision during treatment, and have been shown to induce chromosomal damage in chagastic infants (Gorla, N. B. et al, Mutat. Res. 206, 217-220, 1988). Therefore, a strong medical need exists for new effective drugs for the chemotherapeutic treatment of Trypanosoma cruzi infection. Classically, the identification of enzymes found to be crucial for the establishment or propagation of an infectious disease has been instrumental in the development of successful drugs such as antivirals (e.g. HIV aspartyl protease inhibitors) and anti-bacterials (e.g.beta.-lactam antibiotics). The search for a similar Achilles heel in parasitic infections has examined numerous enzymes (e.g. parasitic dihydrofolate reductase, see Chowdhury, S. F. et al, J. Med. Chem., 42(21), 4300-4312, 1999; trypanothione reductase, see Li, Z. et al, Bioorg. Med. Chem. Lett., 11(2), 251-254, 2001; parasitic glyceraldehydes-3-phosphate dehydrogenase, see Aranov, A. M. et al, J. Med. Chem., 41(24), 4790-4799, 1998). A particularly promising area of research has identified the role of cysteine proteases, encoded by the parasite, that play a pivotal role during the life cycle of the parasite (McKerrow, 3. H., et al, Bioorg. Med. Chem., 7, 639644, 1999). Proteases form a substantial group of biological molecules which to date constitute approximately 2% of all the gene products identified following analysis of several genome sequencing programmes (e.g. see Southan, C. J. Pept. Sci, 6. 453458, 2000). Proteases have evolved to participate in an enormous range of biological processes, mediating their effect by cleavage of peptide amide bonds within the myriad of proteins found in nature. This hydrolytic action is performed by initially recognising, then binding to, particular three-dimensional electronic surfaces displayed by a protein, which aligns the bond for cleavage precisely within the protease catalytic site. Catalytic hydrolysis then commences through nucleophilic attack of the amide bond to be cleaved either via an amino acid side-chain of the protease itself, or through the action of a water molecule that is bound to and activated by the protease. Proteases in which the attacking nucleophile is the thiol side-chain of a Cys residue are known as cysteine proteases. The general classification of `cysteine protease` contains many members found across a wide range of organisms from viruses, bacteria, protozoa, plants and fingi to mammals. Biological investigation of Trypanosoma cruzi infection has highlighted a number of specific enzymes that are crucial for the progression of the parasite's life cycle. One such enzyme, cruzipain, a cathepsin L-like cysteine protease, is a clear therapeutic target for the treatment of Chagas' disease ((a) Cazzulo, J. J. et al, Curr. Pharm. Des. 7, 1143-1156, 2001; (b) Caffrey, C. R. et al, Curr. Drug Targets, 1155162, 2000). Although the precise biological role of cruzipain within the parasite's life cycle remains unclear, elevated cruzipain messenger RNA levels in the epimastigote
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developmental stage indicate a role in the nutritional degradation of host-molecules in lysosomal-like vesicles (Engel, J. C. et al, J. Cell. Sci, 11, 597-606, 1998). The validation of cruzipain as a viable therapeutic target has been achieved with increasing levels of complexity. Addition of a general cysteine protease inhibitor, Z-Phe-Ala-FMK to Trypanosoma cruzi-infected mammalian cell cultures blocked replication and differentiation of the parasite, thus arresting the parasite life cycle (Harth, G., et al, Mol. Biochem. Parasitol. 58, 17-24, 1993). Administration of a vinyl sulphone-based inhibitor in a Trypanosoma cruzi-infected murine animal model not only rescued the mice from lethal infections, but also produced a complete recovery (Engel, J. C. et al, J. Exp. Med, 188(4), 725-734, 1998). Numerous other in vivo studies have confirmed that infections with alternative parasites such as Leishmania major (Selzer, P. M. et al, Proc. Nat'l. Acad. Sci. U.S.A., 96, 11015-11022, 1999), Schistosoma mansoni and Plasmodium falciparium (Olson, J. E. et al, Bioorg. Med. Chem., 7, 633-638, 1999) can be halted or cured by treatment with cysteine protease inhibitors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Cysteine string protein and its role in neurodegenerative diseases Inventor(s): Stahl, Bernd; (Tuebingen, DE), Sudhof, Thomas C.; (Dallas, TX), Tobaben, Soenke; (Goettingen, DE) Correspondence: Baker & Botts; 30 Rockefeller Plaza; New York; NY; 10112 Patent Application Number: 20040064844 Date filed: September 26, 2002 Abstract: The present invention relates to in vitro and in vivo assays for the identification of agents that are useful in the treatment of neurodegenerative diseases that are associated with defects in protein folding. The present further relates to in vitro and in vivo assays for the identification of agents that contribute to the neurodegenerative processes which occur in these diseases. The present invention also relates to in vitro and in vivo models of neurodegenerative diseases. These assays and models will be useful in further understanding the pathogenesis of various neurodegenerative diseases in which defects in protein folding have been implicated, in identifying additional endogenous or environmental factors that contribute to the etiologies of these diseases, and in developing effective therapies for the prevention and/or treatment of these diseases. Excerpt(s): The present invention relates to in vitro and in vivo assays for the identification of agents that can be useful in the treatment of neurodegenerative diseases that are associated with defects in protein folding. The present invention further relates to in vitro and in vivo assays for the identification of agents that could contribute to the neurodegenerative processes which occur in these diseases. The present invention also relates to in vitro and in vivo models of neurodegenerative diseases. These inventions are based, at least in part, on the observations that 1) cysteine string protein (CSP) forms a complex in the presynaptic nerve terminal with the heat shock protein Hsc70 and the small glutamine-rich tetratricopeptide (TPR) protein (SGT), 2) that this complex constitutes an ATP-dependent presynaptic chaperone machine that is essential in maintaining long-term synaptic function, and 3) that mice in which the CSP gene has been disrupted by insertional mutagenesis (CSP knockout mice) suffer from neuronal degeneration that becomes apparent in synapses formed by motoneurons and retinal neurons among other neuronal cell populations. Degeneration of motoneuron synapses in turn leads to ascending motor disease. These assays and models are useful in
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understanding the pathogenesis of various neurodegenerative diseases in which defects in protein folding have been implicated, in identifying additional endogenous or environmental factors that could contribute to the etiologies of these diseases, and in developing effective therapies for the prevention and/or treatment of these diseases. The exocytotic release of neurotransmitter from nerve terminals is a fundamental process underlying most intercellular communication in the nervous system. Synaptic vesicles, the central players in this process, undergo a complex cycle of fusion and fission events. They fuse with the presynaptic membrane in response to a rise in the intracellular Ca.sup.2+ concentration, and release their neurotransmitter cargo into the synaptic cleft. The vesicle membrane is then retrieved by endocytosis (Sudhof, 1995, Nature 375:645-653; Scales and Scheller, 1999, Nature 401:123-124; Sudhof, 2000, Neuron 28:317-320 2000). In the last ten years, enormous progress has been made in identifying and characterizing the essential protein machinery involved in organizing and maintaining the synaptic vesicle cycle. One component of this complex protein machinery is the cysteine string protein (CSP), which is thought to have an important function in the exocytotic release of neurotransmitter, hormones, and enzyme precursors (Buchner and Gundersen, 1997, Trends Neurosci. 20:223-227). CSP is localized on synaptic vesicles (Mastrogiacomo et al., 1994, Science 263:981-982), chromaffin granules (Chamberlain et al., 1996, J. Biol. Chem. 271:19514-19517), and zymogen granules (Braun and Scheller, 1995, Neuropharmacology 34:1361-1369). It is highly conserved during evolution (Buchner and Gundersen, 1997, Trends Neurosci. 20:223-227), reflected by an overall amino acid identity of almost 55% between rat and Drosophila CSP. Due to a unique structural feature, a string of 11 cysteines flanked on either side by two additional cysteines, it was named cysteine string protein (Zinsmaier et al., 1990, J Neurogenet. 7:15-29). Most of the cysteine residues are palmitoylated and required for membrane targeting of CSP (Gundersen et al., 1994, J. Biol. Chem. 269:19197-19199; Chamberlain and Burgoyne, 1998, Biochem. J. 335:205-209). Another striking feature of CSP is that it contains a J domain at the N terminus. The J domain comprises a stretch of 70 amino acids evolutionarily conserved from E. coli to man (Fink, 1999, Physiol. Rev. 79:425-449). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Dihydropyrimidine derivatives as cysteine protease inhibitors Inventor(s): Ding, Qizhu; (Alberta, CA), Kaleta, Jadwiga; (Alberta, CA), Micetich, Ronald G.; (Alberta, CA), Reddy, Andhe V.N.; (Alberta, CA), Singh, Rajeshwar; (Alberta, CA), Thomas, George; (Alberta, CA), Zhou, Nian E.; (Napperville, IL) Correspondence: Rothwell, Figg, Ernst & Manbeck, P.C.; 1425 K Street, N.W.; Suite 800; Washington; DC; 20005; US Patent Application Number: 20040024000 Date filed: April 11, 2003 Abstract: Ditiydropyrimidine derivatives are disclosed, which can be used to inhibit cysteine protease activity. Excerpt(s): This invention relates to novel derivatives of dihydropyrimidine, to pharmaceutical compositions containing such compounds, and to their use in medicine as inhibitors of lysosomal cysteine proteases, particularly the cathepsins and more particularly Cathepsins B, L, K and S. Cysteine proteinases contain a highly reactive cysteine sulfhydryl group and a histidine imidazole group within the active site of the enzyme and are known to play an important role in a number of disease states.
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Cathepsin K can be secreted into the extracellular space and is involved in bone and cartilage remodelling. Cathepsin K is implicated in the pathogenesis of osteoporosis. Cathepsin K inhibitors can prevent osteoporosis in animal models (PNAS. 1997. 94:14249-14254). Cathepsin L inhibitors have also been shown to inhibit osteoporosis (Bone, 1997. 20:465-471). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Dipeptide nitriles Inventor(s): Altmann, Eva; (Reinach, CH), Betschart, Claudia; (Takarazuka, JP), Cowen, Scott Douglas; (Branchburg, NJ), Duzer, John Henry van; (Asbury, NJ), Gohda, Keigo; (Hyogo, JP), Greenspan, Paul David; (New Providence, NJ), Horiuchi, Miyuki; (Kobe, JP), Lattmann, Rene; (Binningen, CH), McQuire, Leslie Wighton; (Warren, NJ), Missbach, Martin; (Gipf-Oberfrick, CH), Sakaki, Junichi; (Hyogo, JP), Takai, Michihiro; (Ibaraki, JP), Teno, Naoki; (Kobe, JP), Tommasi, Ruben Alberto; (Whitehouse Station, NJ) Correspondence: Thomas Hoxie; Novartis, Corporate Intellectual Property; One Health Plaza 430/2; East Hanover; NJ; 07936-1080; US Patent Application Number: 20040029814 Date filed: January 15, 2003 Abstract: N-terminal substituted dipeptide nitrites as defined are useful as inhibitors of cysteine cathepsins, e.g. cathepsins B, K, L and S, and can be used for the treatment of cysteine cathepsin dependent diseases and conditions, including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization). Particular dipeptide nitrites are compounds of formula I, or physiologically-acceptable and -cleavable esters or a salts thereof 1wherein: the symbols are as defined.In particular it has been found that by appropriate choice of groups R, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X.sub.1, Y and L, the relative selectivity of the compounds as inhibitors of the various cysteine cathepsin types, e.g. cathepsins B, K, L and S may be altered, e.g. to obtain inhibitors which selectively inhibit a particular cathepsin type or combination of cathepsin types. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/______ filed Dec. 5, 1997 which was converted from application Ser. No. 08/985,973, and which is herewith incorporated by reference. This invention relates to inhibitors of cysteine proteases, in particular to dipeptide nitrile cathepsin inhibitors and to their pharmaceutical use for the treatment or prophylaxis of diseases or medical conditions in which cathepsins are implicated. The cysteine cathepsins, e.g. cathepsins B, K, L and S, are a class of lysosomal enzymes which are implicated in various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune diseases, respiratory diseases, infectious diseases and immunologically mediated diseases (including transplant rejection). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Genetic sequences encoding dominant-negative chalcone synthase and uses therefore Inventor(s): Choi, Giltsu; (Kwangju, KR), Choi, Goh; (Kwangju, KR), Hanummappa, Mamatha; (Kwangju, KR) Correspondence: Jacobson Holman Pllc; 400 Seventh Street N.W.; Suite 600; Washington; DC; 20004; US Patent Application Number: 20040038407 Date filed: August 21, 2002 Abstract: The invention includes modified Mazus chalcone synthase (CHS) nucleic acids, which encode a modified chalcone synthase that has alanine instead of cysteine at the 165.sup.th amino acid of Mazus CHS and either glycine or lysine instead of methionine at the 138.sup.th amino acid of Mazus CHS. The property of the encoded modified Mazus CHS is characterized by its dominant-negative inhibition of CHS. The invention also includes plants having at least one cell expressing the modified Mazus CHS. Such plants are characterized by the decreased content of anthocyanins. The invention also includes vectors comprising at least a portion of the modified Mazus CHS nucleic acids. The invention also includes methods using such vectors for producing plants having the decreased content of anthocyanins. Excerpt(s): The invention relates to modified Mazus CHS nucleic acids that encode modified CHS enzymes that inhibit CHS dominant-negatively and their uses for genetically altering plants to decrease the content of anthocyanins in the plants. Flower color is an important horticultural trait and is mainly produced by the flavonoid pigments, anthocyanins. Primarily produced to attract pollinators, flavonoids also protect the plant and its reproductive organs from UV damage, pests and pathogen (Brouillard and Cheminat, 1988; Gronquist et al., 2001). Classical breeding methods have been extensively used to develop cultivars with flowers varying in both the color and its intensity. The recent advance of knowledge on flower coloration at the biochemical and molecular level has made it possible to achieve this by genetic engineering (Tanaka et al., 1998). Genetic engineering to alter flower color has been attempted using various genes. Some species lack a particular color due to the absence of a biosynthetic gene or the substrate specificity of an enzyme in the pathway. For example, carnation lacks blue/purple colored flowers due to the absence of F3'5'H, while petunia lacks orange and brick-red flowers due to the inability of its DFR to reduce DHK (Gerats et al., 1982; Forkmann and Ruhnau, 1987). Genetic engineering of blue/purple colored carnation was achieved by introducing petunia F3'5'H gene and orange-colored petunia was developed by introducing DFR from other species (Meyer et al., 1987; Brugliera et al., 2000; Johnson et al., 2001). The modulation of color intensity has been another target for genetic engineering. Expression of biosynthetic genes such as CHS, F3H, and DFR in sense or antisense directions has been the most exploited method (van der Krol et al., 1990; Courtney-Gutterson et al., 1994; Jorgensen et al., 1996; Tanaka et al., 1998). The resulting sense suppression or antisense inhibition is collectively called posttranscriptional gene silencing (PTGS). Though these approaches have been fairly successful in the down-regulation of pigment synthesis, the necessity of cloning the gene of interest from a specific species or closely related species is the major drawback. Further, it is difficult to limit the PTGS to specific tissues (Palauqui et al., 1997; Voinnet and Baulcombe, 1997; Voinnet et al., 1998; Fagard and Vaucheret, 2000; Crete et al., 2001; Vaucheret et al., 2001). Alternatively, transcription factors that can either activate or repress the transcription of anthocyanin biosynthetic genes have been shown to be useful in regulating color intensity in model plants such as Arabidopsis, tobacco, and Petunia (Lloyd et al., 1992; Mol et al., 1998; Borevitz et al., 2000; Aharoni et al., 2001). The
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overexpression of transcription factors, however, generally alters the expression of many genes, thus the commercial viability of such transgenic flowers has yet to be determined (Lloyd et al., 1994; Bruce et al., 2000). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Hydroxamate-containing cysteine and serine protease inhibitors Inventor(s): Bihovsky, Ron; (Wynnewood, PA), Josef, Kurt Allen; (Wilmington, DE), Mallamo, John P.; (Glen Moore, PA) Correspondence: Woodcock Washburn Llp; One Liberty Place, 46th Floor; 1650 Market Street; Philadelphia; PA; 19103; US Patent Application Number: 20040106558 Date filed: November 20, 2003 Abstract: The present invention is directed to hydroxamate-containing inhibitors of cysteine and serine proteases. Methods for the use of the protease inhibitors are also described. Excerpt(s): This patent application claims priority benefit of U.S. Provisional Application Ser. No. 60/101,414, filed Sept. 22, 1998, the disclosure of which is incorporated by reference herein in its entirety. The present invention is directed to novel inhibitors of cysteine or serine proteases, referred to herein as hydroxamates. The present invention is also directed to methods for making these novel compounds, and methods for using the same. Numerous cysteine and serine proteases have been identified in human tissues. A "protease" is an enzyme which degrades proteins into smaller components (peptides). The terms "cysteine protease" and "serine protease" refer to proteases which are distinguished by the presence therein of a cysteine or serine residue which plays a critical role in the catalytic process. Mammalian systems, including humans, normally degrade and process proteins via a variety of enzymes including cysteine and serine proteases. However, when present at elevated levels or when abnormally activated, cysteine and serine proteases may be involved in pathophysiological processes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Malaria vaccine Inventor(s): Corradin, Giampietro; (Lausanne, CH), Rogerro, Mario; (Epalinges, CH) Correspondence: Marshall, Gerstein & Borun Llp; 6300 Sears Tower; 233 S. Wacker Drive; Chicago; IL; 60606; US Patent Application Number: 20040037838 Date filed: June 16, 2003 Abstract: The present invention relates to a vaccine against malaria comprising a polypeptide having the amino acid sequence of the C-terminal part of the circumsporozoite protein of a Plasmodium species, in which polypeptide one or more pairs of cysteine residues are oxidized, and optionally a suitable carrier and/or adjuvant and/or biodegradable microcapsules for use in humans. Excerpt(s): The present invention relates to a vaccine against malaria. The invention further relates to polypeptides that are capable of eliciting an immunological and
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protective response against malaria in a subject and the use thereof in prophylaxis. Malaria is a parasitic disease transmitted during the blood meal of infected mosquitoes which inoculate sporozoites into the mammalian host. Within minutes, sporozoites invade hepatocytes and develop into merozoites intracellularly by asexual schizogony. The merozoites then invade red blood cells, producing the various symptoms associated with the disease. The life-cycle is completed when gametocytes are ingested during the blood meal of the mosquito vectors. Protective immunity against malaria can be obtained by immunizing mice and humans with irradiation-attenuated sporozoites. This immunity is the result of the effect of neutralizing antibodies recognizing free sporozoites in the blood stream and of CD4.sup.+ and CD8.sup.+ T cells which prevent the development of the parasite hepatic forms. Experiments performed in B cell deficient mice have demonstrated that, despite the absence of anti-sporozoite antibodies, protection is induced by irradiated sporozoite immunization. This suggests that T cells specific for proteins present in the intracellular hepatic stage play a predominant role in protection. Therefore, one of the aims in malaria vaccine research is to mimic the protective immune response induced by injection of irradiated sporozoites. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for obtaining plants enriched in cysteine and glutathione content Inventor(s): Brunold, Christian; (Wabern, CH), Perez, Pascual; (Chanonat, FR) Correspondence: Young & Thompson; 745 South 23rd Street 2nd Floor; Arlington; VA; 22202 Patent Application Number: 20040123341 Date filed: November 6, 2002 Abstract: A method for obtaining a plant having an enriched content of cysteine and/or glutathione, including steps which consist in: transforming at least a plant cell with a vector containing an expression cassette including a sequence coding for an adenosine 5'-phosphosulphate reductase (APR); culturing the transformed cell so as to generate a plant containing in its genome the expression cassette. Excerpt(s): The present invention relates to a method for obtaining plants enriched in cysteine and glutathione content, by transgenesis. Higher plants use inorganic sulfate to satisfy their nutritional needs for sulfur. Sulfur is assimilated by plants by reduction of the sulfate to cysteine (Bick and Leustek, 1998). This amino acid is then involved in many functions in the plant (Rennenberg et al., 1990; Schmidt et al., 1992) and in particular participates in the synthesis of sulfur-containing proteins, such as membrane proteins. The reduced sulfur is also found in methionine and several metabolites, such as glutathione, the biosynthetic pathway of which is linked to that of cysteine (Brunold et al., 1997). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Methods of determining deficiencies in intracellular levels of cysteine and glutathione Inventor(s): Crawford, J. Fred; (Houston, TX) Correspondence: Benjamin Aaron Adler, PH.D., J.D.; Adler & Associates; 8011 Candle Lane; Houston; TX; 77071; US Patent Application Number: 20040087023 Date filed: October 29, 2003 Abstract: The present invention provides cell culture media and methods useful for determining levels of intracellular function of glutathione or cysteine and for providing biochemical analysis of antioxidant function in human lymphocytes. Excerpt(s): This is a divisional of U.S. Ser. No. 10/017,625, filed Dec. 13, 2001, which is a divisional of U.S. Ser. No. 08/922,279, filed Sep. 3, 1997, now abandoned. The present invention relates generally to the fields o f nutrition and biochemistry and cellular glutathione metabolism. More specifically, the present invention relates to measurement of levels of intracellular function of cysteine and glutathione so as to provide one measurement an individual's capability of preventing degenerative disease and dealing with oxidative stress. It is now accepted widely that a number of human health conditions, including aging, arthritis, cancer, atherosclerosis, myocardial infarction, stroke, viral infection, pulmonary conditions, bowel disease and neurodegenerative disease, can develop or be worsened by the presence of reactive oxygen molecules, commonly referred to as free radicals. These hostile molecules are normal by-products of physiological processes and are produced by metabolism of oxygen; e.g., via cellular respiration or immune system function (killing of foreign materials), and by numerous enzymatic reactions essential for metabolism. In addition, free radicals are found commonly in the environment. Environmental sources of free radicals include smoke, ionizing radiation, air pollution, chemicals (carcinogens, many petrochemicals, biocides, dyes, solvents, cytostatic drugs, etc.), toxic heavy metals and oxidized or rancid fats. Some of the most common free radicals are super oxide, hydroxyl radical, singlet oxygen, and peroxides, including hydrogen peroxides. Certain valences of iron and copper can catalyze formation of free radicals, which, although short-lived, promote a chain reaction of radical formation, followed by a wake of altered, damaged biological molecules. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Modification of hepatitis b core antigen Inventor(s): Borisova, Galina; (Riga Latvia, GB), Li, Jin-Li; (Beckenham, GB), Page, Mark; (Derby, GB), Pumpens, Paul; (Riga Latvia, GB) Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US Patent Application Number: 20040054139 Date filed: March 11, 2003 Abstract: A protein is provided comprising hepatitis B core antigen (HBcAg) wherein one or more of the four arginine repeats has been deleted, said protein comprising the C-terminal cysteine of HBcAg. The deleted region may be replaced by an epitope from a protein other than HBcAg, in which case the HBcAg acts as a carrier to present the
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epitope to the immune system. The chimeric protein is useful in prophylactic and therapeutic vaccination of a host, for example against hepatitis B virus. Excerpt(s): The invention relates to modified forms of the core antigen of hepatitis B virus (HBV) and to prophylactic and therapeutic vaccines containing the modified antigen. HBV remains a major healthcare problem throughout both the developed and developing world. Infection with the virus can result in an acute or chronic disease which in a proportion of cases may lead to hepatocellular carcinoma and death. The virus is double shelled, and its DNA is protected inside a protein structure called the core antigen (HBcAg). The core is surrounded by the envelope protein known as the surface or S antigen (HBsAg). HBcAg is an unusual antigen which can be used as a delivery vehicle for specific peptides to the immune system. The antigen has been used to present T-helper, B and cytotoxic lymphocyte (CTL) epitopes from a variety of viral and bacterial pathogens, including epitopes from the surface antigen of HBV, envelope proteins from hepatitis A and antigens from hepatitis C virus. For a review see Ulrich et al (1998) Advances in Virus Research 50 141-182. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Modulation of angiogenesis through targeting of cysteine oxygenase activity Inventor(s): Davydov, Ilia V.; (North Potomac, MD), Du, Fangyong; (New Haven, CT), Hu, Rong-gui; (Pasadena, CA), Kwon, Yong Tae; (Wexford, PA), Varshavsky, Alexander; (La Canada, CA) Correspondence: Gray Cary Ware & Freidenrich Llp; 4365 Executive Drive; Suite 1100; San Diego; CA; 92121-2133; US Patent Application Number: 20040023311 Date filed: March 21, 2003 Abstract: The invention provides methods and compositions for modulating angiogenesis in a subject. The methods of modulating angiogenesis in a subject include administering to the subject a modulator of N-terminal cysteine oxygenase activity. The invention also provides a method of identifying such a modulator and a method of in vitro screening for modulators of N-terminal cysteine oxygenase activity. Additionally, the invention provides a method of treating an angiogenesis-related disorder. Excerpt(s): This application claims the benefit of priority under 35 U.S.C.sctn. 119(e) of U.S. Ser. No. 60/366,218, filed Mar. 21, 2002 and U.S. Ser. No. 60/366,207, filed Mar. 21, 2002, the entire contents of which are incorporated herein by reference. The invention relates generally to methods of identification of modulators of angiogenesis and more specifically to modulators of N-terminal cysteine oxygenase activity. Angiogenesis is the growth of new blood vessels. Generally in the body, a balance of angiogenesis growth factors and angiogenesis inhibitors keeps this process of blood vessel growth under control. However, a lack or excess of either angiogenesis growth factors or angiogenesis inhibitors can cause undesired growth of blood vessels or a failure to produce blood vessels. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Monovalent antibody fragments Inventor(s): Chapman, Andrew Paul; (Hampton, GB), King, David John; (Camberley, GB) Correspondence: Cozen O'connor, P.C.; 1900 Market Street; Philadelphia; PA; 191033508; US Patent Application Number: 20040121415 Date filed: December 8, 2003 Abstract: Monovalent antibody fragments are described, each of which has one or more polymer molecules site-specifically attached through a sulphur atom of a cysteine residue located outside of the variable region domain of the antibody. The polymers include synthetic or naturally occurring polymers such as polyalkylenes, polyalkenylenes, polyoxyalkylenes or polysaccharides. Each fragment may be attached to one or more effector or reporter molecules, and is of use in therapy or diagnostics where it has markedly improved binding and/or pharmacokinetic properties when compared to other antibody fragments which have the same number and type of polymer molecules, but in which the polymer molecules are randomly attached. Excerpt(s): This invention relates to modified monovalent antibody fragments, to processes for their preparation, to compositions containing them and to their use in medicine. Antibodies are increasingly being used in the clinic for diagnostic and therapeutic purposes. The aim in each case is to exploit the combination of high specificity and affinity of the antibody-antigen interaction, to enable detection and/or treatment of a particular lesion. The antibody is used alone, or is loaded with another atom or molecule such as a radioisotope or cytotoxic drug. The pharmacokinetics and biodistribution of an antibody play a major role in determining whether its use in the clinic will be successful. Thus the antibody must be capable of being delivered to the site of action and be retained there for a length of time suitable to achieve its purpose. It also should be present only at sub-toxic levels outside of the target and it must be catabolised in a well-defined manner. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Novel antiviral acitivities of primate theta defensins and mammalian cathelicidins Inventor(s): Maury, Wendy; (Coralville, IA), McCray, Paul B.; (Iowa City, IA), Roller, Richard; (Coralville, IA), Stapleton, Jack; (Iowa City, IA), Stinski, Mark; (North Liberty, IA), Tack, Brian; (Iowa City, IA) Correspondence: Steven L. Highlander, ESQ.; Fulbright & Jaworski L.L.P.; Suite 2400; 600 Congress Avenue; Austin; TX; 78701; US Patent Application Number: 20040086535 Date filed: November 25, 2003 Abstract: The present invention relates to the use of anti-viral peptides in the inhibition and treatment of viral infections, in particular infections caused by enveloped viruses. These anti-viral peptides, some natural and others artificial, adopt either amphiphilic alpha-helical or a theta structure where the homodimeric or heterodirner peptides are joined by both cysteine bonds and circularization of the peptides. These agents may be used alone or in combination with more traditional anti-viral pharmaceuticals.
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Excerpt(s): This application claims benefit of the filing dates of U.S. Provisional Patent Application Serial Nos. 60/265,270 and 60/309,368, filed on Jan. 30, 2001 and Aug. 1, 2001, respectively. The entire text of the above-referenced disclosure is specifically incorporated by reference herein in its entirety without disclaimer. The present invention relates generally to the fields of molecular biology and virology. More particularly, it concerns the use of anti-viral peptides for the reduction of virus infectivity and treatment of viral infection. Viral infections continue to be a major cause of disease in the world, with many causing significant mortalities, as well as contributing substantially to health care costs. For example, the epidemic of HIV in the underdeveloped world is both socially and economically devastating. The ongoing spread of HIV in regions of Africa and Asia is well documented. In these areas of the world, transmission between adults primarily occurs through heterosexual contact. Unfortunately, means of controlling sexual transmission of HIV are currently limited to barrier methods such as condoms that are not always culturally acceptable. The incorporation of viricidal compounds into a vaginal cream could potentially have profound effects on the worldwide spread of HIV. Currently, no such compounds are available. This also highlights the general lack of anti-viral drugs, as compared to the numerous anti-bacterial agents available. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Peptides from the E2, E6, and E7 proteins of human papilloma viruses 16 and 18 for detecting and/or diagnosing cervical and other human papillomavirus associated cancers Inventor(s): Hu, Yao Xiong; (Mountain View, CA), Rosenfeld, Mark Jay; (Draper, UT) Correspondence: Pate Pierce & Baird; 215 South State Street, Suite 550; Parkside Tower; Salt Lake City; UT; 84111; US Patent Application Number: 20040110925 Date filed: July 1, 2003 Abstract: An isolated protein sequence or peptide from the E2, E6 or E7 early coding region of human papillomavirus (HPV) that is soluble in an aqueous medium, and characterized by a relative paucity of tryptophan, methionine and cysteine residues, and a relative abundance of glycine and asparagine residues. Also disclosed are isolated protein sequences or peptides from the E2, E6 or E7 early coding regions of HPV 16 and 18 and methodologies for detecting or diagnosing cancer or cellular abnormalities. Detection or diagnosis of Cancer or cellular abnormalities may include detecting or diagnosing pre-cancerous or pre-malignant conditions, cervical dysplasia, cervical carcinoma, koilocytosis, hyperkeratosis, intraepithelial lesions, and other cancers. A methodology for detecting or diagnosing cancer or cellular abnormalities comprises the steps of (1) reacting a sample of body fluid or tissue with isolated protein sequences or peptides; (2) forming an antibody-peptide complex; and (3) detecting the antibodypeptide complex. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial No. 60/394,172, filed Jul. 2, 2002, and entitled "NOVEL PEPTIDES FROM THE E2, E6 AND E7 PROTEINS OF HUMAN PAPILLOMAVIRUSES 16 AND 18 FOR DIAGNOSING OR DETECTING CERVICAL AND OTHER HUMAN PAPILLOMAVIRUS ASSOCIATED CANCERS" and co-pending U.S. patent application Ser. No. 09/828,645, filed Apr. 5, 2001, and entitled "IMMUNOLOGICAL METHODOLOGY FOR DISCERNING HUMAN PAPILLOMAVIRUS," which are incorporated herein by reference. The present
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invention relates generally to the field of peptides reactive with antibodies formed against human papillomavirus (HPV). Some have termed this type of peptide as antigenic or immunoreactive. More particularly, the invention relates to peptides isolated, purified or derived from the early coding region of the E2, E6, and E7 oncoproteins of HPV and method for use for the detection and/or diagnosis of HPV associated epithelial cell abnormalities, precancerous conditions and cancers via an immunoassay. The human papillomaviruses (HPV), named because certain types induce warts or papillomas, cause virtually all cervical cancers (Nobbenhuis et al., "Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening: a prospective study," The Lancet, 354:20-25, 1999; Cuzick et al., "A systematic review of the role of human papilloma virus (HPV) testing within a cervical screening programme: summary and conclusions," British Journal of Cancer, 83:561-565,2000). These encompass not only squamous cell carcinomas (Nobbenhuis et al., 1999) but also adenocarcinomas (Pirog et al., "Prevalence of human papillomavirus DNA in different histological subtypes of cervical adenocarcinoma," American Journal of Pathology, 157:1055-1062,2000). These viruses are also strongly associated with vulvar and vaginal carcinomas (Frisch et al., "Human papillomavirus-associated carcinomas in Hawaii and the mainland US," Cancer 88:1464-1469, 2000; Sugase et al., "Distinct manifestations of human papillomaviruses in the vagina," International Journal of Cancer, 72:412-415, 1997), as well as cancers of the anus (Frisch et al., 2000) and penis (Gregoire et al., "Preferential association of human papillomavirus with high-grade histologic variants of penile-invasive squamous cell carcinoma," Journal of the National Cancer Institute, 87:1705-1709, 1995). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Process for preparing S-(2-aminoethyl)-2-methyl-L-cysteine Inventor(s): Wuts, Peter Guillaume Marie; (Mattawan, MI) Correspondence: Pharmacia & Upjohn; 301 Henrietta ST; 0228-32-Law; Kalamazoo; MI; 49007; US Patent Application Number: 20040122099 Date filed: October 29, 2003 Excerpt(s): This application claims the benefit of the following provisional application: U.S. Ser. No. 60/422,975, filed Nov. 1, 2002, under 35 USC 119(e)(i), which is incorporated herein by reference in its entirety. S-(2-aminoethyl)-2-methyl-L-cysteine is an intermediate in the synthesis of S-[2-(ethanimidoylamino)ethyl]-2-methyl-L-cysteine, a nitric oxide synthase inhibitor useful in the treatment of inflammation disorders. The processes described for the preparation of S-[2-(ethanimidoylamino)ethyl]-2-methyl-Lcysteine, alternatively named S-[2-amino-3-(2-aminoethylsulfanyl)]-2-methyl-propionic acid, (U.S. patent application Publication Nos. 2002/0111493 and 2002/0019563) use complex methodology, costly ion exchange purification, produce product in modest yields, and employ ill-manipulable amino acid intermediates. In other instances, the use of N-protected amino acid esters have been used to provide tractable intermediates. Hydrolysis of these intermediates has been achieved with barium hydroxide in water and subsequent precipitation of barium as its carbonate salt (see, for example, RojasRousseau, A., et al., Tetrahedron (2001), 57(16), 3389-3395; Labrecque, D., et al., Tetrahedron Letters (2001), 42(14), 2645-2648; Spielvogel, D., et al., Tetrahedron Letters (2000), 41(41), 7863; Bai, Y., et al., Journal of Carbohydrate Chemistry (2000), 19(7), 939958; Spielvogel, D., et al., Tetrahedron Letters (2000), 41(41), 7863-7867) to give a solution
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of the free zwiterionic form of the amino acid. Similarly, calcium hydroxide has been described for the hydrolysis of carbamates (see, for example, Rank, A. W., et al., Can. J. Chem. (1981), 59(1), 27-33; Dornow, A., et al., Arch. Pharm. (1957), 290, 20-31; Bortnick, N. M., et al., J. Am. Chem. Soc. (1956), 78, 4358-61) and esters (see, for example, Hirth, G., et al., Helv. Chim. Acta (1985), 68(7), 1863-71). However, these methods have not been utilized in the preparation of the title compound and, thus, there exists a need for an improved process for the preparation of S-(2-aminoethyl)-2-methyl-L-cysteine. The instant invention provides a process for the preparation of S-(2-aminoethyl)-2-methyl-Lcysteine comprised of the steps of (i) esterification of 2-methyl-L-cysteine; (ii) alkylation of the cysteine ester of step (i) to provide an N-protected S-(2-aminoethyl)-2-methyl-L-cysteine ester; and (iii) hydrolysis of the intermediate of step (ii) to provide the title compound in a salt free state. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Process for producing rfrp Inventor(s): Nishimura, Osamu; (Hyogo, JP), Suenaga, Masato; (Yamaguchi, JP), Yamada, Takao; (Osaka, JP) Correspondence: Takeda Pharmaceuticals North America, Inc; Intellectual Property Department; 475 Half Day Road; Suite 500; Lincolnshire; IL; 60069; US Patent Application Number: 20040029215 Date filed: May 23, 2003 Abstract: The present invention is intended to provide an advantageous method of industrially producing RFamide peptides in a large scale. The present invention provides the method of producing RFamide peptides, which comprises subjecting a fusion protein or peptide, in which an RFamide peptide is ligated to the N-terminal of a protein or peptide having a cysteine at the N-terminal, to the reaction for cleavage of a peptide bond on the amino acid side of the cysteine residue. Excerpt(s): The present invention relates to a method of producing a partial peptide of a polypeptide comprising the amino acid sequence represented by SEQ ID NO: 19, NO: 21, NO: 23, NO: 25, NO: 27 or NO: 29, or a salt thereof, which comprises producing a fusion protein or polypeptide, and then subjecting said fusion protein or polypeptide to a reaction of cleaving a peptide bond. Further, the present invention relates to a method of efficiently eliminating the N-terminal Met residue, optionally oxidized, or a diketone of the Met residue from a partial peptide of a polypeptide comprising the amino acid sequence represented by SEQ ID NO: 19, NO: 21, NO: 23, NO: 25, NO: 27 or NO: 29 having a Met residue at the N-terminal, optionally oxidized, or a salt thereof, if desired. In the production of a peptide by recombinant DNA technology, it is more or less common practice to express the peptide in the form of a fusion protein because of frequent decomposition of the peptide within cells. For excision of the target peptide from the fusion protein, a chemical cleavage using cyanogen bromide (Itakura et al., Science, 198, 1056, 1977) and an enzymatic cleavage using factor Xa (Nagai et al., Methods in Enzymology, 153, 46, 1987) are known. Further, as a method for cleavage of a peptide bond in a protein, cleavage of the acylcysteine bond with 2-nitro-5thiocyanobenzoic acid is known ("Seikagaku Jikken Koza 1, Tanpakushitsu-no-Kagaku II (Biochemical Experiment Series 1, Protein Chemistry II)", Japanese Society of Biochemistry ed., Tokyo Kagaku Dojin, 247-250, 1976). However, there is no disclosure on the excision of a partial peptide of a polypeptide comprising the amino acid sequence
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represented by SEQ ID NO: 19, NO: 21, NO: 23, NO: 25, NO: 27 or NO: 29 from a protein. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Regulated apoptosis using chemically induced dimerization of apoptosis factors Inventor(s): Slawin, Kevin M.; (Houston, TX), Spencer, David M.; (Houston, TX) Correspondence: Fulbright & Jaworski, Llp; 1301 Mckinney; Suite 5100; Houston; TX; 77010-3095; US Patent Application Number: 20040040047 Date filed: September 19, 2002 Abstract: The present invention discloses artificial death switches (ADSs) based on chemically induced dimerization of the cysteine proteases, caspase-1 (ICE) and caspase3 (YAMA). In both cases, aggregation of the target protein is achieved by a non-toxic, lipid-permeable, dimeric FK506 analog that binds to an attached FK506-binding protein (FKBP). The intracellular crosslinking of caspase-1 or caspase-3 is sufficient to trigger rapid apoptosis in a Bcl-xL-independent manner, suggesting that these conditional proapoptotic molecules can bypass intracellular checkpoint genes, like Bcl-xL, that limit apoptosis. Since these chimeric molecules are derived from autologous proteins, they should be non-immunogenic and thus ideal for long-lived gene therapy vectors. These properties should also make chemically-induced apoptosis (CIA) useful for developmental studies, for treating hyperproliferative disorders and for developing animal models to a wide variety of diseases. Excerpt(s): The present invention is directed to the field of molecular biology and, in particular, the fields of regulated apoptosis and gene therapy. Over the past several years gene therapy has been evolving as a therapeutic option for numerous benign and malignant human diseases. Approaches to gene therapy fall into several broadly defined categories including: gene replacement therapy for diseases caused by the absence or malfunction of a single gene; immune system activation and vaccine development; and conditionally lethal gene therapy also known as "suicide gene" therapy. An example of a commonly used conditionally lethal gene frequently used for gene therapy of malignant diseases is the thymidine kinase (tk) gene from Herpes simplex virus (HSV). As used in a gene therapy application, the tk gene may be incorporated into a gene therapy and upon introduction of the gene therapy vector into a cell, a copy of the tk gene is introduced into the target cell. The presence of the tk gene renders the cells sensitive to the dideoxy nucleoside analog ganciclovir. When cells expressing tk are contacted with ganciclovir, the tk gene phosphorylates the nucleoside analog resulting in a form of the compound that can be further processed and incorporated into elongating DNA, leading to chain termination (3). Cells lacking the tk gene do not process ganciclovir and thus are not affected. Other genes encoding different enzymatic activities have been used as suicide genes. These include the E. coli purine nucleoside phosphorylase E gene, which generates toxic purines, and the bacterial cytosine deaminase gene which converts 5fluorocytosine to 5-fluorouracil. Both of these genes function by the in situ conversion of a nucleoside analogue into a form that is incorporated into replicating DNA thereby interfering with the replication process. Other conditionally lethal genes that have been employed in gene therapy applications include the E. coli nitroreductase gene (see Drabek, et al. Gene Therapy 4(2):93-100, 1997) that acts by converting the pro-drug CB 1954 into a cytotoxic DNA interstrand crosslinking agent and the hepatic cytochrome P450 2B1 (see Wei, et al. Human Gene Therapy 5(8):969-978, 1994) that acts by
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converting the anticancer drug cyclophospharmide into a toxic DNA-alkylating agent. A problem inherent in all of these systems is the toxic and/or mutagenic nature of the prodrugs employed. In all of the systems just mentioned, the pro-drug, even prior to its conversion into the active form, can have deleterious effects on cells. As a result of this toxicity, these types of gene therapy systems are not appropriate unless the condition of the patient warrants assuming the risks of therapy. Thus, these systems are completely inappropriate for treatment of benign hyperproliferative conditions. Notwithstanding these limitations, vectors incorporating these genes have been developed and tested on various tumor models. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Steroidogenic factor-1 protein variants and methods of making same Inventor(s): Ingraham, Holly A.; (San Francisco, CA), Krylova, Irina; (Oakland, CA) Correspondence: Cathryn Campbell; Mcdermott, Will & Emery; 7th Floor; 4370 LA Jolla Village Drive; San Diego; CA; 92122; US Patent Application Number: 20040092716 Date filed: July 9, 2003 Abstract: The present invention provides a properly folded steroidogenic factor-1 (SF-1)like receptor variant, or active fragment thereof, which has an amino acid sequence that encodes a SF-1-like receptor or an active fragment thereof and that lacks at least one naturally occurring cysteine residue within the ligand-binding domain of the receptor. Such a properly folded SF-1 receptor variant or active fragment thereof can exhibit increased monomer stability as compared to analogous receptor retaining the cysteine residues lacking in the variant. In one embodiment, at least one naturally occurring cysteine residue within the ligand-binding domain of the SF-1-like receptor is substituted with a non-cysteine residue such as serine or threonine. Excerpt(s): This application claims benefit of the filing date of U.S. Provisional Application No. 60/395,371, filed Jul. 12, 2002, and which is incorporated herein by reference. The present invention relates generally to the fields of nuclear receptors and protein expression and, more specifically, to mutants of steroidogenic factor-1 and related monomeric nuclear receptors with improved properties. The orphan nuclear receptor steroidogenic factor-1 (SF-1) is a monomeric binding nuclear receptor that is essential for endocrine organ proliferation, peptide hormone expression and for all steroid metabolism. Recombinant SF-1 protein has been expressed; in E. coli, SF-1 protein is soluble and expressed at reasonable levels. However, a variety of in vitro assays require high concentrations of purified protein. Unfortunately, SF-1 aggregates and is unsuitable for use at high concentrations in vitro. As an example, relatively high concentrations of conformationally uniform protein are required to prepare crystals suitable for X-ray crystallography studies. Because wild type protein produces twinned crystals, X-ray structural analysis cannot be performed. Similarly, wild type protein is not monomeric at the concentrations needed for functional analysis of the receptor using in vitro peptide binding assays. In brief, any application that requires high levels of purified protein cannot be performed with the SF-1 protein preparations currently available. Thus, there is a need for novel forms of SF-1 that exhibit increased stability of the monomeric form of the receptor and that remain monomeric at high protein concentrations. The present invention satisfied this need and provides related advantages as well.
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Synthesis of 2-alkyl amino acids Inventor(s): Chorghade, Mukund S.; (Natick, MA), Gurjar, Mukund K.; (Pune Maharashtra, IN), Mohapatra, Debendra K.; (Orissa, IN) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20040024224 Date filed: May 15, 2003 Abstract: Non-natural amino acids such as 2-alkylated amino acids allow for the synthesis of a wider variety of peptidal and non-peptidal pharmaceutically active agents. A method of preparing a 2-alkyl amino acid involves a Michael-type addition of a nucleophile to a dialkyl 2-methylidenylpropan-1,3-dioate and the conversion of a ester moiety into an amino moiety. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In this method, an aryl nitrile or imidate is condensed with cysteine, a 2-alkyl cysteine, or a cysteine ester. Excerpt(s): This application claims the benefit of U.S. Provisional Application Nos. 60/381,012, 60/381,021, 60/380,894, 60/380,910, 60/380,880, 60/381,017, 60/380,895, 60/380,903, 60/381,013, 60/380,878 and 60/380,909, all of which were filed May 15, 2002. This application also claims the benefit of U.S. Provisional Application No. 60/392,833, filed Jun. 27, 2002. The entire teachings of the above-referenced applications are incorporated herein by reference. Alpha-amino acids are useful starting materials in the synthesis of peptides, as well as non-peptidal, pharmaceutically active peptidomimetic agents. In order to enable the synthesis of a large number of compounds from an amino acid precursor, it is advantageous to have naturally occurring and non-naturally occurring amino acids. Non-naturally occurring amino acids typically differ from natural amino acids by their stereochemistry (e.g., enantiomers), by the addition of alkyl groups or other functionalities, or both. At this time, the enantiomers of naturally occurring amino acids are much more expensive than the naturally occurring amino acids. In addition, there are only a limited number of commercially available amino acids that are functionalized or alkylated at the alphacarbon, and often syntheses involve the use of pyrophoric or otherwise hazardous reagents. Moreover, the syntheses are often difficult to scale up to a commercially useful quantity. Consequently, there is a need for new methodologies of producing such nonnaturally occurring amino acids. Non-naturally occurring amino acids of interest include the (R)- and (S)-isomers of 2-methylcysteine, which are used in the design of pharmaceutically active moieties. Several natural products derived from these isomers have been discovered in the past few years. These natural products include desferrithiocin, from Streptomyces antibioticus; as well as tantazole A, mirabazole C, and thiangazole, all from blue-green algae. These compounds have diverse biological activities ranging from iron chelation to murine solid tumor-selective cytotoxicity to inhibition of HIV-1 infection. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Synthesis of substituted thiazoline carboxylic acids Inventor(s): Chorghade, Mukund S.; (Natick, MA), Gimi, Rayomand H.; (Chelmsford, MA), McDonnell, Peter D.; (Edmunds, GB), Wolstenholme-Hogg, Paul; (Haverhill, GB) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20040082796 Date filed: May 15, 2003 Abstract: A useful and efficient method of preparing an alkylated thiazoline carboxylic acid, or a derivative thereof, comprises coupling a substituted aryl nitrile such as, for example, 2,4-dimethoxybenzonitrile or 4-methoxybenzonitrile, with a cysteine ester to form a substituted thiazoline carboxylic acid ester; optionally hydrolyzing the substituted thiazoline carboxylic acid ester to form a substituted thiazoline carboxylic acid; optionally, protecting the carboxyl group; alkylating the thiazoline ring at the 4carbon position, as indicated in Structural Formula (I), with a compound of the formula R.sub.1--L, wherein R.sub.1 is as defined above and L is a leaving group, in the presence of a phase transfer catalyst; and, optionally, deprotecting the carboxyl group.In one embodiment of the present invention, a cinchona-alkaloid derived phase transfer catalyst is used to alkylate a protected substituted thiazoline carboxylic acid. Excerpt(s): This application claims the benefit of U.S. Provisional Application Nos. 60/381,012, 60/381,021, 60/380,894, 60/380,910, 60/380,880, 60/381,017, 60/380,895, 60/380,903, 60/381,013, 60/380,878 and 60/380,909, all of which were filed May 15, 2002. This application also claims the benefit of U.S. Provisional Application No. 60/392,833, filed Jun. 27, 2002. The entire teachings of the above-referenced applications are incorporated herein by reference. The use of desferrithiocin analogs for iron clearing has been described by Bergeron, et al. in "Desazadesmethyldesferrithiocin Analogues as Orally Effective Iron Chelators," J. Med. Chem., vol. 42, no. 1, 95-108 (1999). Desferrithiocin and related compounds represent an advance in iron chelation therapy for subjects suffering from iron overload disorders. Present therapeutic agents, such as desferroxamine, require parenteral administration and have a very short half--Life in the body, so that patient compliance and treatment cost are serious problems for subjects receiving long-term chelation therapy. Desferrithiocin and related compounds are effective when orally administered, thereby reducing patient compliance issues. The iron clearing efficiency of desferrithiocin analogues has been shown to substantially depend on the stereochemistry at the C-4 position of the thiazoline ring. Desferrithiocin analogues based on (S)-enantiomers have been found to be especially active iron clearing agents in primates. See, for example, Bergeron, et al, "Effects of C-4 Stereochemistry and C-4' Hydroxylation on the Iron Clearing Efficiency and Toxicity of Desferrithiocin Analogues," J. Med. Chem., vol. 42, no. 13, 2432-2440 (1999). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Synthetic vaccine for tick control Inventor(s): Dias Portela, Ricardo Wagner; (Vicosa Minas Gerais, BR), Guzman, Fanny; (Santa Fe de Bogota, CO), Mendes, Marcio Alberto; (Coimba Minas Gerals, CO), Murillo, Manuel Elkin; (Santa Fe de Bogota, CO), Oliveira, Ricardo De Castro; (Vicosa Minas Gerais, BR), Prates, Aline Alencar; (Vicosa Minas Gerais, BR), Salcedo, Joaquim Homan Patarroyo; (Vicosa Minas Gerals, BR), Viloria, Marlene Isabel Vargas; (Vicosa Minas Gerals, BR) Correspondence: Nixon & Vanderhye, PC; 1100 N Glebe Road; 8th Floor; Arlington; VA; 22201-4714; US Patent Application Number: 20040052807 Date filed: May 12, 2003 Abstract: This invention is related to the field of immunology of protein biotechnology and particularly to the construction of synthetic immunogens which result, where inoculated, in the production by cattle of an immune response capable of lesion to the ticks feeding on the inoculated bovines, reducing their number, their weight and their reproductive capacity to such an extent that the constructed immunogen can be used as an effective vaccine for tick control on bovines. The technical object of the invention consists of the design and construction of two synthetic immunogens constituted of a continuous and defined sequence with forty-three (43) amino acids, found in different positions in the sequence of protein Bm86, their polymerization with cysteine in the Nterminal and in the C-terminal, the medicamentous composition based on said peptide(s) and the synthetic vaccine obtained thereby. Excerpt(s): This invention is closely related to the fields of protein biotechnology, immunology and particularly with the construction of synthetic immunogens which result, when inoculated in cattle, in the production by cattle of an immune response capable of lesion to the ticks feeding on the inoculated bovines, reducing the number of bovines, their weight and capacity of reproduction to such an extent that the constructed immunogen can be used as an effective vaccine for tick control in bovines. The tick Boophilus microplus (Canestrini, 1887), belonging to the Ixodoidae family, is the main bovine ectoparasite in Brazil and in all tropical and subtropical countries. This parasite is extremely well adapted to the climate of a large part of the country and, coupled with the presence of its hosts distributed over more than 80% of the nation's territory, constitutes a major problem to cattle raising in Brazil. The associated losses are not limited to the drop in production resulting from the intense hemophagia, but can also be related to other damages such as the inoculation of toxins from the salivary glands, depreciation of the hides, influencing the productive capacity of the animals and, chiefly, the transmission of various microorganisms that cause diseases which seriously affect cattle raising in the nation, such as Babesia bovis and Babesa bigemina, with participation also in the epidemiology of Anaplasma marginale. The damage to livestock caused by ticks manifests itself by various typical actions, such as direct damage by the intense hematophagia originating mainly from the female ticks, and which can be as much as 0.6 to 3 ml per adult female. This results basically in loss of production, and various trials have been conducted to assess this situation. In 1987 (HOLROYD et al., Australian Journal of Experimental Agriculture 28: 1:10) observed that animals which had not been touched by ticks had gained on average 17 kg over a period of three years, as compared to those animals exposed to the parasite. In Brazil, (BRANCO et al 1987, Coletnea de Pesquisas EMBPAPA/CNPO, p. 229-234), found an average weight gain of 34.5 kg in Hereford cattle. In the country, FURLONG 1996 observed a reduced milk production in successive increasing infestations. JONSSON et
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al (Veterinary Parasitology 78: 66-77, 1998) have estimated that each adult female would be responsible for a drop of 8.9 ml in daily milk production and 1.0 g in loss of weight. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Thiol reactive agents as a therapeutic modality Inventor(s): Stamler, Jonathan S.; (Chapel Hill, NC) Correspondence: Bacon & Thomas, Pllc; 625 Slaters Lane; Fourth Floor; Alexandria; VA; 22314 Patent Application Number: 20040110691 Date filed: October 3, 2003 Abstract: A patient with a disease associated with a receptor having a cysteine residue is treated with a thiol reactive agent. The diseases include neurodegenerative diseases. Diseases characterized by skeletal muscle atrophy are also treated. Excerpt(s): This is a continuation-in-part to U.S. application Ser. No. 10/608,120, filed Jun. 30, 2003, which in turn is a continuation of U.S. application Ser. No. 10/280,085, filed Oct. 25, 2002, now U.S. Pat. No. 6,627,602 which in turn is a continuation-in-part of U.S. application Ser. No. 09/986,807, filed Nov. 13, 2001, now U.S. Pat. No. 6,472,390. In one case, this invention is directed to prophylaxis or treatment of a patient with a disease associated with a protein having a cysteine residue. In other cases, the invention is directed to prophylaxis or treatment of a patient with a neurodegenerative or a patient with a disease characterized by skeletal muscle atrophy. It is known that nitric oxide including all redox related forms, congers and donors (NO) regulates the function of most classes of protein by S-nitrosylation, that is, NO binds to or reacts with thiol residues to either inhibit or activate proteins. It is also known that S-nitrosylation can promote the formation of disulfides in the case of proteins containing redox sites comprised of vicinal thiols (i.e., to promote the formation of disulfides by S-nitrosylating at the vicinal thiols) or to inhibit formation of disulfides by S-nitrosylation at other (nonvicinal) sites, with the presence or absence of disulfides modulating the activity of the protein, for example, its reactivity with NO, its activity or its interaction with other proteins, and the effect thereof. Relying on the protein regulating function of NO, U.S. Pat. No. 6,472,390 claims a method for prophylaxis or treatment of a patient with a disease associated with a receptor having a cysteine residue or other cysteine containing protein to inhibit its function, or at risk therefor, comprising administering to said patient an NO donor that donates nitric oxide or a related redox species and provides bioactivity that is identified with nitric oxide. A potential disadvantage in administering NO donor is that such administration acutely lowers blood pressure and such blood pressure lowering may be counterindicated in respect to the disease being treated. In addition, NO can have other toxicities. A discovery in respect to U.S. Pat. No. 6,472,390 is that doses of NO donor which are insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure more than 10%, provide benefit. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Wise/Sost nucleic acid sequences and amino acid sequences Inventor(s): Ellies, Debra; (Kansas City, MO), Krumlauf, Robb; (Mission Hills, KS) Correspondence: Polsinelli Shalton & Welte, P.C.; Suite 1000; 700 W. 47th Street; Kansas City; MO; 64108; US Patent Application Number: 20040023356 Date filed: June 16, 2003 Abstract: The present invention relates to nucleic acid sequences and amino acid sequences which influence bone deposition, the Wnt pathway, ocular development, tooth development, and may bind to LRP. The nucleic acid sequence and polypeptides include Wise and Sost as well as a family of molecules which express a cysteine knot polypeptide. Additionally, the present invention relates to various molecular tools derived from the nucleic acids and polypeptides including vectors, transfected host cells, monochronal antibodies, Fab fragments, and methods for impacting the pathways. Excerpt(s): This application is a non-provisional patent application based on U.S. Provisional Patent Application Serial No. 60/388,970, filed Jun. 14, 2002. The present invention relates to Wise and Sost nucleic acid sequences and related amino acid sequences that can be used to influence bone deposition, the Wnt pathway, tooth development, and ocular development. In particular, the present invention also relates to nucleic acid sequences and amino acid sequences that optionally regulate or suppress bone deposition. The present invention relates to a family of nucleic acid molecules which expresses a family of amino acid sequences, some of which are characterized by a cysteine knot, such as the Wise and Sost proteins. The present invention also relates to resultant molecular biology tools derived from Wise or Sost, including plasmids, transfected host cells, antibodies, tranfected host organisms, and knockout organisms. Finally, the present invention relates to the interaction between Wise or Sost and LRP. To activate and study the Wnt pathway, a wide range of materials and information has been used. Various model organisms explained below are used because of differing developmental characteristics associated with the organisms. Because frogs and mice are exemplary of the organisms of study, they are explained in greater detail below. As will be seen, frogs and mice were used in many of the Examples contained herein. Additionally, various genes and the Wnt pathway are explained. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Zinc finger domain recognition code and uses thereof Inventor(s): Sera, Takashi; (San Diego, CA) Correspondence: Syngenta Biotechnology, INC.; Patent Department; 3054 Cornwallis Road; P.O. Box 12257; Research Triangle Park; NC; 27709-2257; US Patent Application Number: 20040091878 Date filed: January 17, 2003 Excerpt(s): The present invention relates to DNA binding proteins comprising zinc finger domains in which two histidine and two cysteine residues coordinate a central zinc ion. More particularly, the invention relates to the identification of a contextindependent recognition code to design zinc finger domains. This code permits identification of an amino acid for positions -1, 2, 3 and 6 of the.alpha.-helical region of the zinc finger domain from four-base pair nucleotide target sequences. The invention
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includes zinc finger proteins (ZFPs) designed using this recognition code, nucleic acids encoding these ZFPs and methods of using such ZFPs to modulate gene expression, alter genome structure, inhibit viral replication and detect alterations (e.g., nucleotide substitutions, deletions or insertions) in the binding sites for such proteins. In addition, the invention provides a rapid method of assembling a ZFP with three or more zinc finger domains using three sets of 256 oligonucleotides, where each set is designed to target the 256 different 4-base pair targets and allow production of all possible 3-finger ZFPs (i.e., >>10.sup.6) from a total of 768 oligonucleotides. Selective gene expression is modulated by specific interaction of transcription factors with nucleotide sequences within the regulatory region of a gene. Zinc fingers are structural domains found in eukaryotic proteins which control gene transcription. The zinc finger domain of the Cys.sub.2His.sub.2 class of ZFPs is a polypeptide structural motif folded around a bound zinc ion, and has a sequence of the form --X.sub.3-Cys-X.sub.2-4-Cys-X.sub.12His-X.sub.3-5-His-X.sub.4-(SEQ ID NO: 1), wherein X is any amino acid. The zinc finger is an independent folding domain which uses a zinc ion to stabilize the packing of an antiparallel.beta.-sheet against an.alpha.-helix. There is a great deal of sequence variation in the amino acids designated as X, however, the two consensus histidine and cysteine residues are invariant. Although most ZFPs have a similar three dimensional structure, they bind polynucleotides having a wide range of nucleotide sequences. Several reports have discussed how zinc finger domains recognize their target polynucleotides and have attempted to generate a recognition code describing which amino acids in the zinc finger bind to which nucleotides of the target sequence. Most of these studies emphasize a three nucleotide target site. However, the limited sequence recognition information currently available largely relates to context-specific binding. In other words, the binding of the zinc finger domain is dependent on the sequence of the polynucleotides other than those which directly contact amino acids within the zinc finger domain. The present invention addresses these shortcomings and provides a context-independent zinc finger recognition code. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with cysteine, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “cysteine” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on cysteine. You can also use this procedure to view pending patent applications concerning cysteine. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 6. BOOKS ON CYSTEINE Overview This chapter provides bibliographic book references relating to cysteine. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on cysteine include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “cysteine” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on cysteine: •
Numb Toes and Aching Soles: Coping with Peripheral Neuropathy Source: San Antonio, TX: MedPress. 1999. 300 p. Contact: Available from MedPress. P.O. Box 691546, San Antonio, TX 78269. (888) 6339898. Website: www.medpress.com. PRICE: $19.95 for soft back book; $29.95 for case bound book; plus shipping and handling. ISBN 0967110726. Summary: This book serves as a resource for people who experience pain related to peripheral neuropathy. About one half of peripheral neuropathies are related to complications from diabetes mellitus. The book focuses on traditional, conventional, and alternative treatments for neuropathic pain. The book begins with a chapter that defines peripheral neuropathy and discusses this condition in terms of its types, symptoms and effects, causes, and evaluation. The next chapter explains the physical and psychological aspects of peripheral neuropathic pain. The following chapter discusses medications for treating peripheral neuropathic pain, including nonopioid drugs, opioids, and topical
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medications. A discussion of nonopioid drug costs is included. The fourth chapter focuses on other medical therapies for treating peripheral neuropathic pain, including hematologic treatments such as plasmapheresis, immunosuppressant medications, and nerve based treatments such as nerve blocks and direct nerve stimulation. This is followed by a chapter on alternative treatments, including physical therapy; psychotherapeutic methods such as relaxation and meditation training, biofeedback, self hypnosis, and prayer; hyperbaric oxygen therapy; acupuncture; touch therapies such as massage, reflexology, Reiki, Qigong, and therapeutic touch; magnets; and chelation. Treating peripheral neuropathic pain with various nutrients (vitamins A, B, C, and E; minerals such as selenium, magnesium, chromium, and zinc; and herbs such as ginkgo biloba, St. John's wart, bioflavonoids, and others) is the topic of the next chapter. In addition, the chapter provides information on other supplements such as alpha-lipoic acid, gamma linolenic acid, acetyl-L-carnitine, N-acetyl cysteine, glutamine, coenzyme Q10, S-adenosylmethionine, dimethyl sulfoxide, and methyl sulfonyl methane. The focus of the next chapter is on experimental or unapproved drugs, including aldose reductase inhibitors; aminoguanidine; COX-2; ABT-594; SNX-111; lamotrigine; memantine; natural pain relievers such as bimoclomol, cannabinoids, endorphins, and nocistatin/OFQ2; nerve regenerating compounds such as NGF, IGF-1, neutrophin-3, and GPI 1046; nimodipine; peptide T; and PN 401. This is followed by a chapter that examines diabetes and HIV. Diabetes classifications and diabetic neuropathy (types, risk factors, blood sugar control, and treatment approaches) are discussed. The final chapter presents ways of coping with peripheral neuropathy, including exercising, using heat or cold therapy, creating conducive conditions for sleeping, avoiding certain foods, and selecting appropriate footwear. The book concludes with an index.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print®). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “cysteine” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “cysteine” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “cysteine” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
Lysosomal Cysteine Proteinases by Heidrun Kirschke, et al; ISBN: 0198502494; http://www.amazon.com/exec/obidos/ASIN/0198502494/icongroupinterna
•
Proteolytic Enzymes: Serine and Cysteine Peptidases by John N. Abelson, et al; ISBN: 0121821455; http://www.amazon.com/exec/obidos/ASIN/0121821455/icongroupinterna
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CHAPTER 7. PERIODICALS AND NEWS ON CYSTEINE Overview In this chapter, we suggest a number of news sources and present various periodicals that cover cysteine.
News Services and Press Releases One of the simplest ways of tracking press releases on cysteine is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “cysteine” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to cysteine. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “cysteine” (or synonyms). The following was recently listed in this archive for cysteine: •
Cathepsin cysteine proteases promote tumor growth Source: Reuters Medical News Date: June 01, 2004
•
High plasma cysteine associated with decreased risk of breast cancer Source: Reuters Medical News Date: July 14, 2003
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The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “cysteine” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “cysteine” (or synonyms). If you know the name of a company that is relevant to cysteine, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “cysteine” (or synonyms).
Academic Periodicals covering Cysteine Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to cysteine. In addition to these
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sources, you can search for articles covering cysteine that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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CHAPTER 8. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for cysteine. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI® Advice for the Patient® can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with cysteine. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The
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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to cysteine: Acetylcysteine •
Inhalation - U.S. Brands: Mucomyst; Mucomyst-10; Mucosil http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500403.html
Betaine •
Systemic - U.S. Brands: Cystadane http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203077.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult™ Mosby’s Drug Consult™ database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee. If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.
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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
•
National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
•
National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
•
National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
•
National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
•
National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
•
National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
•
National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
10
These publications are typically written by one or more of the various NIH Institutes.
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•
National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
•
National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
•
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
•
National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
•
National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
•
National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
•
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
•
National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
•
National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
•
National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
•
National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
•
National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
•
National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
•
National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
•
Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
•
Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.11 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:12 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
•
HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
•
NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
•
Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
•
Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
•
Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
•
Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
•
MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
11
Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 12 See http://www.nlm.nih.gov/databases/databases.html.
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•
Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
•
Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway13 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “cysteine” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 69613 63 215 237 1192 71320
HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.17 Simply search by “cysteine” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
13
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
14
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists18 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.19 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
18 Adapted 19
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on cysteine can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to cysteine. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to cysteine. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “cysteine”:
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Hemochromatosis http://www.nlm.nih.gov/medlineplus/hemochromatosis.html Hepatitis C http://www.nlm.nih.gov/medlineplus/hepatitisc.html Legionnaires' Disease http://www.nlm.nih.gov/medlineplus/legionnairesdisease.html Severe Acute Respiratory Syndrome http://www.nlm.nih.gov/medlineplus/severeacuterespiratorysyndrome.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on cysteine. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •
Homocysteine Metabolism Source: Mandeville, LA: PamLab, L.L.C. 2004. 1 p. Contact: Available from PamLab, L.L.C. P.O. Box 8950 Mandeville, LA 70470-8950. (985) 893-4097. Fax: (985) 893-6195. E-mail:
[email protected]. Website: www.pamlab.com. PRICE: Contact organization for print copies. Summary: This fact sheet demonstrates how elevated plasma homocysteine levels increase the risk for cardiovascular disease. The fact sheet features an illustration of the process, with five stages labeled. Dietary protein is converted into methionine. Methionine is converted into homocysteine (demethylation). Homocysteine is converted into cysteine (transsulfuration). Homocysteine is converted back into methionine (remethylation). Excess homocysteine accumulates in the bloodstream if metabolism is impaired or defective (for example, in patients with kidney disease). Excess homocysteine can increase the risk for cardiovascular disease. 1 figure. The NIH Search Utility
The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to cysteine. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals
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and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
•
Family Village: http://www.familyvillage.wisc.edu/specific.htm
•
Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
•
Med Help International: http://www.medhelp.org/HealthTopics/A.html
•
Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
•
Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
•
WebMD®Health: http://my.webmd.com/health_topics
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to cysteine. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with cysteine. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about cysteine. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/.
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Simply type in “cysteine” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “cysteine”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “cysteine” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “cysteine” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
21
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)22: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
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Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
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Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
Finding Medical Libraries
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Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
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Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
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On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
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MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
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Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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CYSTEINE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abrin: A toxic lectin from the seeds of jequirity, Abrus precatorius L. Very active poison. Five different proteins have so far been isolated: Abrus agglutinin, the component responsible for hemagglutininating activity, & abrins a-d, the toxic principles each consisting of two peptide chains are held together by disulfide bonds. [NIH] Abscess: A localized, circumscribed collection of pus. [NIH] Acanthosis Nigricans: A circumscribed melanosis consisting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae and other body folds. It occurs in association with endocrine disorders, underlying malignancy, administration of certain drugs, or as in inherited disorder. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcholinesterase: An enzyme that catalyzes the hydrolysis of acetylcholine to choline and acetate. In the CNS, this enzyme plays a role in the function of peripheral neuromuscular junctions. EC 3.1.1.7. [NIH] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect
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criteria for AIDS as defined by the CDC in 1993. [NIH] Acrosome: Cap-like structure covering the nucleus and anterior part of the sperm head. [NIH]
Acrylamide: A colorless, odorless, highly water soluble vinyl monomer formed from the hydration of acrylonitrile. It is primarily used in research laboratories for electrophoresis, chromatography, and electron microscopy and in the sewage and wastewater treatment industries. [NIH] Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics, adhesives and synthetic rubber. [NIH] Actin: Essential component of the cell skeleton. [NIH] Actomyosin: A protein complex of actin and myosin occurring in muscle. It is the essential contractile substance of muscle. [NIH] Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adduction: The rotation of an eye toward the midline (nasally). [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH]
Dictionary 231
Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, oxidative metabolism, or cell respiration. [NIH] Aerobic Respiration: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as oxidative metabolism, cell respiration, or aerobic metabolism. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]
Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60
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per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehyde Reductase: An enzyme that catalyzes reversibly the oxidation of an aldose to an alditol. It possesses broad specificity for many aldoses. EC 1.1.1.21. [NIH] Aldose Reductase Inhibitor: A class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes. Aldose reductase is an enzyme that is normally present in the eye and in many other parts of the body. It helps change glucose (sugar) into a sugar alcohol called sorbitol. Too much sorbitol trapped in eye and nerve cells can damage these cells, leading to retinopathy and neuropathy. Drugs that prevent or slow (inhibit) the action of aldose reductase are being studied as a way to prevent or delay these complications of diabetes. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylate: To treat with an alkylating agent. [EU] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]
Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group. [NIH] Allantois: An embryonic diverticulum of the hindgut of reptiles, birds, and mammals; in man its blood vessels give rise to those of the umbilical cord. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Allografts: A graft of tissue obtained from the body of another animal of the same species but with genotype differing from that of the recipient; tissue graft from a donor of one genotype to a host of another genotype with host and donor being members of the same species. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alpha-Defensins: Defensins found in azurophilic granules of neutrophils and in the secretory granules of intestinal paneth cells. [NIH] Alpha-helices: One of the secondary element of protein. [NIH]
Dictionary 233
Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alternative Splicing: A process whereby multiple protein isoforms are generated from a single gene. Alternative splicing involves the splicing together of nonconsecutive exons during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form messenger RNA. The alternative forms produce proteins in which one part is common while the other part is different. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a conserved sequence which can be represented by a consensus sequence. [NIH]
Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Aminoethyl: A protease inhibitor. [NIH] Aminopeptidases: A subclass of exopeptidases that act on the free N terminus end of a polypeptide liberating a single amino acid residue. EC 3.4.11. [NIH] Amino-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]
Amphetamines: Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopression, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system.
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[NIH]
Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Amyloid beta-Protein: A 4 kD protein, 39-43 amino acids long, expressed by a gene located on chromosome 21. It is the major protein subunit of the vascular and plaque amyloid filaments in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (Down syndrome). The protein is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue. [NIH] Amyotrophy: A type of diabetic neuropathy that causes muscle weakness and wasting. [NIH] Anabaena: A genus of cyanobacteria consisting of trichomes that are untapered with conspicuous constrictions at cross-walls. A firm individual sheath is absent, but a soft covering is often present. Many species are known worldwide as major components of freshwater plankton and also of many saline lakes. The species Anabaena flos-aquae is responsible for acute poisonings of various animals. [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angiogenesis inhibitor: A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of blood vessels from surrounding tissue to a solid tumor. [NIH]
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Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anisotropy: A physical property showing different values in relation to the direction in or along which the measurement is made. The physical property may be with regard to thermal or electric conductivity or light refraction. In crystallography, it describes crystals whose index of refraction varies with the direction of the incident light. It is also called acolotropy and colotropy. The opposite of anisotropy is isotropy wherein the same values characterize the object when measured along axes in all directions. [NIH] Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH] Anthelmintic: An agent that is destructive to worms. [EU] Anthocyanins: Glycosidic pigments in blue, red, and purple flowers and also found as metabolic byproducts in blood and urine. [NIH] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticholinergic: An agent that blocks the parasympathetic nerves. Called also parasympatholytic. [EU] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsants: Drugs used to prevent seizures or reduce their severity. [NIH] Antidepressant: A drug used to treat depression. [NIH] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage
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causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Aneurysm: Aneurysm of the aorta. [NIH] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]
Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apolipoproteins E: Prominent protein constituents of plasma VLDL, chylomicrons, and a subfraction of HDL as well as of remnant lipoproteins which are derived from the lipoprotein lipase-mediated intravascular catabolism of triglyceride-rich lipoproteins. Apolipoproteins E are recognized by the LDL receptor and Apo E receptor. Any defect in the Apo E metabolism leads to increased plasma Apo E levels. A strong association has been found between high levels of Apo E and type III hyperlipoproteinemia. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat
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as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris. [NIH]
Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Aspartate: A synthetic amino acid. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astringents: Agents, usually topical, that cause the contraction of tissues for the control of bleeding or secretions. [NIH] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH]
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Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Auditory: Pertaining to the sense of hearing. [EU] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Avian: A plasmodial infection in birds. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Babesiosis: A group of tick-borne diseases of mammals including zoonoses in humans. They are caused by protozoans of the genus babesia, which parasitize erythrocytes, producing hemolysis. In the U.S., the organism's natural host is mice and transmission is by the deer tick ixodes scapularis. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacteriophage lambda: A temperate inducible phage and type species of the genus lambdalike Phages, in the family Siphoviridae. Its natural host is E. coli K12. Its virion contains linear double-stranded DNA, except for 12 complementary bases at the 5'-termini of the polynucleotide chains. The DNA circularizes on infection. [NIH] Bacteriophages: Viruses whose host is a bacterial cell. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Barium: An element of the alkaline earth group of metals. It has an atomic symbol Ba, atomic number 56, and atomic weight 138. All of its acid-soluble salts are poisonous. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its
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subdivisions is the basal (basement) lamina. [NIH] Baths: The immersion or washing of the body or any of its parts in water or other medium for cleansing or medical treatment. It includes bathing for personal hygiene as well as for medical purposes with the addition of therapeutic agents, such as alkalines, antiseptics, oil, etc. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Beta-Defensins: Defensins found mainly in epithelial cells. [NIH] Beta-Endorphin: A peptide consisting of amino acid sequence 61-91 of the endogenous pituitary hormone beta-lipotropin. The first four amino acids show a common tetrapeptide sequence with methionine- and leucine enkephalin. The compound shows opiate-like activity. Injection of beta-endorphin induces a profound analgesia of the whole body for several hours. This action is reversed after administration of naloxone. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Bioluminescence: The emission of light by living organisms such as the firefly, certain
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mollusks, beetles, fish, bacteria, fungi and protozoa. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bioterrorism: The use of biological agents in terrorism. This includes the malevolent use of bacteria, viruses, or toxins against people, animals, or plants. [NIH] Biotic: Pertaining to living organisms in their ecological rather than their physiological relations. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bladder: The organ that stores urine. [NIH] Blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Coagulation Factors: Endogenous substances, usually proteins, that are involved in the blood coagulation process. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood Substitutes: Substances that can carry oxygen to and carbon dioxide away from the tissues when introduced into the blood stream. They are used to replace hemoglobin in severe hemorrhage and also to perfuse isolated organs. The best known are perfluorocarbon
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emulsions and various hemoglobin solutions. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Hypoxia: Lack of oxygen leading to unconsciousness. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Bronchiseptica: A small, gram-negative, motile bacillus. A normal inhabitant of the respiratory tract in man, dogs, and pigs, but is also associated with canine infectious tracheobronchitis and atrophic rhinitis in pigs. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Busulfan: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]
Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been
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observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue. [NIH] Calcium Hydroxide: Ca(OH)2. A white powder that has many therapeutic uses. Because of its ability to stimulate mineralization, it is found in many dental formulations. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH] Cannabidiol: Compound isolated from Cannabis sativa extract. [NIH] Cannabinoids: Compounds extracted from Cannabis sativa L. and metabolites having the cannabinoid structure. The most active constituents are tetrahydrocannabinol, cannabinol, and cannabidiol. [NIH] Cannabinol: A physiologically inactive constituent of Cannabis sativa L. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (tight junctions) which may limit large molecule movement. [NIH] Capsid: The outer protein protective shell of a virus, which protects the viral nucleic acid. [NIH]
Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH]
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Carboxy: Cannabinoid. [NIH] Carboxylic Acids: Organic compounds containing the carboxy group (-COOH). This group of compounds includes amino acids and fatty acids. Carboxylic acids can be saturated, unsaturated, or aromatic. [NIH] Carboxypeptidases: Enzymes that act at a free C-terminus of a polypeptide to liberate a single amino acid residue. They are further divided based on their catalytic mechanism into serine-type carboxypeptidases EC 3.4.16; metallocarboxypeptidases, EC 3.4.17; and cysteinetype carboxypeptidases, EC 3.4.18. EC 3.4.-. [NIH] Carboxy-terminal: The end of any polypeptide or protein that bears a free carboxyl group. [NIH]
Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Cardiac: Having to do with the heart. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU] Cardiotoxicity: Toxicity that affects the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carmustine: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]
Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotid Arteries: Either of the two principal arteries on both sides of the neck that supply blood to the head and neck; each divides into two branches, the internal carotid artery and the external carotid artery. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Catalyse: To speed up a chemical reaction. [EU]
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Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction. [NIH] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Cathepsin D: An intracellular proteinase found in a variety of tissue. It has specificity similar to but narrower than that of pepsin A. The enzyme is involved in catabolism of cartilage and connective tissue. EC 3.4.23.5. (Formerly EC 3.4.4.23). [NIH] Cathepsins: A group of lysosomal proteinases or endopeptidases found in aqueous extracts of a variety of animal tissue. They function optimally within an acidic pH range. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Caustic: An escharotic or corrosive agent. Called also cauterant. [EU] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Communication: Any of several ways in which living cells of an organism communicate with one another, whether by direct contact between cells or by means of chemical signals carried by neurotransmitter substances, hormones, and cyclic AMP. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH]
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Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chelation: Combination with a metal in complexes in which the metal is part of a ring. [EU] Chemoprevention: The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer. [NIH] Chemoprotective: A quality of some drugs used in cancer treatment. Chemoprotective agents protect healthy tissue from the toxic effects of anticancer drugs. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapeutics: Noun plural but singular or plural in constructions : chemotherapy. [EU]
Chemotherapy: Treatment with anticancer drugs. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Chloroplasts: Plant cell inclusion bodies that contain the photosynthetic pigment chlorophyll, which is associated with the membrane of thylakoids. Chloroplasts occur in cells of leaves and young stems of higher plants. [NIH]
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Cholecystokinin: A 33-amino acid peptide secreted by the upper intestinal mucosa and also found in the central nervous system. It causes gallbladder contraction, release of pancreatic exocrine (or digestive) enzymes, and affects other gastrointestinal functions. Cholecystokinin may be the mediator of satiety. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Chorion: The outermost extraembryonic membrane. [NIH] Chromaffin Granules: Granules in the adrenal glands and various other organs, which are concerned with the synthesis, storage, metabolism, and secretion of epinephrine and norepinephrine. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic phase: Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Chymopapain: A cysteine endopeptidase isolated from papaya latex. Preferential cleavage at glutamic and aspartic acid residues. EC 3.4.22.6. [NIH] Chymotrypsin: A serine endopeptidase secreted by the pancreas as its zymogen, chymotrypsinogen and carried in the pancreatic juice to the duodenum where it is activated
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by trypsin. It selectively cleaves aromatic amino acids on the carboxyl side. [NIH] Cinchona: A genus of rubiaceous South American trees that yields the toxic cinchona alkaloids from their bark; quinine, quinidine, chinconine, cinchonidine and others are used to treat malaria and cardiac arrhythmias. [NIH] Cinchona Alkaloids: Alkaloids extracted from various species of Cinchona. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Cleave: A double-stranded cut in DNA with a restriction endonuclease. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to erythrocytosis. [NIH] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual
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amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Collateral Circulation: Maintenance of blood flow to an organ despite obstruction of a principal vessel. Blood flow is maintained through small vessels. [NIH] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU]
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Complement Activation: The sequential activation of serum components C1 through C9, initiated by an erythrocyte-antibody complex or by microbial polysaccharides and properdin, and producing an inflammatory response. [NIH] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Concomitant: Accompanying; accessory; joined with another. [EU] Condoms: A sheath that is worn over the penis during sexual behavior in order to prevent pregnancy or spread of sexually transmitted disease. [NIH] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Congenita: Displacement, subluxation, or malposition of the crystalline lens. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH]
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Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Disease: Disorder of cardiac function due to an imbalance between myocardial function and the capacity of the coronary vessels to supply sufficient flow for normal function. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronary Vessels: The veins and arteries of the heart. [NIH] Corpus: The body of the uterus. [NIH] Corpuscle: A small mass or body; a sensory nerve end bulb; a cell, especially that of the blood or the lymph. [NIH] Corrosion: Irreversible destruction of skin tissue. [NIH]
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Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Coumarin: A fluorescent dye. [NIH] Cowpox: A mild, eruptive skin disease of milk cows caused by cowpox virus, with lesions occurring principally on the udder and teats. Human infection may occur while milking an infected animal. [NIH] Cowpox Virus: A species of orthopoxvirus that is the etiologic agent of cowpox. It is closely related to but antigenically different from vaccina virus. [NIH] Critical Care: Health care provided to a critically ill patient during a medical emergency or crisis. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Croton Oil: Viscous, nauseating oil obtained from the shrub Croton tiglium (Euphorbaceae). It is a vesicant and skin irritant used as pharmacologic standard for skin inflammation and allergy and causes skin cancer. It was formerly used as an emetic and cathartic with frequent mortality. [NIH] Cryopreservation: Preservation of cells, tissues, organs, or embryos by freezing. In histological preparations, cryopreservation or cryofixation is used to maintain the existing form, structure, and chemical composition of all the constituent elements of the specimens. [NIH]
Crystallins: A heterogeneous family of water-soluble structural proteins found in cells of the vertebrate lens. The presence of these proteins accounts for the transparency of the lens. The family is composed of four major groups, alpha, beta, gamma, and delta, and several minor groups, which are classed on the basis of size, charge, immunological properties, and vertebrate source. Alpha, beta, and delta crystallins occur in avian and reptilian lenses, while alpha, beta, and gamma crystallins occur in all other lenses. [NIH] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyanide: An extremely toxic class of compounds that can be lethal on inhaling of ingesting in minute quantities. [NIH] Cyanobacteria: A subgroup of the oxygenic photosynthetic bacteria comprised of unicellular to multicellular photosynthetic bacteria possessing chlorophyll a and carrying out oxygenic photosynthesis. Cyanobacteria are the only known organisms capable of fixing both carbon dioxide (in the presence of light) and nitrogen. Formerly called blue-green algae, cyanobacteria were traditionally treated as algae. By the late 19th century, however, it was realized that the blue-green algae were unique and lacked the traditional nucleus and
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chloroplasts of the green and other algae. The comparison of nucleotide base sequence data from 16S and 5S rRNA indicates that cyanobacteria represent a moderately deep phylogenetic unit within the gram-negative bacteria. [NIH] Cyanogen Bromide: Cyanogen bromide (CNBr). A compound used in molecular biology to digest some proteins and as a coupling reagent for phosphoroamidate or pyrophosphate internucleotide bonds in DNA duplexes. [NIH] Cyanosis: A bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cystamine: A radiation-protective agent that interferes with sulfhydryl enzymes. It may also protect against carbon tetrachloride liver damage. [NIH] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [NIH] Cystatins: A homologous group of endogenous cysteine proteinase inhibitors. Four distinct families are recognized within the cystatin superfamily: cystatin B or stefins; cystatin C or post-gamma-globulin; egg-white or chicken cystatin; and kininogen cystatin. The cystatins inhibit most Cysteine Endopeptidases of the papain type, and other peptidases which have a sulfhydryl group at the active site. [NIH] Cysteamine: A radiation-protective agent that oxidizes in air to form cystamine. It can be given intravenously or orally to treat radiation sickness. The bitartrate has been used for the oral treatment of nephropathic cystinosis. [NIH] Cysteine Endopeptidases: Endopeptidases which have a cysteine involved in the catalytic process. This group of enzymes is inactivated by sulfhydryl reagents. EC 3.4.22. [NIH] Cysteine Proteinase Inhibitors: Exogenous and endogenous compounds which inhibit cysteine endopeptidases. [NIH] Cysteine Synthase: An enzyme that catalyzes the biosynthesis of cysteine in microorganisms and plants from O-acetyl-L-serine and hydrogen sulfide. EC 4.2.99.8. [NIH] Cysteinyl: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and
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cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]
Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Defensins: Family of antimicrobial peptides that have been identified in humans, animals, and plants. They are thought to play a role in host defenses against infections, inflammation, wound repair, and acquired immunity. Based on the disulfide pairing of their characteristic six cysteine residues, they are divided into alpha-defensins and beta-defensins. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of
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sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demethylation: Process that releases substantial amounts of carbon dioxide in the liver. [NIH]
Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]
Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Depreciation: Decline in value of capital assets of a permanent or fixed nature over time with use. [NIH] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermatosis: Any skin disease, especially one not characterized by inflammation. [EU] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desquamation: The shedding of epithelial elements, chiefly of the skin, in scales or small sheets; exfoliation. [EU] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina
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and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diacylglycerol Kinase: An enzyme of the transferase class that uses ATP to catalyze the phosphorylation of diacylglycerol to a phosphatidate. EC 2.7.1.107. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU] Dichlorvos: An organophosphorus insecticide that inhibits acetylcholinesterase. [NIH] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]
Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Digitalis: A genus of toxic herbaceous Eurasian plants of the Scrophulaceae which yield cardiotonic glycosides. The most useful are Digitalis lanata and D. purpurea. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Dimethyl Sulfoxide: A highly polar organic liquid, that is used widely as a chemical solvent. Because of its ability to penetrate biological membranes, it is used as a vehicle for topical application of pharmaceuticals. It is also used to protect tissue during cryopreservation. Dimethyl sulfoxide shows a range of pharmacological activity including analgesia and anti-inflammation. [NIH] Dipeptidases: Exopeptidases that specifically act on dipeptides. EC 3.4.13. [NIH] Dipeptides: Peptides composed of two amino acid units. [NIH] Dipeptidyl Peptidases: Enzymes which cleave dipeptides from the amino terminal of a polypeptide. Dipeptidyl peptidase I, II, III, IV are known. They hydrolyze the betanaphthylamides of glycine-arginine, lysine-alanine, arginine-arginine and glycine-proline, respectively. Dipeptidyl peptidase I is cathepsin C. EC 3.4.14.-. [NIH]
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Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Disulphides: A covalent bridge formed by the oxidation of two cysteine residues to a cystine residue. The-S-S-bond is very strong and its presence confers additional stability. [NIH]
Dithiothreitol: A reagent commonly used in biochemical studies as a protective agent to prevent the oxidation of SH (thiol) groups and for reducing disulphides to dithiols. [NIH] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of single-stranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH]
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Doxycycline: A synthetic tetracycline derivative with a range of antimicrobial activity and mode of action similar to that of tetracycline, but more effective against many species. Animal studies suggest that it may cause less tooth staining than other tetracyclines. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Costs: The amount that a health care institution or organization pays for its drugs. It is one component of the final price that is charged to the consumer (fees, pharmaceutical or prescription fees). [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysentery: Any of various disorders marked by inflammation of the intestines, especially of the colon, and attended by pain in the abdomen, tenesmus, and frequent stools containing blood and mucus. Causes include chemical irritants, bacteria, protozoa, or parasitic worms. [EU]
Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles and glands. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU]
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Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]
Electroplating: Coating with a metal or alloy by electrolysis. [NIH] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Emulsions: Colloids of two immiscible liquids where either phase may be either fatty or aqueous; lipid-in-water emulsions are usually liquid, like milk or lotion and water-in-lipid emulsions tend to be creams. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endorphin: Opioid peptides derived from beta-lipotropin. Endorphin is the most potent naturally occurring analgesic agent. It is present in pituitary, brain, and peripheral tissues. [NIH]
Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium,
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lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enkephalin: A natural opiate painkiller, in the hypothalamus. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]
Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Precursors: Physiologically inactive substances that can be converted to active enzymes. [NIH] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum
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epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelial ovarian cancer: Cancer that occurs in the cells lining the ovaries. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erythrocyte Membrane: The semipermeable outer portion of the red corpuscle. It is known as a 'ghost' after hemolysis. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Esterification: The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]
Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Eukaryote: An organism (or a cell) that carries its genetic material physically constrained within a nuclear membrane, separate from the cytoplasm. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a
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peripheral sense organ. [NIH] Excipient: Any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; a vehicle. [EU] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excitotoxicity: Excessive exposure to glutamate or related compounds can kill brain neurons, presumably by overstimulating them. [NIH] Exfoliation: A falling off in scales or layers. [EU] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Exopeptidases: A sub-subclass of peptide hydrolases that act only near the ends of polypeptide chains. Exopeptidases are further divided into aminopeptidases, EC 3.4.11; dipeptidases, EC 3.4.13; dipeptidyl peptidases & tripeptidyl peptidases, EC 3.4.14; peptidyldipeptidases, EC 3.4.15; carboxypeptidases, EC 3.4.16 - EC 3.4.18, and omega peptidases, EC 3.4.19. EC 3.4.-. [NIH] Exotoxin: Toxic substance excreted by living bacterial cells. [NIH] Expander: Any of several colloidal substances of high molecular weight. used as a blood or plasma substitute in transfusion for increasing the volume of the circulating blood. called also extender. [NIH] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extender: Any of several colloidal substances of high molecular weight, used as a blood or plasma substitute in transfusion for increasing the volume of the circulating blood. [NIH] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of
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Cysteine
macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Facial: Of or pertaining to the face. [EU] Facial Nerve: The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. [NIH] Factor V: Heat- and storage-labile plasma glycoprotein which accelerates the conversion of prothrombin to thrombin in blood coagulation. Factor V accomplishes this by forming a complex with factor Xa, phospholipid, and calcium (prothrombinase complex). Deficiency of factor V leads to Owren's disease. [NIH] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Farnesyl: Enzyme which adds 15 carbon atoms to the Ras precursor protein. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]
Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fees, Pharmaceutical: Amounts charged to the patient or third-party payer for medication. It includes the pharmacist's professional fee and cost of ingredients, containers, etc. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fertilizers: Substances or mixtures that are added to the soil to supply nutrients or to make available nutrients already present in the soil, in order to increase plant growth and productivity. [NIH] Fetal Membranes: Thin layers of tissue which surround the embryo or fetus and provide for its nutrition, respiration, excretion and protection; they are the yolk sac, allantois, amnion, and chorion. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH]
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Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filariasis: Infections with nematodes of the superfamily Filarioidea. The presence of living worms in the body is mainly asymptomatic but the death of adult worms leads to granulomatous inflammation and permanent fibrosis. Organisms of the genus Elaeophora infect wild elk and domestic sheep causing ischaemic necrosis of the brain, blindness, and dermatosis of the face. [NIH] Filarioidea: A superfamily of nematodes of the suborder Spirurina. Its organisms possess a filiform body and a mouth surrounded by papillae. [NIH] Flatus: Gas passed through the rectum. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescence Polarization: Measurement of the polarization of fluorescent light from solutions or microscopic specimens. It is used to provide information concerning molecular size, shape, and conformation, molecular anisotropy, electronic energy transfer, molecular interaction, including dye and coenzyme binding, and the antigen-antibody reaction. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Focal Adhesions: An anchoring junction of the cell to a non-cellular substrate. It is composed of a specialized area of the plasma membrane where bundles of microfilaments terminate and attach to the transmembrane linkers, integrins, which in turn attach through their extracellular domains to extracellular matrix proteins. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers
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other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fucose: Deoxysugar. [NIH] Fucosyltransferases: Enzymes catalyzing the transfer of fucose from a nucleoside diphosphate fucose to an acceptor molecule which is frequently another carbohydrate, a glycoprotein, or a glycolipid molecule. Elevated activity of some fucosyltransferases in human serum may serve as an indicator of malignancy. The class includes EC 2.4.1.65; EC 2.4.1.68; EC 2.4.1.69; EC 2.4.1.89. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] GABA: The most common inhibitory neurotransmitter in the central nervous system. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid.
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[NIH]
Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Expression Regulation: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action at the level of transcription or translation. These processes include gene activation and genetic induction. [NIH]
Gene Fusion: Fusion of structural genes to analyze protein behavior or fusion of regulatory sequences with structural genes to determine mechanisms of regulation. [NIH] Gene Rearrangement: The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development. [NIH] Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetic transcription: The process by which the genetic information encoded in the gene, represented as a linear sequence of deoxyribonucleotides, is copied into an exactly complementary sequence of ribonucleotides known as messenger RNA. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase
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arrest in human and murine cell lines. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ cell tumors: Tumors that begin in the cells that give rise to sperm or eggs. They can occur virtually anywhere in the body and can be either benign or malignant. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germinal Center: The activated center of a lymphoid follicle in secondary lymphoid tissue where B-lymphocytes are stimulated by antigens and helper T cells (T-lymphocytes, helperinducer) are stimulated to generate memory cells. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Ginkgo biloba: Exclusive species of the genus Ginkgo, family Ginkgoacea. It produces extracts of medicinal interest. Ginkgo may refer to the genus or species. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Gliosis: The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glottis: The vocal apparatus of the larynx, consisting of the true vocal cords (plica vocalis) and the opening between them (rima glottidis). [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamate Decarboxylase: A pyridoxal-phosphate protein that catalyzes the alphadecarboxylation of L-glutamic acid to form gamma-aminobutyric acid and carbon dioxide. The enzyme is found in bacteria and in invertebrate and vertebrate nervous systems. It is the rate-limiting enzyme in determining gaba levels in normal nervous tissues. The brain enzyme also acts on L-cysteate, L-cysteine sulfinate, and L-aspartate. EC 4.1.1.15. [NIH] Glutamate-Cysteine Ligase: One of the enzymes active in the gamma-glutamyl cycle. It
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catalyzes the synthesis of gamma-glutamylcysteine from glutamate and cysteine in the presence of ATP with the formation of ADP and orthophosphate. EC 6.3.2.2. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]
Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycols: A generic grouping for dihydric alcohols with the hydroxy groups (-OH) located on different carbon atoms. They are viscous liquids with high boiling points for their molecular weights. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gold Compounds: Inorganic compounds that contain gold as an integral part of the molecule. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]
GP41: 41-kD HIV transmembrane envelope glycoprotein which mediates the fusion of the viral membrane with the membrane of the target cell. [NIH] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a
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Cysteine
microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Health Policy: Decisions, usually developed by government policymakers, for determining present and future objectives pertaining to the health care system. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH]
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Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hematopoietic growth factors: A group of proteins that cause blood cells to grow and mature. [NIH] Hematopoietic tissue: Tissue in which new blood cells are formed. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemocytes: Any blood or formed element especially in invertebrates. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH] Hemoglobin C: A commonly occurring abnormal hemoglobin in which lysine replaces a glutamic acid residue at the sixth position of the beta chains. It results in reduced plasticity of erythrocytes. [NIH] Hemoglobin E: An abnormal hemoglobin that results from the substitution of lysine for glutamic acid at position 26 of the beta chain. It is most frequently observed in southeast Asian populations. [NIH] Hemoglobin M: A group of abnormal hemoglobins in which amino acid substitutions take place in either the alpha or beta chains but near the heme iron. This results in facilitated oxidation of the hemoglobin to yield excess methemoglobin which leads to cyanosis. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular
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Cysteine
weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Heparin-binding: Protein that stimulates the proliferation of endothelial cells. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis B: Hepatitis caused by hepatitis B virus. It may be transmitted by transfusion of contaminated blood or blood products. [NIH] Hepatoblastoma: A type of liver tumor that occurs in infants and children. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocyte: A liver cell. [NIH] Hepatoma: A liver tumor. [NIH] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histamine Release: The secretion of histamine from mast cell and basophil granules by exocytosis. This can be initiated by a number of factors, all of which involve binding of IgE, cross-linked by antigen, to the mast cell or basophil's Fc receptors. Once released, histamine binds to a number of different target cell receptors and exerts a wide variety of effects. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]
Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hookworms: A parasitic infection that may affect workers exposed to warm moist soil in
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which the larvae of the worm lives. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hydration: Combining with water. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]
Hydrogen Cyanide: HCN. A toxic liquid or colorless gas. It is found in the smoke of various tobacco products and released by combustion of nitrogen-containing organic materials. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrogenation: Specific method of reduction in which hydrogen is added to a substance by the direct use of gaseous hydrogen. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxides: Inorganic compounds that contain the OH- group. [NIH] Hydroxyl Radical: The univalent radical OH that is present in hydroxides, alcohols, phenols, glycols. [NIH] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH]
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Cysteine
Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Hyperbaric oxygen: Oxygen that is at an atmospheric pressure higher than the pressure at sea level. Breathing hyperbaric oxygen to enhance the effectiveness of radiation therapy is being studied. [NIH] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [NIH] Hyperkeratosis: 1. Hypertrophy of the corneous layer of the skin. 2a. Any of various conditions marked by hyperkeratosis. 2b. A disease of cattle marked by thickening and wringling of the hide and formation of papillary outgrowths on the buccal mucous membranes, often accompanied by watery discharge from eyes and nose, diarrhoea, loss of condition, and abortion of pregnant animals, and now believed to result from ingestion of the chlorinated naphthalene of various lubricating oils. [EU] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hyperoxia: An abnormal increase in the amount of oxygen in the tissues and organs. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Ibotenic Acid: Neurotoxic isoxazole substance found in Amanita muscaria and A. pantherina. It causes motor depression, ataxia, and changes in mood, perceptions and feelings, and is a potent excitatory amino acid agonist. [NIH] Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immersion: The placing of a body or a part thereof into a liquid. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH]
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Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunoconjugates: Combinations of diagnostic or therapeutic substances linked with specific immune substances such as immunoglobulins, monoclonal antibodies or antigens. Often the diagnostic or therapeutic substance is a radionuclide. These conjugates are useful tools for specific targeting of drugs and radioisotopes in the chemotherapy and radioimmunotherapy of certain cancers. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogen: A substance that is capable of causing antibody formation. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunotoxins: Semisynthetic conjugates of various toxic molecules, including radioactive isotopes and bacterial or plant toxins, with specific immune substances such as immunoglobulins, monoclonal antibodies, and antigens. The antitumor or antiviral immune substance carries the toxin to the tumor or infected cell where the toxin exerts its poisonous effect. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH]
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In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Incubation period: The period of time likely to elapse between exposure to the agent of the disease and the onset of clinical symptoms. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Infectious Diarrhea: Diarrhea caused by infection from bacteria, viruses, or parasites. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]
Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU]
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Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Integrase: An enzyme that inserts DNA into the host genome. It is encoded by the pol gene of retroviruses and also by temperate bacteriophages, the best known being bacteriophage lambda. EC 2.7.7.-. [NIH] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interindividual: Occurring between two or more individuals. [EU] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-12: A heterodimeric cytokine that stimulates the production of interferon gamma from T-cells and natural killer cells, and also induces differentiation of Th1 helper cells. It is an initiator of cell-mediated immunity. [NIH] Interleukin-18: Cytokine which resembles IL-1 structurally and IL-12 functionally. It enhances the cytotoxic activity of NK cells and CTLs, and appears to play a role both as
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neuroimmunomodulator and in the induction of mucosal immunity. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intraepithelial: Within the layer of cells that form the surface or lining of an organ. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Exchange: Reversible chemical reaction between a solid, often an ION exchange resin, and a fluid whereby ions may be exchanged from one substance to another. This technique is used in water purification, in research, and in industry. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from
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the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iron Chelating Agents: Organic chemicals that form two or more coordination links with an iron ion. Once coordination has occurred, the complex formed is called a chelate. The ironbinding porphyrin group of hemoglobin is an example of a metal chelate found in biological systems. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Irritants: Drugs that act locally on cutaneous or mucosal surfaces to produce inflammation; those that cause redness due to hyperemia are rubefacients; those that raise blisters are vesicants and those that penetrate sebaceous glands and cause abscesses are pustulants; tear gases and mustard gases are also irritants. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isocitrate Lyase: A key enzyme in the glyoxylate cycle. It catalyzes the conversion of isocitrate to succinate and glyoxylate. EC 4.1.3.1. [NIH] Isoleucine: An essential branched-chain amino acid found in many proteins. It is an isomer of LEUCINE. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] Ivermectin: A mixture of ivermectin component B1a (RN 71827-03-7) and B1b (RN 70209-813), which is a semisynthetic product from Streptomyces avermitilis. A potent macrocyclic lactone disaccharide antiparasitic agent used to prevent and treat parasite infestations in animals. The compound has activity against internal and external parasites and has been found effective against arthropods, insects, nematodes, filarioidea, platyhelminths, and protozoa. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [NIH]
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Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kinetic: Pertaining to or producing motion. [EU] Kininogens: Endogenous peptides present in most body fluids. Certain enzymes convert them to active kinins which are involved in inflammation, blood clotting, complement reactions, etc. Kininogens belong to the cystatin superfamily. They are cysteine proteinase inhibitors. High-molecular-weight kininogen (HMWK) is split by plasma kallikrein to produce bradykinin. low-molecular-weight kininogen (LMWK) is split by tissue kallikrein to produce kallidin. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] LCD: Low-calorie diet. Caloric restriction of about 800 to 1,500 calories (approximately 12 to 15 kcal/kg of body weight) per day. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Leishmaniasis: A disease caused by any of a number of species of protozoa in the genus Leishmania. There are four major clinical types of this infection: cutaneous (Old and New World), diffuse cutaneous, mucocutaneous, and visceral leishmaniasis. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH]
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Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lipoprotein Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. The enzyme hydrolyzes triacylglycerols in chylomicrons, very-low-density lipoproteins, low-density lipoproteins, and diacylglycerols. It occurs on capillary endothelial surfaces, especially in mammary, muscle, and adipose tissue. Genetic deficiency of the enzyme causes familial hyperlipoproteinemia Type I. (Dorland, 27th ed) EC 3.1.1.34. [NIH] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number
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3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]
Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Mitochondria: Yellow discoloration of the liver due to fatty degeneration of liver parenchymal cells; the cause may be chemical poisoning. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Luminescence: The property of giving off light without emitting a corresponding degree of heat. It includes the luminescence of inorganic matter or the bioluminescence of human matter, invertebrates and other living organisms. For the luminescence of bacteria, bacterial luminescence is available. [NIH] Lyases: A class of enzymes that catalyze the cleavage of C-C, C-O, and C-N, and other bonds by other means than by hydrolysis or oxidation. (Enzyme Nomenclature, 1992) EC 4. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]
Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH]
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Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Malondialdehyde: The dialdehyde of malonic acid. [NIH] Mammary: Pertaining to the mamma, or breast. [EU] Manic: Affected with mania. [EU] Mannans: Polysaccharides consisting of mannose units. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in
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wound healing, angiogenesis, and tumor cell metastasis. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]
Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melanosis: Disorders of increased melanin pigmentation that develop without preceding inflammatory disease. [NIH] Melanosomes: Melanin-containing organelles found in melanocytes and melanophores. [NIH]
Memantine: Amantadine derivative that has some dopaminergic effects. It has been proposed as an antiparkinson agent. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Fusion: The adherence of cell membranes, intracellular membranes, or artifical membrane models of either to each other or to viruses, parasites, or interstitial particles through a variety of chemical and physical processes. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH]
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Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mercaptopropionylglycine: Sulfhydryl acylated derivative of glycine used in treatment of liver diseases, as a detoxicant and in therapy of myopia. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesna: A sulfhydryl compound used to prevent urothelial toxicity by inactivating metabolites from antineoplastic agents, such as ifosfamide or cyclophosphamide. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Methionine Adenosyltransferase: An enzyme that catalyzes the synthesis of Sadenosylmethionine from methionine and ATP. EC 2.5.1.6. [NIH] Micelles: Electrically charged colloidal particles or ions consisting of oriented molecules; aggregates of a number of molecules held loosely together by secondary bonds. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microfilaments: The smallest of the cytoskeletal filaments. They are composed chiefly of actin. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH]
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Milligram: A measure of weight. A milligram is approximately 450,000-times smaller than a pound and 28,000-times smaller than an ounce. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular mass: The sum of the atomic masses of all atoms in a molecule, based on a scale in which the atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16, respectively. For example, the molecular mass of water, which has two atoms of hydrogen and one atom of oxygen, is 18 (i.e., 2 + 16). [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Molting: Casting off feathers, hair, or cuticle. Molting is a process of sloughing or desquamation, especially the shedding of an outer covering and the development of a new one. This phenomenon permits growth in arthropods, skin renewal in amphibians and reptiles, and the shedding of winter coats in birds and mammals. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoamine: Enzyme that breaks down dopamine in the astrocytes and microglia. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH]
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Mononuclear: A cell with one nucleus. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]
Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motor Neurons: Neurons which activate muscle cells. [NIH] Mucocutaneous: Pertaining to or affecting the mucous membrane and the skin. [EU] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscle Relaxation: That phase of a muscle twitch during which a muscle returns to a resting position. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mycobacterium: A genus of gram-positive, aerobic bacteria. Most species are free-living in soil and water, but the major habitat for some is the diseased tissue of warm-blooded hosts. [NIH]
Mycobacterium tuberculosis: A species of gram-positive, aerobic bacteria that produces tuberculosis in man, other primates, dogs, and some animals which have contact with man. Growth tends to be in serpentine, cordlike masses in which the bacilli show a parallel orientation. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result
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in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]
Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myopia: That error of refraction in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina, as a result of the eyeball being too long from front to back (axial m.) or of an increased strength in refractive power of the media of the eye (index m.). Called also nearsightedness, because the near point is less distant than it is in emmetropia with an equal amplitude of accommodation. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonia: Prolonged failure of muscle relaxation after contraction. This may occur after voluntary contractions, muscle percussion, or electrical stimulation of the muscle. Myotonia is a characteristic feature of myotonic disorders. [NIH] Myristate: Pharmacological activator of protein kinase C. [NIH] N-acetyl: Analgesic agent. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Natural killer cells: NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH]
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Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephron: A tiny part of the kidneys. Each kidney is made up of about 1 million nephrons, which are the working units of the kidneys, removing wastes and extra fluids from the blood. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrotoxic: Toxic or destructive to kidney cells. [EU] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural Pathways: Neural tracts connecting one part of the nervous system with another. [NIH]
Neuraminidase: An enzyme that catalyzes the hydrolysis of alpha-2,3, alpha-2,6-, and alpha-2,8-glycosidic linkages (at a decreasing rate, respectively) of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrate. (From Enzyme Nomenclature, 1992) EC 3.2.1.18. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neuroglia: The non-neuronal cells of the nervous system. They are divided into macroglia (astrocytes, oligodendroglia, and schwann cells) and microglia. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular milieu, participate in the blood-brain and blood-retina barriers, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitters, but their role in signaling (as in many other functions) is unclear. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord.
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Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]
Neurotoxin: A substance that is poisonous to nerve tissue. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophil: A type of white blood cell. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nifurtimox: Possibly effective against parasites. Synonyms: Lampit; Bayer 2502. [NIH] Nimodipine: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure. [NIH] Nisin: A 34-amino acid polypeptide antibiotic produced by Streptococcus lactis. It has been used as a food preservative in canned fruits and vegetables, and cheese. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]
Nitriles: Organic compounds containing the -CN radical. The concept is distinguished from cyanides, which denotes inorganic salts of hydrogen cyanide. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nitrogen Dioxide: Nitrogen oxide (NO2). A highly poisonous gas. Exposure produces
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inflammation of lungs that may only cause slight pain or pass unnoticed, but resulting edema several days later may cause death. (From Merck, 11th ed) It is a major atmospheric pollutant that is able to absorb UV light that does not reach the earth's surface. [NIH] Nitrogenase: An enzyme system that catalyzes the fixing of nitrogen in soil bacteria and blue-green algae (cyanobacteria). EC 1.18.6.1. [NIH] Nitrosamines: A class of compounds that contain a -NH2 and a -NO radical. Many members of this group have carcinogenic and mutagenic properties. [NIH] Nitrosation: Conversion into nitroso compounds. An example is the reaction of nitrites with amino compounds to form carcinogenic N-nitrosamines. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Oligopeptides: Peptides composed of between two and twelve amino acids. [NIH] Onchocerciasis: Infection with nematodes of the genus Onchocerca. Characteristics include the presence of firm subcutaneous nodules filled with adult worms, pruritus, and ocular lesions. [NIH] Oncogenes: Genes which can potentially induce neoplastic transformation. They include genes for growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. When these genes are constitutively expressed after structural and/or regulatory changes, uncontrolled cell proliferation may result. Viral oncogenes have prefix "v-" before the gene symbol; cellular oncogenes (protooncogenes) have the prefix "c-" before the gene symbol. [NIH] On-line: A sexually-reproducing population derived from a common parentage. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU]
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Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [NIH]
Orbit: One of the two cavities in the skull which contains an eyeball. Each eye is located in a bony socket or orbit. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Orthopoxvirus: A genus of the family Poxviridae, subfamily Chordopoxvirninae, comprising many species infecting mammals. Viruses of this genus cause generalized infections and a rash in some hosts. The type species is Vaccinia virus. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Ouabain: A cardioactive glycoside consisting of rhamnose and ouabagenin, obtained from the seeds of Strophanthus gratus and other plants of the Apocynaceae; used like digitalis. It is commonly used in cell biological studies as an inhibitor of the NA(+)-K(+)-exchanging atpase. [NIH] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous
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antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]
Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH] Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Papain: A proteolytic enzyme obtained from Carica papaya. It is also the name used for a purified mixture of papain and chymopapain that is used as a topical enzymatic debriding
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agent. EC 3.4.22.2. [NIH] Papillary: Pertaining to or resembling papilla, or nipple. [EU] Papilloma: A benign epithelial neoplasm which may arise from the skin, mucous membranes or glandular ducts. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Paramyxovirus: A genus of the family Paramyxoviridae (subfamily Paramyxovirinae) where all the virions have both hemagglutinin and neuraminidase activities and encode a C protein. Human parainfluenza virus 1 is the type species. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parenteral Nutrition: The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). [NIH] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Pelvic: Pertaining to the pelvis. [EU] Penicillamine: 3-Mercapto-D-valine. The most characteristic degradation product of the penicillin antibiotics. It is used as an antirheumatic and as a chelating agent in Wilson's disease. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penile Erection: The state of the penis when the erectile tissue becomes filled with blood and causes the penis to become rigid and elevated. [NIH]
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Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Fragments: Partial proteins formed by partial hydrolysis of complete proteins. [NIH] Peptide Hydrolases: A subclass of enzymes from the hydrolase class that catalyze the hydrolysis of peptide bonds. Exopeptidases and endopeptidases make up the sub-subclasses for this group. EC 3.4. [NIH] Peptide Mapping: Analysis of peptides generated from the digestion of a protein by a specific protease for the purpose of indentifing the protein or to look for polymorphisms. [NIH]
Perforation: 1. The act of boring or piercing through a part. 2. A hole made through a part or substance. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodicity: The tendency of a phenomenon to recur at regular intervals; in biological systems, the recurrence of certain activities (including hormonal, cellular, neural) may be annual, seasonal, monthly, daily, or more frequently (ultradian). [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]
Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Periplasm: The space between the inner and outer membranes of a cell that is shared with the cell wall. [NIH] Peristalsis: The rippling motion of muscles in the intestine or other tubular organs characterized by the alternate contraction and relaxation of the muscles that propel the contents onward. [NIH] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [EU] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and
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peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Peroxisome Proliferators: A class of nongenotoxic carcinogens that induce the production of hepatic peroxisomes and induce hepatic neoplasms after long-term administration. [NIH] Pertussis: An acute, highly contagious infection of the respiratory tract, most frequently affecting young children, usually caused by Bordetella pertussis; a similar illness has been associated with infection by B. parapertussis and B. bronchiseptica. It is characterized by a catarrhal stage, beginning after an incubation period of about two weeks, with slight fever, sneezing, running at the nose, and a dry cough. In a week or two the paroxysmal stage begins, with the characteristic paroxysmal cough, consisting of a deep inspiration, followed by a series of quick, short coughs, continuing until the air is expelled from the lungs; the close of the paroxysm is marked by a long-drawn, shrill, whooping inspiration, due to spasmodic closure of the glottis. This stage lasts three to four weeks, after which the convalescent stage begins, in which paroxysms grow less frequent and less violent, and finally cease. Called also whooping cough. [EU] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for
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the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Phosphotyrosine: An amino acid that occurs in endogenous proteins. Tyrosine phosphorylation and dephosphorylation plays a role in cellular signal transduction and possibly in cell growth control and carcinogenesis. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Physical Therapy: The restoration of function and the prevention of disability following disease or injury with the use of light, heat, cold, water, electricity, ultrasound, and exercise. [NIH]
Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Physostigmine: A cholinesterase inhibitor that is rapidly absorbed through membranes. It can be applied topically to the conjunctiva. It also can cross the blood-brain barrier and is used when central nervous system effects are desired, as in the treatment of severe anticholinergic toxicity. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH]
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Plasma expander: Artificial plasma extender. [EU] Plasma Kallikrein: A peptidohydrolytic enzyme that is formed from prekallikrein by factor XIIA. It activates factor XII, factor VII, and plasminogen. It is selective for both arginine and to a lesser extent lysinebonds. EC 3.4.21.34. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Plasmodium: A genus of coccidian protozoa that comprise the malaria parasites of mammals. Four species infect humans (although occasional infections with primate malarias may occur). These are Plasmodium falciparum, Plasmodium malariae, P. ovale, and Plasmodium vivax. Species causing infection in vertebrates other than man include: Plasmodium berghei, Plasmodium chabaudi, P. vinckei, and Plasmodium yoelii in rodents; P. brasilianum, Plasmodium cynomolgi, and Plasmodium knowlesi in monkeys; and Plasmodium gallinaceum in chickens. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platyhelminths: A phylum of acoelomate, bilaterally symmetrical flatworms, without a definite anus. It includes three classes: Cestoda, Turbellaria, and Trematoda. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This
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results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Pollen: The male fertilizing element of flowering plants analogous to sperm in animals. It is released from the anthers as yellow dust, to be carried by insect or other vectors, including wind, to the ovary (stigma) of other flowers to produce the embryo enclosed by the seed. The pollens of many plants are allergenic. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polycystic Ovary Syndrome: Clinical symptom complex characterized by oligomenorrhea or amenorrhea, anovulation, and regularly associated with bilateral polycystic ovaries. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]
Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH]
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Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Precipitation: The act or process of precipitating. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [NIH] Prescription Fees: The charge levied on the consumer for drugs or therapy prescribed under written order of a physician or other health professional. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proinsulin: The substance made first in the pancreas that is then made into insulin. When insulin is purified from the pancreas of pork or beef, all the proinsulin is not fully removed. When some people use these insulins, the proinsulin can cause the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin is injected. The purified insulins have less proinsulin and other impurities than the other types of insulins. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH]
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Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proprioception: The mechanism involved in the self-regulation of posture and movement through stimuli originating in the receptors imbedded in the joints, tendons, muscles, and labyrinth. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Folding: A rapid biochemical reaction involved in the formation of proteins. It begins even before a protein has been completely synthesized and proceeds through discrete intermediates (primary, secondary, and tertiary structures) before the final structure (quaternary structure) is developed. [NIH] Protein Isoforms: Different forms of a protein that may be produced from different genes, or from the same gene by alternative splicing. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Protein Subunits: Single chains of amino acids that are the units of a multimeric protein. They can be identical or non-identical subunits. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH]
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Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [NIH]
Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]
Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Proxy: A person authorized to decide or act for another person, for example, a person having durable power of attorney. [NIH] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
Pulmonary: Relating to the lungs. [NIH]
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Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Purified Insulins: Insulins with much less of the impure proinsulin. It is thought that the use of purified insulins may help avoid or reduce some of the problems of people with diabetes such as allergic reactions. [NIH] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyridoxal Phosphate: 3-Hydroxy-2-methyl-5-((phosphonooxy)methyl)-4pyridinecarboxaldehyde. An enzyme co-factor vitamin. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Pyrogenic: Inducing fever. [EU] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quiescent: Marked by a state of inactivity or repose. [EU] Quinidine: An optical isomer of quinine, extracted from the bark of the Cinchona tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular action potential, and decreases automaticity. Quinidine also blocks muscarinic and alphaadrenergic neurotransmission. [NIH] Quinine: An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Quinine is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Quinine is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive
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substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombinant Proteins: Proteins prepared by recombinant DNA technology. [NIH] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor
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cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Reentry: Reexcitation caused by continuous propagation of the same impulse for one or more cycles. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU]
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Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Rhamnose: A methylpentose whose L- isomer is found naturally in many plant glycosides and some gram-negative bacterial lipopolysaccharides. [NIH] Rheology: The study of the deformation and flow of matter, usually liquids or fluids, and of the plastic flow of solids. The concept covers consistency, dilatancy, liquefaction, resistance to flow, shearing, thixotrophy, and viscosity. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rotenone: A botanical insecticide that is an inhibitor of mitochondrial electron transport. [NIH]
Saccule: The smaller of the 2 sacs within the vestibule of the ear. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH]
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Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Schizogony: Reproduction by fission. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Sebaceous gland: Gland that secretes sebum. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Selenocysteine: A naturally occurring amino acid in both eukaryotic and prokaryotic organisms. It is found in tRNAs and in the catalytic site of some enzymes. The genes for glutathione peroxidase and formate dehydrogenase contain the TGA codon, which codes for this amino acid. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs
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discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septal Nuclei: Neural nuclei situated in the septal region. They have afferent and cholinergic efferent connections with a variety of forebrain and brainstem areas including the hippocampus, the lateral hypothalamus, the tegmentum, and the amygdala. Included are the dorsal, lateral, medial, and triangular septal nuclei, septofimbrial nucleus, nucleus of diagonal band, nucleus of anterior commissure, and the nucleus of stria terminalis. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Shunt: A surgically created diversion of fluid (e.g., blood or cerebrospinal fluid) from one area of the body to another area of the body. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter)
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is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smallpox: A generalized virus infection with a vesicular rash. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solium: Tapeworm of the genus Taenia. The adult form is found in the small intestine of humans and some apes and the metacestode (Cysticercus cellulosae) in the skeletal and cardiac muscle of pigs and in the brain of humans. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Sorbitol: A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. [NIH]
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Soybean Oil: Oil from soybean or soybean plant. [NIH] Spasmodic: Of the nature of a spasm. [EU] Spasmogenic: Capable of producing convulsions. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrophotometry: The art or process of comparing photometrically the relative intensities of the light in different parts of the spectrum. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Sperm Head: The anterior, usually ovoid, nucleus-containing part of spermatozoa. [NIH] Sperm Maturation: Posttesticular ripening of spermatozoa. [NIH] Spermatids: Male germ cells derived from spermatocytes and developing into spermatozoa. [NIH]
Spermatocytes: Male germ cells derived from spermatogonia and developing into spermatids. [NIH] Spermatogenesis: Process of formation and development of spermatozoa, including spermatocytogenesis and spermiogenesis. [NIH] Spermatozoa: Mature male germ cells that develop in the seminiferous tubules of the testes. Each consists of a head, a body, and a tail that provides propulsion. The head consists mainly of chromatin. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sporozoite: In the sporozoa the product of schizogony of the zygote. [NIH] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and
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digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [NIH] Stabilization: The creation of a stable state. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stellate: Star shaped. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stomatitis: Inflammation of the oral mucosa, due to local or systemic factors which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. [EU]
Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptococcal: Caused by infection due to any species of streptococcus. [NIH] Streptococci: A genus of spherical Gram-positive bacteria occurring in chains or pairs. They are widely distributed in nature, being important pathogens but often found as normal commensals in the mouth, skin, and intestine of humans and other animals. [NIH] Streptococcus: A genus of gram-positive, coccoid bacteria whose organisms occur in pairs or chains. No endospores are produced. Many species exist as commensals or parasites on man or animals with some being highly pathogenic. A few species are saprophytes and occur in the natural environment. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stria: 1. A streak, or line. 2. A narrow bandlike structure; a general term for such longitudinal collections of nerve fibres in the brain. [EU] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH]
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Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Submandibular: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [NIH]
Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [NIH]
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Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Syncytium: A living nucleated tissue without apparent cellular structure; a tissue composed of a mass of nucleated protoplasm without cell boundaries. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Tenesmus: Straining, especially ineffectual and painful straining at stool or in urination. [EU] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terminalis: A groove on the lateral surface of the right atrium. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and
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the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetrachloroethylene: A chlorinated hyrocarbon used as an industrial solvent and cooling liquid in electrical transformers. Chronic exposure to this compoud may pose a health hazard to animals and humans. It is considered a potential carcinogen. Tetrachlorethylene was formerly used as anthelmintic for hookworms, but less toxic products are now used. [NIH]
Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Tetrahydrocannabinol: A psychoactive compound extracted from the resin of Cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (THC) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound. Dronabinol is a synthetic form of delta-9-THC. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thioredoxin: A hydrogen-carrying protein that participates in a variety of biochemical reactions including ribonucleotide reduction. Thioredoxin is oxidized from a dithiol to a disulfide during ribonucleotide reduction. The disulfide form is then reduced by NADPH in a reaction catalyzed by thioredoxin reductase. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation,
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contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thylakoids: Membranous cisternae of the chloroplast containing photosynthetic pigments, reaction centers, and the electron-transport chain. Each thylakoid consists of a flattened sac of membrane enclosing a narrow intra-thylakoid space (Lackie and Dow, Dictionary of Cell Biology, 2nd ed). Individual thylakoids are interconnected and tend to stack to form aggregates called grana. They are found in cyanobacteria and all plants. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]
Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. [NIH] Thymidylate Synthase: An enzyme of the transferase class that catalyzes the reaction 5,10methylenetetrahydrofolate and dUMP to dihydrofolate and dTMP in the synthesis of thymidine triphosphate. (From Dorland, 27th ed) EC 2.1.1.45. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tick Control: Chemical, biological, or medical measures designed to prevent the spread of ticks or the concomitant infestations which result in tick-borne diseases. It includes the veterinary as well as the public health aspects of tick and mite control. [NIH] Tick-Borne Diseases: Bacterial, viral, or parasitic diseases transmitted to humans and animals by the bite of infected ticks. The families Ixodidae and Argasidae contain many bloodsucking species that are important pests of man and domestic birds and mammals and probably exceed all other arthropods in the number and variety of disease agents they transmit. Many of the tick-borne diseases are zoonotic. [NIH] Ticks: Blood-sucking arachnids of the order Acarina. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH]
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Cysteine
Topical: On the surface of the body. [NIH] Topotecan: An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerase. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transaminase: Aminotransferase (= a subclass of enzymes of the transferase class that catalyse the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally 2-keto acid). Most of these enzymes are pyridoxal-phosphate-proteins. [EU]
Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH]
Dictionary 315
Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocating: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [NIH] Triad: Trivalent. [NIH] Trichloroacetic Acid: A strong acid used as a protein precipitant in clinical chemistry and also as a caustic for removing warts. [NIH] Trichloroethylene: A highly volatile inhalation anesthetic used mainly in short surgical procedures where light anesthesia with good analgesia is required. It is also used as an industrial solvent. Prolonged exposure to high concentrations of the vapor can lead to cardiotoxicity and neurological impairment. [NIH] Trichomoniasis: An infection with the protozoan parasite Trichomonas vaginalis. [NIH] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]
Trophic: Of or pertaining to nutrition. [EU] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tumor model: A type of animal model which can be used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU]
316
Cysteine
Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]
Tunicamycin: An N-acetylglycosamine containing antiviral antibiotic obtained from Streptomyces lysosuperificus. It is also active against some bacteria and fungi, because it inhibits the glucosylation of proteins. Tunicamycin is used as tool in the study of microbial biosynthetic mechanisms. [NIH] Typhimurium: Microbial assay which measures his-his+ reversion by chemicals which cause base substitutions or frameshift mutations in the genome of this organism. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Univalent: Pertaining to an unpaired chromosome during the zygotene stage of prophase to first metaphase in meiosis. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]
Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urothelium: The epithelial lining of the urinary tract. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine. [NIH] Vaccinia Virus: The type species of Orthopoxvirus, related to cowpox virus, but whose true origin is unknown. It has been used as a live vaccine against smallpox. It is also used as a vector for inserting foreign DNA into animals. Rabbitpox virus is a subspecies of vaccinia
Dictionary 317
virus. [NIH] Vacuole: A fluid-filled cavity within the cytoplasm of a cell. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]
Variola: A generalized virus infection with a vesicular rash. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venter: Belly. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Remodeling: The geometric and structural changes that the ventricle undergoes, usually following myocardial infarction. It comprises expansion of the infarct and dilatation of the healthy ventricle segments. While most prevalent in the left ventricle, it can also occur in the right ventricle. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH]
318
Cysteine
Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Virion: The infective system of a virus, composed of the viral genome, a protein core, and a protein coat called a capsid, which may be naked or enclosed in a lipoprotein envelope called the peplos. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Viscotoxin: A member of a group of small proteins produced by mistletoe plants that are able to kill cells and may stimulate the immune system. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Voltage-gated: It is opened by the altered charge distribution across the cell membrane. [NIH]
Volvulus: A twisting of the stomach or large intestine. May be caused by the stomach being in the wrong position, a foreign substance, or abnormal joining of one part of the stomach or intestine to another. Volvulus can lead to blockage, perforation, peritonitis, and poor blood flow. [NIH] Wart: A raised growth on the surface of the skin or other organ. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Whooping Cough: A respiratory infection caused by Bordetella pertussis and characterized by paroxysmal coughing ending in a prolonged crowing intake of breath. [NIH] Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH]
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Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH] Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc. [NIH]
Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Yolk Sac: An embryonic membrane formed from endoderm and mesoderm. In reptiles and birds it incorporates the yolk into the digestive tract for nourishing the embryo. In placental mammals its nutritional function is vestigial; however, it is the source of most of the intestinal mucosa and the site of formation of the germ cells. It is sometimes called the vitelline sac, which should not be confused with the vitelline membrane of the egg. [NIH] Zoster: A virus infection of the Gasserian ganglion and its nerve branches, characterized by discrete areas of vesiculation of the epithelium of the forehead, the nose, the eyelids, and the cornea together with subepithelial infiltration. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
321
INDEX A Abdomen, 229, 241, 257, 260, 276, 280, 309, 318 Abdominal, 46, 86, 229, 291, 293, 316 Abdominal Pain, 229, 293, 316 Aberrant, 5, 28, 229 Abrin, 158, 229 Abscess, 229, 306 Acanthosis Nigricans, 111, 229 Acatalasia, 229, 243 Acceptor, 18, 27, 60, 229, 264, 279, 291, 313, 314 Acetaminophen, 21, 42, 132, 133, 134, 138, 229 Acetylcholine, 4, 100, 162, 229, 246, 288 Acetylcholinesterase, 116, 128, 229, 255 Acetylcysteine, 111, 124, 126, 127, 128, 131, 132, 208, 229 Acquired Immunodeficiency Syndrome, 169, 229 Acrosome, 57, 230 Acrylamide, 99, 230 Acrylonitrile, 230 Actin, 33, 230, 283, 286 Actomyosin, 33, 230 Acute lymphoblastic leukemia, 230 Acute lymphocytic leukemia, 7, 230 Acute myelogenous leukemia, 8, 230 Acute myeloid leukemia, 230 Acute nonlymphocytic leukemia, 230 Acyl, 230, 260 Adaptability, 18, 230, 244 Adaptation, 230, 285, 296 Adduct, 42, 230 Adduction, 42, 230 Adenine, 157, 230, 301 Adenocarcinoma, 190, 230, 270 Adenosine, 53, 65, 185, 230, 237, 242, 294, 312 Adenovirus, 78, 162, 167, 230 Adjuvant, 184, 231 Adrenal Glands, 231, 246 Adrenal Medulla, 231, 244, 260, 289 Adrenergic, 43, 96, 231, 256, 260, 301, 311 Adverse Effect, 231, 306 Aerobic, 20, 38, 62, 151, 231, 284, 285, 291 Aerobic Metabolism, 20, 231, 291 Aerobic Respiration, 231, 291
Afferent, 231, 262, 306 Affinity, 34, 57, 109, 173, 188, 231, 237, 287, 307 Agar, 231, 251, 295 Agonist, 4, 34, 231, 256, 272, 286, 288 Airway, 47, 161, 231 Alanine, 9, 28, 59, 78, 165, 171, 183, 231, 255 Albumin, 71, 89, 94, 231, 290, 296 Aldehyde Reductase, 4, 232 Aldose Reductase Inhibitor, 202, 232 Algorithms, 232, 240 Alimentary, 232, 292 Alkaline, 157, 232, 233, 238, 242 Alkaloid, 195, 232, 247, 288, 301, 312 Alkylate, 195, 232 Alkylating Agents, 16, 130, 232, 241, 243 Alkylation, 16, 80, 191, 232 Allantois, 232, 262 Allergen, 84, 89, 100, 110, 232 Allogeneic, 101, 232 Allografts, 162, 232 Alpha Particles, 232, 301 Alpha-1, 232, 295 Alpha-Defensins, 232, 253 Alpha-helices, 18, 232 Alternative medicine, 204, 233 Alternative Splicing, 173, 233, 299 Ameliorating, 166, 233 Amenorrhea, 233, 297 Amino Acid Motifs, 233, 250 Amino Acid Sequence, 35, 150, 152, 184, 191, 193, 198, 233, 235, 239, 250, 261, 265 Amino Acid Substitution, 62, 233, 269 Aminoethyl, 190, 233 Aminopeptidases, 233, 261 Amino-terminal, 39, 64, 104, 233 Ammonia, 27, 233, 267, 310 Amnion, 233, 262 Amphetamines, 233, 247 Amygdala, 233, 238, 306, 312 Amyloid, 5, 129, 130, 131, 234 Amyloid beta-Protein, 130, 131, 234 Amyotrophy, 162, 234 Anabaena, 124, 234 Anaerobic, 38, 151, 234 Anaesthesia, 234, 274 Anal, 11, 234
322
Cysteine
Analgesic, 229, 234, 258, 286, 301 Analog, 159, 167, 174, 192, 234, 263, 264 Analogous, 24, 57, 169, 193, 234, 297, 314 Anaphylatoxins, 19, 234, 248 Anatomical, 15, 16, 234, 255, 273, 283, 305 Anemia, 138, 234, 247, 263, 269, 281 Anesthesia, 231, 234, 315 Anesthetics, 57, 234, 260 Aneurysm, 234, 236, 317 Angiogenesis inhibitor, 187, 234 Animal model, 14, 40, 45, 47, 180, 182, 192, 235, 315 Anions, 232, 235, 277, 306, 310 Anisotropy, 235, 263 Anovulation, 235, 297 Anthelmintic, 235, 312 Anthocyanins, 183, 235 Antiarrhythmic, 12, 235 Antibacterial, 167, 235, 308 Antibiotic, 166, 174, 235, 288, 292, 308, 312, 316 Antibodies, 42, 55, 80, 82, 107, 150, 169, 185, 188, 190, 198, 235, 268, 269, 272, 273, 284, 295, 302 Antibody, 22, 24, 65, 68, 75, 76, 94, 152, 188, 189, 231, 235, 248, 249, 259, 260, 263, 268, 270, 273, 274, 277, 282, 284, 302, 308, 319 Anticholinergic, 235, 295 Anticoagulant, 235, 299 Anticonvulsants, 12, 139, 235 Antidepressant, 17, 235 Antifungal, 91, 167, 235 Antigen-Antibody Complex, 235, 248 Antigen-presenting cell, 236, 254 Anti-infective, 236, 271, 276 Anti-inflammatory, 177, 229, 236, 237, 266 Anti-Inflammatory Agents, 177, 236, 237 Antimetabolite, 236, 263 Antimicrobial, 154, 166, 174, 236, 253, 257 Antineoplastic, 49, 232, 236, 240, 252, 263, 265, 283, 291, 314 Antineoplastic Agents, 49, 232, 236, 283 Antioxidant, 13, 20, 21, 41, 62, 73, 79, 91, 124, 129, 133, 186, 236, 291 Antipyretic, 229, 236, 301 Antiviral, 60, 88, 157, 167, 188, 229, 236, 273, 275, 316 Anus, 190, 234, 236, 248, 296 Aorta, 236, 317 Aortic Aneurysm, 46, 86, 236 Aplastic anemia, 8, 236
Apolipoproteins, 18, 236, 279 Apolipoproteins E, 18, 236 Applicability, 166, 236 Aqueous, 9, 17, 30, 32, 54, 151, 158, 189, 236, 238, 244, 253, 258, 271, 278, 279 Arachidonic Acid, 28, 236, 279, 299 Arginine, 20, 63, 76, 82, 86, 87, 99, 109, 159, 167, 186, 234, 237, 255, 288, 296, 315 Arterial, 197, 237, 246, 272, 299, 311 Arteries, 162, 236, 237, 240, 241, 243, 250, 280, 285, 313 Arteriolar, 237, 241 Arterioles, 237, 241, 242, 285 Arteriosus, 237, 301 Artery, 136, 234, 237, 243, 250, 258, 286, 292, 301, 303 Articular, 237, 290 Aspartate, 16, 27, 49, 163, 237, 266 Aspartic Acid, 16, 237, 246 Aspirin, 85, 237 Assay, 24, 48, 73, 77, 83, 128, 152, 165, 237, 273, 316 Astringents, 237, 283 Astrocytes, 13, 28, 237, 266, 283, 284, 287 Astrocytoma, 45, 237 Asymptomatic, 80, 229, 237, 263, 291 Ataxia, 51, 237, 272, 312 Atmospheric Pressure, 106, 237, 272 ATP, 6, 55, 125, 175, 180, 237, 255, 256, 265, 267, 277, 283, 294, 299, 313, 314 Atrophy, 197, 238, 287 Attenuated, 20, 46, 155, 185, 238, 255 Auditory, 96, 238 Autodigestion, 238, 291 Autoimmune disease, 12, 34, 53, 68, 157, 182, 238 Autologous, 192, 238 Avian, 63, 238, 251 Axons, 31, 238, 287, 290 B Babesiosis, 238, 301 Bacterial Infections, 174, 238 Bacteriophage lambda, 238, 275 Bacteriophages, 238, 275 Bacterium, 238, 249 Barium, 190, 238 Basal Ganglia, 237, 238, 264 Basal Ganglia Diseases, 237, 238 Base, 9, 38, 58, 157, 171, 198, 230, 238, 252, 253, 254, 263, 265, 278, 297, 311, 316 Base Sequence, 171, 238, 252, 263, 265 Basement Membrane, 45, 238, 261, 278
323
Baths, 158, 239 Benign, 192, 239, 264, 266, 287, 292, 302 Benzodiazepines, 146, 239 Beta-Defensins, 37, 239, 253 Beta-Endorphin, 116, 239 Beta-pleated, 234, 239 Bilateral, 239, 297 Bile, 239, 264, 280, 309, 311 Bile Acids, 239, 309, 311 Biliary, 239, 291 Biliary Tract, 239, 291 Bilirubin, 232, 239 Binding Sites, 16, 17, 84, 92, 199, 239 Bioavailability, 24, 161, 239 Bioavailable, 76, 239 Biochemical reactions, 239, 312 Biological response modifier, 239, 275 Biological therapy, 239, 268 Biological Transport, 239, 255 Bioluminescence, 239, 280 Biosynthesis, 24, 50, 62, 63, 64, 65, 66, 71, 79, 100, 112, 163, 165, 237, 240, 252, 299, 306 Biotechnology, 61, 66, 94, 128, 129, 159, 196, 204, 213, 240 Bioterrorism, 59, 240 Biotic, 177, 240 Biotransformation, 42, 71, 72, 240 Bladder, 45, 240, 249, 287, 299, 316 Blast phase, 240, 246 Blastocyst, 240, 295 Bleomycin, 58, 87, 240 Blood Cell Count, 240, 269 Blood Coagulation, 161, 240, 242, 262, 312 Blood Coagulation Factors, 240 Blood Glucose, 240, 269, 275 Blood Platelets, 240, 306 Blood pressure, 160, 161, 197, 240, 243, 272, 284, 288, 307 Blood Substitutes, 160, 240 Blood transfusion, 160, 179, 241 Blood-Brain Barrier, 241, 295 Blot, 7, 241 Body Fluids, 241, 257, 278, 307 Bone Marrow Transplantation, 21, 101, 241 Bone Resorption, 9, 54, 162, 241 Bowel, 186, 234, 241, 274, 276, 309, 316 Brachytherapy, 241, 276, 277, 301, 319 Bradykinin, 20, 241, 277, 278, 288, 296 Brain Hypoxia, 35, 241, 312 Breeding, 183, 241
Bronchiseptica, 241, 294 Buccal, 124, 125, 131, 241, 272, 309 Busulfan, 101, 241 Bypass, 192, 241, 286 C Caffeine, 241, 301 Calcium Channels, 75, 242 Calcium Hydroxide, 191, 242 Calmodulin, 12, 242 Calpain, 78, 132, 162, 242 Cannabidiol, 242 Cannabinoids, 202, 242 Cannabinol, 242 Capillary, 159, 173, 241, 242, 279, 317 Capillary Permeability, 241, 242 Capsid, 242, 318 Carbohydrate, 190, 242, 264, 267, 297 Carbon Dioxide, 151, 240, 242, 251, 253, 254, 264, 266, 295, 303 Carboxy, 89, 173, 243 Carboxylic Acids, 195, 243 Carboxypeptidases, 243, 261 Carboxy-terminal, 89, 173, 243 Carcinogen, 30, 230, 243, 312 Carcinogenesis, 13, 124, 125, 126, 130, 131, 243, 295 Carcinogenic, 232, 243, 274, 289, 298, 309 Carcinoma, 71, 79, 98, 104, 113, 189, 190, 243, 254 Cardiac, 10, 31, 46, 95, 235, 241, 242, 243, 247, 250, 257, 260, 261, 285, 286, 301, 307, 309 Cardiomyopathy, 179, 243 Cardiotonic, 31, 243, 255 Cardiotoxicity, 243, 315 Cardiovascular, 5, 30, 32, 46, 72, 96, 105, 135, 218, 242, 243, 279, 306 Cardiovascular disease, 5, 32, 46, 72, 96, 105, 218, 243 Carmustine, 72, 243 Carnitine, 202, 243 Carotene, 243, 303 Carotid Arteries, 162, 243 Caspase, 7, 8, 11, 12, 26, 33, 46, 49, 52, 57, 70, 93, 105, 192, 243 Catabolism, 236, 243, 244 Catalase, 13, 229, 243 Catalyse, 243, 314 Catalytic Domain, 20, 33, 244 Cataract, 56, 244 Catecholamine, 10, 244, 256 Cathepsin D, 182, 244
324
Cysteine
Cathepsins, 13, 23, 46, 47, 74, 90, 97, 114, 163, 177, 181, 182, 244 Cations, 244, 277 Caudal, 244, 272, 297 Causal, 10, 244, 269 Caustic, 244, 315 Cell Communication, 61, 244 Cell Cycle, 10, 31, 45, 52, 58, 244, 247, 300 Cell Death, 6, 7, 10, 12, 13, 26, 33, 35, 41, 48, 70, 93, 102, 130, 163, 175, 236, 244, 286 Cell Differentiation, 9, 244, 307 Cell Division, 238, 244, 268, 282, 284, 295, 299, 305 Cell membrane, 16, 49, 239, 242, 244, 254, 261, 264, 276, 282, 294, 297, 318 Cell proliferation, 22, 31, 172, 244, 276, 289, 307 Cell Respiration, 231, 244, 284, 291, 303 Cell Survival, 53, 244, 268 Cell Transplantation, 101, 244 Centrifugation, 245, 269, 283 Ceramide, 8, 245 Cerebellar, 237, 245, 302 Cerebral, 35, 237, 238, 241, 245, 260, 281 Cerebral Cortex, 237, 245, 260 Cerebrospinal, 245, 306 Cerebrospinal fluid, 245, 306 Cerebrovascular, 238, 243, 245, 288, 312 Cerebrum, 245 Cervical, 135, 189, 190, 245 Cervix, 245, 303 Character, 245, 253 Chelation, 194, 195, 202, 245 Chemoprevention, 124, 245 Chemoprotective, 127, 245 Chemotactic Factors, 245, 248 Chemotherapeutic agent, 48, 58, 245 Chemotherapeutics, 8, 245 Chemotherapy, 15, 49, 58, 70, 88, 139, 167, 245, 273 Chimeras, 71, 245 Chlorophyll, 245, 251, 264 Chloroplasts, 64, 245, 252 Cholecystokinin, 6, 246 Cholesterol, 5, 21, 130, 136, 162, 239, 246, 250, 272, 279, 280, 309 Cholesterol Esters, 246, 279 Choline, 119, 229, 246 Cholinergic, 124, 246, 288, 306 Chondrocytes, 246, 263 Chorion, 246, 262
Chromaffin Granules, 181, 246 Chromatin, 236, 246, 259, 280, 308 Chromium, 38, 202, 246 Chromosomal, 44, 87, 179, 246, 296, 304 Chromosome, 234, 246, 249, 268, 279, 305, 315, 316 Chronic Disease, 37, 187, 246 Chronic myelogenous leukemia, 240, 246 Chronic phase, 179, 246 Chronic renal, 246, 297, 316 Chylomicrons, 236, 246, 279 Chymopapain, 246, 291 Chymotrypsin, 165, 246 Cinchona, 195, 247, 301 Cinchona Alkaloids, 247 Cirrhosis, 137, 247, 269 CIS, 43, 50, 247, 303 Cisplatin, 58, 88, 96, 107, 119, 247 Clamp, 58, 247 Cleave, 19, 176, 247, 255 Clinical Medicine, 72, 247, 298 Clinical trial, 3, 213, 247, 302 Cloning, 60, 100, 129, 183, 240, 247, 275, 279 Clot Retraction, 247, 296 Coagulation, 161, 240, 247, 269, 296 Cobalt, 171, 247 Coca, 247 Cocaine, 16, 17, 110, 247 Codon, 50, 247, 265, 305 Coenzyme, 36, 202, 248, 263 Cofactor, 10, 61, 248, 299, 312 Colitis, 248 Collagen, 46, 47, 158, 159, 177, 238, 248, 262, 263, 281, 296, 298 Collapse, 4, 101, 248 Collateral Circulation, 159, 248 Colloidal, 232, 248, 258, 261, 283, 306 Colon, 104, 135, 248, 257, 274, 278, 316 Combinatorial, 41, 165, 166, 248 Complement, 19, 20, 57, 170, 234, 248, 249, 265, 275, 278, 281, 296 Complement Activation, 20, 234, 249 Complementary and alternative medicine, 123, 143, 249 Complementary medicine, 123, 249 Complementation, 19, 50, 249 Compliance, 11, 160, 195, 249 Computational Biology, 213, 249 Concomitant, 249, 313 Condoms, 189, 249 Cones, 249, 303
325
Confounding, 43, 249 Congenita, 249, 301 Conjugated, 249, 253 Conjugation, 8, 30, 157, 240, 249 Conjunctiva, 249, 295 Connective Tissue, 20, 93, 106, 136, 159, 241, 244, 248, 249, 250, 254, 263, 264, 280, 283, 300 Connective Tissue Cells, 249, 250 Consciousness, 234, 250, 254, 256, 300 Consensus Sequence, 91, 233, 250 Conserved Sequence, 43, 174, 233, 250 Constriction, 250, 277 Consultation, 14, 250 Contraindications, ii, 250 Conus, 250, 301 Coordination, 36, 250, 277 Cornea, 250, 309, 319 Corneum, 68, 250, 260 Coronary, 70, 104, 105, 136, 182, 243, 250, 272, 285 Coronary Disease, 182, 250 Coronary heart disease, 104, 243, 250 Coronary Thrombosis, 250, 285 Coronary Vessels, 250 Corpus, 250, 293, 298, 318 Corpuscle, 250, 260 Corrosion, 151, 250 Cortex, 251, 270, 298, 303 Cortical, 16, 43, 251, 261, 305, 312 Corticosteroids, 142, 251, 266 Cortisol, 232, 251 Coumarin, 109, 165, 166, 251 Cowpox, 251, 316 Cowpox Virus, 251, 316 Critical Care, 26, 251 Crossing-over, 251, 302 Croton Oil, 251, 294 Cryopreservation, 251, 255 Crystallins, 56, 251 Culture Media, 186, 231, 251 Curative, 251, 288, 312 Cutaneous, 251, 277, 278, 316 Cyanide, 146, 158, 251 Cyanobacteria, 234, 251, 289, 313 Cyanogen Bromide, 191, 252 Cyanosis, 252, 269 Cyclic, 27, 33, 35, 67, 86, 176, 178, 242, 244, 252, 268, 288, 312 Cyclophosphamide, 139, 252, 272, 283 Cystamine, 151, 252 Cystathionine beta-Synthase, 252, 272
Cystatins, 15, 42, 56, 88, 112, 146, 173, 252 Cysteamine, 36, 83, 151, 252 Cysteine Endopeptidases, 133, 252 Cysteine Proteinase Inhibitors, 42, 94, 252, 278 Cysteine Synthase, 64, 107, 252 Cysteinyl, 18, 63, 95, 252 Cystine, 23, 29, 48, 62, 89, 110, 151, 155, 159, 164, 167, 252, 256 Cytochrome, 6, 7, 27, 33, 79, 103, 192, 252, 291 Cytokine, 22, 47, 84, 101, 131, 168, 175, 253, 275 Cytomegalovirus, 253, 264 Cytomegalovirus Infections, 253, 264 Cytoplasm, 7, 33, 36, 168, 236, 244, 253, 259, 260, 268, 280, 286, 304, 311, 317 Cytosine, 38, 66, 192, 253, 301 Cytoskeletal Proteins, 242, 253 Cytostatic, 186, 253 Cytotoxic, 7, 21, 42, 83, 97, 154, 155, 157, 161, 187, 188, 192, 253, 275, 302, 307 Cytotoxicity, 42, 72, 79, 126, 132, 154, 194, 247, 253 D De novo, 9, 84, 253 Decarboxylation, 253, 266, 270 Decidua, 253, 295 Defense Mechanisms, 20, 166, 253, 275 Defensins, 37, 167, 188, 232, 239, 253 Degenerative, 161, 186, 250, 253, 266, 270, 290, 304 Deletion, 46, 55, 68, 236, 253 Delivery of Health Care, 253, 268 Dementia, 229, 253 Demethylation, 218, 254 Denaturation, 172, 254 Dendrites, 254, 287 Dendritic, 178, 254, 282 Dendritic cell, 178, 254 Deoxyribonucleic, 101, 254, 304 Deoxyribonucleic acid, 101, 254, 304 Deoxyribonucleotides, 254, 265 Depolarization, 57, 254, 307 Depreciation, 196, 254 Depressive Disorder, 254, 280 Deprivation, 48, 254 Dermatosis, 254, 263 Dermis, 158, 254, 310 DES, 234, 254 Desquamation, 158, 254, 284 Detoxification, 24, 254
326
Cysteine
Deuterium, 254, 271 Diabetes Mellitus, 201, 254, 266, 269 Diabetic Retinopathy, 4, 254, 295 Diacylglycerol Kinase, 109, 255 Diagnostic procedure, 149, 204, 255 Dialyzer, 255, 269 Diarrhea, 7, 255, 274 Diarrhoea, 255, 272 Diastolic, 255, 272 Dichlorvos, 128, 255 Dietary Fats, 255, 279 Diffusion, 32, 239, 242, 255, 274, 276 Digestion, 42, 93, 232, 239, 241, 255, 276, 279, 280, 293, 309 Digestive tract, 255, 307, 308, 309, 319 Digitalis, 255, 290 Dihydrotestosterone, 255, 303 Dilatation, Pathologic, 255, 317 Dilation, 241, 255, 317 Dilution, 14, 255 Dimerization, 22, 62, 64, 86, 173, 192, 255 Dimethyl, 202, 255 Dimethyl Sulfoxide, 202, 255 Dipeptidases, 8, 255, 261 Dipeptides, 255 Dipeptidyl Peptidases, 255, 261 Diploid, 249, 256, 295, 315 Discrete, 16, 256, 299, 319 Discrimination, 54, 256 Disease Progression, 256, 318 Dissection, 165, 256 Dissociation, 48, 55, 231, 256, 277 Dissociative Disorders, 256 Distal, 146, 256, 257, 293, 300 Disulphides, 256 Dithiothreitol, 41, 256 DNA Topoisomerase, 256, 265 Dopamine, 9, 16, 17, 110, 247, 256, 284, 288, 294 Dorsal, 256, 297, 306 Dose-dependent, 72, 256 Doxycycline, 41, 257 Drive, ii, vi, 3, 14, 58, 115, 257, 277 Drug Costs, 202, 257 Drug Interactions, 208, 257 Duct, 257, 261, 304, 310 Duodenum, 239, 246, 257, 291, 309 Dyes, 186, 234, 257, 310 Dysentery, 7, 257 Dysplasia, 135, 189, 257 Dystrophy, 99, 137, 162, 257
E Edema, 26, 155, 254, 257, 286, 289, 316 Effector, 6, 12, 23, 178, 188, 229, 248, 257 Effector cell, 178, 257 Efferent, 257, 262, 306 Efficacy, 26, 34, 57, 160, 257 Elastic, 127, 257, 310 Elastin, 46, 47, 158, 248, 257, 262 Elective, 108, 257 Electrocoagulation, 247, 257 Electrode, 95, 257 Electrolyte, 257, 297, 307, 316 Electrons, 236, 238, 258, 277, 281, 290, 291, 301, 302 Electrophoresis, 38, 44, 129, 230, 258 Electroplating, 258, 310 Elementary Particles, 258, 281, 288, 300 Emaciation, 229, 258 Embolus, 258, 274 Embryo, 233, 240, 244, 258, 262, 274, 297, 319 Emphysema, 47, 136, 177, 258 Empirical, 9, 258 Emulsions, 231, 241, 258 Encephalopathy, 14, 258 Endemic, 258, 281, 308 Endocrine System, 258, 287 Endocytosis, 54, 181, 258 Endorphin, 116, 239, 258 Endothelial cell, 47, 75, 77, 86, 106, 159, 161, 172, 241, 258, 263, 270, 312 Endothelium, 161, 173, 258, 259, 288, 296 Endothelium, Lymphatic, 258 Endothelium, Vascular, 258, 259 Endothelium-derived, 259, 288 Endotoxic, 259, 279 Endotoxin, 166, 259, 315 End-stage renal, 246, 259, 297 Enkephalin, 239, 259 Enteropeptidase, 259, 315 Environmental Health, 71, 112, 212, 214, 259 Enzyme Precursors, 181, 259 Enzyme-Linked Immunosorbent Assay, 80, 259 Eosinophils, 23, 90, 91, 259, 268 Epidemic, 189, 259, 308 Epidermal, 74, 82, 150, 259, 278, 282 Epidermal Growth Factor, 74, 259 Epidermis, 158, 250, 254, 259, 271, 278 Epidermoid carcinoma, 260, 308, 309 Epigastric, 260, 291
327
Epinephrine, 231, 246, 256, 260, 288, 289, 316 Epithelial, 26, 75, 85, 86, 89, 94, 151, 161, 167, 190, 230, 239, 253, 254, 259, 260, 278, 292, 316 Epithelial Cells, 26, 89, 161, 239, 259, 260, 278 Epithelial ovarian cancer, 85, 260 Epithelium, 26, 174, 238, 258, 260, 292, 319 Epitope, 22, 186, 260 Erectile, 260, 292, 293 Erythrocyte Membrane, 49, 260 Erythrocytes, 49, 160, 234, 238, 240, 241, 242, 260, 269, 302 Erythropoietin, 160, 260 Esterification, 191, 260 Estrogen, 80, 260 Estrogen receptor, 80, 260 Ethanol, 260, 262 Ether, 71, 260 Eukaryote, 102, 260 Eukaryotic Cells, 54, 154, 253, 260, 273, 290, 316 Evoke, 260, 309 Excipient, 156, 261 Excitability, 12, 61, 261, 301 Excitation, 61, 233, 261, 288 Excitatory, 28, 162, 261, 266, 267, 272 Excitotoxicity, 28, 161, 261 Exfoliation, 254, 261 Exhaustion, 261, 281 Exocrine, 246, 261, 291 Exocytosis, 23, 111, 261, 270, 311 Exogenous, 24, 174, 240, 252, 258, 261, 265 Exon, 233, 261 Exopeptidases, 146, 233, 255, 261, 293 Exotoxin, 44, 261 Expander, 261 Expiration, 261, 303 Extender, 261, 296 External-beam radiation, 261, 277, 301, 319 Extracellular Matrix, 19, 23, 155, 158, 249, 250, 261, 263, 275, 281 Extracellular Matrix Proteins, 261, 263, 281 Extracellular Space, 45, 182, 261, 262 Extraction, 38, 262 Extrapyramidal, 256, 262 Eye Infections, 230, 262 F Facial, 262, 292
Facial Nerve, 262, 292 Factor V, 262, 301 Fallopian tube, 262, 303 Family Planning, 213, 262 Farnesyl, 65, 262 Fat, 236, 241, 243, 245, 250, 258, 262, 279, 297, 307, 310, 315 Fatigue, 262, 269 Fatty acids, 71, 232, 243, 262, 299 Fees, Pharmaceutical, 257, 262 Fermentation, 163, 164, 165, 177, 262 Fertilizers, 262, 310 Fetal Membranes, 101, 262 Fetus, 260, 262, 295, 316 Fibrin, 240, 247, 262, 293, 296, 312 Fibrinogen, 82, 262, 263, 296, 312 Fibroblast Growth Factor, 75, 77, 263 Fibroblasts, 18, 79, 105, 158, 250, 263 Fibrosis, 136, 159, 263, 305 Filariasis, 15, 263 Filarioidea, 263, 277 Flatus, 263, 264 Fluorescence, 6, 11, 18, 29, 39, 61, 152, 263 Fluorescence Polarization, 152, 263 Fluorouracil, 140, 192, 263 Focal Adhesions, 45, 263 Folate, 69, 73, 119, 263 Fold, 11, 18, 36, 57, 165, 263 Folic Acid, 78, 118, 119, 263 Forearm, 240, 263 Frameshift, 263, 264, 316 Frameshift Mutation, 264, 316 Free Radicals, 5, 35, 139, 155, 186, 236, 256, 264, 286 Fucose, 264 Fucosyltransferases, 90, 264 Fungus, 65, 264 G GABA, 264, 266, 307 Gallbladder, 229, 239, 246, 264 Ganciclovir, 192, 264 Ganglia, 229, 238, 264, 287, 293 Ganglion, 264, 290, 319 Gap Junctions, 264, 311 Gas, 34, 77, 85, 98, 233, 242, 255, 263, 264, 271, 288, 303 Gas exchange, 264, 303 Gastric, 99, 238, 243, 259, 264, 270 Gastrin, 264, 271 Gastrointestinal, 85, 241, 246, 260, 265, 279, 281, 306, 310 Gastrointestinal tract, 260, 265, 279, 306
328
Cysteine
Gene Expression, 15, 16, 37, 43, 44, 48, 51, 72, 80, 89, 125, 174, 199, 265 Gene Expression Regulation, 89, 265 Gene Fusion, 157, 265 Gene Rearrangement, 44, 265 Gene Silencing, 78, 183, 265 Gene Targeting, 39, 50, 265 Gene Therapy, 59, 86, 130, 161, 192, 230, 265 Genetic Code, 18, 265, 289 Genetic Engineering, 154, 183, 240, 247, 265 Genetic Markers, 47, 265 Genetic transcription, 155, 265, 314 Genetics, 48, 82, 101, 111, 131, 150, 249, 265 Genistein, 133, 265 Genotype, 232, 266, 294 Germ cell tumors, 58, 266 Germ Cells, 266, 282, 289, 290, 307, 308, 311, 319 Germinal Center, 177, 266 Gestation, 266, 293, 295 Ginkgo biloba, 202, 266 Ginseng, 142, 266 Gland, 43, 231, 266, 280, 291, 292, 295, 299, 305, 309, 310, 313 Glioma, 72, 266 Gliosis, 13, 266 Glomerulus, 161, 266 Glottis, 266, 294 Glucocorticoid, 70, 100, 109, 266 Glucose, 29, 48, 55, 69, 75, 95, 232, 240, 246, 254, 266, 267, 269, 274, 275, 295, 305, 307 Glucose Intolerance, 254, 266 Glucuronic Acid, 266, 269 Glutamate, 9, 20, 21, 28, 34, 70, 80, 87, 91, 104, 105, 110, 112, 125, 145, 261, 266, 267 Glutamate Decarboxylase, 104, 266 Glutamate-Cysteine Ligase, 20, 70, 91, 105, 125, 266 Glutamic Acid, 263, 266, 267, 269, 288, 298 Glutamine, 67, 124, 140, 180, 202, 267 Glutathione Peroxidase, 267, 305 Glycine, 34, 96, 155, 163, 183, 189, 255, 267, 283, 288, 306 Glycogen, 267, 295 Glycols, 267, 271 Glycosaminoglycans, 262, 267, 300 Glycoside, 267, 290, 305 Glycosidic, 157, 235, 267, 287, 295
Glycosylation, 90, 160, 170, 267 Gold Compounds, 159, 267 Gonad, 267 Gonadal, 58, 267, 309 Governing Board, 267, 298 Gp120, 169, 267 GP41, 169, 267 Grade, 128, 190, 267 Graft, 157, 232, 268, 286 Graft-versus-host disease, 157, 268 Gram-negative, 51, 241, 252, 259, 268, 304 Gram-positive, 268, 285, 309 Granule, 268, 304 Granulocytes, 268, 307, 318 Grasses, 263, 268 Growth factors, 168, 187, 268, 283, 289 Guanine, 38, 268, 301 Guanylate Cyclase, 268, 288 H Habitat, 268, 285 Hair follicles, 254, 268 Half-Life, 67, 268 Haploid, 268, 295 Haptens, 231, 268 Health Care Costs, 189, 268 Health Expenditures, 268 Health Policy, 28, 268 Heart attack, 243, 268 Heart failure, 10, 179, 269 Hematocrit, 132, 240, 269 Hematopoietic growth factors, 8, 269 Hematopoietic tissue, 8, 241, 269 Hemochromatosis, 218, 269 Hemocytes, 167, 269 Hemodialysis, 83, 113, 255, 269 Hemoglobin, 160, 234, 240, 252, 260, 269, 277, 279 Hemoglobin A, 160, 161, 269 Hemoglobin C, 160, 269 Hemoglobin E, 160, 269 Hemoglobin M, 161, 252, 269 Hemoglobinopathies, 265, 269 Hemolysis, 238, 260, 269 Hemorrhage, 21, 240, 255, 257, 269, 286, 309 Hemostasis, 269, 275, 306 Heparin, 159, 172, 269, 270 Heparin-binding, 172, 270 Hepatic, 36, 96, 185, 192, 232, 270, 294 Hepatitis, 110, 186, 187, 218, 270, 318 Hepatitis B, 186, 270 Hepatoblastoma, 84, 270
329
Hepatocellular, 187, 270 Hepatocellular carcinoma, 187, 270 Hepatocyte, 36, 270 Hepatoma, 85, 127, 270 Hepatotoxicity, 42, 132, 270 Hereditary, 270, 287, 293 Heredity, 265, 270 Heterogeneity, 37, 231, 270 Hippocampus, 270, 306 Histamine, 234, 270 Histamine Release, 234, 270 Histidine, 42, 117, 181, 198, 270 Homeostasis, 28, 53, 54, 161, 270 Homodimer, 39, 270 Homogeneous, 152, 270 Homologous, 15, 19, 46, 167, 251, 252, 265, 270, 305, 311, 315 Hookworms, 270, 312 Hormonal, 238, 271, 293 Hormone, 22, 53, 55, 193, 239, 251, 254, 260, 264, 271, 275, 276, 282, 298, 304, 306, 312, 313 Horny layer, 260, 271 Horseradish Peroxidase, 259, 271 Human papillomavirus, 189, 190, 271 Hybrid, 40, 271 Hydration, 171, 230, 271 Hydrogen Bonding, 16, 271 Hydrogen Cyanide, 271, 288 Hydrogen Peroxide, 5, 33, 75, 94, 186, 243, 267, 271, 279, 310 Hydrogenation, 239, 271 Hydrolysis, 28, 55, 91, 179, 190, 229, 240, 247, 271, 277, 280, 287, 293, 294, 297, 300, 315 Hydrophilic, 17, 54, 271 Hydrophobic, 18, 32, 56, 271, 279 Hydroxides, 271 Hydroxyl Radical, 186, 271 Hydroxylation, 157, 195, 271 Hydroxylysine, 248, 271 Hydroxyproline, 248, 271 Hyperbaric, 202, 272 Hyperbaric oxygen, 202, 272 Hyperhomocysteinemia, 88, 252, 272 Hyperkeratosis, 189, 272 Hyperlipoproteinemia, 236, 272, 279 Hyperoxia, 26, 272 Hyperplasia, 162, 272 Hypersensitivity, 232, 272, 279, 304 Hypertension, 160, 243, 272, 316 Hypertrophy, 150, 272
Hypoglycemia, 162, 272 Hypothalamus, 259, 272, 295, 306 Hypoxia, 35, 38, 43, 48, 58, 100, 272 Hypoxic, 35, 272 I Ibotenic Acid, 129, 272 Ifosfamide, 272, 283 Imidazole, 181, 270, 272 Immersion, 239, 272 Immune response, 12, 20, 178, 185, 196, 231, 235, 236, 238, 268, 272, 273, 281, 310, 316, 318 Immune Sera, 272, 273 Immune system, 161, 186, 187, 192, 236, 239, 257, 272, 273, 279, 281, 294, 316, 318 Immunity, 13, 68, 80, 82, 91, 99, 177, 185, 229, 231, 253, 273, 275, 276, 314 Immunization, 20, 59, 185, 273 Immunoassay, 152, 190, 259, 273 Immunocompromised, 25, 273 Immunoconjugates, 157, 273 Immunodeficiency, 37, 107, 114, 167, 169, 229, 273 Immunogen, 169, 196, 273 Immunogenic, 20, 192, 273, 279 Immunoglobulins, 273, 296 Immunohistochemistry, 26, 273 Immunologic, 41, 245, 273, 302 Immunology, 24, 40, 76, 84, 89, 90, 97, 100, 128, 177, 196, 231, 271, 273 Immunosuppressant, 202, 232, 263, 273 Immunosuppressive, 252, 266, 272, 273 Immunotoxins, 157, 273, 302 Impairment, 105, 237, 262, 273, 315 Implant radiation, 273, 276, 277, 301, 319 In situ, 8, 26, 27, 33, 38, 192, 273 In Situ Hybridization, 26, 273 Incision, 274, 276 Incompetence, 83, 274 Incubation, 274, 294 Incubation period, 274, 294 Induction, 8, 41, 44, 46, 52, 72, 80, 125, 128, 175, 265, 274, 276 Infarction, 10, 274, 303 Infectious Diarrhea, 29, 274 Infiltration, 162, 274, 319 Inflammatory bowel disease, 89, 274 Infusion, 274, 286, 314 Ingestion, 272, 274, 297 Inhalation, 72, 208, 274, 297, 315 Initiation, 7, 22, 26, 178, 274, 314 Initiator, 274, 275
330
Cysteine
Inorganic, 185, 247, 267, 271, 274, 280, 285, 288 Inositol, 111, 274 Inotropic, 256, 274 Insecticides, 275, 319 Insertional, 19, 180, 275 Insight, 9, 16, 19, 26, 27, 31, 32, 38, 41, 48, 55, 275 Insulin, 101, 105, 164, 275, 298 Insulin-dependent diabetes mellitus, 275 Integrase, 107, 275 Integrins, 263, 275 Interferon, 47, 91, 99, 133, 141, 275, 280 Interferon-alpha, 275 Interindividual, 71, 275 Interleukin-1, 68, 91, 99, 163, 275 Interleukin-12, 91, 99, 275 Interleukin-18, 68, 275 Interleukin-2, 275, 276 Interleukins, 168, 276 Internal Medicine, 23, 26, 276 Internal radiation, 276, 277, 301, 319 Interstitial, 241, 262, 276, 277, 282, 319 Intestinal, 99, 167, 232, 243, 246, 259, 276, 319 Intestinal Mucosa, 246, 276, 319 Intestine, 241, 276, 278, 293, 309, 318 Intoxication, 276, 319 Intracellular Membranes, 276, 282 Intraepithelial, 189, 276 Intramuscular, 276, 292 Intravascular, 161, 236, 276 Intravenous, 110, 116, 274, 276, 292 Intrinsic, 52, 57, 168, 231, 238, 276 Invasive, 23, 45, 72, 92, 190, 273, 276, 281 Invertebrates, 269, 276, 280 Involuntary, 238, 276, 286, 303, 307 Iodine, 146, 276 Ion Channels, 11, 17, 43, 60, 237, 276, 287, 311 Ion Exchange, 190, 276 Ion Transport, 31, 52, 276 Ionization, 106, 124, 277 Ionizing, 48, 186, 232, 277, 302 Ions, 5, 12, 16, 17, 31, 60, 124, 159, 238, 242, 256, 257, 271, 276, 277, 283, 284, 297, 300 Iron Chelating Agents, 194, 277 Irradiation, 171, 185, 277, 319 Irritants, 257, 277 Ischemia, 10, 43, 162, 175, 238, 277, 286, 303 Isocitrate Lyase, 131, 277
Isoleucine, 163, 171, 277 Isozymes, 109, 277 Ivermectin, 15, 277 K Kallidin, 241, 277, 278 Kb, 212, 278 Keratin, 278 Keratinocytes, 37, 278 Keto, 4, 28, 278, 314 Kidney Disease, 89, 113, 212, 218, 278 Kinetic, 4, 32, 94, 124, 165, 277, 278 Kininogens, 106, 173, 278 L Labile, 38, 169, 248, 262, 278 Labyrinth, 278, 299, 317 Laminin, 238, 262, 278 Large Intestine, 255, 276, 278, 302, 307, 318 Latency, 13, 278 LCD, 95, 278 Lectin, 229, 278, 282 Leishmaniasis, 69, 81, 278 Lens, 56, 103, 244, 249, 251, 278 Lesion, 188, 196, 266, 279, 280 Lethal, 21, 32, 39, 60, 180, 192, 251, 279 Leucine, 100, 171, 239, 279 Leukemia, 7, 13, 97, 102, 246, 265, 279 Leukotrienes, 8, 237, 279 Life cycle, 49, 179, 279 Ligament, 262, 279, 299 Ligands, 27, 92, 275, 279 Ligase, 21, 24, 80, 87, 112, 145, 279 Ligation, 49, 64, 279 Linkage, 22, 42, 58, 111, 265, 279 Lipase, 28, 279 Lipid A, 18, 32, 279 Lipid Peroxidation, 130, 279, 291 Lipopolysaccharide, 99, 131, 268, 279 Lipoprotein, 5, 18, 98, 236, 268, 279, 280, 318 Lipoprotein Lipase, 236, 279 Liposome, 162, 279 Lithium, 16, 279 Liver Mitochondria, 28, 280 Localization, 25, 58, 73, 77, 80, 87, 97, 111, 165, 273, 280 Localized, 7, 53, 57, 90, 181, 229, 274, 278, 280, 295 Locomotion, 280, 295 Loop, 18, 51, 52, 76, 88, 95, 116, 117, 141, 157, 280 Low-density lipoprotein, 279, 280 Luminescence, 29, 280
331
Lyases, 27, 280 Lymph, 55, 245, 250, 258, 280, 310 Lymph node, 245, 280 Lymphatic, 258, 274, 280, 283, 307, 313 Lymphatic system, 280, 307, 313 Lymphoblasts, 230, 280 Lymphocyte Count, 132, 229, 280 Lymphocytes, 169, 186, 229, 235, 254, 266, 273, 275, 276, 280, 286, 313, 318 Lymphocytic, 246, 280 Lymphoid, 7, 235, 251, 266, 280, 281 Lymphoma, 45, 49, 70, 281 Lysine, 20, 42, 76, 87, 153, 163, 167, 183, 255, 269, 271, 281, 315 M Macrophage, 21, 23, 47, 275, 281 Magnetic Resonance Imaging, 281 Magnetic Resonance Spectroscopy, 35, 281 Major Histocompatibility Complex, 12, 281 Malaria, 40, 49, 50, 80, 184, 247, 281, 296 Malaria, Falciparum, 281 Malaria, Vivax, 281 Malignancy, 229, 264, 281, 292 Malignant, 53, 133, 155, 189, 192, 229, 230, 236, 266, 281, 287, 302, 304 Malignant tumor, 281, 304 Malnutrition, 116, 125, 232, 238, 281 Malondialdehyde, 14, 281 Mammary, 79, 279, 281 Manic, 280, 281 Mannans, 264, 281 Matrix metalloproteinase, 98, 99, 133, 281 Meat, 126, 255, 282 Medial, 282, 306 Mediate, 6, 10, 16, 23, 31, 43, 57, 75, 168, 256, 282 Mediator, 246, 276, 282, 306 Medicament, 155, 177, 282 MEDLINE, 213, 282 Medullary, 71, 113, 282 Megaloblastic, 263, 282 Meiosis, 282, 311, 316 Melanin, 157, 282, 294, 316 Melanocytes, 157, 282 Melanoma, 93, 282 Melanosis, 229, 282 Melanosomes, 282 Memantine, 202, 282 Membrane Fusion, 169, 282 Membrane Glycoproteins, 282
Membrane Proteins, 51, 53, 185, 282 Memory, 254, 266, 282 Meninges, 245, 283 Mental, iv, 3, 212, 214, 245, 253, 256, 262, 274, 282, 283, 300, 305, 316 Mental Processes, 256, 283, 300 Mercaptopropionylglycine, 83, 283 Mercury, 28, 283 Mesenchymal, 47, 259, 283 Mesna, 104, 283 Metabolite, 8, 30, 36, 42, 44, 160, 240, 255, 283, 298 Metastasis, 54, 163, 182, 282, 283 Methionine Adenosyltransferase, 116, 283 Micelles, 53, 283 Microbe, 283, 314 Microfilaments, 263, 283 Microglia, 237, 283, 284, 287 Microorganism, 164, 248, 283, 292, 318 Microscopy, 55, 230, 238, 271, 283 Microsomal, 42, 283 Microtubules, 283, 291 Migration, 47, 179, 283, 287 Milligram, 167, 284 Mineralization, 242, 284 Mitochondria, 7, 13, 28, 31, 33, 46, 284, 286, 290 Mitochondrial Swelling, 284, 286 Mitosis, 236, 284 Mitotic, 123, 284 Mobility, 44, 116, 152, 284 Modeling, 54, 56, 100, 284 Modulator, 41, 187, 284 Molecular mass, 154, 172, 284 Molecular Structure, 284, 315 Molecule, 7, 18, 32, 37, 40, 47, 49, 55, 152, 160, 162, 179, 188, 235, 238, 239, 242, 248, 256, 257, 259, 260, 261, 264, 267, 271, 275, 278, 284, 290, 291, 295, 296, 297, 300, 302, 306, 310, 314, 317 Molting, 15, 284 Monitor, 6, 24, 80, 166, 284, 289 Monoamine, 109, 284 Monoclonal, 75, 92, 152, 273, 277, 284, 302, 319 Monoclonal antibodies, 92, 273, 284 Monocyte, 23, 99, 284 Mononuclear, 171, 285, 315 Morphogenesis, 42, 61, 65, 285 Morphological, 12, 35, 49, 258, 264, 282, 285 Morphology, 42, 244, 285
332
Cysteine
Motility, 285, 306 Motor Neurons, 5, 285 Mucocutaneous, 278, 285 Mucolytic, 229, 285 Mucosa, 37, 89, 285, 309 Mucositis, 285, 313 Mucus, 257, 285, 316 Multidrug resistance, 85, 128, 130, 131, 285 Muscle Fibers, 285, 286 Muscle Relaxation, 285, 286 Mutagenesis, 6, 17, 18, 27, 29, 33, 34, 43, 48, 51, 53, 54, 55, 56, 69, 73, 75, 97, 170, 180, 285 Mutagenic, 193, 232, 285, 289 Mutagens, 264, 285 Mycobacterium, 13, 24, 30, 55, 285, 315 Mycobacterium tuberculosis, 13, 24, 30, 55, 285 Myelogenous, 285 Myocardial infarction, 10, 21, 70, 163, 173, 186, 250, 285, 286, 317 Myocardial Ischemia, 250, 285 Myocardial Reperfusion, 286, 303 Myocardial Reperfusion Injury, 286, 303 Myocardium, 285, 286 Myofibrils, 242, 286 Myopia, 283, 286, 303 Myosin, 33, 230, 286 Myotonia, 12, 286, 301 Myristate, 49, 286 N Naloxone, 239, 286 Natural killer cells, 275, 286 NCI, 1, 211, 247, 286 Necrosis, 6, 21, 31, 84, 236, 263, 274, 285, 286, 303, 306 Neoplasia, 71, 287 Neoplasm, 287, 292, 315 Nephron, 266, 287 Nephropathy, 4, 278, 287 Nephrotoxic, 30, 64, 83, 287 Nerve Fibers, 158, 287 Nerve Growth Factor, 10, 130, 287 Nervous System, 13, 41, 146, 150, 161, 162, 181, 229, 231, 233, 234, 241, 242, 245, 246, 247, 257, 264, 266, 267, 279, 282, 283, 287, 288, 293, 295, 306, 311, 312 Neural, 150, 231, 234, 283, 287, 293, 306 Neural Pathways, 150, 287 Neuraminidase, 64, 287, 292
Neurodegenerative Diseases, 12, 43, 180, 197, 238, 287 Neuroendocrine, 57, 287 Neurogenic, 150, 287 Neuroglia, 266, 287 Neuromuscular, 146, 229, 287, 316 Neuromuscular Junction, 146, 229, 287 Neuronal, 4, 10, 13, 28, 35, 39, 51, 59, 70, 96, 131, 150, 180, 242, 287 Neuropathy, 4, 201, 232, 234, 287, 293 Neuropeptide, 55, 288 Neurophysiology, 254, 288 Neurotoxicity, 28, 129, 162, 288 Neurotoxin, 153, 288 Neutrons, 232, 277, 288, 301 Neutrophil, 165, 288 Niacin, 288, 315 Nicotine, 4, 123, 288 Nifurtimox, 179, 288 Nimodipine, 202, 288 Nisin, 44, 288 Nitric Oxide, 10, 32, 33, 34, 35, 43, 79, 85, 98, 104, 105, 159, 161, 171, 175, 190, 197, 288 Nitriles, 182, 288 Nitrogen, 16, 32, 44, 175, 232, 251, 252, 261, 267, 271, 284, 288, 289, 315 Nitrogen Dioxide, 32, 288 Nitrogenase, 124, 289 Nitrosamines, 289 Nitrosation, 32, 289 Norepinephrine, 17, 231, 246, 256, 288, 289 Nuclear, 7, 35, 49, 56, 58, 80, 101, 131, 193, 238, 247, 249, 258, 260, 264, 265, 286, 289 Nuclei, 35, 232, 233, 249, 258, 265, 281, 284, 288, 289, 300, 306 O Ocular, 198, 289 Oligomenorrhea, 289, 297 Oligopeptides, 152, 176, 177, 289 Onchocerciasis, 15, 289 Oncogenes, 10, 289, 300 On-line, 14, 98, 227, 289 Oocytes, 4, 29, 289 Opacity, 244, 289 Operon, 289, 303 Opiate, 239, 259, 286, 289 Opportunistic Infections, 229, 290 Opsin, 290, 303, 304 Optic Disk, 250, 255, 290 Orbit, 290 Orbital, 9, 290
333
Organ Culture, 290, 313 Organelles, 16, 245, 253, 282, 290, 296 Orthopoxvirus, 60, 251, 290, 316 Osmotic, 232, 284, 290, 306 Osteoarthritis, 182, 290 Osteoporosis, 9, 54, 137, 177, 182, 290 Ouabain, 32, 290 Ovalbumin, 13, 290 Ovaries, 260, 290, 297, 303 Ovary, 29, 267, 290, 297 Overexpress, 46, 290 Ovum, 253, 266, 279, 290, 298, 319 Oxidants, 23, 290 Oxidation-Reduction, 240, 290, 291 Oxidative metabolism, 231, 279, 291 Oxidative Phosphorylation, 175, 291 Oxidative Stress, 5, 9, 13, 21, 36, 41, 44, 48, 62, 63, 112, 124, 132, 154, 155, 175, 186, 291 Oxygen Consumption, 291, 303 Oxygenase, 62, 187, 291 P Paclitaxel, 49, 142, 291 Palate, 291, 309 Palliative, 291, 312 Pancreas, 164, 229, 246, 269, 275, 279, 291, 298, 315 Pancreatic, 6, 243, 246, 291 Pancreatic Juice, 246, 291 Pancreatitis, 6, 291 Papain, 49, 57, 90, 93, 165, 177, 252, 291 Papillary, 272, 292 Papilloma, 189, 190, 292 Papillomavirus, 190, 292 Paramyxovirus, 73, 292 Parasite, 15, 25, 40, 49, 178, 185, 196, 277, 292, 315 Parasitic, 15, 90, 179, 185, 257, 270, 292, 313 Parenteral, 127, 195, 292 Parenteral Nutrition, 127, 292 Parotid, 42, 292 Paroxysmal, 292, 294, 318 Particle, 6, 279, 292, 314 Patch, 58, 250, 292 Pathogen, 20, 25, 44, 59, 183, 274, 292 Pathologic, 6, 236, 250, 272, 292 Pathologic Processes, 236, 292 Pathophysiology, 20, 26, 292 Patient Compliance, 195, 292 Patient Education, 218, 222, 224, 227, 292 Pelvic, 292, 299
Penicillamine, 146, 292 Penicillin, 292, 317 Penile Erection, 161, 292 Penis, 190, 249, 292, 293, 303 Pepsin, 244, 293 Peptide, 6, 11, 19, 20, 32, 49, 50, 61, 84, 85, 89, 93, 129, 146, 155, 157, 161, 162, 164, 165, 166, 167, 169, 171, 174, 176, 178, 179, 189, 190, 191, 193, 196, 202, 229, 239, 246, 259, 261, 263, 278, 293, 297, 299, 300 Peptide Fragments, 169, 293 Peptide Hydrolases, 261, 293 Peptide Mapping, 6, 293 Perforation, 293, 318 Perfusion, 160, 272, 293 Perinatal, 46, 293 Periodicity, 54, 293 Periodontitis, 20, 91, 293 Peripheral Nervous System, 287, 288, 293, 310 Peripheral Neuropathy, 201, 293 Peripheral stem cells, 268, 293 Periplasm, 53, 293 Peristalsis, 161, 293 Peritonitis, 293, 318 Peroxidase, 8, 91, 279, 293 Peroxide, 5, 294 Peroxisome Proliferators, 14, 294 Pertussis, 73, 294, 318 PH, 81, 152, 294 Phagocyte, 290, 294 Pharmacodynamics, 104, 294 Pharmacokinetic, 8, 188, 294 Pharmacologic, 11, 153, 172, 234, 251, 268, 294, 314 Phenotype, 23, 40, 43, 45, 59, 60, 69, 71, 91, 105, 249, 294 Phenyl, 14, 42, 294 Phenylalanine, 53, 294, 316 Phorbol, 49, 109, 294 Phorbol Esters, 109, 294 Phospholipases, 294, 307 Phospholipids, 262, 274, 279, 294 Phosphorus, 242, 294, 295 Phosphorylase, 192, 242, 295 Phosphorylated, 167, 168, 248, 295 Phosphorylates, 192, 295 Phosphorylation, 32, 33, 35, 126, 168, 255, 295, 299 Phosphotyrosine, 168, 295 Photocoagulation, 247, 295
334
Cysteine
Physical Therapy, 202, 295 Physiologic, 33, 231, 240, 268, 295, 302 Physiology, 12, 28, 29, 30, 41, 43, 54, 67, 87, 90, 110, 230, 288, 295 Physostigmine, 116, 295 Pigment, 157, 183, 239, 245, 282, 295 Pigmentation, 155, 282, 295 Pituitary Gland, 263, 295 Placenta, 79, 295, 298 Plaque, 21, 182, 234, 295 Plasma cells, 235, 295 Plasma expander, 161, 296 Plasma Kallikrein, 278, 296 Plasma protein, 231, 259, 296, 300, 306 Plasmapheresis, 202, 296 Plasmid, 7, 38, 86, 162, 296, 317 Plasmin, 165, 296 Plasminogen Activators, 296 Plasmodium, 40, 49, 78, 180, 184, 281, 296 Plasticity, 161, 269, 296 Plastids, 290, 296 Platelet Activation, 296, 307 Platelet Aggregation, 161, 162, 234, 288, 296, 312 Platelets, 242, 288, 296 Platyhelminths, 277, 296 Pneumonia, 250, 296 Point Mutation, 56, 296 Poisoning, 134, 276, 280, 283, 297 Pollen, 123, 297 Polycystic, 101, 297 Polycystic Ovary Syndrome, 101, 297 Polyethylene, 161, 297 Polymerase, 6, 61, 297, 303 Polymers, 151, 156, 188, 297, 299 Polymorphic, 47, 246, 297 Polymorphism, 69, 70, 88, 105, 297 Polysaccharide, 235, 297, 300 Polyunsaturated fat, 126, 297, 313 Posterior, 82, 234, 237, 256, 291, 297 Postmenopausal, 290, 297 Postnatal, 297, 309 Postsynaptic, 297, 307, 311 Post-translational, 24, 44, 297 Potassium, 43, 97, 297, 301 Potassium Channels, 43, 297 Potentiates, 275, 298 Potentiation, 298, 307 Practice Guidelines, 214, 298 Precancerous, 75, 190, 298 Precipitation, 190, 298
Precursor, 13, 25, 40, 57, 70, 150, 164, 169, 170, 194, 237, 246, 252, 256, 257, 259, 262, 289, 294, 298, 300, 315, 316, 317 Premalignant, 298 Prescription Fees, 257, 298 Presynaptic, 180, 288, 298, 311 Probe, 4, 13, 25, 53, 298 Prodrug, 93, 298 Progeny, 249, 298 Progesterone, 298, 309 Progression, 31, 36, 45, 46, 58, 89, 133, 179, 235, 298, 315 Progressive, 13, 244, 246, 247, 254, 286, 287, 290, 296, 298, 315 Proinsulin, 164, 298, 301 Projection, 253, 289, 298, 302 Proline, 19, 61, 154, 248, 255, 271, 298 Promoter, 5, 35, 43, 44, 76, 91, 127, 298 Prone, 126, 133, 298 Prophase, 289, 299, 311, 316 Prophylaxis, 182, 185, 197, 299, 316 Proprioception, 30, 299 Prospective study, 67, 190, 299 Prostaglandins, 237, 299 Prostate, 92, 129, 299, 303 Protease Inhibitors, 56, 74, 99, 102, 116, 146, 162, 176, 177, 178, 179, 181, 184, 299 Protein Conformation, 233, 278, 299 Protein Folding, 5, 180, 299 Protein Isoforms, 233, 299 Protein Kinases, 175, 289, 299 Protein Subunits, 41, 299 Protein-Tyrosine Kinase, 265, 299 Proteoglycan, 91, 300 Prothrombin, 262, 300, 312 Protons, 232, 271, 277, 281, 300, 301 Proto-Oncogene Proteins, 291, 300 Proto-Oncogene Proteins c-mos, 291, 300 Protozoa, 179, 240, 249, 257, 277, 278, 283, 296, 300 Protozoan, 281, 300, 315 Proximal, 31, 57, 64, 107, 128, 174, 256, 298, 300, 306 Proxy, 22, 300 Pruritus, 289, 300, 316 Psychic, 283, 300, 305 Psychoactive, 300, 312, 319 Psychology, 256, 300 Public Health, 214, 300, 313 Public Policy, 213, 300 Publishing, 61, 300
335
Pulmonary, 13, 26, 32, 82, 135, 167, 186, 197, 240, 279, 300, 301, 310, 317 Pulmonary Artery, 197, 240, 301, 317 Pulse, 284, 301 Purified Insulins, 298, 301 Purifying, 155, 167, 168, 301 Purines, 192, 238, 301, 306 Pyridoxal, 68, 252, 266, 301, 314 Pyridoxal Phosphate, 68, 252, 301 Pyrimidines, 238, 301, 306 Pyrogenic, 44, 301 Q Quaternary, 299, 301 Quiescent, 52, 301 Quinidine, 247, 301 Quinine, 83, 247, 301 R Race, 283, 301 Radiation, 48, 58, 186, 252, 258, 261, 263, 264, 272, 276, 277, 301, 302, 319 Radiation therapy, 261, 272, 276, 277, 301, 319 Radioactive, 268, 271, 273, 276, 277, 284, 289, 301, 302, 319 Radioimmunotherapy, 273, 302 Radioisotope, 188, 302 Radiolabeled, 277, 302, 319 Radiotherapy, 241, 277, 302, 319 Randomized, 257, 302 Reactive Oxygen Species, 8, 10, 13, 20, 48, 175, 302 Reagent, 52, 126, 157, 170, 252, 256, 302 Receptors, Serotonin, 302, 306 Recombinant, 4, 19, 33, 46, 72, 96, 103, 116, 150, 153, 160, 161, 167, 168, 191, 193, 302, 317 Recombinant Proteins, 160, 302 Recombination, 46, 145, 249, 265, 302 Rectum, 236, 248, 255, 263, 264, 274, 278, 299, 302 Recur, 293, 302 Recurrence, 245, 293, 302 Red blood cells, 49, 185, 260, 291, 302, 305 Red Nucleus, 237, 302 Reductase, 4, 24, 27, 50, 64, 79, 130, 163, 179, 185, 232, 303, 312 Reentry, 10, 303 Refer, 1, 162, 184, 241, 248, 266, 280, 288, 302, 303, 314 Reflex, 202, 303 Refraction, 235, 286, 303, 308 Refractory, 58, 257, 303
Regeneration, 31, 159, 172, 263, 303 Regimen, 257, 292, 303 Reperfusion, 10, 39, 175, 286, 303 Reperfusion Injury, 10, 39, 175, 303 Repressor, 35, 289, 303 Reproductive system, 57, 303 Respiration, 28, 186, 242, 262, 284, 303 Respiratory failure, 26, 303 Retina, 249, 250, 254, 278, 286, 287, 303, 304 Retinal, 180, 255, 290, 303, 304 Retinoid, 36, 304 Retinol, 36, 95, 303, 304 Retinopathy, 4, 232, 254, 304 Retroviral vector, 130, 265, 304 Retrovirus, 13, 304 Reversion, 65, 98, 304, 316 Rhabdomyosarcoma, 45, 304 Rhamnose, 290, 304 Rheology, 156, 304 Rheumatoid, 9, 23, 163, 182, 291, 304 Rheumatoid arthritis, 9, 23, 163, 182, 304 Rhodopsin, 290, 303, 304 Ribonucleic acid, 63, 304 Ribose, 6, 126, 230, 304 Ribosome, 157, 304, 314 Rigidity, 295, 304 Risk factor, 39, 96, 202, 272, 299, 304 Rod, 99, 238, 247, 304 Rotenone, 126, 304 S Saccule, 304, 317 Saline, 234, 304 Saliva, 304, 305 Salivary, 42, 91, 196, 253, 262, 304, 305, 310 Salivary glands, 42, 196, 253, 262, 304, 305 Saponins, 305, 309 Schizogony, 40, 185, 305, 308 Schizoid, 305, 319 Schizophrenia, 305, 319 Schizotypal Personality Disorder, 305, 319 Sclerosis, 5, 59, 79, 163, 305 Screening, 152, 165, 187, 190, 247, 305 Sebaceous, 254, 277, 305 Sebaceous gland, 254, 277, 305 Secondary tumor, 283, 305 Secretion, 16, 23, 47, 116, 131, 246, 259, 270, 275, 276, 283, 285, 305 Secretory, 16, 81, 91, 99, 102, 232, 305, 311 Segregation, 302, 305 Seizures, 57, 104, 235, 292, 305 Selenium, 64, 119, 202, 305
336
Cysteine
Selenocysteine, 50, 64, 109, 305 Semen, 299, 305 Semisynthetic, 50, 273, 277, 306 Senile, 290, 306 Sensor, 36, 60, 94, 306 Sepsis, 174, 306 Septal, 125, 306 Septal Nuclei, 125, 306 Septic, 163, 306 Sequencing, 179, 306 Sequester, 306, 311 Serologic, 273, 306 Serotonin, 17, 288, 302, 306, 315 Serous, 258, 306 Serum, 47, 79, 94, 95, 99, 146, 231, 234, 248, 249, 264, 272, 280, 293, 306, 315 Serum Albumin, 95, 99, 306 Shock, 38, 94, 138, 163, 180, 306, 315 Shunt, 26, 306 Side effect, 57, 153, 207, 231, 239, 252, 306, 314 Signal Transduction, 7, 48, 49, 54, 168, 274, 295, 306 Skeletal, 49, 125, 197, 247, 286, 301, 307 Skeleton, 50, 230, 307 Skull, 290, 307, 311 Small intestine, 29, 246, 257, 271, 276, 307, 315 Smallpox, 59, 307, 316 Smooth muscle, 33, 47, 172, 233, 234, 241, 242, 250, 270, 307, 310 Sneezing, 294, 307 Sodium, 17, 29, 57, 60, 301, 307, 310 Soft tissue, 241, 307 Solid tumor, 194, 234, 240, 307 Solium, 67, 307 Solvent, 4, 255, 260, 290, 307, 312, 315 Soma, 307 Somatic, 73, 170, 282, 284, 293, 307 Sorbitol, 232, 307 Soybean Oil, 297, 308 Spasmodic, 294, 308 Spasmogenic, 234, 308 Specialist, 219, 255, 308 Specificity, 15, 18, 19, 20, 24, 38, 49, 60, 87, 90, 93, 165, 170, 173, 178, 188, 231, 232, 242, 244, 308 Spectrophotometry, 32, 308 Spectroscopic, 14, 281, 308 Spectrum, 154, 283, 308 Sperm, 57, 81, 230, 246, 266, 297, 308 Sperm Head, 230, 308
Sperm Maturation, 57, 308 Spermatids, 174, 308 Spermatocytes, 308 Spermatogenesis, 174, 308 Spermatozoa, 306, 308 Spinal cord, 59, 237, 245, 246, 264, 283, 287, 293, 303, 308 Spinous, 259, 278, 308 Sporadic, 287, 308 Sporozoite, 185, 308 Squamous, 74, 110, 190, 260, 308, 309 Squamous cell carcinoma, 74, 110, 190, 260, 308 Squamous cells, 308, 309 Stabilization, 62, 169, 309 Steel, 151, 247, 309 Stellate, 96, 309 Stem Cells, 9, 260, 293, 309 Steroid, 31, 55, 109, 193, 251, 305, 309 Stimulant, 241, 270, 277, 309, 317 Stimulus, 26, 126, 257, 261, 276, 278, 303, 309, 312 Stomach, 138, 229, 238, 255, 264, 265, 271, 293, 307, 309, 318 Stomatitis, 167, 309 Stool, 248, 278, 309, 311 Strand, 38, 51, 297, 309 Streptococcal, 24, 44, 86, 108, 309 Streptococci, 86, 309 Streptococcus, 44, 66, 82, 95, 108, 288, 309 Stress, 10, 14, 20, 24, 31, 32, 38, 41, 48, 53, 154, 155, 244, 251, 291, 304, 309 Stria, 306, 309 Stroke, 21, 39, 55, 113, 138, 162, 176, 186, 212, 243, 309 Stroma, 161, 309 Stromal, 159, 309 Structure-Activity Relationship, 14, 310 Subacute, 75, 274, 310 Subclinical, 274, 305, 310 Subcutaneous, 257, 289, 292, 310 Submandibular, 42, 310 Submaxillary, 259, 310 Subspecies, 308, 310, 316 Substance P, 283, 305, 310 Substrate Specificity, 15, 18, 25, 91, 100, 165, 183, 310 Sulfur, 56, 64, 65, 66, 119, 146, 163, 164, 185, 261, 310 Sulfuric acid, 55, 310 Superoxide, 5, 38, 59, 79, 126, 310 Superoxide Dismutase, 5, 59, 310
337
Supplementation, 125, 130, 131, 132, 133, 153, 163, 310 Suppression, 8, 153, 183, 265, 310 Surfactant, 71, 310 Sweat, 254, 310 Sweat Glands, 254, 310 Sympathomimetic, 256, 260, 289, 311 Symphysis, 299, 311 Symptomatic, 291, 311 Synapse, 231, 287, 298, 311, 315 Synapsis, 311 Synaptic, 16, 17, 161, 180, 288, 307, 311 Synaptic Transmission, 17, 288, 311 Synaptic Vesicles, 181, 311 Syncytium, 169, 311 Synergistic, 38, 99, 311 Systemic, 20, 37, 79, 208, 236, 240, 260, 274, 277, 301, 309, 311, 314, 316, 319 Systolic, 272, 311 T Taurine, 84, 104, 125, 127, 143, 311 Temporal, 165, 233, 270, 311 Tenesmus, 257, 311 Teratogenic, 232, 311 Terminalis, 306, 311 Terminator, 248, 311 Testicular, 59, 311 Testis, 174, 311 Testosterone, 303, 312 Tetrachloroethylene, 27, 312 Tetracycline, 5, 63, 257, 312 Tetrahydrocannabinol, 242, 312 Thalamic, 237, 312 Thalamic Diseases, 237, 312 Theophylline, 301, 312 Therapeutics, 17, 45, 67, 79, 93, 107, 160, 174, 176, 208, 312 Thermal, 39, 235, 256, 288, 312 Thioredoxin, 48, 50, 64, 312 Threonine, 36, 127, 163, 171, 174, 193, 300, 306, 312 Threshold, 261, 272, 312 Thrombin, 165, 262, 263, 296, 299, 300, 312 Thrombomodulin, 299, 312 Thrombosis, 21, 105, 106, 275, 299, 309, 312 Thromboxanes, 237, 312 Thylakoids, 245, 313 Thymidine, 192, 313 Thymidine Kinase, 192, 313 Thymidylate Synthase, 9, 65, 107, 313 Thymus, 273, 280, 313
Thyroid, 71, 113, 276, 313, 316 Thyroxine, 232, 294, 313 Tick Control, 196, 313 Tick-Borne Diseases, 238, 313 Ticks, 196, 313 Tissue Culture, 43, 313 Tolerance, 230, 266, 313 Tone, 161, 313 Tonic, 243, 313 Tonus, 313 Topical, 133, 201, 237, 255, 260, 271, 291, 314 Topotecan, 49, 314 Torsion, 274, 314 Toxicity, 5, 31, 59, 96, 107, 111, 159, 161, 193, 195, 243, 257, 283, 295, 314 Toxicology, 8, 16, 30, 72, 77, 79, 80, 85, 99, 107, 109, 116, 214, 314 Toxin, 11, 32, 73, 259, 273, 313, 314 Trace element, 246, 247, 314 Trachea, 313, 314 Traction, 247, 314 Transaminase, 65, 314 Transcriptase, 107, 304, 314 Transcription Factors, 58, 183, 199, 289, 314 Transduction, 30, 34, 48, 306, 314 Transfection, 45, 240, 265, 314 Transfer Factor, 273, 314 Transferases, 64, 267, 314 Transfusion, 161, 261, 270, 314 Translation, 19, 157, 169, 265, 314 Translational, 24, 44, 45, 265, 315 Translocating, 31, 315 Translocation, 31, 37, 55, 315 Transmitter, 229, 237, 256, 276, 282, 287, 289, 311, 315 Transplantation, 88, 246, 273, 281, 315 Trauma, 173, 238, 286, 291, 312, 315 Trees, 247, 315 Triad, 132, 315 Trichloroacetic Acid, 72, 315 Trichloroethylene, 27, 30, 315 Trichomoniasis, 80, 315 Tricyclic, 14, 315 Triglyceride, 236, 272, 315 Trisomy, 234, 315 Trophic, 10, 48, 315 Trypsin, 6, 63, 165, 172, 247, 259, 315 Tryptophan, 6, 18, 161, 163, 171, 189, 248, 306, 315 Tuberculosis, 24, 285, 315
338
Cysteine
Tumor model, 193, 315 Tumor Necrosis Factor, 21, 315 Tumour, 84, 264, 315 Tunica, 285, 316 Tunicamycin, 131, 316 Typhimurium, 20, 65, 316 Tyrosine, 5, 10, 22, 32, 35, 64, 65, 111, 124, 153, 157, 168, 173, 256, 295, 299, 316 U Ubiquitin, 37, 110, 316 Ulcerative colitis, 23, 274, 316 Unconscious, 234, 253, 316 Univalent, 271, 291, 316 Uraemia, 291, 316 Ureters, 316 Urethra, 293, 299, 316 Urinary, 45, 71, 109, 111, 112, 113, 131, 316, 319 Urinary tract, 45, 316 Urine, 76, 83, 88, 161, 235, 240, 259, 316 Urothelium, 45, 316 Uterus, 245, 250, 253, 290, 298, 303, 316, 317 V Vaccination, 59, 187, 316 Vaccine, 40, 184, 192, 196, 231, 316 Vaccinia, 60, 290, 316 Vaccinia Virus, 60, 316 Vacuole, 7, 25, 317 Vagina, 190, 245, 254, 303, 317 Vaginal, 37, 189, 190, 317 Valine, 171, 292, 317 Variola, 59, 316, 317 Vascular, 47, 101, 137, 159, 161, 172, 234, 254, 258, 259, 272, 274, 288, 295, 296, 317 Vascular endothelial growth factor, 172, 317 Vasculitis, 291, 317 Vasodilation, 161, 317 Vasodilator, 241, 256, 270, 286, 317 Vasomotor, 70, 105, 317 Vector, 162, 185, 192, 275, 314, 316, 317 Vein, 75, 234, 276, 289, 292, 317 Venous, 240, 299, 317 Venter, 317 Ventral, 150, 272, 317 Ventricle, 233, 270, 272, 301, 311, 317 Ventricular, 11, 31, 286, 317 Ventricular Remodeling, 11, 317 Venules, 241, 242, 258, 317 Vertebrae, 308, 317
Vesicular, 167, 283, 307, 317 Vestibule, 67, 304, 317 Veterinary Medicine, 213, 317 Viral Hepatitis, 101, 318 Viral Load, 132, 318 Virion, 169, 238, 318 Virulence, 7, 19, 25, 44, 113, 238, 314, 318 Virus, 13, 37, 59, 61, 63, 64, 66, 73, 86, 88, 107, 114, 128, 162, 167, 169, 187, 189, 190, 192, 229, 242, 251, 265, 267, 270, 271, 275, 290, 292, 295, 304, 307, 314, 316, 317, 318, 319 Viscera, 307, 318 Visceral, 81, 278, 318 Viscosity, 152, 229, 304, 318 Viscotoxin, 129, 318 Vitamin A, 274, 304, 318 Vitreous, 255, 278, 303, 318 Vitro, 5, 6, 7, 8, 13, 14, 15, 16, 21, 23, 35, 37, 38, 42, 45, 46, 49, 53, 56, 57, 65, 71, 77, 86, 93, 94, 101, 103, 168, 176, 180, 187, 193, 265, 270, 274, 313, 318 Vivo, 5, 6, 7, 8, 10, 11, 13, 14, 15, 16, 23, 27, 35, 36, 39, 42, 45, 46, 49, 50, 53, 55, 56, 57, 65, 67, 75, 79, 116, 133, 153, 161, 168, 174, 176, 180, 265, 270, 274, 290, 312, 318 Voltage-gated, 51, 60, 97, 103, 318 Volvulus, 15, 318 W Wart, 202, 318 White blood cell, 230, 235, 240, 246, 280, 281, 284, 285, 286, 288, 295, 318 Whooping Cough, 294, 318 Windpipe, 313, 318 Withdrawal, 10, 48, 319 Womb, 303, 316, 319 Wound Healing, 159, 263, 275, 282, 319 X Xanthine, 54, 319 Xenobiotics, 21, 28, 319 Xenograft, 235, 315, 319 X-ray, 14, 30, 193, 263, 277, 289, 301, 302, 319 X-ray therapy, 277, 319 Y Yeasts, 264, 294, 319 Yolk Sac, 262, 319 Z Zoster, 86, 319 Zygote, 249, 308, 319 Zymogen, 12, 66, 83, 181, 246, 299, 319
339
340
Cysteine
