METHIONINE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
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., 1960Methionine: 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: 0-497-00723-1 1. Methionine-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 methionine. 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 METHIONINE ............................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Methionine .................................................................................... 5 E-Journals: PubMed Central ....................................................................................................... 66 The National Library of Medicine: PubMed ................................................................................ 75 CHAPTER 2. NUTRITION AND METHIONINE................................................................................. 123 Overview.................................................................................................................................... 123 Finding Nutrition Studies on Methionine................................................................................. 123 Federal Resources on Nutrition ................................................................................................. 126 Additional Web Resources ......................................................................................................... 127 CHAPTER 3. ALTERNATIVE MEDICINE AND METHIONINE .......................................................... 129 Overview.................................................................................................................................... 129 The Combined Health Information Database............................................................................. 129 National Center for Complementary and Alternative Medicine................................................ 130 Additional Web Resources ......................................................................................................... 144 General References ..................................................................................................................... 150 CHAPTER 4. DISSERTATIONS ON METHIONINE ............................................................................ 151 Overview.................................................................................................................................... 151 Dissertations on Methionine...................................................................................................... 151 Keeping Current ........................................................................................................................ 152 CHAPTER 5. PATENTS ON METHIONINE ....................................................................................... 153 Overview.................................................................................................................................... 153 Patents on Methionine............................................................................................................... 153 Patent Applications on Methionine ........................................................................................... 171 Keeping Current ........................................................................................................................ 191 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 195 Overview.................................................................................................................................... 195 NIH Guidelines.......................................................................................................................... 195 NIH Databases........................................................................................................................... 197 Other Commercial Databases..................................................................................................... 199 The Genome Project and Methionine......................................................................................... 199 APPENDIX B. PATIENT RESOURCES ............................................................................................... 205 Overview.................................................................................................................................... 205 Patient Guideline Sources.......................................................................................................... 205 Finding Associations.................................................................................................................. 207 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 209 Overview.................................................................................................................................... 209 Preparation................................................................................................................................. 209 Finding a Local Medical Library................................................................................................ 209 Medical Libraries in the U.S. and Canada ................................................................................. 209 ONLINE GLOSSARIES................................................................................................................ 215 Online Dictionary Directories ................................................................................................... 215 METHIONINE DICTIONARY.................................................................................................... 217 INDEX .............................................................................................................................................. 305
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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 methionine 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 methionine, 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 methionine, 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 methionine. 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 methionine, 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 methionine. 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 METHIONINE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on methionine.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and methionine, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “methionine” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Importance of Amino Acid Supplements for Dialysis Patients Source: For Patients Only. 14(2): 13-14. March-April 2001. Contact: Available from For Patients Only. 18 East 41st Street, New York, NY 10017. (818) 704-5555. Fax (818) 704-6500. Summary: Amino acids are required by everyone, not just people on dialysis, to maintain body tissues and to promote a normal rate of growth. However, amino acids are removed from the blood during dialysis. This article reviews the importance of amino acid supplements for dialysis patients. Amino acids are the building blocks of protein, and amino acid supplements can be thought of as predigested protein. Eggs, milk, cheese, meat, poultry, and fish are considered good quality protein because they provide essential amino acids. Essential amino acids are those that cannot be made in
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sufficient amounts by the body and must be present in the diet. They include L histidine, L isoleucine, L leucine, L lysine, L methionine, L phenylalanine, L threonine, L tryptophan, L tyrosine, and L valine. The author explains why serum albumin levels are measured and why low serum albumin (SA) levels are a concern; dialysis patients with a low SA level have more frequent and longer hospitalizations, and increased incidence of infection as well as a greater risk of dying. Low SA levels have also been independently associated with decreased physical and social functioning or a poor quality of life. The author concludes by describing how amino acid supplements can help patients improve serum albumin levels without increasing the quantity of food eaten or the amounts of liquids ingested each day. Amino acid supplements are available to kidney patients in two forms: Aminess N tablets and Nutramine T powder. 6 references. •
Emerging Cardiac Risk Factors Source: Patient Care. 35(10): 38-40, 43-44,46, 49-50. May 30, 2001. Contact: Available from Medical Economics. 5 Paragon Drive, Montvale, NJ 07645. (800) 432-4570. Fax (201) 573-4956. Summary: Recent findings support the existence of additional cardiac risk factors, traits that might allow better identification of patients who are at risk for a heart attack. This article summarizes the findings regarding four of those risk factors: C reactive protein (CRP), homocysteine, lipoprotein a, and fibrinogen. The research in CRP supports the intriguing theory that, like rheumatoid arthritis, atherosclerosis is an inflammatory disease. A number of prospective studies indicate that as levels of CRP rise, so does the risk of a future myocardial infarction (MI, heart attack) or stroke. The CRP test described in the article is not the same assay used to assess inflammation due to other causes, such as rheumatic disease or acute infection. Homocysteine is generated during metabolism of methionine, an essential amino acid. Research has shown that rises in fasting homocysteine levels increased the likelihood of coronary heart disease (CHD). Ingestion of folate reduces homocysteine levels, regardless of the process responsible for elevations. Although lipoprotein A levels do not fluctuate in response to low density lipoprotein (LDL) and high density lipoprotein (HDL) concentrations, their atherogenic (creating heart disease) effect is blunted with LDL concentrations are reduced. Fibrinogen, a plasma protein, has been implicated in other processes that fuel vascular disease. As with other emerging risk factors, fibrinogen can be brought under control when the traditional risk factors (smoking, weight problems, lack of exercise) are addressed. 2 tables. 21 references.
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Functional Vitamin B12 Deficiency and Alzheimer Disease Source: Neurology. 58: 1395-1399. May 2002. Summary: This article explores the association between Alzheimer's disease (AD) and vitamin B12 deficiency. Moderately elevated total serum homocysteine is associated with an increased risk of atherothrombotic vascular events. Accordingly, serum homocysteine is increased in patients with vascular dementia but is also increased in clinically diagnosed and histologically confirmed AD. It is generally considered that homocysteine accumulation increases the potential for endothelial and neuronal oxidative damage in these diseases. A complementary model of oxidative stress-induced hyperhomocystinemia is proposed by the authors. The hypothesis accounts for several unusual features relating to single-carbon metabolism and AD, including the absence of macrocytic anemia in these patients. It is suggested that cerebral oxidative stress
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augments the oxidation of an intermediate form of vitamin B12 (cob[I]alamin) generated in the methionine synthase reaction, thereby impairing the metabolism of homocysteine. Oxidative stress also compromises the intraneuronal reduction of the vitamin to its metabolically active state. Currently available pharmaceutic forms of vitamin B12 are unlikely to be utilized by neurons under these conditions. Glutathionylcobalamin might be preferable for the treatment of such patients. 3 figures, 32 references. (AA). •
Methotrexate for Inflammatory Bowel Disease: Pharmacology and Preliminary Results Source: Mayo Clinic Proceedings. 71(1): 69-80. January 1996. Summary: This article reviews the limited published experience with methotrexate treatment for inflammatory bowel disease (IBD). The authors examine the proposed anti-inflammatory and immune-modifying mechanism of action and pharmacologic properties of methotrexate, and detail its limiting toxicities. Long-term low-dose methotrexate therapy (25 mg or less once a week) inhibits production of thymidylate, purines, and methionine, and leads to accumulation of adenosine, a potent antiinflammatory substance. These actions inhibit cellular proliferation, decrease formation of antibodies, and decrease production of mediators of inflammation such as interleukins and eicosanoids. Three uncontrolled trials and two controlled trials have demonstrated efficacy of low-dose methotrexate therapy for inducing remission in Crohn's disease and possibly in ulcerative colitis. Methotrexate may also help maintain remission for both diseases. Although methotrexate is generally well tolerated for longterm use at low dose, several serious toxicities potentially limit its use.
Federally Funded Research on Methionine The U.S. Government supports a variety of research studies relating to methionine. 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 methionine. 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 methionine. The following is typical of the type of information found when searching the CRISP database for methionine:
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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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Project Title: A BACTERIAL FACTORY FOR PRODUCTION OF MEMBRANE PROTEINS Principal Investigator & Institution: Laible, Philip D.; None; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: (verbatim from the applicant's abstract) Membranes and the proteins embedded within them compartmentalize specialized machinery that provides the means by which cells and organelles communicate, generate energy, take up nutrients, excrete wastes, transduce signals by transporting metabolites between internal compartments, and build gradients of ions (and other small molecules) which are used to fuel all normal cellular activities in healthy organisms. Structural information for membrane proteins is exceedingly scarce - it is notoriously difficult to purify quantities of native material that are sufficient for crystallization attempts. Today's methods for the overproduction of protein cannot deal with membrane proteins, thus this important class is virtually ignored. In order for significant advances to be made, innovative strategies are needed rather than incremental advances in existing technology. We have exploited the unique physiology of the Rhodobacter species of photosynthetic bacteria to overexpress heterologous proteins, and have recently shown that a human outer membrane protein is expressed and incorporated into induced membranes of this organism. We now propose to develop this system to be a general one for the expression of functional membrane proteins - from any organism - in quantities that are sufficient for biochemical studies and crystallization trials for structure determination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: A RANDOMIZED, CONTROLLED TRIAL FOR HOMOCYSTEINE Principal Investigator & Institution: Bostom, Andrew G.; Associate Professor of Medicine; Rhode Island Hospital (Providence, Ri) Providence, Ri 029034923 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JAN-2006 Summary: (Adapted from the application) This multicenter, randomized, double-blind controlled clinical trial has been designed to determine whether total homocysteine (tHcy)-lowering treatment with a standard multivitamin augmented by a high dose combination of folic acid, vitamin B12, and vitamin B6, versus treatment with a standard multivitamin devoid of these three B-vitamins, reduces the pooled rate of recurrent and de novo cardiovascular disease outcomes (i.e., pooled occurrence of non-fatal and fatal arteriosclerotic outcomes, including coronary heart, cerebrovascular, and peripheral vascular disease events= primary outcome), among clinically stable renal transplant recipients who have mild to moderately elevated tHcy levels. The basic eligibility criteria are age 35 to 75 years old, functioning renal allograft for greater than six-months with serum creatinine based creatinine clearance greater than 30 mL/min, and a screening random tHcy level greater than12 uM/L. Patients will be stratified based on the presence/absence of clinical CVD, and randomly assigned to treatment with a standard multivitamin containing a high dose combination of folic acid, vitamin B6, and vitamin B12, or an identical multivitamin devoid of these three micronutrients. Randomized patients will also undergo a methionine loading test. All patients will receive standard clinical management for traditional CVD risk factor reduction. The study is designed to recruit 4000 patients (2000 in each group) over a two-year period for 83% power to detect a 25% treatment effect. Follow-up continues until occurrence of de novo or recurrent non-fatal CVD, or death, or a maximum of four-years. Data analysis will be performed on the basis of original randomization (intention to treat)
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using the log-rank test of difference in survival-without-endpoint curves. In the current era of cereal grain flour fortified with physiologic amounts of folic acid, RTRs comprise a patient population particularly well-suited to test the tenable hypothesis that tHcylowering treatment will reduce CVD outcomes, given: a) their persistent excess prevalence of mild hyperhomocysteinemia post-fortification, in contrast, for example, to coronary heart disease patients with normal renal function; b) the demonstrated capability of B-vitamin treatment regimens featuring supraphysiologic amounts of folic acid to successfully "normalize" tHcy levels in RTRs. Furthermore, overall "conditions" in the RTR population (i.e., renal impairment, mild to moderate hyperhomocysteinemia which can be normalized by supraphysiologic dose B-vitamin supplements, and high CVD event rates) are representative of the larger population of patients with chronic renal insufficiency, who are not yet dialysis-dependent. Accordingly, findings from the proposed trial are very likely to be generalizable to the much more sizable population of patients with renal insufficiency progressing to end-stage renal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACCESSORY CELLS FOR IMMATURE T LYMPHOCYTES Principal Investigator & Institution: Staerz, Uwe D.; Chairman and Chief Scientific Officer; Institute for Therapeutic Biology 1899 Gaylord St Denver, Co 80206 Timing: Fiscal Year 2004; Project Start 01-FEB-1991; Project End 31-MAR-2009 Summary: (provided by applicant): The focus of this research grant has been the study of cellular interactions that guide T lymphocyte development in the thymus. In our last competitive renewal application (1997), we had argued that to understand positive selection, a natural, i.e. physiological, ligand of positive selection had to be identified. We had hypothesized that this goal could be best achieved, if by design the number of peptide candidates was severely limited. We had therefore proposed to produce a T cell antigen receptor transgenic (TCRtrans+) mouse using a CD8 + cytotoxic T lymphocyte (CTL) cell line that recognized peptides presented on the non-classical MHC class Ib molecule H2-M3 wt. This experimental design was based on the rational that H2-M3 wt MHC molecules preferentially bound peptides carrying a formylated Methionine (fM) in the N-terminal position. We had predicted further that in the thymus an H2-M3 with restricted CTL was selected on endogenous fM-peptides, whose only source were the thirteen genes of the mitochondrial genome. As originally proposed, we established an H2-M3 wt-restricted CTL line (C10.4), identified its cognate fM peptide (AttM), produced a C10.4 TCR transgenic mouse (C10+) and defined its physiological ligand of positive selection as the ND1 fM-peptide (ND1). Having identified the positively selecting and the cognate ligand during the previous funding period, we now present experiments aiming further to analyze how recognition of these ligands is used to guide thymic selection. To be able to control thymocyte recognition events, we have now reduced the complexity of C10+ thymic selection model to a two-cell in vitro thymic selection system, in which cloned lines of thymic epithelial cells (TECs) supported the selection and maturation of double positive (DP) into single positive (SP) thymocytes. We will provide evidence that this C10+ in vitro thymic selection model offers unique opportunities to define how thymic recognition events are translated into the development of T cells. More specifically, we are proposing to investigate how antigen recognition, accessory cell functions, signal delivery and thymocyte maturation states are integrated to guide the selection, maturation and lineage commitment of alpha/betaT lymphocytes in the thymus. Since it has not been established that thymic selection of MHC class II-restricted T lymphocytes fully mimicked that of MHC class I-restricted T
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lymphocytes, we will adapt our in vitro thymic selection model to be used with H-2Ekrestricted AND TCRtrans+ (AND+) T cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ADOHCY HYDROLASE INHIBITORS AS ANTIPARASITIC AGENTS Principal Investigator & Institution: Borchardt, Ronald T.; Solon E. Summerfield Distinguished Profe; Pharmaceutical Chemistry; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2003; Project Start 01-DEC-1980; Project End 31-JAN-2007 Summary: (provided by applicant): S-Adenosyl-L-homocysteine (AdoHcy) hydrolase (EC 3 3 1 1) in mammalian cells and certain parasites [e.g., Leishmania, Plasmodium, Trypansoma] plays a key role in controlling the intracellular levels of AdoHcy by catalyzing its metabolism to homocysteine (Hcy) and adenosine (Ado). By controlling intracellular levels of AdoHcy, this enzyme plays a pivotal role in regulating Sadenosyl-L-methionine (AdoMet)-dependent methyltransferases which are crucial for the viability of mammalian cells and parasites (e.g., AdoMet-dependent methyltransferases in parasites are involved in mRNA capping and in trans-splicing). When these biochemical processes are inhibited by elevating intracellular levels of AdoHcy using known inhibitors of human AdoHcy hydrolase, antiparasitic effects were observed in vitro and in vivo. These results suggest that, if specific inhibitors of parasite AdoHcy hydrolases could be designed, they would have clinical potential as antiparasitic agents. Crucial for the clinical success of these compounds would be their lack of inhibitory effects on human AdoHcy hydrolase, thus, minimizing toxic effects to mammalian cells. Recently, our laboratory has cloned and overexpressed AdoHcy hydrolases from Leishmania (L) donovani and Trypansoma (T) cruzi and differences in their binding of NAD + compared to the human enzyme (i.e., the Kd for binding of NAD+ to human AdoHcy hydrolase is 120 nM compared to Kd values of approx 1-2 uM for the parasite enzymes) were observed. These differences in NAD+ affinity explain why 3'-deoxyadenosine (3'- deoxy-Ado) is a potent inhibitor of the L donovani and T cruzi enzymes but it has no effect on the human AdoHcy hydrolase. Based on these important new discoveries, we plan during the next grant period to (i) optimize the structural features of 3'-deoxy-Ado for binding to the NAD+ binding site of L donovani, T cruzi, as well as Plasmodium (P) falciparium, AdoHcy hydrolases, (ii) to elucidate the structural basis for the differences in the binding of NAD + to the human and parasite enzymes, and (iii) to elucidate the relationships of structure, catalytic activity and susceptibility to inhibition and their differences between the human and parasite enzymes. The outcome of this research program should be the identification of specific inhibitors of parasite AdoHcy hydiolases that have clinical potential as antiparasitic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ALTERED METHIONINE METABOLISM IN ALCOHOLIC LIVER INJURY Principal Investigator & Institution: Lu, Shelly Chi-Loo.; Professor of Medicine; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (Adapted from the Applicant's Abstract): Altered hepatic methionine metabolism and hyperhomocysteinemia are well recognized in alcoholic liver disease
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but the exact mechanisms and pathogenetic consequences are not well defined. The protective mechanisms of SAM in alcoholic liver injury also remain ill defined. We hypothesize that abnormal hepatic methionine metabolism has important pathogenetic consequences in the development of alcoholic liver injury. This hypothesis is based on several novel key findings. First, using the Tsukamoto-French intragastric ethanolfeeding model, we observed a switch in the expression of methionine adenosyltransferase (MAT), the key enzyme that catabolizes methionine to form Sadenosyl-methionine (SAM) in both whole liver and Kupffer cells. In the liver, this was associated with decreased SAM level and global DNA hypomethylation. Second, homocysteine in pathologically relevant concentrations induced the expression of tissue inhibitor of metalloproteinases-4 (TIMP- 1) and a 1(I) procollagen in a hepatic stellate cell line and collagen production in primary cultures of hepatic stellate cells. The current proposal will extend these findings, test several hypotheses and examine the protective mechanisms of SAM. The aims are: 1) examine changes in hepatic methionine metabolism during the development of ethanol-induced liver injury and the effect of SAM treatment - using the intragastric ethanol and high fat feeding, define stagespecific changes in methionine metabolism, examine key enzymes that affect the steady state SAM and homocysteine levels, investigate consequence of these changes and the effect of SAM treatment; 2) define the role of homocysteine in ethanol-induced liver fibrosis -evaluate the effect of homocysteine on markers of fibrogenesis in primary cultures of stellate cells and examine biological markers such as collagen production and proliferation, test the hypothesis that there is increased homocysteine release from hepatocytes of ethanol-fed animals due to abnormalities in methionine metabolism, which can exert paracrine effects on stellate cells to induce fibrogenesis; 3) examine changes in MAT expression and SAM homeostasis in Kupffer cells during the course of ethanol-induced liver injury and the effect of SAM treatment - test the hypothesis that the switch in MAT expression in Kupffer cells may result in lower SAM level and induce TNF expression, examine the effect of SAM treatment on TNF expression in vitro in LPS-stimulated normal Kupffer cells, ex-vivo in Kupffer cells obtained from ethanol-fed animals, and in vivo, investigate the mechanisms of SAM's suppressive effect on TNF expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AMINO ACID THERAPY FOR HOT FLASHES/POSTMENOPAUSAL WOMEN Principal Investigator & Institution: Guttuso, Thomas J.; Neurology; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Hot flashes affect approximately 75% of postmenopausal women. Although hormone replacement therapy (HRT) is highly effective in reducing hot flashes, long-term HRT is associated with increased rates of breast cancer and heart disease. Safe, effective, and well-tolerated hot flash alternative therapies are needed. We have shown the anticonvulsant gabapentin to be effective in the treatment of hot flashes in postmenopausal women; however, 50% of patients receiving gabapentin reported side effects of sleepiness or dizziness. Gabapentin is known to bind to the alpha2delta subunit of voltage-gated calcium channels (VGCCs) in the central nervous system (CNS). The amino acids L-methionine and L-norleucine also bind to the alpha2delta subunit with high affinity. Recently, we have noted a 75-100% reduction in hot flash frequency among 5 women after initiating either open-label oral L-methionine or L-norleucine therapy. Long-term L-methionine therapy may carry
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increased cardiovascular risks by increasing serum homocysteine levels while Lnorleucine therapy will not increase homocysteine levels. Over the 5-year career development award, the applicant will principally pursue clinical research examining the safety, tolerability, and efficacy of L-norleucine therapy in hot flash treatment. The clinical research will be performed in the University's General Clinical Research Center under the mentorship of Drs. Kieburtz and Guzick. In addition to this clinical work, the applicant will concurrently pursue basic science training in the laboratory of co mentor Dr. Richfield on better elucidating the mechanism of action of L-norleucine therapy in the treatment of hot flashes and on optimizing future hot flash therapies. Direct mentored training will occur throughout the 5-year award. The applicant will participate in one clinical research meeting and one basic science journal club meeting every week. In addition, formal didactic training in epidemiology and neuroscience will occur at the University. The applicant will also attend two didactic training seminars in complementary & alternative medicine at The Osher Institute at Harvard Medical School and at the Duke Center for Integrative Medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIODYNAMICS: SPECTROSCOPY
VIBRATIONAL
ECHO
CORRELATION
Principal Investigator & Institution: Fayer, Michael D.; Chemistry; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 01-APR-2000; Project End 31-MAR-2008 Summary: Research is proposed to study dynamics and structure of biologically important systems including heme proteins, proteins with multiple metal centers, water in nanoscopic environments, and water-protein interactions in nanoscopic environments. Building on our current work and recent experimental and theoretical advances make possible the application of Vibrational Echo Correlation Spectroscopy, a powerful new approach to the study of these problems. Vibrational echo correlation spectroscopy with full phase information will be used to directly examine the structural degrees of freedom and dynamical interactions of biologically important systems in a manner that is akin to multidimensional NMR. The new research expands our currently successful application of multidimensional vibrational echo methods. Extending work on myoglobin-CO, mutants will be used to unravel structural dynamics throughout the protein. Experiments on hemoglobin-CO will relate the allosteric affect to protein dynamics at the active site and examine the temperature dependence of structural evolution. Cytochrome c mutant M80A, where the axial methionine residue is replaced with an alanine binds both CO and CN-, in the Fe+2 and Fe+3 oxidation states, respectively. This mutant will be studied to address fundamental dynamical differences that occur in the protein when the oxidation state of the heme group is changed. Proteins with multiple Cu centers will be studied. First, hemocyanin will be studied with CO bound at the active site, and insights into the active site protein dynamics gained from studies of hemocyanin will be applied to other binuclear copper proteins such as tyrosinase. The hemocyanin experiments are a precursor to the study of trinuclear Cu proteins such as laccase, ascorbic oxidase, and ceruloplasmin. Multiple azide anions will be bound to these electronically coupled Cu centers to study the dynamics and vibrational mode coupling between the azide ligands. Vibrational echo correlation spectroscopy provides a new type of analytical tool for the study of coupled metal centers that will also be applied to the several multiple metal centers in carbon monoxide dehydrogenasetacetyI-CoA synthase (CODH/ACS). Building on recent fundamentally new studies of water dynamics, the biologically important issue of the
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dynamics of water in nanoscopic environments will be studied. In addition, waterprotein dynamical interactions and water-protein hydrogen bond dynamics in nanoscopic water environments will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOINORGANIC COPPER COORDINATION CHEMISTRY Principal Investigator & Institution: Karlin, Kenneth D.; Professor; Chemistry; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-APR-1991; Project End 31-MAR-2007 Summary: (provided by applicant): The goal of the proposed research is to further develop fundamental aspects of copper coordination chemistry relevant to its essential role in the biochemical processing of dioxygen (O2) and nitrogen oxides (NOx). Many questions remain concerning copper(I)/O2 interactions, formation of adducts, derived structures and their associated spectrocopy, O-O bond cleavage, and substrate oxidation chemistries. These may also be relevant to situations of oxidative stress, e.g., in neurological disorders such as Alzheimer's or prion diseases. Copper-NOx investigations are relevant to the active site chemistry in nitrous oxide reductase, and the possibly crucial role of copper ion in nitric oxide (.NO) biochemistry, including (cysteine) thiol nitrosylation chemistry, or mediation of nitroxyl (NO-) chemistry and peroxynitrite oxidative stress. The research methods break down into sub-projects, directed along various themes, questions or chemical systems. These include, (1) amplification of basic Cu/O2 chemistry: study sub-millisecond CuI/O2 interactions by Cu(I)/carbon monoxide photochemical triggering, and ligand electronic effects on Cu/O2 binding and hydroxylation, (2) study of Cu-superoxides, (3) mechanistic investigation of Cun/O2 mediated substrate oxidations, including probing dicopper side-on peroxo vs. bis-mu-oxo interconversion, and protonation-reduction of Cu(III)2(O)2 moieties, (4) generation of relevant chemistry with methionine (thioether) type ligands, and O-O cleavage chemistry with Cu(n)-OOR species, (5) modeling of amino-acid modified Cu-protein active-site cofactors, their biogenesis and chemistry, (6) elucidation of copper ion chemistry with.NO, NO-, peroxynitrite, their relationship to Cu/O2 derived species, and study of Cu mediated dentirosylation, i.e., Cu(I) + RSNO, (7) development of O2-chemistry with tricopper Cu3-cluster complexes relevant to copper oxidases, and (8) elaboration of new Cu-sulfide chemistry and N2O reactivity relevant to nitrous oxide reductase. The proposed studies contribute to a broader understanding of copper biochemistry, to protein activation/reduction of O2 and/or NOx, as applied to other metals (i.e., heme or non-heme iron) and disease states. Potential applications include development of enzyme inhibitors and relevant disease therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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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
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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 •
Project Title: CATALYTIC MECHANISM OF BIOTIN SYNTHASE Principal Investigator & Institution: Jarrett, Joseph T.; Associate Professor; Biochemistry and Biophysics; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2004; Project Start 01-APR-1999; Project End 31-MAR-2008 Summary: (provided by applicant): Biotin is an essential vitamin used as a cofactor in carboxylation reactions central to human metabolism, particularly in enzymes involved in fatty acid biosynthesis, gluconeogenesis, and branched-chain amino acid catabolism. Biotin is biosynthesized in microbes and plants through a four-step pathway that terminates with addition of sulfur and formation of the thiophane ring. This sulfur insertion is an impressive feat of enzyme catalysis that requires removal of two unactivated hydrogen atoms from the substrate dethiobiotin. In E. coli, sulfur insertion is catalyzed by the homodimeric iron-sulfur protein biotin synthase (BS), requires flavodoxin and S-adenosylmethionine (AdoMet), and produces methionine and 5'deoxyadenosine. Collectively these traits indicate that biotin synthase is an AdoMetdependent radical enzyme that catalyzes reductive cleavage of the AdoMet sulfonium to produce 5'-deoxyadenosyl radicals. We have proposed and provided evidence for a mechanism in which AdoMet coordinates a [4Fe-4S] 2+ cluster and subsequent electron transfer into the AdoMet/[4Fe-4S] 2+ cluster complex results in production of a 5'deoxyadenosyl radical. This radical abstracts a hydrogen atom from the substrate, dethiobiotin, generating a substrate carbon radical. The substrate radical is quenched by a sulfur atom from the [2Fe-2S] 2+ cluster, generating 9-mercaptodethiobiotin as a discrete intermediate. A second AdoMet cleavage triggers a similar reaction sequence, leading to formation of the second C-S bond in the product biotin. We have solved the crystal structure of E. coil biotin synthase with substrates bound and the relative positions of the respective reactants strongly supports this mechanistic proposal. Armed with knowledge derived from the structure, along with the expertise we have developed in anaerobic biochemistry, we are poised to test several key aspects of this mechanism. First, we will use the structure as a guide and test the roles of several conserved protein residues in catalysis. Second, we have developed a half-turnover reaction that will allow us to study the formation of 9-mercaptodethiobiotin and the associated iron-sulfur cluster states using stopped-flow and quench-flow kinetic methods. Finally, since the mechanism we propose describes a single turnover that results in destruction of the [2Fe-2S] 2+ cluster, we are examining possible mechanisms for cluster reassembly that facilitate multiple enzyme turnovers in vivo. A detailed knowledge of the chemical requirements for production of 5'-deoxyadenosyl radicals and for controlled utilization of these radicals for substrate activation and biotin formation will contribute to our expanding understanding of the general features common to all radical enzymes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CONTROL OF ARG-2 GENE EXPRESSION IN NEUROSPORA Principal Investigator & Institution: Sachs, Matthew S.; Associate Professor; Environmental and Biomolecular Systems; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-MAY-1992; Project End 31-MAY-2006 Summary: (provided by applicant): The goal of this work is to understand how a peptide encoded by an upstream open reading frame (uORF) controls the movement of ribosomes on mRNA and regulates gene expression. The arginine attenuator peptide (AAP) is encoded by a uORF in mRNAs specifying a fungal arginine (Arg) biosynthetic enzyme and reduces gene expression when Arg is high. AAP-mediated regulation is observed in vitro using extracts from fungi and wheat germ. The nascent AAP causes the ribosome to stall in response to Arg. Stalled ribosomes block access to the downstream start coclon that initiates enzyme synthesis. The AAP is a unique eukaryotic peptide because its synthesis can arrest ribosomes involved in both termination and elongation. Its study provides exceptional opportunities to examine central translational processes that are still not understood. It will provide valuable information on events within the ribosome for evaluating the functions of antibiotics that interfere with translation. Since uORFs that control gene expression are found in animals, plants, fungi, viruses and bacteria, the proposed work is directly relevant to understanding these important regulatory elements.In a working model for regulation, the nascent AAP stalls the ribosome by adopting a conformation that, with Arg, interferes with decoding at the ribosomal A site, or with other steps crucial for translation. The proposed studies will test and refine models for AAP-mediated regulation. Specific aims are: 1. Directly examine the regulatory mechanism by (a) establishing whether stalled ribosomes contain the nascent AAP covalently linked to tRNA to determine whether peptidyl transferase activity is blocked, (b) using photocross-linking of the nascent chain to the ribosome to examine conformational changes in the interaction between the nascent AAP and the ribosome in response to Arg, (c) using photocros s-linking of Arg analogs to determine whether Arg interacts with the AAP or with the translational machinery, and (d) determining whether regulation requires only translational components conserved between prokaryotes and eukaryotes. 2. Examine mutations in nonsense-mediated mRNA decay (NMD) for their effects on mRNA stability and AAP-termination codon recognition. NMD mutations eliminate regulation by the uORF-encoded AAP in vivo. 3. Identify additional transacting genes important for translational control by examining mutations in fungi that affect Arg-specific regulation or translation in vivo for their effects on AAP-mediated ribosome stalling in vitro. Cloning and identification of the genes and analysis of their functions should provide a rational explanation of the mutations. 4. Obtain an in-depth understanding of regulatory function by mutational analysis of stalling sites in combination with the use of antibiotics affecting translation and trans-acting mutants affecting regulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENT OF NOVEL FLUORINATED AMINO ACIDS Principal Investigator & Institution: Goodman, Mark M.; Professor of Radiology; Radiology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 05-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): The objective of this research project is to develop [18F]radiotracers that can be used to image brain and systemic tumors in vivo based
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upon amino acid transport with the imaging technique Positron Emission Tomography (PET). Our approach will focus on the development of [18F]cyclobutyl and [18F]branched nonmetabolized amino acids that move across tumor capillaries by carrier-mediated facilitated transport involving either the "L" large-neutral amino acid or "A" alanine amino acid transport systems. Preliminary evaluation of amino acids labeled with positron emitters and which are substrates for the "L" and "A" transport systems have shown excellent potential in clinical oncology for tumor imaging in patients with brain and systemic tumors. The development of this class of radiotracers with optimal imaging properties remains an active area of investigation. Our choice of cyclobutyl and branched nonmetabolized amino acids as suitable radiopharmaceuticals for imaging tumors stems from our preliminary in vitro studies in rat 9L gliosarcoma cells demonstrating that fluorine containing cyclobutyl analogs show high and selective uptake by the type "L" transport system while the fluorine containing (R,S) alpha-amino isobutyric acid (AIB) analogs show high and selective uptake by the type "A" transport system. Secondly, our preliminary in vivo studies in rats with intracranial 9L rat tumor implants displayed high 6:1 tumor to brain ratios for [18F]cyclobutyl nonmetabolized amino acids and even higher 37-100:1 tumor to brain ratios for the [18F]AIB nonmetabolized amino acids. Finally, low uptake of the cyclobutyl analogs in the kidney, lungs and muscle in rats and low uptake of the AIB analogs in lungs and muscle strongly support our proposed studies to evaluate [18F]cyclobutyl/AIB analogs in tumor bearing mice implanted with human derived tumors in order to determine their potential as imaging agents for systemic solid tumors. The Specific Aims of this proposal are: 1) to synthesize nonmetabolized amino acids that have high uptake in human derived tumors and high selectivity for either the "L" large-neutral amino acid or "A" alanine amino acid transport systems; 2) to synthesize the precursors for 18F-labeling and to prepare the corresponding [18F]amino acids for the in vitro and in vivo evaluation studies; 3) to determine the uptake and transport mechanism of the [18F]amino acids in different tumor cell lines with different malignant phenotypes; 4) to determine the biodistribution and metabolic stability of the most promising "L"-type and "A"-type selective amino acids in tumor-bearing mice with human (DU145) prostate tumors, (SKOV3) ovarian tumors, (A549) lung tumors, (EB) colon tumors, (HTB-46) renal tumors, and (MDA MB468) breast tumors. Our hypotheses include: 1) [18F]cyclobutyl and [18F]AIB analogs will demonstrate high selectivity for the "L" and "A" transport systems, respectively in a number of common human tumors and high tumor to normal tissue ratios in vivo; 2) [18F]cyclobutyl and [18F]AIB analogs will provide clinically useful and important information, especially in brain, kidney, and prostate tumors, which cannot be obtained using other currently available imaging modalities including PET imaging with 2-[18F]FDG) or [11C]-methyl]- methionine or by contrast enhanced computed tomography (CT) and magnetic resonance imaging (MRI); 3) [18F]cyclobutyl and [18F]AIB analogs will provide substantial logistical and economic benefits for tumor imaging in a nuclear medicine clinic as compared to [11C]amino acids, due to the [18F] half-life (t1/2=110 min), a large number of doses can be prepared from a single batch production ,the alternative [11C] (t1/2=20 min,) can only provide relatively few doses from each batch production of [11C]amino acid. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIETARY & GENETIC CONTRIBUTIONS TO INTESTINAL TUMORIGENE Principal Investigator & Institution: Edelmann, Winfried; Associate Professor; Montefiore Medical Center (Bronx, Ny) Bronx, Ny 104672490 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008
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Summary: (provided by applicant): Project 1 is fundamental to the overall program. In this project, we will develop a matrix of data that defines how the major nutritional and genetic factors responsible for colonic cancer interact to alter intestinal homeostasis and probability of tumor formation. We will use three mouse genetic models: two already established and well characterized by us - the Apc1638 and the Muc2 mouse - and a third under construction, the Msh2G674S mutant mouse. Each of these will be compared to wild-type mice. Each model will be maintained on control AIN76A diet as well as a new western style high risk diet (nwdiet#1) that is sufficient to induce premalignant changes and tumor formation in wild-type mice - a diet high in fat and phosphate, low in calcium, vitamin D, choline, methionine and folate. Additional groups will consist of wild-type mice and each of the genetic models maintained on the nwdiet#1 with calcium and vitamin D reconstituted back to control levels, and for the Apc1638 mice and wild type mice, groups in which each of the other constituents of the nwdiet#1 will be reconstituted individually. The primary endpoint is tumor formation, with detailed, standardized analysis also carried out by the Histopathology Core to evaluate alterations in cell proliferation, apoptosis, lineage specific differentiation, and cell migration. The Genomics Core will perform microarray analysis utilizing RNA from each of four mice in each dietary/genetic group. Microarray analysis of the wild-type mice maintained on the control and nwdiet#1, as well as the nwdiet#1 with each component added back, has already been completed. The arrays are 27,000 member mouse cDNA arrays fabricated by the Albert Einstein Core Microarray facility, and the methodology for generation and analysis of the data has been well-established in our group. These data will be analyzed by the Genomics and the Biostatistics Cores in collaboration, and altered expression of important sequences confirmed through a combination of Real-Time PCR, laser capture microdissection and related methodologies in the Histopathology Core. The data will be fundamental in identifying genes and pathways that are modified by genetic and/or dietary factors in establishing relative risk for tumor formation, and the analysis will be instructed by microarray data bases we have already developed (published and unpublished) that dissect intestinal cell maturation pathways. These data will be highly interactive in interpreting similar data to be generated from biopsies of patients in Project 3. The data will also be integrated with data to be generated by the Genomics Core on genome wide alterations in methylation, to determine the extent to which altered gene expression is dependent upon altered locus methylation, and to identify subsets of genes regulated in this manner. Sequences identified in this Project will be prioritized for application of unique technological resources in the Genomics Core for functional studies, utilizing methods of Imaging of Transcription Sites in situ, and high-throughput Structural Proteomics. Finally, the tissue from the mice in this Project will be banked by the Histopathology Core. The tissues will be distributed to Project 2 for studies on the role of the ?-cateninTcf -- c-myc/cyclin D1/cdk4 -- p21/p27 pathway, and its intersections with machinery of the cell cycle, and investigation of a novel method of regulation of c-myc transcription by nutritional factors. The tissue is also used by the Histopathology Core for the generation of Tissue Arrays. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIETARY PROTEIN INTAKE AND HUMAN AA METABOLISM Principal Investigator & Institution: Young, Vernon R.; Professor of Nutritional Biochemistry; None; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 01-SEP-1983; Project End 31-MAR-2006
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Summary: This application concerns the dynamic aspects of whole-body acid metabolism in adult humans, with reference to the dietary importance of the nutritionally "dispensable" (non-essential) or "conditionally indispensable" amino acids. Our hypothesis is that, despite a constitutive capacity for de novo synthesis, their cellular availability for tissue/organ protein synthesis and other functions in vivo is determined by the nitrogen and amino acid composition of the diet. We also hypothesize that there is a strict dietary need for a preformed source of alpha-amino nitrogen, additional to that from the indispensable amino acids. A major focus here is on sulfur amino acid (SAA) interrelationships. We hypothesize that dietary cystine is a more efficient source as a glutathione (GSH) precursor than methionine. The SAA aims are: (i) to further explore the interrelationships between methionine and cysteine (or procysteine) intakes on methionine/cyst(e)ine and GSH metabolism in healthy adults, including measurement of isotopic enrichments of plasma homocysteine (hcy)and cystathionine; (ii) to measure rates of GSH synthesis using L-2 5-13C oxothiazolidine-4carboxylic acid (OTZ) as labeled precursor and to use L- 2-13C OTZ as a marker of GSH metabolism; (iii) to study the metabolism of homocysteine, using labeled metaprobes, in relation to SAA intake; (iv) to further refine and improve upon our tracer model of GSH metabolism using measurements of isotopic labeling in glutamyl-cysteine and cysteinyl glycine; (v) to begin to accumulate the data necessary for the eventual construction of a compartmental model of GSH metabolism. With respect to dietary alpha-amino acid nitrogen intake we will (i) use the 24h indicator (13C-leucine) amino acid oxidation technique to evaluate the requirement for a source of alpha-amino N, including an assessment of its role in GSH homeostasis and (ii) use of 15N-homoarginine as a metaprobe for assessing of arginine metabolism. The proposed studies will further establish the quantitative and metabolic role played by the non-specific nitrogen component of the "protein" intake in whole-body protein (nitrogen) and specific amino acid homeostasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOCTORAL TRAINING/BIOCHEMISTRY/TRANSSULFURATION ENZYMES Principal Investigator & Institution: Hudson, Andre O.; Biotech Ctr/Agric & Environ; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): The broad, long-term objective of the project is to understand the structure and function relationship of enzymes that catalyze reactions around cystathione, a central intermediate in the trans-sulfuration pathways that interconvert cysteine and homocysteine. The trans-sulfuration enzymes play important roles in supplying cysteine and methionine for growth and in regulating the homeostasis of these amino acids. Certain genetic diseases in humans, such as homocysteinemia, are caused by mutations in the genes for these enzymes.The specific aim of project is to characterize the enzymatic function and physiological role of a gene encoded by locus At1g33320 of the genetic model plant Arabidopsis thaliana. Based on sequence homology this gene was proposed to encode cystathionine gamma-synthase, a carbonoxygen lyase. However, preliminary evidence suggests that it functions as cystathionine beta-lyase, a carbon-sulfur tyase. This hypothesis will be examined by carrying out in vitro enzyme kinetic experiments, and by examining the function of the enzyme under in vivo conditions using a genetic complementation test. The physiological role of the gene product will also be explored by studying its expression, its subcellular
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localization, and by examining the phenotype resulting from knock-out mutation of the gene. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOUBLE-BLIND STUDY OF SAME VS ESCITALOPRAM IN MDD Principal Investigator & Institution: Price, Lawrence H.; Professor of Psychiatry; Butler Hospital (Providence, Ri) 345 Blackstone Blvd Providence, Ri 02906 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Major depressive disorder (MDD) is a common, typically recurrent and disabling disorder, costing the U.S. over $44 billion/year in direct and indirect costs, and with point prevalence rates estimated at 5%-9% for women, and 2%-3% for men. More than one third of patients suffering from MDD appear to use alternative therapies in the U.S. Routinely prescribed in Europe for nearly 30 years and released four years ago in the U.S. as an over-the-counter dietary supplement, s-adenosyl-l-methionine (SAMe) has gained significant popularity as an agent marketed for improving mood and emotional well being. A number of relatively small double-blind studies have shown that parenteral or oral preparations of SAMe, compared with a number of standard tricyclic antidepressants, were generally equally effective, and tended to produce fewer side effects A relatively smaller number of studies have also examined the efficacy of SAMe compared to placebo, with the majority of these studies showing a significant advantage of SAMe over placebo. The recent report of the Southern California Evidence-Based Practice Center for the U.S. Department of Health and Human Services [Agency for Healthcare Research and Quality (AHRQ Publication 2002; http://www.ahrq.gov) ] states that "The results of these studies justify additional randomized clinical trials to evaluate the efficacy and tolerability of SAMe for treatment of depression." No adequately powered placebocontrolled study of SAMe in depression has ever been conducted in the U.S. We therefore propose a five-year, placebo-controlled, two-site study to assess the efficacy and safety of SAMe and of a standard selective serotonin reuptake inhibitor (SSRI), escitalopram in outpatients with MDD. This proposal is a parallel comparison of the efficacy and safety of SAMe, escitalopram, and placebo, with a crossover phase during which non-responders to any of these three treatments receive open-label treatment with the combination of escitalopram and SAMe. It is important to assess the efficacy of this combination therapy because patients frequently self-medicate with SAMe during standard antidepressant treatment. The primary aim of the proposed study is to test the acute antidepressant efficacy and tolerability of both SAMe and escitalopram, each compared to placebo, for the treatment of MDD. Secondary aims are to assess the acute effects of SAMe or escitalopram vs. placebo on remission rates, quality of life, and psychosocial functioning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DRUG DISCOVERY AGAINST CRYPTOSPORIDIUM PARVUM Principal Investigator & Institution: Keithly, Janet S.; Director of Parasitology Laboratory; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2002; Project Start 10-MAR-2001; Project End 31-JAN-2004 Summary: Cryptosporidium parvum causes one of the opportunistic infections (0I) in AIDS patients for which no treatment is yet known. Although many drugs have been tested against this 0I. knowledge about the presence of target enzymes, biosynthetic pathways, and expression or regulation are virtually unknown. Our preliminary
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biochemical, molecular and ultrastructural data indicate that C. parvum has a mitochondrion for generating energy, and that an unusual fusion gene pyruvate: ferredoxin oxidoreductase/cytochrome P450 (PFO/P450) is important for its function. Unexpectedly. this apicomplexan PFO/P450 fusion most closely resembles that of Euglena gracilis. and in both, the C-terminus appears to function in methionine biosynthesis. C. parvum encodes S-adenosyl-methionine synthetase (SAMS) and Sadenosylhomocysteine hydrolase (SAHH). both of which are essential for its plant-like polyamine biosynthetic pathway. These genes appear to be functional since transcripts were detected by RT-PCR both in sporozoites and intracellular stages. Together this discovery suggests energy metabolism and polyamine biosynthesis in C. parvum are interrelated, thus different from that of humans. The long-term goal of this proposal is to determine whether these pathways in C. parvum can serve as a rational target for drug development. The specific aims of this application are: 1. Characterize the C. parvum SAHH, SAMS & PFO/P450 gene structure, transcription and subcellular localization during the life cycle of the parasite. 2. Elucidate the function of SAHH, SAMS, & PFO in vitro using recombinant proteins. 3. Determine whether CpSAHH and CpPFO/P450 can serve as rational targets for drug development by screening specific analogs against C. parvum in vitro and in vivo. Completion of these specific aims will either support or refute our hypothesis that energy metabolism and polyamine biosynthesis in C. parvum are interrelated and sufficiently different from humans to be exploited for chemotherapy. If the pathway is verified as a parasite-specific target, then a major obstacle in the treatment of this OI in AIDS patients will have been overcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LEISHMANIA
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Principal Investigator & Institution: Beverley, Stephen M.; Professor; Molecular Microbiology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-DEC-1984; Project End 31-DEC-2007 Summary: (provided by the applicant): Leishmania are important tropical parasites, causing disease in more than 10 million people worldwide; more than 400 million people are at risk for infection in endemic regions. Currently, there are no vaccines available against leishmaniasis, and the only approved chemotherapies are marginally effective, difficult to administer, and have significant toxicity. An underlying tenet of our work is that improved understanding of key pathways required for parasite virulence and viability may provide opportunities for the development of improved therapies; several of the pathways identified in this project offer good opportunities. Leishmania are pteridine auxotrophs and our studies have revealed a fascinating and unique complexity of pteridine salvage and utilization, involving specific transporters (BT1 and FT1) and reductases (PTR1 and DHFR-TS), and now we plan to study the enzymes that utilize pteridines for the synthesis of key metabolites, determine their role in metabolism, and assess their effect on parasite virulence and survival. Our previous studies revealed for the first time a role for biopterin specifically in parasite differentiation to the infective metacyclic stage, and possibly other pathways relevant to parasite infectivity and virulence. Our aims include: 1) Studies of the Leishmania requirement for tetrahydrobiopterin (H4B) throughout the infectious cycle, and how loss of the broad spectrum pteridine reductase PTR1 leads to elevated virulence in both fly and mammalian hosts. 2) Identification of enzymes that utilize H4B as cofactors and functional dissection of their role in parasite survival and virulence, including studies of a novel aromatic amino acid hydroxylase (AAAH). Significantly, WT Leishmania
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synthesizes catecholamines while aaahknockouts do not, and the role of parasitesynthesized catecholamines in virulence will be sought. 3) Studies of folate metabolic enzymes such as methylene tetrahydrofolate reductase and two isoforms of methionine synthase, which play key roles in intermediary metabolism and additionally may be targets of a new class of antifolates whose action is primarily outside of their ability to inhibit DHFR and PTR1. Powerful genetic and bioinformatic screens will be used to identify new biopterin and folate utilizing enzymes and drug targets in aims 2 and 3. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENZYMES IN THE CRYSTALLINE STATE Principal Investigator & Institution: Ludwig, Martha L.; Professor; Biophysics Research Division; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2004; Project Start 01-SEP-1977; Project End 31-AUG-2008 Summary: (provided by applicant): The long-term goal is to relate molecular structure to specificity and reactivity in selected enzymes, with an emphasis on enzymes that require vitamin-based cofactors or essential metals. Three of the enzymes to be studied, B12dependent methionine synthase (MetH), methylenetetrahydrofolate reductase (MTHFR), and betaine-homocysteine methyltransferase (BHMT), are key catalysts in the metabolism of one-carbon units and control the cellular and plasma levels of homocysteine and methionine. These metabolites are believed to be important indicators of risk for cardiovascular disease and neural tube defects. High-resolution xray analysis will be the primary tool to examine local and global conformation changes that are fundamental features of catalysis and control in these enzymes. Mutagenesis and biophysical techniques will also be employed to determine how these enzymes exploit conformation changes and how mutation leads to dysfunction. Descriptions of domain rearrangements will be obtained for B12-dependent methionine synthase (MetH), a prototype for complex proteins that undergo large domain movements. In MetH from E. coli, a large enzyme with four ligand binding modules, the B12-binding domain is required to move long distances to interact in turn with homocysteine, methyltetrahydrofolate, and S-adenosylmethionine. Structures of each module were determined earlier; the current goal is to understand how the modules interact and what drives their movements. Impairment of human methionine synthase, an ortholog of the E. coli enzyme, is responsible for many of the manifestations of B12 deficiency. Comparisons will be made with B12-independent methionine synthase, which catalyzes methylation of homocysteine without requiring an intermediate methyl carrier. Structure-function studies of human BHMT, an important enzyme in homocysteine homeostasis in liver, are aimed at understanding the conformation changes that produce ordered binding of substrates. The structure of methylenetetrahydrofolate reductase (MTHFR) from E. coli has been determined as a model for the catalytic module of human MTHFR, an enzyme that lies at a critical branch point in one-carbon metabolism and is allosterically controlled by S-adenosylmethionine. The bacterial model has been used to show how folates protect the activity of MTHFR, thereby lowering homocysteine levels. The larger human enzyme, containing both catalytic and regulatory modules, has now been expressed by our collaborators; structural studies are aimed at understanding the regulatory mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENZYMOLOGY OF HOMOSERINE ACYLATION IN METHIONINE BIOSYNT Principal Investigator & Institution: Born, Timothy L.; Chemistry and Biochemistry; George Mason University Fairfax, Va 220304444 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): The methionine biosynthetic pathway, absent in mammals, produces two compounds required for bacterial survival, methionine and Sadenosylmethionine. Disruption of this pathway prevents bacterial growth unless sufficient methionine is obtained from the environment. Therefore, enzymes in this pathway may potentially be targets for novel antibacterial compounds. The first unique step in methionine biosynthesis, acylation of the g-hydroxyl of homoserine, controls flux of homoserine into the pathway. This acylation is catalyzed by one of two enzymes, homoserine transacetylase (HTA) or homoserine transsuccinylase (HTS). The long-term goals of this project are to ascertain whether these enzymes are potential targets for antibacterial agents and to design inhibitors that will function as lead compounds. Initial kinetic characterizations of both enzymes have been reported. In this proposal three specific aims will be pursued. First, the amino acids comprising the Ser-Asp-His catalytic triad of HTA will be identified. This will be accomplished through the combination of sequence alignments, site-directed mutagenesis and steady-state kinetic characterization. Second, the active site residues of HTS, which are different from those of HTA, will be identified. This will be accomplished through a combination of sequence alignment, site-directed mutagenesis, chemical modification, and steady-state kinetic characterization. Third, structural analysis of HTA, HTS, and select mutants will be pursued in an effort to correlate function with structure. All three of these aims directly support the long-term goals of this project. The proposed experiments will be used to train both undergraduate and Master's level students in the area of biochemistry Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FOLATE, 1-CARBON NUTRIENTS, GENE VARIANTS & COLON CANCER Principal Investigator & Institution: Hunter, David J.; Director; Epidemiology; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 18-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Most of the over twenty epidemiologic studies that have examined the relationship between dietary folate intake and the risk of developing colorectal neoplasms, have reported that higher folate intakes are associated with lower risk. Animal studies, using either carcinogen-induced or genetically engineered rodent models of colorectal cancer, have indicated an inverse relationship between dietary folate and the risk of colorectal cancer. The folate metabolic pathway influences genomic methylation and the supply of nucleotides for DNA synthesis; these can also be influenced by adequacy of supply of vitamins B12, B6, and B2, all co-factors for critical enzymatic reactions in the pathway. The overall long-term objective of our Team is to establish the role of folate and other nutritional contributors to one-carbon metabolism in colorectal cancer by combining animal, mechanistic, human observational studies and clinical trials. We will accomplish this by establishing a Cooperative Specialized Center for the study of Folate, One carbon nutrients, Gene variants and Colorectal cancer. This Center will be a Collaborative Program between Harvard and Tufts Universities in Boston, Dartmouth University in New Hampshire, the International Agency for Research in Cancer and the University of Bergen in Europe, Variagenics Inc. in Boston,
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and the Division of Cancer Prevention and the Center for Cancer Research at the NCI. We are organized into three projects, developmental projects, and two cores. Project 1 will pool data from three large prospective cohort studies with 2,700 expected colorectal cancer cases to establish whether higher intake of folic acid reduces risk of colorectal cancer and examine whether this reduced risk is greater among persons with low methionine intake, low plasma folate, vitamins B12, B6, and B2 levels, consumers of more than one alcoholic beverage per day, and homozygotes for the methylenetetrahydrofolatereductase (MTHFR) C677T polymorphism, and compound heterozygotes for the MTHFR A1298C polymorphism. Project 2 will validate mouse models of colon carcinogenesis as systems to examine modification of risk by folate and other contributors to one-carbon metabolism. Project 3 will assess whether the degree of uracil misincorporation and genomic methylation in peripheral blood lymphocytes and distal colon biopsies represent biomarkers of one-carbon nutrient adequacy and colorectal adenoma risk, using data and samples from two randomized clinical trials of folate supplementation. The projects will be supported by innovative Developmental Projects. In initial Developmental Project 1 transgenic mice with the null allele of MTHFR, and the homologous C677T polymorphism; these mice will be available for incorporation into feeding studies in Project 2. In Developmental Project 2 we will explore five folate-metabolism genes for polymorphisms that influence plasma folate and homocysteine levels. All Projects will be supported by the Administrative and Statistical Core (based at the Harvard School of Public Health), and the Measurement Core (based at the Human Nutrition Research Center at Tufts University). These highly interrelated studies will help integrate epidemiologic and mechanistic observations and help provide a basis for public health recommendations on optimal levels of folate and B vitamin intake. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FOLIC ACID REQUIREMENTS AND ONE CARBON METABOLISM Principal Investigator & Institution: Shane, Barry; Professor and Chair; Nutritional Scis & Toxicology; University of California Berkeley Berkeley, Ca 947205940 Timing: Fiscal Year 2002; Project Start 01-JAN-1990; Project End 31-DEC-2004 Summary: Folylpolyglutamates are coenzymes in, and potential regulators of, a large number of reactions known collectively as one carbon (1-C) metabolism. These reactions which include the metabolic cycles for the synthesis of thymidylate, purines and the amino acids, methionine, serine and glycine, are compartmentalized in the mitochondria and cytosol of cells. This application is for the continuation of a series of studies aimed at investigating the control of the 1-C metabolism in cells and animals, and the role that mitochondrial folate metabolism plays in this process. The new application has five specific aims that are designed to test four hypotheses. The specific aims are: (1) to investigate the interrelationship between mitochondrial and cytosolic 1C metabolism; (2) to study the regulation of 1-C entry and loss from the folate pool via the two compartmental forms of serine hydroxymethyltransferase; (3) to study the heterozygous disruption of the mouse methionine synthase gene and other genes for folate-dependent enzymes on the flux of 1-C units through the various metabolic cycles; (4) to investigate the use of the mouse methionine synthase heterozygous knockout as a model for the pathological and metabolic effects of vitamin B12 deficiency; and (5) to examine the regulation of expression of methionine synthase, methylenetetrahydrofolate reductase and serine hydroxymethyltransferase and to clone and characterize additional other genes of folate-dependent 1-C metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE-ENVIRONMENT CARCINOGENESIS
INTERACTION
AND
COLON
Principal Investigator & Institution: Chen, Jia; Community and Preventive Med; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 21-SEP-1998; Project End 31-DEC-2003 Summary: Jia Chen received her Sc.D. in 1994 in the fields of Toxicology and Environmental Engineering from Massachusetts Institute of Technology. Since 1995 she has been working as a Research Associate in Medicine at Harvard Medical School and a Research Fellow at Harvard School of Public Health. She is interested in an academic research career in molecular epidemiology studying genetic susceptibility to cancer. David J. Hunter, MBBS, MPH, ScD, has extensive experience in chronic disease and molecular epidemiology. He has mentored numerous graduate students and postdoctoral fellows; two graduate students he co- supervised are now postdoctoral fellows in the NCI Genetic Epidemiology Program. He is a co-investigator of the Nurses' Health Study I and Health Professionals Follow-Up Study based at Harvard. Dr. Hunter is familiar with the research methods proposed in this project and he will oversee Dr. Chen's research activities and education. Dr. Chen proposes to use the resources of three large well-characterized cohort studies (the Nurses' Health Study I, the Health Professionals Follow-Up Study, and the Physicians Health Study) to prospectively assess gene-nutrient and other gene-environment interactions in the etiology of colorectal adenoma and carcinoma. Specifically, she will assess whether polymorphisms in the alcohol dehydrogenase type 3 (ADH3), cytochrome P450IIE1 (CYP2E1), and methylenetetrahydrofolate reductase (MTHFR) genes are associated with these cancers and whether they modify associations with intake of folate, methionine and alcohol, as well as other potentially carcinogenic or anticarcinogenic nutrients on risk of colon cancer and polyps. In addition, she will modify the existing PCR- RFLP based genotyping methods and adapt more flexible and efficient technologies while maintaining high accuracy. The proposed study would be valuable as positive associations would clearly implicate the substrates of the gene product as environmental carcinogenic exposures, clarifying colon cancer etiology and pointing to preventive dietary and other lifestyle modifications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METABOLISM
GENETIC
EFFECTS-FOLATE-DEPENDENT
ONE-CARBON
Principal Investigator & Institution: Gregory, Jesse F.; Professor; Food Science & Human Nutrition; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-DEC-2004 Summary: One-carbon (Cl) metabolism consists of the generation of carbon units for use in cellular processes including DNA synthesis, regeneration of methionine (Met) from homocysteine (Hcy), and methylation of many biological compounds. Conditions that impair one-carbon metabolism (e.g. folate deficiency) are associated with elevation in plasma Hcy and increased risk of vascular disease, certain cancers, and neural tube defects. A common mutation of methylene-tetrahydrofolate reductase (MTHFR), known as the "thermolabile" or C677T mutant, has been associated with elevations in plasma IIcy (especially in low folate status), lower plasma folate, altered distribution of erythrocyte folate, potentially increased risk of vascular disease, and decreased risk of colon cancer. The in vivo metabolic effects of the C677T mutation have not been determined directly. Our overall hypothesis is that the rate of acquisition and generation
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of methyl groups from serine (primary source of C1 units) is reduced in individuals homozygous for the C677T mutation, and that the genotypic effect is greatest when folate nutriture is inadequate. We also hypothesize that the rate of folate-dependent synthesis of nucleotides (purines and thymidylate) will be reduced in folate deficiency but may be enhanced by the C677T mutation. The proposed studies will determine nutritional and genetic dependence of the flow of Cl units from serine (Ser) to Met and from Ser to nucleotides. This protocol also will allow measurement of the transsulfuration pathway of Hcy catabolism important in disposal of excess Hcy. Specific aims. To determine: (a) The kinetics by which Ser serves as a donor of Cl units for methyl group synthesis and nucleotide synthesis and the possible degree of impairment caused by the C677T mutation and/or low folate status. (b) The influence of the C677T mutation and folate status on cellular Cl status as reflected by the distribution of folate species in erythrocytes. (C) The influence of the C677T mutation and folate status on homocysteine catabolism. (d) The relative contributions of cytosolic and mitochondrial metabolism in the generation of Cl units for synthesis of methyl groups and nucleotides. (e) The significance of mitochondrial glycine cleavage in generation of Cl units. Protocol: In the main protocol, healthy adequately nourished human subjects (20-30 yr) will be classified by MTHFR genotype, (homozygous control and homozygous mutant). Subjects will be given infusions with 13C-serine as primary precursor initially and following 8-wk dietary depletion of 120 ugld folate to evaluate the effect of nutritional and genotypic effects on Cl kinetics. Two variations of this study will be conducted to determine the relative roles of mitochondrial and cytosolic routes of Cl generation from serine and the role of the mitochondrial glycine cleavage pathway. In total, these studies will yield new functional data regarding the effects of folate deficiency, and the influence of common polymorphism of MTHFR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETICS OF PROSTATE CANCER RISK & AGRESSIVENESS Principal Investigator & Institution: Casey, Graham; Associate; Molecular Medicine; Cleveland Clinic Lerner Col/Med-Cwru Cleveland, Oh 44195 Timing: Fiscal Year 2003; Project Start 12-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): We hypothesize that multiple genes are involved in risk of prostate cancer and tumor aggressiveness and that many of these genetic risk factors will be represented by low penetrance gene mutations, each accounting for a small effect on risk. We propose to build upon two promising areas of our research program concerned with the influence of genes on prostate cancer risk and tumor aggressiveness. We have localized prostate tumor aggressiveness genes to 7q32-q33 and 19q13.1 through whole genome linkage analysis of sib pairs and loss of heterozygosity studies. We have identified a strong candidate, podocalyxin (PODXL), on 7q32-q33 in which in-frame deletions and SNPs independently are associated with markers of tumor aggressiveness. We will also build upon our studies investigating the impact of single nucleotide polymorphisms (SNPs) in candidate genes involved in metabolic pathways involved in prostate growth on prostate cancer risk and tumor aggressiveness. Thus our Specific Aims are: Specific Aim 1: To further characterize candidate prostate tumor aggressiveness loci identified through whole genome linkage analysis. We will determine whether PODXL functions as a prostate tumor aggressiveness gene by developing stable transfectants expressing wild-type or variant-containing PODXL and assessing their effect on in vitro and in vivo growth of prostate cancer cells. We will also determine PODXL expression in prostate tumors by in situ hybridization and immunohistochemical staining using tissue microarrays. We will further pursue the
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identification of the 19q13.1 aggressiveness gene using complementary approaches, including positional cloning methods and use of the public Human Genome Project (HGP) and Celera databases. The relationship between the 19q13.1 candidate gene(s) and prostate tumor aggressiveness will be evaluated by mutation analyses followed by association studies. Candidates will be further evaluated by in situ hybridization and immunohistochemical staining. Specific Aim 2: To determine the impact of single nucleotide polymorphisms (SNPs) in candidate genes on prostate cancer risk and tumor aggressiveness. We will study SNPs in candidate genes involved in 1) vitamin D metabolism (vitamin D receptor, 1-alpha-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24)), 2) insulin-like growth factor signaling (IGFBP-3), 3) folate metabolism (5,10Methylene-tetrahydrofolate reductase (MTHFR) and Methionine Synthase (MTR)), and 4) steroid hormone metabolism (CYP3A7). For SNP association studies, we will employ a fully recruited population consisting of 943 men in 431 families with at least one brother affected with prostate cancer. Epidemiologic and clinical data have been collected, as well as biospecimens and banked DNA. The relationship between these genetic factors and prostate cancer risk and aggressiveness will be statistically evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GONOCOCCAL INFECTION AND GENE EXPRESSION IN FEMALE MICE Principal Investigator & Institution: Jerse, Ann E.; Associate Professor; Henry M. Jackson Fdn for the Adv Mil/Med Rockville, Md 20852 Timing: Fiscal Year 2004; Project Start 01-FEB-1999; Project End 31-MAY-2009 Summary: (provided by applicant): The capacity of N. gonorrhoeae to evade innate defenses in the female genital tract is hypothesized to be multifactorial and complex. Antioxidant factors may protect gonococci from killing by reactive oxygen species produced by phagocytes. Sialyltranferase (Lst) and other factors promote evasion of complement-mediated defenses. Evidence that these factors protect gonococci against evasion of innate host defenses is based primarily on in vitro assays. With the support of the first award, we developed the first reproducible small animal model of gonococcal genital tract infection. This model provides us with a valuable and unique research tool to test gonococcal interactions with host innate defenses. To satisfy the need for in vivo studies on factors hypothesized to contribute to evasion of PMN and complementmediated killing, here we will i.) measure the relative contribution of the known antioxidant defenses of N. gonorrhoeae (catalase, cytochrome C peroxidase, manganese uptake, methionine sulfoxide reductase) in protection from killing by human PMNs and in survival during experimental murine genital tract infection. We will construct single and double mutants in genes hypothesized to directly defend against oxidative stress (kat, ccp, mntC, msrA), and test their capacity to survive opsonophagocytic killing by human and murine PMNs, and to infect normal mice and NADPH oxidase-deficient mice; ii.) define the role of gonococcal sialyltransferase in conferring resistance to opsonophagocytic killing by murine PMNs and in enhancing survival of N. gonorrhoeae in the murine lower genital tract We will determine if Lst-deficient gonococci are more senstive to PMN killing due to increased uptake or the induction of a stronger respiratory burst. We will utilize C3 and C4-deficient mice and NADPHdeficient mice to test predictions made from PMN killing assays, iii.) Determine the basis for the observed increased infectivity of anaerobically grown N. gonorrhoeae for estradiol-treated mice and for increased resistance to the bactericidal activity of normal human serum. We will test mutants in genes that may confer increased survival in vivo
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as identified by DNA microarray technology to see if they are responsible for anaerobically-induced increased infectivity. We will assess the role of anaerobically induced nitrite reductase (AniA) in conferring an advantage in vivo and increased resistance to serum by testing the infectivity of an aniA mutant in mice, and by utilizing AniA-specific antiserum to block interactions between anaerobically grown gonococci and complement. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: H2-M3 RESTRICTED T CELL RESPONSES Principal Investigator & Institution: Pamer, Eric G.; Professor/ Chief, Infectious Diseases; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-MAY-2005 Summary: (Adapted from the Investigator's abstract): MHC class Ib molecules are members of a diverse family of non-polymorphic proteins that present bacterial peptides to cytolytic T lymphocytes (CTL). The murine H2-M3 molecule is an MHC class Ib molecule that binds short, hydrophobic peptides that contain N-formyl methionine at the amino terminus. Murine infection with Listeria monocytogenes, an intracellular bacterium, elicits CTL that recognize bacterial N-formylated peptides complexed with the H2-M3 MHC class Ib molecule. To enable direct identification of H2-M3 restricted T cells during bacterial infection, tetrameric H2-M3 molecules were complexed with one of the N-formylated L. monocytogenes peptides. These studies demonstrated that H2-M3 restricted T cell responses following primary infection occur more rapidly than H2-KDa restricted T cell responses. H2-M3 restricted T cells are cytolytic and secrete gamma-interferon, suggesting they play an important role in bacterial clearance. Interestingly, H2-M3 restricted memory T cell responses are attenuated compared to H2-KDa restricted responses. The specific aims of this application are: 1) To characterize H2-M3 restricted CTL responses in liver and gut of orally infected mice, providing insights into the role of MHC class Ib restricted T cells responses at a mucosal site following the natural route of L. monocytogenes infection; 2) To determine the mechanisms responsible for accelerated H2-M3 restricted T cell responses during primary infection with L. monocytogenes; and 3) To investigate the basis for attenuated H2-M3 restricted memory T cell responses in mice reinfected with L. monocytogenes. The studies proposed in this application will provide an unprecedented view of MHC class Ib restricted T cell responses to bacterial infection and will test the hypotheses that H2-M3 restricted T cells play a prominent role in intestinal immunity and that intestinal bacterial flora can influence pathogen specific T cell repertoires. Additionally, these experiments may provide novel insights into the factors driving in vivo T cell expansion and memory generation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HOMOCYSTEINE AND COAGULATION IN SICKLE CELL DISEASE Principal Investigator & Institution: Balasa, Vinod; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2003; Project Start 11-JUL-2003; Project End 31-MAR-2008 Summary: The coagulation system and endothelial cells are believed to contribute to the vascular pathology of sickle cell disease (SCD). Elevated plasma homocysteine (Hcy) is associated with vascular disease and thrombosis in the general population and is believed to induce endothelial cell dysfunction and activate the coagulation system. Patients with SCD exhibit activation of coagulation and an increase in activated
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circulating endothelial cells (CEC). Preliminary data demonstrate that hyperhomocysteinemia (HHcy) is present in 38% of patients with SCD and that a majority (62%) of these individuals have pyridoxine deficiency, compared to race and age-matched controls. It is hypothesized that HHcy is associated with activation of coagulation and CEC in SCD and that a lowering of Hcy with pyridoxine supplementation will reduce this activation. Therefore, the aims of this study are to determine the following in patients with SCD: (1) prevalence of HHcy and its association with vitamin cofactor deficiencies (2) correlation of HHcy with activation of CEC and coagulation (3) responsiveness of HHcy to pyridoxine supplementation (4) correlation of a decrease in Hcy levels with reduction in the activation of CEC and coagulation. The following laboratory determinations will be made in patients with SCD and in race and age-matched controls: fasting and post-methionine load Hcy, levels of red cell folate, serum vitamin B12, pyridoxal 5'-phosphate, the C677T MTHFR genotype; markers of activation of coagulation (prothrombin fragment 1.2, thrombin:antithrombin complexes), and fibrinolysis (plasmin:antiplasmin complexes, D-dimer); enumeration of CECs and the presence of activation markers VCAM-1 and tissue factor on CECs. SCD patients with HHcy will be randomized to receive a 6-week trial of pyridoxine supplementation or placebo and levels of Hcy, pyridoxine, and determination of markers of activation of coagulation and CECs will be repeated. This study is a collaborative trial open to all the sickle cell centers and at least 248 SCD patients and 248 controls will be recruited. Hey levels will be regressed on age in the controls and 95% confidence intervals will be determined. The chi-square statistic will be used to test the difference. Linear regression will be used to determine the relationship between Hcy and the activation markers. Paired t-tests will be used to test the other hypotheses. Pyridoxine supplementation is a simple therapy with the potential to reduce thrombotic complications of sickle cell disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HOMOCYSTEINE, ER STRESS AND ALCOHOLIC LIVER INJURY Principal Investigator & Institution: Kaplowitz, Neil; Chief, Gastroenterology Section; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 31-MAR-2009 Summary: (provided by applicant): The pathogenesis of alcoholic liver disease (ALD) remains uncertain despite considerable recent progress. We present a new hypothesis which builds upon the known effect of alcohol on homocysteine metabolism by linking this to the ER stress response and consequent fatty liver, necrosis, and apoptosis which we have observed in the intragastric ethanol fed mouse model. Our preliminary results indicate that feeding betaine reverses the hyperhomocysteinemia, ER stress and liver pathology in response to alcohol. Five aims are proposed which build on this hypothesis and preliminary results. First, we will complete a detailed characterization of ethanolinduced ER stress including the cellular and zonal compartmentation alcoholic mouse liver, the effect of ethanol on the susceptibility to ER stress and apoptotic signaling, and the effect of ER stress on susceptibility to TNF. Second, we will attempt to ascertain the contribution of key components of the ER stress response to alcoholic liver disease by exploiting various mice which have gene deletions of specific components of the ER stress response (e.g. SREBP-1, CHOP, caspase 12) or other signaling mechanisms for regulating SREBP (LXRa null mice). Third, we will determine the mechanism of hyperhomocysteinemia in response to ethanol by assessing substrate pool sizes, homocysteine metabolizing enzyme expression and tracer kinetics. These studies will
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allow us to determine that the liver is the major source of homocysteine and whether decreased remethylation and/or transulfuration are primarily responsible for excess homocysteine. Fourth, we will determine the role of homocysteine in ethanol-induced ER stress. We will employ several different strategies to strengthen the evidence for linkage of homocysteine and the ER stress response to ethanol. We will determine if alcoholic liver injury is potentiated by concomitantly raising homocysteine with either excess dietary methionine or guanidinoacetate or use of cystathionine a- synthase +/mice. In addition, we will assess the effect of SAMe feeding on homocysteine, ER stress and liver injury and determine if TNF acts upstream of homocysteine by assessing homocysteine and ER stress in response to ethanol feeding in TNF-R1 null mice. Fifth, we will determine the mechanism of action of betaine feeding in protecting against ethanol by comparing it to taurine, dimethlysulfoniopropriate, and by determining if betaine protects in MAT1A null mice. In addition, we will assess the global effects of betaine feeding on hepatic gene expression to look for clues of alternative effects of betaine which might also contribute to its protective action. We anticipate that we will obtain important new knowledge which can be applied to the prevention and treatment of ALD Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HYPERHOMOCYSTEINEMIA IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Diaz-Arrastia, Ramon R.; Associate Professor; Neurology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2004 Summary: In the past years, two independent case control studies have established a correlation between elevated homocysteine levels and Alzheimer's Disease (AD). Since vitamin supplementation with folic acid, vitamin B12, and pyridoxine can lower homocysteine levels, this association raises the exciting possibility that polyvitamin therapy may decrease the incidence of AD. The goal of this proposal is to obtain pilot data necessary to design a large multicenter trial to determine whether vitamin therapy lowers the risk of AD. We plan to do this through the following specific aims: (a) Determine whether fasting or post-methionine load (PML) are best associated with AD. The published studies analyzed homocysteine levels in fasting or randomly drawn serum samples. Since many patients have elevations in homocysteine levels only after a methionine load, and both fasting and PML hyperhomocysteinemia may be associated with dementia, we will determine whether fasting hyperhomocysteinemia, PML hyperhomocysteinemia, or both, are linked to a higher risk of AD. We will also determine whether plasma levels of S-adenosylhomocysteine (SAH) and Sadenosylmethionine (SAM) are nire sensitive markers of functional hyperhomocysteinemia (b) Determine the relative importance of nutritional and genetic factors as determinants of hyperhomocysteinemia. Elevated homocysteine levels result from a complex interplay of genetic and acquired factors, and the link between hyperhomocysteinemia and AD has so far been reported only in Europeans. In an attempt to determine which of these factors is most important in an ethnically and culturally heterogeneous US population, we will administer a nutritional questionnaire and measure vitamin levels in our patients, as well as determine the allelic frequency of the C677T polymorphism of MTHFR, a major genetic determinant of hyperhomocysteinemia. (c) Determine whether vitamin therapy is effective in lowering homocysteine levels in patients with hyperhomocysteinemia. All subjects will be treated sequentially for 12 weeks first with low dose vitamin supplementation, followed by high-dose vitamin supplementation. The effectiveness, compliance rates, and potential
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side effects of these therapies will be monitored. Each of these specific aims is essential to rationally design a large multicenter trial to determine whether polyvitamin therapy lowers AD risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMAGING OF ONCOGENE ACTIVATION Principal Investigator & Institution: Vande Woude, George F.; Director, Bri Basic Research Program; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 14-JUN-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The primary aim of this study is to develop novel molecular imaging methodologies to visualize and measure the expression and activity of tyrosine kinase growth factor receptor in vivo. The Met tyrosine kinase growth factor receptor and its ligand hepatocyte growth factor/scatter factor (HGF/SF), important genes in development, tumorigenicity and metastasis, will serve as a model. We propose to evaluate and image the expression and activity of Met and HGF/SF both at the cellular and organism levels by comparing different imaging modalities (confocal microscopy, MRI, PET and ultrasound) to conventional biochemical analysis. Using imaging techniques with fluorescence and/or luminescence tagged Met and HGF/SF we will directly image and measure the presence of these important molecules in normal tissues and tumors. We will, in parallel, perform direct analysis of Met and HGF/SF in normal and tumor tissue by IP and western blot. We will use this information together with molecular imaging in animal models to evaluate and quantify the efficacy of both standard therapeutics (e.g. drugs, radiation and hormones) and neutralizing antibodies to Met and HGF/SF for potential utilization of imaging technologies in human cancer. Specific Aims: 1. We will measure Met interaction with its ligand (HGF/SF) and its signal transduction substrates at the sub-cellular level using fluorescence tagged proteins. 2. We will develop molecular imaging techniques to determine in animal models, the presence of Met and HGF/SF, using fluorescence tagged proteins in xenograph tumors and in transgenic and "knocked in" animals. These animals models should allow real-time observation of Met mediated tumorigenesis. 3) We will develop non-invasive "indirect" metabolic molecular imaging methodologies for assessing Met activity at the organism level and in tissues as well as during tumor formation. We wiill be measured real-time in vivo using imaging modalities of MRIBOLD, MRS,PET and Doppler ultrasound to assess their diagnostic potential. 4) We will quantify and characterize the combinatorial effect of a variety of Met signal transduction inhibitors in vivo on tumors and metastasis. The effects will be studied in animal models using direct and indirect molecular imaging modalities during therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMPACT OF PAH CARCINOGEN-DNA ADDUCTS ON DNA METHYLATION Principal Investigator & Institution: Geacintov, Nicholas E.; Professor; Chemistry; New York University 15 Washington Place New York, Ny 10003 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-JUL-2004 Summary: (provided by applicant) This research will be done primarily in Russia as an extension of NIH grant # R0l CA 20851. The methylation of DNA plays an important role in the control of gene expression in mammalian cells. The enzymes involved in this process are DNA methyltransferases (MTases) which recognize CpG sequences in DNA
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and catalyze the transfer of methyl group from S-adenosyl-L-methionine to form 5methylcytosine. In different types of tumors, aberrant or accidental methylation of CpG islands in the promoter region has been observed for many cancer-related genes resulting in the silencing of their expression. The polycyclic aromatic hydrocarbons (PAR) such as benzo[a]pyrene or dibenzo[a,1]pyrene are ubiquitous environmental pollutants. They are metabolized in vivo to highly genotoxic dihydrodiol epoxides (DE). Furthermore these diol epoxides bind to cellular DNA causing mutations, thus contributing to the initiation of tumorigenesis. The question how MTases function when carcinogen lesions are present in DNA is still open. It is generally assumed that the target cytosine flipping-out-mechanism, first found for HhaI Mtase occurs in the case of all cytosine-C5-DNAMtases from pro- and eukaryotes. Hence, one of the possibilities may be that distortions of DNA produced by bulky carcinogens which favor extrahelical position of cytosine (displacement of bases, bending, and destabilisation of the double helix) should facilitate DNA methylation. The purpose of this project is to reveal the relationship between DNA methylation and carcinogenic DNA modifications such as PAH lesions, taking prokaryotic cytosine-C5-DNA Mtases EcoRII, SssI and HhaI (recognition sites CCA/TGG, CG, and GCGC, respectively) as models. The general hypothesis to test is that PAR DE-modified DNA can be methylated by DNA MTases with different efficiencies as compared to unmodified DNA. Specific aim I is to obtain experimental evidences of base-flipping mechanism for EcoRII and SssI Mtases using kinetic and fluorescence studies of the interaction of these enzymes with 2-aminopurine or 2-pyrimidinone- containing substrates analogs. Specific aim 2 has several components: (i) synthesize a number of stereoisomeric carcinogen-modified substrate analogs of EcoRII, SssI and HhaI Mtases with PAH-guanine and PAH-adenine lesions positioned within the recognition sites of the enzymes, (ii) study PAR-DNA adduct conformations and thermodynamic stabilities, (iii) examine the binding of the adducts to the enzymes, and (iv) investigate the susceptibilities of carcinogen-modified sequences to methylation by the enzymes. The longer range goal of this project is to discover the relationship between the structural features of carcinogen-DNA lesions and the modified DNA sequences, the catalytic mechanisms of DNA methylation, and the susceptibilities of PAH-modified DNA sequences to methylation. The results should provide novel insights into the mechanisms of carcinogenesis associated with the formation of the stereoisomeric PAR diol epoxide-DNA lesions and their impact on biological methylation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHIBITION OF ANGIOGENESIS BY TNP 470 AND OVALICIN Principal Investigator & Institution: Liu, Jun O.; Professor; Pharmacol & Molecular Sciences; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 05-AUG-1998; Project End 31-MAY-2008 Summary: (provided by applicant): The post-translational processing of initiator methionine during protein synthesis is a universal biological process that is conserved from prokaryotes to eukaryotes. Methionine aminopeptidases are the enzymes catalyzing the removal of initiator methionine. One gene is known in prokaryotes while two genes are known in eukaryotes encoding methionine aminopeptidases. The importance of initiator methionine processing is underscored by the fact that deletion of the methionine aminopeptidase genes in either prokaryotes or eukaryotes is lethal. Of the two methionine aminopeptidase genes in eukaryotes, the type 2 enzyme (MetAP2) has been shown to be the direct target for the fumagillin family of angiogenesis inhibitors, including its analog TNP-470. Work in the past several years has provided
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Methionine
strong evidence that MetAP2 is a physiologically relevant target for TNP-470. It has also been found that inhibition of endothelial cell proliferation by TNP-470 is mediated by the tumor suppressor gene p53. Thus, TNP-470 is capable of activating p53, which induces the expression of p21that is responsible for the cell cycle blockade of endothelial cells. These studies reveal a unique role of MetAP2 in the progression of the endothelial cell cycle. Recently, a novel anticancer drug entering Phase II clinical trial known as bengamide was found to inhibit both MetAP2 and MetAP1 in vitro and to block cell cycle in both G1 and G2/M phase. It is hypothesized that MetAP1 may play a role in the cell cycle at the G2/M phase. The major objective of the current proposal is to further delineate the physiological functions of MetAP1 and MetAP2 employing yeast as a model system and to identify isoform-specific inhibitors for MetAP1 and MetAP2 by high throughput screens. The functions of the different domains in MetAP1 and MetAP2 will be investigated by creating various yeast mutants expressing different domains of these enzymes and determining the phenotypic changes using DNA microarray. The different known activators of p53 will be systematically examined to identify potential mediators of p53 activation by TNP-470. Molecular probes of bengamide will be prepared to confirm its interaction with MetAP1 and MetAP2. High throughput screens will be conducted to identify specific inhibitors for MetAP1 and MetAP2. The newly identified inhibitors for MetAP1 will be employed to assess the physiological role of MetAP1 in the cell cycle progression in the G2/M phase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION
INTEGRATIVE
NEUROBIOLOGY
OF
CARDIOVASCULAR
Principal Investigator & Institution: Abboud, Francois M.; Edith K. Pearson Professor; Iowa Cardiovascular Center; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-DEC-1976; Project End 31-DEC-2002 Summary: This Program Project renewal focuses on Integrative Neurobiology of Cardiovascular Regulation. It has represented the major scientific emphasis of the Cardiovascular Research Center at Iowa since 1971. The strong cohesive interactions between senior basic scientists and clinical investigators is complemented by innovative directions with the recruitment of outstanding new scientists. The scope extends from work in cellular/molecular biology to integrative neuroscience; from gene transfer in cultured cells to genetically engineered animals; and from studies in isolated systems to mechanistic research in humans. There are five major Projects, each with tightly related interactive Parts. "Central RAS and Cardiovascular Regulation" defines the central action of angiotensin by selective targeting of central nuclei for gene transfer, regulation of gene expression, chemical ablation and cellular electrophysiology. "Modulation of Sensory Inputs by CGRP" is a coordinated effort to explore the activation of trigeminal afferents by nociceptive stimuli and subarachnoid hemorrhage (SAH). Changes in the expression of CGRP may mediate the disabling autonomic responses to pain and the devastating vasospasm in SAH, and hold the promise of therapeutic gene transfer. In "Leptin and Central Autonomic Drive" the focus is on the effect of leptin, at the level of hypothalamus, in transducing the activation of sympathetic pathways. The availability of genetic models of obesity and the convergence of diverse scientific expertise, provide a unique opportunity to clarify the autonomic-leptin interaction, and to extend the work to obese humans. Our experience in the mechanisms of baroceptor activation and new interests in the biology and biophysics of ion channels will be merged on "Cellular/Molecular Mechanism of Mechanosensation and Excitation of Baroreceptor Neurons." Four separate but interrelated Parts will pursue the concepts that
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ENaC/degenerin family members are the BR sensors, and that methionine oxidationreduction is important in the regulation of BR ion channels by autocrine factors. These are novel and important concepts. "Nitrosyl Factors and Neurovascular Control" Extends ongoing work on the interaction between glutamatergic and nitroxidergic neurons in the NTS, which influences the central mediation of the baroreflex often impaired in hypertension and aging. A second Part addresses the novel hypothesis that "preformed stores"of nitrosyl factors, at the neuro-endothelial-vascular interface, represent a major mechanism of regulation of vascular tone. Essential Core functions will support these projects in the areas of "Imaging," "Transgenic Animals," and "VectorMediated Gene Transfer." The tract record of productivity, creative interactions, innovative concepts and state-of-the-art approaches promise the optimal realization of the work whereby the scientific outcome will be far greater than the sum of the components. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LIPOTROPE STIMULATES BREAST CANCER CELL DEATH Principal Investigator & Institution: Park, Chung S.; Professor; Animal and Range Sciences; North Dakota State University Fargo, Nd 581055756 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Lipotropes (methyl group containing nutrients including choline, methionine, folic acid, and vitamin B12) have been shown to have oncostatic action on mammary cancer. We hypothesize that excess lipotropes may alter expression of apoptosis-related genes including bcl-2 gene, via alterations in DNA methylation, and consequently increase the sensitivity of cancer cells to programmed cell death. Specific aims of the proposed study are: 1) to confirm if excess lipotropes increase the susceptibility of breast cancer cells to apoptosis, 2) to investigate if lipotrope-supplementation alters the expression of certain genes involved in the regulation of apoptosis, and 3) to examine if an excess of lipotropes affects genomic methylation patterns of apoptosis-related genes. Tamoxifen (TAM), an anti-cancer agent, will be used to induce apoptosis in breast cancer cells. Two breast cancer cell lines, MCF-7 and T47D, as well as a normal mammary cell line, MCF-10A, will be tested in this study. Cells will be cultured in preincubation medium until 80 percent confluent and then switched to apoptosis induction media (TAM added) with (treatment) or without (control) excess lipotropes. Apoptosis will be accessed by immunohistochemistry, electrophoretic DNA fragmentation patterns, and caspase assay. Expression of apoptosis-related genes will be elucidated by gene array methodology and Northern analysis. The genomic DNA methylation patterns of apoptosis-related genes will be analyzed by methylation specific PCR and HPLC. Direct molecular and biochemical information on the possible effect of excess lipotropes upon breast cancer cell death could ultimately lead to the development of dietary compounds and chemotherapeutic agents that would reduce and treat breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM OF BCL-X EXPRESSION IN LYMPHOCYTES AND CANCER Principal Investigator & Institution: Boise, Lawrence H.; Associate Professor; Microbiology and Immunology; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2003
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Methionine
Summary: (Adapted from Investigator's abstract): Programmed cell death or apoptosis is a cellular suicide process that is necessary to maintain homeostasis in multicellular organisms. In recent years several genes have been cloned that function to either induce or inhibit apoptosis. Many of these genes share homology with the anti-apoptotic oncogene bcl-2. One of these genes, bcl-xL, can function in a similar fashion as bcl-2, yet displays a different pattern of expression. Specifically in lymphocytes Bcl-2 is expressed at high levels regardless of the activation state of the cell while Bcl-xL is expressed only upon cell activation. In addition, upregulation of bcl-x but not bcl-2 occurs in tumor cells following irradiation or induction of multidrug resistance. The objectives of this proposal are to determine the molecular mechanisms by which bcl-x expression is regulated. Specifically to characterize the bcl-x promoter and determine the cis elements which are involved in regulation of gene expression during lymphocyte activation as well induction of drug resistance in tumor cells. A fragment of genomic DNA which extends 2.7 kb 5' of the start methionine has been isolated. This fragment has two putative TATA boxes within 1 kb of the start ATG. The first specific aim is to determine usage of these TATA boxes by primer extension analysis and RNase protection analysis. Functional analysis will be carried out by subcloning promoter fragments into reporter constructs and determining regions of the promoter required for responsiveness to different activation signals. In addition, the cloned fragment contains a GC rich region that displays differential methylation in drug sensitive and drug resistant cell lines. The final aim of this proposal is to determine the methylation pattern of the bcl-x CpG island by sequencing of sodium bisulfite-treated DNA to reveal methylation sites. The role of methylation of the CpG island on bcl-x expression will be determined by in vitro methylation of reporter constructs. While bcl-x overexpression has not been shown to lead to any specific tumors, it's expression has been demonstrated in several types of tumors including breast, prostrate and the Reed-Sternberg cells of Hodgkin's lymphoma. Understanding the mechanisms by which bcl-x is controlled may result in the development of ways to increase the efficacy of cancer chemotherapy through decreasing the apoptotic threshold of the tumor cell. In addition determination of the methylation state of bcl-x in tumors may be a good indicator of the outcome of cancer chemotherapy of a given tumor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISTIC STUDIES OF LIPOIC ACID SYNTHASE Principal Investigator & Institution: Booker, Squire J.; Assistant Professor; Biochem and Molecular Biology; Pennsylvania State University-Univ Park 110 Technology Center University Park, Pa 16802 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Lipoic acid is an essential sulfur-containing cofactor of several multienzyme complexes that are involved in primary metabolism. It has been known for a number of years to be derived directly from octanoic acid, but the mechanism of sulfur insertion into the unactivated fatty acid has remained obscure. Recently, a gene has been cloned which appears to be the catalytic core of the enzymatic activity that is involved in the sulfur insertion reaction. Signature motifs within its deduced primary sequence and initial spectroscopic characterization of the protein collectively indicate that this "lipoic acid synthase" belongs to an emerging class of enzymes that contain iron-sulfur clusters, and that use S-adenosyl-L-methionine as a means of generating carbon-centered radical intermediates in enzymatic reactions. The roles of S-adenosyl-L-methionine and iron-sulfur clusters in this class of enzymes represent departures from the roles that they have traditionally been assigned in
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biochemical textbooks. Iron-sulfur clusters have traditionally been thought of as electron transfer agents or Lewis acid catalysts, while S-adenosyl-L-methionine is still considered to be mainly a cellular methylating agent. The experiments proposed herein seek to reveal the "new" molecular enzymology associated with these cofactors. Several experimental mechanisms are discussed, and experiments are proposed that will distinguish among them. Aside from the involvement of lipoic acid as a cofactor in enzyme complexes of energy metabolism, it is known to modulate glucose metabolism in patients with type II diabetes and to serve as a general cellular antioxidant, among many other things. There is significant evidence that lipoic acid can be endogenously synthesized in mammalian cells. Experiments outlined in this proposal will lay a foundation upon which studies to address whether the inability to synthesize lipoic acid endogenously can lead to a compromising of cellular function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISTIC STUDIES ON A CO2+ DEPENDENT MAP FROM E COLI Principal Investigator & Institution: Holz, Richard C.; Associate Professor; Chemistry and Biochemistry; Utah State University 1415 Old Main Hill Logan, Ut 843221415 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2002 Summary: Thee long range goals of this research are to define the reaction mechanism and substrate specificity of the cobalt(II)-dependent methionine aminopeptidase from Escherichia coli (MAP). In eukaryotic as well as in prokaryotic cells, methiomine aminopeptidases selectively cleave methionine residues from the N-termini of terminal polypeptide chains. In the cytosol of eukaryotes, all proteins are initiated with an Nterminal methionine. The composition of mature N-termini play important roles in the directed degradation and cellular targeting of proteins involved in signal transduction, protein trafficking, cancer cell growth, and viral infection. Recently, one of the two MAP's found in yeast was shown to be the target of the angiogenic chemotherapeutic agents fumagilln and its analog AGM 1470. Therefore, MAP's appear to play a critical role in the proliferation of endothelial cells and likely serve as important targets for inhibiting the growth and proliferation of tumors. As isolated from several bacterial and mammalian sources, MAPs are maximally stimulated by two g-atoms of Co(II). On the other hand, the addition of Zn(II) or Mg(II) to apo- MAP's do not provide active enzymes. The MAP from E. coli has been shown by X-ray crystallography to contain a dinuclear cobalt(II) active site. Therefore, MAP is a member of a new class of cobaltcontaining enzymes that includes mammalian MAP' isolated from both porcine liver and humans. Our approach will be to utilize the X-ray crystal structures of the MAP's from E. coli and P. furiosus in conjunction with site mutagenesis, biochemical, and spectroscopic methods to gain fingerprints of each step in the catalytic mechanism. The MAP from E. coli is an ideal enzyme for a study of this type because it is small, highly soluble, readily available in large amounts, and is capable of being genetically manipulated. The specific aims of this proposal are to: 1) define the structural and magnetic properties of the dicobalt(II) an diiron(II) MAP enzymes, 2) characterize how substrate analog inhibitors interact with both the dicobalt(II) and diiron(II) MAP enzymes, 3) determine whether the nucleophilic hydroxide moiety, a key element in the proposed peptide bond cleavage mechanism, is coordinated to one or both metal ions in MAP, 4) prepare and purify variant enzymes with altered active site carboxylic acid, histidine, threonine, and tyrosine residues, 5) provide evidence for and propose a detailed mechanism for MAP. It is anticipated that the successful completion of the studies described in this proposal will provide new insights into the hydrolytic reaction
34
Methionine
catalyzed by MAP and will ultimately assist in the design and synthesis of new chemotherapeutic agents targeted specifically to MAP's. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METABOLISM AND EXCITABILITY IN RODENT HIPPOCAMPUS Principal Investigator & Institution: Williamson, Anne D.; Assistant Professor; Neurosurgery; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-JAN-2007 Summary: (provided by applicant): Both excitatory and inhibitory synaptic transmission rely on the supply of glutamate. Glutamate is synthesized de novo from glucose and also recycled through the glutamate-glutamine cycle between neurons and astrocytes. GABA used for synaptic transmission is also dependent on neuronal-glial cycling as GABA is synthesized from glutamate which can enter interneurons either via uptake or through glutamine. The main goal of this proposal is to test the broad hypothesis that cellular excitability is intimately tied to the status of glutamate-glutamine-GABA cycling and specifically that GABAergic transmission is more sensitive than excitatory transmission to disruption in cycling during periods of sustained neuronal activity because of the added energy-dependent steps needed for the synthesis of GABA. In Specific Aim 1 we will interrupt cycling a several different levels including blockade of the synthetic enzymes of glutamine, glutamate and GABA as well as by blocking glutamine uptake. The effect of these metabolic inhibitors on synaptic inhibition will be examined physiologically. In Specific Aim 2, we will use mass spectometry to measure the changes in the levels of glutamate, glutamine and GABA induced by alterations in neurotransmitter cycling in both the tissue and in the bathing medium to address the time-dependent changes in transmitter levels. In Specific Aim 3 will use 13C isomer spectroscopy to assess the effect of those compounds that cross the blood brain barrier (the GS inhibitor methionine sulfoximine and the glutamine transporter MeAIB) on glutamate-glutamine-GABA cycling in control animals. These experiments should provide important data on the regulation of normal synaptic transmission as well as an understanding of the pathology of a number of neurological disorders where changes in neural energetics have been seen including epilepsy, ALS and Huntington's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: METHIONINE RECYCLING PATHWAYS IN KLEBSIELLA Principal Investigator & Institution: Lawrence, Jeffrey G.; Biological Sciences; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2006 Summary: (provided by applicant): Sulfur is a critical component of numerous universally-distributed, indispensable biomolecules. In most bacteria, sulfur is assimilated organically into cysteine, which serves as the sulfur donor for all other sulfurbearing molecules in the cell. Methionine is made is a separately controlled process, using cysteine as a sulfur donor. Klebsiella aerogenes is distinct from the related model organism Escherichia coli in employing at least 2 distinct pathways to recycle methionine-bound sulfur back into the cysteine pool. One pathway appears specific in directing reverse transsulfurylation (creating cysteine from methionine), and the likely generates an inorganic sulfur intermediate from methanethiol. Therefore, sulfur amino-acid metabolism in E. coli - used as a model organism for understanding the physiology of numerous organisms by homology - represents remnant metabolism and provides an incomplete view of this universally distributed physiology. These
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recycling pathways may play a role in Klebsiella exploitation of a pathogenic lifestyle, where sulfur may be limiting, and may play significant roles in recycling abundant global pools of organic sulfur compounds. Using genetic and molecular methods, these recycling pathways will be examined. (1) The identified genes for cysteine and methionine biosyntheses will be characterized physically and genetically via insertion mutagenesis, gene knock-out and gene fusion. (2) Insertion mutagenesis will define each methionine recycling pathway genetically. Both enzyme assays and nutritional testing will elucidate the steps of each recycling pathway. (3) Fusions to the lacZ reporter gene will be used to identify global regulatory proteins, and to infer their synergistic modes of action. In this way, characterization of these pathways sheds light on the evolution of complex metabolism, and on the selective forces that lead to gene acquisition, gene loss, and genome change. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METHIONINE SULFOXIDE REDUCTION, SELENIUM AND AGING Principal Investigator & Institution: Gladyshev, Vadim N.; Biochemistry; University of Nebraska Lincoln Lincoln, Ne 685880430 Timing: Fiscal Year 2003; Project Start 15-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Methionine sulfoxide (Met(O)) reduction is an essential metabolic pathway that provides protection against oxidative stress and regulates protein function. Met(O) are formed in the presence of reactive oxygen species and are reduced back to methionine by peptide Met(O) reductases. One Met(O) reductase (MsrA) has been known for decades and has recently been shown to regulate lifespan in animals. MsrA, however, is only specific for methionine-S-sulfoxides. The P.I. identified and characterized a second mammalian Met(O) reductase (SelR1) that is specific for methionine-R-sulfoxides. SelR1 is a selenocysteine-contain Jng protein and dietary selenium affects its expression. This raises a possibility that SelR1 may also be involved in delaying the aging process through reduction in levels of Met(O) and that supplementation of diet with selenium may provide means of extending the lifespan of certain segments of the human population. To directly characterize the role of SelR1 in aging, the pathway of Met(O) reduction in mammals will be analyzed with an emphasis on the function of selenoproteinSelR1 and characterization of the lifespan of animals that are either deficient or enriched in SelR1. A combination of biochemical and cell biology approaches and mouse model systems will be used to address the following specific questions (specific aims): 1) What are the properties and reaction mechanisms of SelR1 and its homologs? Three SelR isozymes have been identified in mammals. Wildtype and mutant forms of these proteins will be characterized and their catalytic activities, substrate specificity, metal-binding properties and the ability to complement yeast strains determined; 2) What are the tissue expression patterns, cellular locations and regulation of expression of Met(O) reductases? Hypotheses will be tested that SelR isozymes are located in different cellular compartments and that a single MsrA gene gives rise to two forms of the enzyme. In addition, efficiency of selenocysteine insertion and regulation of SelR1 expression by dietary selenium will be determined; 3) What is the role of SelR in aging? SelR1 knockout mice will generated and the hypothesis tested that these animals are characterized by a reduced lifespan. Transgenic mice overexpressing SelR1 will also be generated to determine whether these animals have increased lifespan. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Methionine
Project Title: METHOD FOR NEONATAL SCREENING FOR HOMOCYSTINURIA Principal Investigator & Institution: Rozzell, James D.; President; Biocatalytics, Inc. Suite 103 Pasadena, Ca 91106 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-JAN-2003 Summary: (Applicant's description) In Phase 1 an enzymatic assay for homocysteine was developed with sensitivity down to concentrations of 10-20 micromolar, well below the range of 50-500 micromolar that is indicative of homocystinuria. The feasibility of a test strip for homocysteine detection was demonstrated using an immobilized form of the enzyme and a colorimetric visualization method, providing results within 20 minutes. In Phase 2, the test strip assay will be perfected for use in the neonatal screening for homocystinuria to replace the flawed Guthrie test, which cannot detect homocysteine. Immobilization of the enzyme will be optimized for loading and activity, and the visualization chemistry will be refined. Stability and shelf life will be evaluated and improved as necessary. Expression of the methionine gamma-lyase gene will be increased to reduce the cost of enzyme. The solution assay will be further developed to make the assay viable for routine blood testing. Enzyme selectivity for homocysteine will be enhanced by directed evolution of existing clones. Sample preparation procedures will be optimized to remove potentially interfering substances in physiological fluids. Sensitivity will be improved 5 to 10 fold using fluorescent substrates, with the goal of precise, reproducible quantitation of homocysteine down to the range of 5-10 micromolar. PROPOSED COMMERCIAL APPLICATION: Neonatal screening assay for homocystinuria; home and doctor's office test strip for measurement of L-methionine and L-homocysteine concentrations in urine or blood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: METHYLATION EPIDEMIOLOGY
AND
OXIDATION
IN
BREAST
CANCER
Principal Investigator & Institution: Freudenheim, Jo L.; Professor; Social and Preventive Medicine; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: (provided by applicant): There is considerable epidemiologic evidence that alcohol intake is related to risk of breast cancer and that intake of vegetables and fruits may reduce risk. Utilizing an existing case control study, we propose to examine two etiological mechanisms, one-carbon metabolism and/or oxidative stress and breast cancer. Our first aim is to examine the relation of elements related to one-carbon metabolism with risk. We propose a) to investigate genetic variation in enzymes important in one-carbon metabolism (methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MS) and cystathione B-synthase (CBS)) in relation to risk and to investigate interaction of these genetic factors with dietary folate and alcohol with breast cancer risk; b) to investigate the association of dietary folate and alcohol and these genetic factors with total p53 mutations and with particular p53 mutations and c) to investigate the association of dietary folate and alcohol and these genetic factors with hypermethylation of the p16 gene, the BRCA1 gene and the estrogen receptor gene in breast tumors. Our second aim is to examine elements related to oxidative stress and antioxidants with risk. We propose to a) examine the relation of genetic variation in an enzyme important in the control of oxidative balance (manganese superoxide dismutase (MnSOD)) and to examine interactions of this genetic factor with dietary factors both oxidants and antioxidants; and b) to investigate the association between dietary sources
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of oxidants and antioxidants with total and particular p53 mutations. By combining information on intake, genetic susceptibility and tumor characteristics, it will be possible to make clearer inferences about the role of these two mechanisms in breast cancer etiology, with potentially important public health implications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MINORITY PREDOCTORAL FELLOWSHIP PROGRAM Principal Investigator & Institution: Farias, Martin; Integrative Physiology; University of North Texas Hlth Sci Ctr Fort Worth, Tx 761072699 Timing: Fiscal Year 2002; Project Start 12-JUN-2002; Project End 31-JAN-2003 Summary: (provided by applicant): The long term objective of this proposal is to characterize the paracrine environment of the sinoatrial node of the dog. Specifically, we want to understand the actions of enkephalins and nitric oxide on heart rate control. We will use an innovative cardiac microdialysis technique to achieve this objective. We will also employ various agents such as NOS inhibitors and donors plus opioid agonists and antagonists to accomplish the following specific aims. This proposal will test the hypothesis that: MEAP acting on delta II opioid receptors located prejunctionally in the sinoatrial node suppresses vagal bradycardia by interrupting the NOcGMP pathway. 1. We will demonstrate that the delta II opioid receptor subtype is responsible for the vagolytic effect of nodal enkephalins. 2. That the NO-cGMP pathway in the SA node is required for normal vagal function in the dog. 3. That nodal MEAP suppresses vagal function by interrupting the NO-cGMP pathway. 4. That MEAP interrupts the NOcGMP pathway prejunctionally in order to attenuate vagal bradycardia. Information obtained from this work will provide new insights into cardiac pathologies that involve autonomic dysfunction and may allow the creation of innovative therapies to help treat such pathologies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FUNCTION
MODIFICATION
OF
ALPHA-CRYSTALLIN
CHAPERONE
Principal Investigator & Institution: Abraham, Edathara C.; Professor; Biochem and Molecular Biology; University of Arkansas Med Scis Ltl Rock Little Rock, Ar 72205 Timing: Fiscal Year 2002; Project Start 01-JUN-1996; Project End 31-MAY-2004 Summary: The objective of this proposal is to elucidate the effect of some common posttranslational modifications of alpha-crystallin (alphaA and alphaB) on the molecular chaperone property, i.e., the ability of alpha-crystallin to protect other proteins from denaturation and aggregation. By choosing biologically relevant modifications different domains of alphaA- and alphaB-crystallins will be targeted for in vitro structural modifications which in turn will be correlated with changes in chaperone function. Studying in vitro modification will facilitate the characterization of in vivo modifications that cause a decline in chaperone like property of human alpha-crystallin. This is the first study ever where posttranslational modifications that occur in vivo and that can be inflicted in vitro will be correlated with chaperone activity and chaperonetarget protein binding. The specific aims of this proposal are based on our most recent findings that glycation, oxidation and mixed disulfide formation have inhibitory effects on alpha-crystallin chaperone function and that both aging and diabetes decrease the chaperone property. The following specific aims are hypothesis driven, each designed to test a specific hypothesis: 1) In vitro modifications of calf or young human alphacrystallin by oxidation with H2O2, by glycation with ascorbic acid and fructose, and by
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Methionine
mixed disulfide formation with GSSG will be used to test the hypothesis that such posttranslational modifications will influence the chaperone function as determined by the ability of alpha-crystallin to protect beta- and gamma-crystallin from thermal denaturation and aggregation. In addition, we will study the combined effect of more than one type of modification hoping to show a synergistic effect by two treatments. 2) With both alphaL and alphaH fractions from 1 month to 90 years old human lenses it will be shown whether with increasing age increasing levels of posttranslationally modified alpha-crystallin with altered chaperone function accumulates. 3) Since diabetic lenses are exposed to higher levels of oxidation and glycation than age-matched nondiabetic lenses we will test the possibility that the alpha-crystallin chaperone function is altered even more in diabetic human or rat lenses. 4) We will identify the protein modifications in alphaA- and alphaB-crystallins that will be introduced in vitro or that occur in vivo by mass spectral analysis and correlate with changes in chaperone function including chaperone-target protein binding. These analyses will identify the types of modifications that produce a decrease in the chaperone property. 5) We will investigate the mechanism of the loss of chaperone function due to in vitro modifications or in vivo modifications during aging or diabetes. We will test the hypothesis that posttranslational modifications affect the chaperone-target protein binding leading to reduced chaperone function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR CARCINOGENESIS
MECHANISMS
OF
DIET-INDUCED
Principal Investigator & Institution: Jacob, Samson T.; Professor and Chairman; Molecular & Cellular Biochemistry; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Epidemiological and clinical studies have demonstrated that folate deficiency in humans could lead to susceptibility to certain types of cancers. Premalignant dysplasia could be reversed by folate supplementation. Elucidation of the molecular mechanisms underlying folate deficiency and predisposition to cancer is, therefore, of critical importance in determining the role of folate and other dietary elements in cancer prevention. An excellent rat model system is available to study the role of diet low in methionine, choline and folate (lipotrope-deficient or LD diet) on the induction of hepatocarcinogenesis in the absence of any exogenous xenobiotic agents. It is known that a key tumor suppressor (p53) gene is methylated in the hepatoma induced by LD diet. Using this model system, we will (a) explore by Bisulfite genomic sequencing and Ms-SNuPe (Methylation- sensitive single nucleotide primer extension) the methylation status of CpG dinucleotides on p53 promoter at different stages of hepatocarcinogenesis (b) investigate the role of methylation of specific CpG dinucleotides in p53 promoter inactivation by transient transfection assay (c) investigate the mechanism of methylation-mediated alteration in chromatin structure and identify the key factors involved in consequent silencing of p53 promoter with progression of tumorigenesis, by restriction endonuclease accessibility assay and chromatin immunoprecipitation (ChIP) with antibodies specific to methyl CpG binding proteins (MeCPs) (d) study the regulation of expression and activity of different DNA methyltransferase isozymes (involved in maintenance and de novo methylation) during hepatocarcinogenesis induced by LD diet (e) identify the proteins that interact with de novo methylases (f) clone the genes, specifically the three genes that are methylated in preneoplastic liver as detected by RLGS technique, identify them, investigate their expression levels at
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different stages of tumorigenesis and study functional significance of silencing of these genes in tumorigenesis. It is hoped that this study will yield important information concerning the relationship of folate/methyl deficiency to regional hypermethylation of growth/tumor suppressor genes or genes encoding proteins that suppress the growth regulatory genes at different stages of tumorigenesis, and their silencing that lead to tumor formation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CANCER
MOLECULAR-NUTRIENT
INTERACTIONS
IN
INTESTINAL
Principal Investigator & Institution: Augenlicht, Leonard H.; Professor and Director; Montefiore Medical Center (Bronx, Ny) Bronx, Ny 104672490 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This application is submitted by the New York Colon Cancer Study Group (NYCCSG) investigators who have been exceptionally successful, individually and in collaboration, in studying genetic/molecular and dietary factors, and their interaction, in the development of intestinal cancer. This application brings powerful technologies at the Albert Einstein/Montefiore Cancer Center, the Strang Cancer Prevention Center at Rockefeller University, and the University of Nebraska School of Medicine, to the question of how a Western-style diet that mimics the major risk factors for colon cancer - high in fat and phosphate, low in calcium, vitamin D, choline, methionine, folate and fiber - interacts with genetic factors to increase probability of tumor formation in the intestinal tract. In project 1, novel mouse genetic models of intestinal cancer made at Einstein/Montefiore, including the Apc1636+/- mouse, the Muc2-/- mouse and a new mouse model with a point mutation that mimics a true human pathogenic allele, the Msh2G674S mouse, will be studied for modulation of cell maturation and tumor formation by the Western-style diet and the effects of partial reversal with calcium and vitamin D3. For the Apc1638 mouse, this will be extended to understanding the contribution of each component of the diet. Microarray analysis, utilizing a 27,000 member cDNA array, will establish a matrix of data, which defines the contributions of each dietary and each genetic component to the response, the underlying mechanisms, and how they interact on a molecular level. In Project 2, tissues from Project 1 will be utilized to specifically determine how the genetic and dietary factors, alone and in combination, recruit and modulate the b-catenin-Tcf -c-myc/cyclinD1 -- cdk4/p21/p27 pathway, and Augenlicht, L related signaling and cell cycle machinery. Moreover, we will extend our analysis of the utilization, as well as mechanisms, of a block to c-myc transcription, which may be a key to how some nutritional factors can modulate tumor formation. This will make use of novel transcriptional imaging methods developed at Einstein and used by collaborating investigators in this Program. Project 3 extends the work of Projects 1 and 2 to human subjects, who will be maintained in the Rockefeller General Clinical Research Center (GCRC) and fed diets in which defined components (e.g., calcium and vitamin D3) are modulated. Biopsies taken during, and at completion of cross-over design studies will permit us to dissect how specific dietary components modulate intestinal cell maturation, biomarkers and profiles of gene expression, and how this relates to the alterations by similar dietary components in the mouse models, and to extensive gene expression data bases we have already developed that dissect cell maturation pathways in colonic cells. The four cores are Administration, Histopathology, Genomics, and Biostatistics. The Histopathology Core has extensive experience and standardized methodologies, and also incorporates laser capture microdissection, Real-Time PCR
40
Methionine
analysis, and tissue arrays. The Genomics Core capitalizes on the Einstein Microarray Facility, which is at the forefront of development and implementation of methods of gene expression profiling, and the extensive experience the facility, and members of this program have with such analyses. Moreover, this Core also includes sophisticated and novel methodology for analysis of locus specific and genome wide DNA methylation, transcriptional imaging of multiple genes simultaneously in situ, and high-throughput structural proteomics for determination of three dimensional structure of sequences with particularly interesting profiles of expression, but of currently unknown function. The Biostatistics Core at the North Shore University Hospital has already participated with members of this program on another National Cancer Institute (NCI) supported program that makes extensive use of microarray analysis of gene expression. Finally, a Pilot Project Program will provide new technologies to the Cores and new projects to supplement those proposed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MTHFR POLYMORPHISMS IN PANCREATIC CANCER IN SF BAY AREA Principal Investigator & Institution: Holly, Elizabeth A.; Professor; Epidemiology and Biostatistics; University of California San Francisco 3333 California Street, Suite 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2002; Project Start 03-JAN-2001; Project End 31-DEC-2003 Summary: The capacity for DNA repair is essential to maintain both genetic integrity and normal cellular function and to control abnormal cell growth. Folate is required for biosynthesis of oligonucleotides needed for DNA repair mechanisms and inadequate folate has been associated with human cancer. The methylenetetrahydrofolate reductase (MTHFR) enzyme is critical in the regulation of folate and methionine metabolism. Because folate is important in DNA synthesis, repair and methylation, it may play a role in cancer prevention and recent evidence suggests that this is the case. The overall goal of this study is to determine whether the prevalence of the C677T and A1298C polymorphisms in the MTHTR gene differs between pancreatic cancer patients and control subjects. DNA will be examined from 334 cases and 966 control participants who had blood drawn in the large population-based case-control study that included 550 pancreatic cancer patients and 1600 controls. All genetic testing will be done using the UCSF Comprehensive Cancer Center Genome Core facilities and laboratory personnel. Data analyses for the variables collected in the interviews in the large study and for the MTHFR genetic component also will be completed variables collected in the interviews in the large study and for the MTHFR genetic component also will be completed under the proposed work. The specific aims are to: 1) identify and compare the incidence of MTHFR C677T and A1298C polymorphisms in pancreatic cancer patients and control subjects; 2) evaluate the relationships between MTHFR polymorphisms and other exposures that also may be related to risk for pancreatic cancer such as dietary folate, smoking and alcohol consumption; and 3) perform analyses of other dietary factors and other data collected in the parent study. Data will be analyzed using stratification and multiple logistic regression for all risk factors that could potentially confound or modify the association between the MTHFR polymorphisms and pancreatic cancer such as dietary folate, smoking and alcohol consumption. Data from other risk factors also will be analyzed. While a relationship between low serum folate and risk for pancreatic has been reported there is no data to describe polymorphisms in MTHFR genes among pancreatic cancer patients and control subjects. These questionnaire- and genetics-based
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analyses will provide new and provocative data of public health importance for this devastating disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYELOPEROXIDASE VASCULATURE
AND
NO
SIGNALING
IN
THE
Principal Investigator & Institution: White, C Roger.; Associate Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 20-AUG-2001; Project End 31-JUL-2005 Summary: (provided by the applicant): The heme protein myeloperoxidase (MPO) plays an important role in the host defense response. Myeloperoxidase catalyzes the addition of chloride to hydrogen peroxide, resulting in the formation of the chlorinating species hypochlorous acid (HOCI) Hypochlorous acid reacts avidly with numerous cellular targets including thiols, amines, nucleotides and unsaturated fatty acids. Recent evidence suggests that MPO and HOCI contribute to the pathogenesis of cardiovascular disease. In this application, we present data suggesting that MPO-derived HOCI contributes to the development of endothelial dysfunction by reducing nitric oxide (NO) bioavailability. MPO effectively binds to the arterial wall and is associated with a significant increase in tissue enzymatic activity. Results of in vitro studies showed that MPO-derived HOCI impairs acetylcholine-induced relaxation but does not affect relaxation induced by an NO donor. These data suggest that the endothelium is a target of MPO-dependent injury. HOCI mediates the inhibitory effects of MPO since endothelial dysfunction could be prevented by addition of the HOC scavenger Lmethionine. There are several components of the endothelial NO synthetic pathway that may be modified by HOCI including NO synthase (NOS III) activity, L-arginine substrate and NOS Ill-dependent cofactors. In this proposal, we will identify mechanisms underlying the inhibitory effects of MPO-derived HOCI on NO bioavailability by 1) defining the effects of MPO on endothelial NO signaling processes; 2) characterizing the role of L-arginine derived N-chloramines in MPO-dependent endothelial cell injury; and 3) by determining whether inhibitors of MPO prevent endothelial dysfunction in a rodent model of ischemia-reperfusion. The HOCIdependent modification of L-arginine may represent a common pathogenic mechanism underlying endothelial dysfunction in diverse cardiovascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW AMINO ACIDS FOR PROTEIN ENGINEERING Principal Investigator & Institution: Tirrell, David A.; Professor; None; California Institute of Technology Mail Code 201-15 Pasadena, Ca 91125 Timing: Fiscal Year 2002; Project Start 01-JAN-2001; Project End 31-DEC-2003 Summary: Protein engineering is a powerful tool for design if novel liquid crystal phases, macromolecular surface arrays, reversible hydrogels, and artificial extracellular matrices for use in tissue regeneration and repair. In vivo microbial expression of artificial genes provides a means of preparing such non-natural proteins in high yields. The target structure is encoded into an artificial gene, and the gene is expressed in an appropriate microbial host. However, in vivo protein engineering poses a challenge in that the pool of potential monomers is restricted to the natural proteinogenic amino acids and those analogs that can be activated and charged to transfer RNAs. Tirrell and others have successfully incorporated analogs of methionine, isoleucine, leucine, and phenylalanine through the action of their respective aminoacyl-tRNA synthases.
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Methionine
Analogs with olefinic and acetylenic functional groups have been shown to serve as methionine surrogates in bacterial protein synthesis. Incorporation of such functional groups creates important new opportunities for chemical derivatization, extending the range of materials properties that can be designed into protein-based polymers. For example, recent advances in the chemistry of olefin metathesis have led to the development of transition metal carbenes that catalyze efficient cyclization of peptides containing olefinic side chains. The objective of this proposal is to combine fast computational analog screening methods and experiments - both in vivo and in vitro to find new amino acids for use in protein engineering. This collaboration will lead to fast and efficient discovery of non-natural amino acid analogs with new and useful functionality and will provide a basis for building novel protein-like polymers with desired properties. The computational methods to be used here have already been tested for design of analogs for phenylalanine and will be extended to new substrates for Phe, Met, Ile, Leu, and Val tRNA synthetases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITROUS OXIDE AND WOUND INFECTIONS Principal Investigator & Institution: Sessler, Daniel I.; None; University of Louisville Jouett Hall, Belknap Campus Louisville, Ky 40292 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Nitrous oxide remains the most commonly used anesthetic and has been given to several billion patients. In vitro, even brief exposure to nitrous oxide inactivates methionine synthetase, which reduces induction of enzymes required for immune function. Nitrous oxide also reduces chemotactic migration by monocytes. However, nitrous oxide improves neutrophil chemotaxis and facilitates oxygen radical formation, and may therefore augment the efficacy of oxidative killing by neutrophils - the primary defense against pathogenic bacteria. Preliminary results in 200 patients suggest that the beneficial effects of nitrous oxide on wound healing outweigh its toxicities. We will thus test the hypothesis that the incidence of postoperative wound infection will be less in patients given 60% nitrous oxide than in those given 60% nitrogen during elective colon surgery. We propose to study up to 1000 patients undergoing elective colon resection. Perioperative antibiotic, anesthetic, fluid, and oxygen management will be set by protocol. Patients will be anesthetized with isoflurane in 40% inspired oxygen, with the remaining ventilatory mixture randomly assigned as nitrous oxide or nitrogen. Surgical wounds will be evaluated daily by a physician blinded to group assignment. Wounds will be considered infected when they meet CDC criteria or pus is detected and they are culture-positive for pathogenic bacteria. As a secondary outcome, incidence of nosocomial pneumonia in the two groups will be determined. Results will be analyzed by Fisher Exact and unpaired, twotailed t-tests; P < 0.05 will be considered statistically significant. We anticipate showing that substituting nitrous oxide for nitrogen reduces the incidence of surgical wound infection. Confirming our hypothesis would thus allow clinicians to make a minor modification in anesthetic practice that might reduce the incidence of a complication responsible for considerable perioperative morbidity and cost. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NOVEL ANTIMICROBIAL AGENTS AGAINST M. TUBERCULOSIS Principal Investigator & Institution: Horwitz, Marcus A.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024
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Timing: Fiscal Year 2004; Project Start 15-JUL-2004; Project End 31-OCT-2008 Summary: (provided by applicant): M. tuberculosis is the world's leading cause of death from a single infectious agent and the leading cause of death in AIDS patients. The emergence of multidrug resistant tuberculosis poses a major threat to the public health, giving new urgency to research aimed at combating this ancient scourge. Moreover, multidrug resistant strains of M. tuberculosis (MDRTB) are a potential weapon of bioterrorism, and such strains have been classified as NIAID/CDC Category C Bioterrorism Agents. Studies proposed in this grant application build upon advances made in collaborative efforts between the Horwitz laboratory at UCLA and the Griffith laboratory at the U. of Wisconsin over the past two years to develop novel antimicrobials against M. tuberculosis for treatment of drug resistant organisms. During the past several years, the Horwitz and Griffith laboratories have laid the groundwork for the development of a new antimicrobial strategy against M. tuberculosis - targeting M. tuberculosis glutamine synthetase (GS). Thus, Horwitz et al. demonstrated that M. tuberculosis GS is a promising antimicrobial target, and that the high production of this enzyme is correlated with pathogenicity in mycobacteria and with the presence of a poly-L-glutamate/glutamine structure in the cell wall of pathogenic mycobacteria. Horwitz et al. showed further that inhibition of GS with L-methionine-SR-sulfoximine (MSO) inhibits M. tuberculosis growth in cell-free culture, in human macrophages, and in vivo in guinea pigs challenged by aerosol with M. tuberculosis. In combination with ascorbate, MSO is almost as potent as isoniazid, the leading antituberculous drug. Importantly, working in a collaboration during the past year, the Horwitz and Griffith laboratories have identified analogs of MSO that are highly potent against M. tuberculosis in vitro but lack certain drawbacks of MSO. This application has two major goals: 1) Develop novel MSO analogs that are better drug candidates than MSO because they are a) more selective for glutamine synthetase (GS) vs gamma-glutamylcysteine synthetase (gamma -GCS); and/or b) less well taken up into the brain where MSO exerts its major toxicity in sensitive species; and/or c) even more selective for M. tuberculosis GS vs. mammalian GS, and test the toxicity of the analogs in mice. 2) Test the novel MSO analogs for their capacity to inhibit M. tuberculosis growth in broth culture, in human macrophages, and in guinea pigs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ORAL ANTIOXIDANT/ANTICYTOKINE THERAPY FOR ALD Principal Investigator & Institution: Hill, Daniell B.; Associate Professor of Medicine; Medicine; University of Louisville Jouett Hall, Belknap Campus Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Alcoholic liver disease (ALD) remains the leading major cause of liver disease and liver related mortality in the United States. Alcohol metabolism and ALD are associated with lipid peroxidation and oxidative stress with decreased levels of nutritional antioxidants such as reduced glutathione (GSH) and vitamin E. Animal studies have clearly shown that treatment with GSH precursors, such as N-.acetylcysteine (NAC) and S-adenosyl- L-methionine (Adomet or SAMe), ameliorates alcohol/endotoxin liver injury. We postulate that chronic alcohol abuse causes increased gut permeability and endotoxemia, depletion of nutritional antioxidants (e.g., GSH, Vit E), generation of reactive oxygen intermediates, activation of NFKB, increased TNF production, increased IL-8 production with neutrophil infiltration, Adomet deficiency, mitochondrial GSH depletion, increased susceptibility to hepatic TNF cytotoxicity, and liver injury. We have chosen a combination of two nutritional supplements which inhibit cytokine production in effector cells (e.g. Kupffer
44
Methionine
cells) and which attenuate liver metabolic abnormalities and enhance cytoprotection in target cells (e.g. hepatocytes). Because there is no ideal model system and animal studies to date all support beneficial effects of Adomet/NAC therapy, we are proposing human studies. The two agents to be used, NAC and SAMe, are already commercially available as over-the-counter nutritional supplements. The specific objectives of this proposal are to: I) Determine an oral dose of Adomet in stable alcoholic cirrhotics that when given for 21 days significantly improves methionine clearance, increases Adomet levels, and attenuates cytokine production; 2) Determine in stable alcoholic cirrhotics an oral dose of NAC that when given for 21 days significantly increases whole blood GSH levels and decreases cytokine production; and 3) Determine in stable alcoholic cirrhotics whether giving Adomet and NAC together for a 21 day period provides a degree of improvement in methionine clearance, whole blood GSH values and cytokine levels at least as significant as with either drug alone, and determine that this combination is well tolerated. The data from these studies will be useful in designing clinical trials using these agents in the treatment of acute alcoholic hepatitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OXIDATIVE STRESS IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Markesbery, William R.; Professor of Pathology & Neurology; Sanders-Brown Ky Res Ctr/Aging; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 01-DEC-1994; Project End 31-JAN-2007 Summary: Alzheimer's disease is a major health problem affecting 4 million persons in the USA. The key to understanding AD is determining the etiology and pathogenesis of neuron degeneration in specific brain regions. This application is for a five year renewal of the Program Project Grant (P01AG05119) at the University of Kentucky (UK) SandersBrown Center on Aging. The major goal of this program proje4ct is to gain an understanding of brain oxidation in AD. The program project is composed of two cores and four closely interrelated projects. Each project has human (AD and control), genealtered animal and cell culture components. Each project has published and preliminary data relevant to specimens from longitudinally followed AD and control subjects that have short post-mortem interval autopsies. Project by Markesbery examines the hypothesis that oxidation of DNA and RNA oxidation. Project by Butterfield is aimed at defining the molecular mechanisms and sequela of Abeta-associated oxidative stress in AD. Special emphasis will be placed on the action of methionine in Abeta (1- 42) in oxidative stress and neuron toxicity. Project by St. Clair examines the hypothesis that the ability of mitochondria to remove superoxide radicals without inflicting self injury plays a central role in regulating free radical mediated neurodegeneration in AD. This study will investigate the mechanism by which increased expression of manganese superoxide dismutase can be safely achieved in the brain. Project by Kindy is designed to understand the interaction between the receptor for advanced glycation endproducts, Abeta and oxidative stress. A coordination and administration Core will provide supervision and coordination of the research projects, financial management, statistical support, internal and external scientific review and procurement of tissue from the Uk ADRC. The Animal Core provides transgenic, knockout and knockin mice for all four projects. This program project has the potential of identifying molecular targets for development of therapeutic agents aimed at decreasing neuron injury and improving the outcome of AD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OXIDATIVE STRESS, HOMOCYSTEINE AND ALZHEIMER'S DISEASE Principal Investigator & Institution: Pratico, Domenico; Assistant Professor; Pharmacology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia for which there is no effective therapy. Although the causative events(s) responsible for the disease is not known, it is evident that some environmental elements by interacting with endogenous factors could play a role in its pathogenesis. Epidemiological studies have shown that high blood levels of homocysteine (Hcy), a condition known as hyperhomocysteinemia (HHcy) is a risk factor for developing AD. Hcy derives from the conversion of methionine through reactions that are dependent on the presence of necessary vitamins (i.e., B6, B12 and folate). Since cellular exposure in vitro to Hcy induces oxidative stress and inflammatory reactions, we want to test the hypothesis that these mechanisms mediate in vivo the link between AD and HHcy. Previously, we have shown that lipid peroxidation is increased in selective areas of AD brains, and in AD patients where it correlates with disease severity. Inflammation also occurs in AD, and it does do with the full complexity of local and peripheral inflammatory responses. Transgenic mice over-expressing the Swedish mutation of the amyloid precursor protein (Tg2576) manifest signs of brain lipid peroxidation and inflammation. Our longterm goal is to define the effects of long-term exposure to HHcy in two different models of AD-like amyloidosis (Tg2576 and the APP/YAC Tg mice). First, we will test the hypothesis that diet-induced HHcy exacerbates brain oxidative stress and inflammation, accelerates behavioral impairments and brain amyloid/3 peptide deposition in these mice. Second, by cross-breeding AD Tg mice with Tg mice that are deficient for a key enzyme in Hcy metabolism, we will investigate whether genetic-induced HHcy exacerbates brain oxidative stress, inflammatory responses, behavioral impairments, and amyloid beta peptide levels and deposition. In summary, this proposal tests the hypothesis that long-term exposure to high Hcy levels exacerbates ADlike phenotype in two different mouse models of AD-like amyloidosis, and investigates some of the molecular and cellular mechanisms that could account for this effect. These studies will be a necessary basis before prevention studies aimed to reduce Hcy levels are initiated in patients at risk for AD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AMYLOIDOSIS
PATHOGENESIS
OF
HEREDITARY
TRANSTHYRETIN
Principal Investigator & Institution: Benson, Merrill D.; Professor; Medical and Molecular Genetics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-AUG-1990; Project End 31-MAR-2004 Summary: (from abstract): The overall objective of this proposal is to define the pathophysiology of the autosomal dominant transthyretin amyloidoses. These diseases, while considered rare, are actually being recognized in increased numbers of kindreds throughout the world and especially in the United States. Transthyretin amyloidosis is usually associated with peripheral neuropathy, nephropathy, and cardiomyopathy which present as late-onset (adult) disease with high degrees of morbidity and mortality. To date at least 72 variants of transthyretin (TTR) have been found to be associated with systemic amyloidosis which is inherited as an autosomal dominant
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Methionine
disease. Of particular concern is the fact that: 1) it has recently been shown that there are elderly individuals who develop transthyretin amyloid cardiomyopathy (senile cardiac amyloldosis) in the absence of any detectible mutation in transthyretin; and, 2) there is a high prevalence of one particular transthyretin mutation (isoleucine 122) in the American Black population and this is manifest as amyloid cardiomyopathy. These two findings suggest that, as the population ages, amyloid heart disease will become of greater significance to the American population. Previous studies have centered on determining structural changes of transthyretin which are related to amyloid formation. Structures of amyloid forming variants methionine 30, serine 84, alanine 60, arginine 10, tyrosine 77 have been compared to structures of non amyloid forming threonine 109, serine 6, methionine 119 and normal transthyretin. No common structural change has been found to explain initiation of the fibril forming process but preliminary data suggest that solvent accessability to variant transthyretin dimers may allow a proteolysis event which could lead to the initiation of fibril formation. Metabolic studies using radiolabelled variant and normal transthyretins have suggested increased plasma clearance of variant proteins. The Specific Aims will test the hypothesis that single amino acid substitutions in transthyretin result in changes in tertiary structure of the transthyretin molecule which allow alterations in metabolism of the variant molecule and its associated normal monomers to lead to amyloid formation. Transthyretin proteins isolated from tissues of patients with amyloidosis will be studied to characterize proteolytic peptides and determine if partial proteolysis with generation of carboxyl terminal peptides is a factor in amyloid fibril formation. Fibril forming potential of these fragments will be tested by producing recombinant protein of residues 49 - 127 and testing fibril formation with and without full-length transthyretin in vitro. A new Specific Aim will test the hypothesis that the ratio of the various tetrameric forms of transthyretin affects the propensity to form amyloid fibrils. To accomplish this aim a dual expression system in baculovirus coexpressing normal TTR and variant TIR has been developed. These studies are directed at developing methods to prevent amyloid formation from variant TTR proteins and, thereby providing therapeutic options for a disease which at the present time has no specific therapy other than liver transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHARMACOGENETICS OF METHOTREXATE IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Bridges, S Louis.; Associate Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 31-DEC-2006 Summary: Methotrexate (MTX) is one of the most effective drugs for RA, but 20- 30% of patients have suboptimal clinical responses to MTX, and 15-25% have side effects limiting its use. Thus, it is important to elucidate influences on MTX efficacy and toxicity. We will test the hypothesis that single nucleotide polymorphisms (SNPs) in genes encoding key enzymes involved in folate or MTX metabolism or in the mechanism of actions of MTX (e.g. the adenosine pathway) influence clinical responses to MTX. We are uniquely positioned to utilize clinical outcomes (ACR response criteria, radiographic progression and toxicities) and genomic DNA from patients in two completed clinical trials: 153 MTX-treated RA patients from an Immunex trial comparing MTX and etanercept, and 79 MTX-treated RA patients from a UAB trial of folic acid supplementation. HLA DRB1 alleles and a total of 5 known SNPs in the following 4 key genes will be genotyped: 1) 5,10- methylenetetrahydrofolate reductase
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(MTHFR); 2) 5-methyl- tetrahydrofolate-homocysteine methyltransferase (methionine synthase) (MTR); 3) methionine synthase reductase (MTRR); and 4) adenosine receptor A2A [A(2A)R]. These SNPs were chosen on the basis of being common enough in the general population to allow meaningful analyses, their key roles in relevant pathways, and evidence of their biological activity. Through the MCRC Methodology Core, we will look for associations between SNP alleles and MTX efficacy or toxicity. Although these known SNPs are important, SNP haplotypes may be even more informative, aqs they allow characterization of the effect of multiple SNPs working in concert. Therefore, we will use both "in silico" in sequencing approaches to identify novel SNP haplotypes in these 4 and 3 other critical genes: dihydrofolate reductase (DHFR), 5- aminoimidazole-4carboxamide ribonucleotide transformylase (AICAR- T), and aldehyde oxidase (AO). In addition to data mining of public domain and proprietary (i.e. Celera) SNP databases, we will perform SNP discovery on 40 individuals from two racial/ethnic groups [20 African-American (A-A) and 20 Caucasian]. Differences in frequencies of novel haplotype related to disease status or race/ethnicity will be sought by analysis of 108AA Ra patients and 53-AA controls; 336 RA patients (mostly Caucasian); and 800 controls (mostly Caucasian) from established cohorts. Based on results from these studies, the role of selected novel SNP haplotypes on MTX efficacy and toxicity will be tested in patients from the folic acid and Immunex trials. We will compare the predictive power of two approaches to genetic profiling: the single SNP approach and the SNP haplotype approach. These studies may provide clinically useful markers of MTX efficacy or toxicity in RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PILOT--DEVELOP MTHFR NULL AND C677T POLYMORPHIC MICE Principal Investigator & Institution: Kucherlapati, Raju S.; Professor; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 18-SEP-2003; Project End 31-AUG-2008 Summary: Methylenetetrahydrofolate reductase (MTHFR) is a protein that is important in folate metabolism. Its enzymatic activity is to convert 5, 10-methylenetetrahydrofolate to 5'-methyl tetrahydrofolate, which in turn is important in the methylation of homocysteine to methionine. Several variants and mutations in the gene for MTHFR have been described. Moderate or severe deficiencies of this enzyme lead to a number of disorders including hyperhomocystenuria and homocystenuria. The clinical outcome of the deficiency include peripheral neuropathy, developmental delay, hypotonia and seizures [1]. Mild forms of the reduced MTHFR activity are present in high frequencies in the general population. These variant forms of these enzymes lead to mild homocystinuria. High level of homocysteine is a risk factor for arterial disease [2-4]. The genes for human and mouse MTHFR have been isolated and characterized [4-7]. The human gene encodes a protein 656 amino acids in length and the mouse gene encodes a 654 aa protein. There is a high level of conservation between the human and mouse genes. At the amino acid level, the two proteins are 90% identical [5]. The exon-intron organization of the two genes is also identical. Both genes have 11 exons. Although several different size transcripts have been described [6, 7], all of them encode the identical protein. Several variants of the human MTHFR gene have been described. Of these, the C677T variant that converts an alanine codon to valine is the most studied. This is a very common polymorphism and has an allele frequency of approximately 35% in the North American population. The amino acid change leads to a thermolabile enzyme that causes a predisposition of homocystenuria when folate levels are low [4, 8, 9]. In this developmental project, we propose to make mice that have a null allele of the
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Mthfr gene and a second mouse that carries the homologous C677T variation. Based on the high level of identity between the two proteins and the complete conservation of the 10 amino acids on either side of the variation in the mouse and human genes suggests that the mouse will truly mimic the functional aspects of the C677T polymorphism in humans. Availability of these mice would help us in better defining the role of MTHFR and C677T variant on folate metabolism and how these genetic changes would affect colon cancer susceptibility under different nutritional folate levels. The steps that are involved in generating the mice are as follows: 1. Isolation of a mouse BAC from the 129/SvEvTac strain genomic library, 2. Modification of the gene, 3. Transfection of mouse ES cells with the gene modification construct and screening the colonies for the desired modification, 4. Injection of the modified ES cells into blastocysts to generate chimeras and 5. Mate the chimeras for germ-line transmission of the modified allele. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PILOT--IMAGING OF METASTASIS Principal Investigator & Institution: Tsarfaty, Galia; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 14-JUN-2002; Project End 31-MAR-2007 Summary: Pilot Project 2--The primary aim of this study is to develop novel molecular imaging methodology to visualize and quantify the expression and activity of tyrosine kinase growth factor receptor and mitochondria uncoupling proteins in metastasis. The Met tyrosine kinase growth factor receptor, its ligand hepatocyte and Mimp (ref), a novel Met-HGF/SF-induced protein will serve as a model. Using novel molecular imaging modalities we will analyze the effects of Met and HGF/SF overexpression on mammary tumors and metastasis formation. Subsequently, using a Tet inducible Mimp we will examine the effects of Mimp expression on Met-HGF/SF-induced metastasis. Preliminary results suggest that Mimp reduces Met-HGF/SF-induced metastasis. The combined expression of Met and Mimp which is inhibitory and its down-stream effects may shed light on the involvement of mitochondrial uncoupling activities in regulating HGF/SF-induced metastasis. Our specific aims are: 1) to image overexpression of Met and HGF/SF in an in vitro invasion process and in tumor and metastasis formation. 2) to characterize the effect of Mimp induction on the tumorigenic/metastatic potential in in-vitro and in vivo systems. 3) to develop molecular imaging modalities for Mimpluciferase and Mimp-DsRed in tumorigenicity and metastasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PILOT--PREDICT PLASMA FOLATE AND HOMOCYSTEINE BY SNPS IN FOLATE METABOLISM Principal Investigator & Institution: Rimm, Eric B.; Associate Professor; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 18-SEP-2003; Project End 31-AUG-2008 Summary: We propose to assess the genotype-phenotype relation of variants in five genes that synthesize or metabolize 5-methylTHF or homocysteine. The five genes are: MTHFD1 (5,10 methylenetetrahydrofolate dehydrogenase), MTHFR (methylenetetrahydrofolate reductase), MTR (Methionine Synthase), MTRR (Methionine Synthase Reductase), and SAHH (S-adenosylhomocysteine hydrolase). We will explore SNPs or newly defined haplotypes in these genes in relation to plasma folate and homocysteine already assessed among 943 men and women; a population over-sampled to represent a wide range of alcohol consumption.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PLACEBO-CONTROLLED STUDY OF SAME VS.ESCITALOPRAM IN MDD Principal Investigator & Institution: Fava, Maurizio; Professor of Psychiatry Harvard Medical; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Major depressive disorder (MDD) is a common, typically recurrent and disabling disorder, costing the U.S. over $44 billion/year in direct and indirect costs, and with point prevalence rates estimated at 5%-9% for women, and 2%-3% for men. More than one third of patients suffering from MDD appear to use alternative therapies in the U.S. Routinely prescribed in Europe for nearly 30 years and released four years ago in the U.S. as an over-the-counter dietary supplement, s-adenosyl-l-methionine (SAMe) has gained significant popularity as an agent marketed for improving mood and emotional well being. A number of relatively small double-blind studies have shown that parenteral or oral preparations of SAMe, compared with a number of standard tricyclic antidepressants, were generally equally effective, and tended to produce fewer side effects A relatively smaller number of studies have also examined the efficacy of SAMe compared to placebo, with the majority of these studies showing a significant advantage of SAMe over placebo. The recent report of the Southern California Evidence-Based Practice Center for the U.S. Department of Health and Human Services [Agency for Healthcare Research and Quality (AHRQ Publication 2002; http://www.ahrq.gov) ] states that "The results of these studies justify additional randomized clinical trials to evaluate the efficacy and tolerability of SAMe for treatment of depression." No adequately powered placebocontrolled study of SAMe in depression has ever been conducted in the U.S. We therefore propose a five-year, placebo-controlled, two-site study to assess the efficacy and safety of SAMe and of a standard selective serotonin reuptake inhibitor (SSRI), escitalopram in outpatients with MDD. This proposal is a parallel comparison of the efficacy and safety of SAMe, escitalopram, and placebo, with a crossover phase during which non-responders to any of these three treatments receive open-label treatment with the combination of escitalopram and SAMe. It is important to assess the efficacy of this combination therapy because patients frequently self-medicate with SAMe during standard antidepressant treatment. The primary aim of the proposed study is to test the acute antidepressant efficacy and tolerability of both SAMe and escitalopram, each compared to placebo, for the treatment of MDD. Secondary aims are to assess the acute effects of SAMe or escitalopram vs. placebo on remission rates, quality of life, and psychosocial functioning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROTEIN/RNA INTERACTIONS IN SPLICE SITE SELECTION Principal Investigator & Institution: Xu, Rui-Ming; Associate Professor; Cold Spring Harbor Laboratory 1 Bungtown Road Cold Spring Harbor, Ny 11724 Timing: Fiscal Year 2003; Project Start 01-JAN-1998; Project End 31-MAR-2007 Summary: (provided by applicant): Most human genes are interrupted by non-coding sequences known as introns. The nascent transcript must be processed to remove the introns and to join the coding sequence into a contiguous mature mRNA molecule. The human genome project provided an estimate that only 1 to 1.5% of the approximately 3x10/9 base pair (bp) genome is spanned by coding sequences or exons, whereas introns
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occupy approximately 24% of the genome. It is apparent that the cellular machinery is presented with a formidable task to precisely locate the splice sites within a gene's transcript. Another dimension of complexity is added when certain exon sequences are skipped or included, a phenomenon known as alternative splicing. Alternative splicing occurs in a large number of human genes and it plays important roles in regulating gene expression during development and differentiation. Alternative splicing is also responsible for generating molecular diversity in certain cells, such as neurons. Splicing of pre-mRNA involves an ordered assembly of components, including small nuclear ribonucleoprotein particles (snRNP) and additional protein splicing factors, resulting in the formation of a large 50-60S complex, termed the spliceosome. We are interested in understanding the molecular mechanism of splice site recognition from a structural standpoint. In this proposal, we focus our study on several well characterized human splicing factors that are important for splice site selection, namely, SR proteins, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and the U2 auxiliary factor (U2AF). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RCT OF SAME IN ALCOHOLIC LIVER DISEASE Principal Investigator & Institution: Mendler, Michel H.; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2007 Summary: (provided by applicant): Background: Alcoholic liver disease is one of the most important causes of chronic liver disease in this country. There is currently no treatment for chronic alcoholic liver disease other than abstinence. Hepatic methionine metabolism is abnormal in these patients and one of the consequences is depletion of Sadenosylmethionine (SAMe) levels, which can affect numerous important cellular processes. SAMe has been increasingly utilized for the treatment of liver diseases although the protective mechanisms remain unclear. A recent randomized double-blind trial using SAMe in patients with alcoholic liver disease and found improvement in 2year survival in those with less advanced liver disease. However, important changes in methionine metabolism and histological changes were not included in the study. Aim: The goal of this study is to determine the effect of SAMe administration on key metabolic abnormalities of the methionine cycle and on the recovery from alcoholic liver disease. Methods: This is a randomized, double blind, placebo-controlled trial. Thirty patients with stable alcoholic hepatitis (Maddrey Score < 32) without cirrhosis who meet entry criteria will receive either 400 mg of SAMe (n=15) or placebo (n=15) three times a day for the duration of one year. History, physical assessment, various blood tests and a liver biopsy will be performed prior to treatment. Patients will have repeat blood tests on subsequent follow-up visits every month for the first two months, then every two months thereafter. They will also be encouraged to abstain from alcohol during these visits. A post-treatment liver biopsy will be obtained at the end of the trial. The primary outcome parameters include serum homocysteine, SAMe and TNFalpha levels, and the expression of key hepatic enzymes of the methionine cycle and of hepatic SAMe and glutathione levels. Histological progression of alcoholic liver disease, clinical and biochemical indices of liver disease, and quality of life assessment will also be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REACTION MECHANISMS OF MAMMALIAN B12-DEPENDENT ENZYMES Principal Investigator & Institution: Banerjee, Ruma; Willa Cather Professor of Biochemistry; Biochemistry; University of Nebraska Lincoln Lincoln, Ne 685880430 Timing: Fiscal Year 2002; Project Start 01-FEB-1993; Project End 31-JAN-2003 Summary: (adapted from the applicant's abstract) Mammals have two known B12dependent enzymes that conduct essential housekeeping functions: methionine synthase and methylmalonyl-CoA mutase. Impairments in methionine synthase lead to megaloblastic anemia and hyperhomocysteinemia, the latter being a graded risk factor for atherosclerotic cardiovascular diseases. Dysfunction of methylmalonyl-CoA mutase leads to methylmalonic aciduria, leading to metabolic aberrations that can be fatal. This proposal focuses on elucidating the reaction mechanisms of these two enzymes, as well as the mechanism by which the cofactor regulates the activity of methionine synthase. Chemically, B12 is a novel cofactor, and catalyzes distinct biochemical transformations in association with these two enzymes. Thus, methionine synthase catalyzes a displacement reaction in which the cobalt-carbon bond of B12 breaks heterolytically, while the mutase catalyzes a rearrangement reaction in which the cobalt-carbon bond breaks homolytically. A combination of spectroscopic, kinetic and molecular genetic techniques will be used to explore the mechanisms of these reactions, and to map and characterize the mutations in patients with inborn errors affecting these enzymes. The redox-active proteins that activate mammalian methionine synthase under physiological conditions will be identified and characterized, as these represent additional targets for mutations that could lead to hyperhomocysteinemia. The level at which B12 exerts control over methionine synthase and causes the observed induction in enzyme activity when presented to cells in culture will also be examined. These studies on the native and mutant B12 enzymes will make inroads into our understanding of novel reaction mechanisms of clinically important enzymes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REACTIONS OF VIT B12 COMPOUNDS & ENZYMES WITH NO AND N2O Principal Investigator & Institution: Birke, Ronald L.; Professor; City College of New York 138Th St and Convent Ave New York, Ny 10031 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: Our long-term objectives are to understand the functions of vitamin B 12 compounds in enzymatic reactions and as therapeutic agents in terms of their chemical properties. Some specific goals of this research project are to investigate the interactions of nitrogen oxides, NO and N20, and nitrite anion with vitamin B12 (cobalamin) compounds in vitro in order to understand their effects on enzymatic reactions of methionine synthase, B 12-MS, and their effectiveness for sequestering trauma induced NO in vivo. One hypothesis is that redox reactions of NO and N20 with the Co(II) and Co(I) forms of cobalamin can effect enzyme functioning. Specifically, we plan to study the complexes formed and the redox behavior of systems of NO, N20, and the nitrite anion with various cobalamin compounds in their three cobalt oxidation states using electrochemical measurements, UV-VIS spectroscopy, resonance Raman spectroscopy (RRS), surface enhanced resonance Raman spectroscopy (SERRS), and electron paramagnetic resonance (EPR) spectroscopy. Nitrogen species formed as reaction products will be investigated by gas chromatography-mass spectrometry (GC-MS), We will also study the reductive cleavage mechanism for the activation of methylcobalamin
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and adenosylcobalamin. Our aim is to measure equilibrium binding constants, redox reaction rates, and electrochemical reduction potentials for cobalamin redox couples and also to determine the structure of NO binding in their nitrosyl complexes. Experiments will also investigate the solvent and pH effects on the equilibrium and kinetic properties of the complexes. In addition, we will investigate the inactivation of pure methionine synthase obtained from a recombinant strain of E. Coil which overproduces the enzyme. We will compare NO and N20 inactivation by various means including deactivation in an electrochemical cell which produces the cob(I)alamin form of the enzyme, analysis of the inactivated enzyme by twodimensional polyacrylamide gel electrophoresis, and stopped-flow kinetic measurements of enzyme catalysis in the presence of NO and N20. Additionally, we will correlate our chemical studies with the effect of various cobalamin compounds on NO generated at the surface of endothelium cells in physiological experiments to be done at Ohio University. These results should help in understanding how NO and N20 work in inhibiting B 12-MS function, if NO can act as a regulator for MS-B 12, and how cobalamins can detoxify organisms with elevated levels of NO which cause the condition of hypotension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REACTIVE OXYGEN SPECIES AND AGING Principal Investigator & Institution: Michaelis, Elias K.; Professor and Chairman; Medicinal Chemistry; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2002; Project Start 01-SEP-1995; Project End 31-MAR-2006 Summary: Aging in mammals is associated with progressive loss of muscle mass, bone demineralization, vascular calcification and progressive hypertension, sensory perception deficits, hypo functioning immune systems, and loss of tissue elasticity. The original program project proposal five years ago was based on the two hypotheses of cell aging, the free radical theory and the Ca2+ hypothesis of aging, that we believe explain many of the cell and molecular changes that occur with aging. Chronic imbalances between oxidant and anti-oxidant processes in cells cause oxidative stress during aging and progressive deterioration of macromolecular structures such as proteins, DNA, and lipids. Progressive deterioration of processes that control [Ca2+]i leads down a path of cellular deterioration and organ malfunction. One of the operating mechanisms for the loss of the capacity of cells to handle the rise in [Ca2}]i may be oxidant-induced protein and membrane damage, especially of proteins that regulate Ca2+ entry into cells, transport out of cells, transport into intracellular organelles, or release from such organelles. The research performed in our laboratories under the auspices of the program project has contributed substantial and detailed new information to support the two major hypotheses of aging. We have provided chemical evidence for the presence of post-translational modification of proteins brought about by ROS. These modifications occur in proteins that regulate intracellular Ca2+ and the function of Ca2+ as an intracellular messenger. The current program project renewal application expands upon the work already accomplished and attempts to define not only the chemical and biochemical modifications due to increasing oxidative stress during aging, but also the cellular and physiological consequences of such modifications. An additional focus of the proposed work is that of cellular mechanisms for protein repair or degradation following insults produced by oxidation. The areas of focus in the continuation of this program project are: a) characterization of the pathways of repair or degradation of calmodulin and the Ca-ATPases b) mechanisms of protein repair by methionine sulfoxide reductase c) age-dependent changes in NMDA receptor
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function, intracellular calcium channels, protein phosphatases and kinases, and the multi- catalytic proteases d) chemical sensitivity of tyrosine nitration, sulfhydryl group oxidation, and the chemical nature of protein carbonyl groups. To accomplish these goals we will continue to use the expertise of the protein and peptide analysis core. We have also established a new core in cell culture and molecular biology that will assist us in our investigations of changes in cell biology, cell physiology and molecular biology. It is our hope and expectation that the studied proposed in this program will provide us with new insights into basic biological and chemical processes associated with aging. And, that this program will also provide us with targets for potential therapeutic intervention to ameliorate the gradual deterioration in cell and organ functions that occur with aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF FOLATE METABOLISM Principal Investigator & Institution: Matthews, Rowena G.; Professor; Biological Chemistry; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-APR-1978; Project End 31-MAR-2005 Summary: (Verbatim from the Applicant's Abstract):One carbon units bound to tetrahydrofolate are utilized for the de novo biosynthesis of purines and thymidylate and for the provision of methyl groups for the biological methylation reactions that involve adenosylmethionine as the methyl donor. The long term goals of this research are to study the catalytic mechanisms of enzymes that use tetrahydrofolate derivatives as cofactors, and to study the regulation of one carbon metabolism. Because the availability of one carbon units is one of the factors that limits the rate of growth of cells, these studies are relevant to the design of chemotherapeutic inhibitors of folatedependent enzymes. They are also relevant to our understanding of the factors that control the level of plasma homocysteine, an independent risk factor for the development of cardiovascular disease. The proposed studies focus on three folatedependent enzymes: human methylenetetrahydrofolate reductase (MTHFR), which catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate in a reaction which commits one-carbon units to provision of methyl groups for adenosylmethionine-dependent methylations, and cobalamin-dependent and cobalamin-independent methionine synthases from Escherichia coli. Methionine synthases catalyze methyl transfer from methyltetrahydrofolate to homocysteine, to produce tetrahydrofolate and methionine. Based on research with MTHFR from E. coli, a model has been developed in which enzyme activity is regulated by the availability of folate derivatives; this model will be tested for its applicability to the regulation of the human MTHFR. Studies of the catalytic mechanisms of cobalamin-dependent and cobalamin-independent methionine synthases from Escherichia coli are also proposed. These studies will focus on the mechanism of activation of the substrate, methyltetrahydrofolate, for transfer of the methyl group and on the catalytic role of the essential zinc ions in these two enzymes, and will employ a wide variety of kinetic, spectroscopic, and stereochemical techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF METHIONINE METABOLISM IN BACILLUS SUBTILIS Principal Investigator & Institution: Henkin, Tina M.; Professor; Microbiology; Ohio State University 1960 Kenny Road Columbus, Oh 43210
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Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: (provided by applicant): A novel global regulation system for control of genes involved in methionine metabolism has been uncovered in Bacillus subtilis. Genes utilizing this mechanism, designated the S box family, contain in their mRNA leader regions a complex set of conserved primary sequence and structural elements, including a transcriptional terminator, competing antiterminator, and antiantiterminator. Genetic analyses indicate that during growth in methionine, sequences in the leader are required for stabilization of the anti-antiterminator, which prevents formation of the antiterminator, which in turn allows termination. The molecular mechanism for control of the leader RNA structure in response to methionine levels is unknown, although preliminary studies suggest that binding of a regulatory factor is required to prevent readthrough. This system is widely used for control of methioninerelated genes in a variety of Gram-positive bacteria, including important pathogens such as Staphylococcus aureus, and is also found in the Gram-negative bacteria Chlorobium tepidum and Geobacter sulforreducens. Eleven transcriptional units are controlled by this mechanism in B. subtilis alone, so the total number of genes involved is high. The major goal of this study is to further investigate the molecular mechanism of transcription termination control, and to elucidate the physiological role of this system, using a combination of genetic and biochemical approaches. The required cis-acting sequence elements will be identified by site-directed mutagenesis. The trans-acting regulatory factors required for the methionine response will be identified, and the system will be examined both in vivo and in vitro. A requirement for ppGpp for efficient readthrough in vivo has been demonstrated, and the molecular basis for this requirement will be examined. Finally, the physiological role of genes of unknown function which appear to be regulated by this mechanism will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REPAIR, DEGRADATION, AND CALCIUM REGULATION IN MUSCLE Principal Investigator & Institution: Bigelow, Diana; Professor; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2002; Project Start 15-JUN-2002; Project End 31-MAR-2003 Summary: Our long term goal is to understand the cellular processes that are responsible for the accumulation of oxidized calcium regulatory proteins in senescent muscle and how these related to their prolonged contraction and relaxation times. Here, we focus on the ryanodine receptor (RyR) and the sarcoplasmic reticulum (SR) CaATPase, two calcium regulatory proteins that, together, play a major role in eliciting intracellular calcium transients in muscle. Their respective roles consist of calcium release to initiate muscle contraction, and the rate-limiting active resequestration of cytosolic calcium into the SR lumen to allow relaxation. Our previous work has shown specific and substantive levels of 3-nitrotyrosine (3Ngamma) modification of the SERCA2a isoform of the Ca-ATPase in heart and skeletal muscle which increases with age of the animal. 3NY is a characteristic product of peroxynitrite (ONOO-), and suggests the simultaneous generation of superoxide (O2.-) and nitric oxide (NO.) in myocytes. We hypothesize that accumulation of 3Ngamma modification of SERCA2a during aging is due to defects in cellular mechanisms designed to minimize reactive oxygen species (ROS), or those involved in the degradation of oxidized proteins. We therefore propose to focus on gaining a detailed understanding of degradation pathways or whether increased levels of ROS overwhelm the normal functioning of these pathways. We further hypothesize that the presence of the strong thiol oxidant,
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ONOO-, in myocytes will functionally alter the cysteine-rich RyR and its methionine rich regulator, calmodulin. The latter protein has been previously shown to be oxidized in aging. In addition, ONOO-, formation may deplete NO> which regulates the RyR., both directly and through the FK binding protein. Therefore, we propose the following specific aims: (1) Identify cellular pathways for the degradation of SERCA2a, and possible defects in aging; and (2) Characterize the regulation of the RyR by oxidized CaM, and other regulatory molecules in senescent muscle. Knowledge of cellular mechanisms that lead to accumulation, and altered regulation by oxidized proteins will be essential for the design of therapeutic approaches for maintenance of optimal heart and skeletal muscle function during aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REVERSIBLE OXIDATION OF METHIONINE IN AGING Principal Investigator & Institution: Hoshi, Toshinori; Physiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Oxidation of amino acids by reactive oxygen species is considered to accelerate aging. The amino acid methionine is readily oxidized to form two epimers of methionine sulfoxide, methionine-R-sulfoxide (met-R-O) and methionine-S-sulfoxide (met-S-O). The enzyme methionine sulfoxide reductase A (MSRA) reduces met-S-O while the enzyme methionine sulfoxide reductase B (MSRB) reduces met-R-O. Multiple forms of MSRA and MSRB that differ in tissue and subcellular distributions are now known. Increasing evidence suggests that methionine oxidation may be an important determinant of the time course of normal aging. However, there is no systematic information available how the met-R/S-contents and MSRA/B activities change with age. Furthermore, it is not known whether different MSR forms play similar roles in aging. Using the model organism Drosophila, the study proposed here will provide a comprehensive view of the roles of methionine oxidation and MSRs in normal biology of aging. Age-dependent changes in the oxidized methionine contents and MSR activities in different tissues and subcellular fractions are systematically measured. Different forms of MSRs are overexressed in different tissues and subcellular regions to compare their efficacies in lifespan extension and delaying the onset of decline in the physical activity level and reproductive vigor. Furthermore, gene expression profiles in the long-living MSRA flies are systematically compared with those of control flies. The study will also test whether a food supplement, S-methyI-Lcysteine, could act to extend the animal lifespan by participating in the reversible methionine oxidation cycle involving the MSR system. The results expected should prove valuable in designing interventions to extend lifespan. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: S SANGUIS ADHESION--MOLECULAR BASIS OF SPECIFICITY Principal Investigator & Institution: Herzberg, Mark C.; Professor; Polymer Science & Engineering; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-APR-1990; Project End 31-MAR-2004 Summary: Density-dependent surface growth may switch sessile phenotypes to planktonic. During years 08-13, sessile and planktonic S. sanguis and S. gordonii cells will be compared to test the hypothesis that expression of adhesin proteins is regulated by the process of adhesion. Specifically, we will (1) compare the adhesion specificities of
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PAAP+ S. sanguis and PAAP- S. gordonii in a biofilm model that facilitates adhesion, protein biosynthesis and growth at 37 C for 6 hours in chemically-defined synthetic medium. In this model, the two wild-type strains and selected mutants will tagged with different antibiotic resistance markers. The strains will be incubated alone or together to determine if adhesion is competitive when binding to saliva-coated hydroxyapatite in the presence or absence of specific antibodies against salivary antigens, or simulated pellicles formed from purified salivary macromolecules. Since preferred binding sites show discrete distributions on coated enamel chips, the two strains will be compared microscopically for topological distribution of binding. To learn if they express different adhesin phenotypes, (2) sessile and planktonic cells will be recovered periodically from the biofilm model and altered expression of streptococcal surface macromolecules will be analyzed by pulse-labeling, autoradiography and Western immunoblotting with antibodies against known proteins. Novel surface proteins regulated during adhesion will be analyzed by amino acid microsequencing, PCR synthesis of the target gene, insertional inactivation, analysis of the mutant for defects in adhesion and finally cloning and sequencing of the complete gene. Selected experiments will be simulated on enamel chips to determine the ultrastructural morphology of resultant biofilms. The specificity of adhesin proteins requires protection against oxidative stress. Preliminary data show partial cloning of the S. gordonii msrA gene, which encodes methionine sulfoxide reductase, a purported adhesin maintenance factor. To analyze posttranslational modification and functional maintenance of adhesin proteins, (3) an msrAnegative mutant will be constructed and the methionine-rich diversity region of the adhesin, antigen I/II (SspA/SspB) will be analyzed for altered structure and function. These studies will serve as a definitive test of the hypothesis that the process of adhesion regulates expression of required proteins in a biofilm model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SAME AND FOLATE DEFICIENCY IN ALCOHOLIC MIRCROPIGS Principal Investigator & Institution: Halsted, Charles H.; Professor; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): The overall hypothesis of the proposed research is that the pathogenesis of alcoholic liver disease (ALD) is regulated by changes in intrahepatic methionine metabolism that result from chronic ethanol consumption. Previously, we found that the combination of dietary ethanol and a folate deficient diet both maximized perturbations in methionine metabolism and accelerated the development of ALD in micropigs. The objective of the proposed research is to prove the hypothesis by demonstrating that the biochemical and histopathological features of ALD can be prevented or reversed by provision of supplemental S-adenosylmethionine (SAM) or folic acid to pigs maintained on chronic ethanol feeding with and without folate deficient diet. The first specific aim is to determine the efficacy and metabolic effects of intervention with SAM or folic acid in the prevention and treatment of ALD in micropigs. The second specific aim is to study the effects of abnormal methionine metabolism on known mediators and signal pathways of alcoholic liver injury. Micropigs will be fed diets with ethanol that are either folate sufficient or deficient and with or without supplemental SAM during development of liver injury, and with or without supplemental SAM or folic acid after development of alcoholic liver injury. Data collection will include methionine metabolites in plasma and liver, liver histopathology, markers of inflammation, necrosis, and apoptosis, products of lipid,
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protein, and DNA oxidation, antioxidant enzymes, and signal pathways of apoptosis. The data will be interpreted to confirm the role and establish potential mechanisms for abnormal methionine metabolism in the pathogenesis of ALD. While furthering understanding of interactions of methionine metabolites on pathways of liver injury, the project may establish novel approaches to the prevention and treatment of ALD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SAME, RXRALPHA-MEDIATED PATHWAYS AND ALD Principal Investigator & Institution: Wan, Yu-Jui Y.; Professor; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 905022052 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The goal of this project is to study the mechanism underlying nuclear receptor retinoid x receptor et (RXR-alpha)-mediated pathways on regulating S-adenosyl-L-methionine (SAMe) homeostasis. The main hypothesis is that RXR-alpha-mediated pathways either directly or indirectly control SAMe synthesis and alter the levels of glutathione and phosphatidylcholine in the liver, which consequently play a crucial role in the development of alcoholic liver disease (ALD). Most of the retinol and alcohol studies rely on either feeding animals with excess amount of retinoids or introducing animals with retinol deficient diet. Feeding animals with retinoids can be toxic. Retinol deficiency can also cause many unwanted effects. Knockout technology avoids these potential problems. Tissue specific knockout further allows studying the function of the gene in a cell type specific manner without affecting the gene function systemically. We have established an animal model in that the RXRalpha gene is knocked out only in the hepatocyte. RXR-alpha is highly expressed in the liver and is required for almost all the nuclear receptor-mediated pathways. Therefore, hepatocyte RXR-alpha deficient mouse serves as an excellent model for studying retinoid signaling in alcoholic liver disease. When hepatocyte RXR-alpha is deficient, liver retinoic acid is elevated, alcohol elimination rate is increased and alcohol-induced liver damage becomes more severe. In addition, the expression of more than ten genes encoding enzymes involved in the SAMe pathway is altered. Those data indicate that RXR-alpha, SAMe and ALD are intricately interlinked. Two specific aims are proposed to study the direct and indirect effect of RXR-alpha on SAMe homeostasis. First is to examine how RXR-alpha-mediated pathways regulate alcohol metabolism, which may indirectly control SAMe synthesis and affect the development of ALD. Second is to characterize how RXR-alpha-mediated pathways regulate genes encoding enzymes in the SAMe pathway and directly control SAMe homeostasis. RXR-alpha-mediated pathways including PPARcz and 3' and RXR-alpha homodimer and others will be studied. The effect of those nuclear receptor ligands on regulating SAMe synthesis will be analyzed. The proposed study not only allows us to understand how nuclear receptors regulate SAMe homeostasis, it also provides an opportunity to identify potential therapeutical targets and treatment agents for ALD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURAL BASIS--ALTERED CALCIUM HOMEOSTASIS OF AGING Principal Investigator & Institution: Squier, Thomas C.; Associate Professor; Battelle Pacific Northwest Laboratories Box 999, 902 Battelle Blvd Richland, Wa 99352 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004
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Summary: (Abstract from the Application). The long term goal is to identify the molecular mechanisms that result in the age-dependent loss of critical cellular functions, which correlate with an increased sensitivity to stress and diminished capabilities of the elderly. These investigators have focused on identification of the proposed linkage between oxidative stress and decreased calcium regulation observed during aging. Based on previous findings which demonstrate that during aging, multiple methionines in the calcium regulatory protein calmodulin (CaM) are oxidatively modified to their corresponding sulfoxides resulting in a reduced ability to activate the PM-Ca-ATPase, and the key role that CaM plays in intracellular signaling, they hypothesize that agerelated decreases in CaM function are responsible for the loss of calcium homeostasis observed in senescent cells. The accumulation of oxidatively modified CaM (CaMox) that is functionally inactive during aging is consistent with a decreased function of cellular repair and degradative enzymes in senescent animals. Thus the specific activity of methionine sulfoxide reductase (MsrA), which is able to repair oxidized CaM in vitro and fully restore CaMox function, may be compromised during aging. Likewise, the age relationship decreases in the function of the proteasome, which normally selectively degrades oxidized proteins, may result in the accumulation of inactive CaMox. Therefore, to identify the molecular mechanisms that result in the loss of CaM function, and recognition features that normally promote Cal repair and turnover, they propose the following specific aims: (1) Identify how methionine oxidation in CaM alters target protein activation, (2) Determine recognition elements in CaMox (oxidized) that promote methionine sulfoxide repair by MsrA, and (3) Discover mechanisms of degradation of CaMox by the proteasome. These measurements will involve a multidisciplinary approach that will combine biochemical measurements of the function of genetically engineered CaM mutants with altered sensitivities to oxidative stress and spectroscopic measurements of CaMox structure using FT-IR, flex, and NMR spray. Additional single-molecule measurements will permit the resolution of structural heterogeneity in individual CaMox molecules and identification of the mechanisms of CaM, recognition by MsrA and the proteasome. An understanding of the cellular mechanisms that modify calcium homeostasis under conditions of oxidative stress and the role of CaM oxidation in modifying target protein activation will be important to the development of new therapies to alleviate the decline in cellular functions associated with aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SUBTLE DISTURBANCES OF COBALAMIN STATUS Principal Investigator & Institution: Carmel, Ralph; Director of Research; New York Methodist Hospital 506 60Th St New York, Ny 11215 Timing: Fiscal Year 2003; Project Start 01-SEP-1983; Project End 31-AUG-2008 Summary: (provided by applicant): Low cobalamin (vitamin B12) levels are frequent, especially in the elderly, several million of whom are affected. Most often the low levels reflect "subclinical cobalamin deficiency", an asymptomatic state marked only by metabolic evidence of cobalamin insufficiency. It is unclear if these persons need intervention because progression to clinical deficiency may be uncommon, and many people with low levels have no deficiency at all. The proposal aims to study whether nitrous oxide (N2O), used in most general anesthesia in the US, worsens cobalamin status in elderly people who have unrecognized subclinical cobalamin deficiency. The reason for concern is that N2O inactivates cobalamin and therefore can cause neurological dysfunction in some patients with underlying clinically expressed cobalamin deficiency. The elderly are known to have an increased risk of postoperative
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cognitive complications. The study will recruit patients >60 years old who are scheduled for elective surgery in which N2O use for more than 1 hour is planned. Patients will be randomized in a blinded fashion to receive a standard anesthetic regimen of several agents, in which N2O is either included or replaced by air; the two regimens are equally safe and effective. They will undergo cognitive function and depression scale testing, blood testing of cobalamin-related metabolism, and clinical evaluation before surgery and at 48 hours, 14 days and 28 days after surgery. Those with cognitive changes will be treated with cobalamin and reevaluated after 3 months. Statistical analysis will compare the subgroups' metabolic, neuropsychological, demographic, genetic and clinical data. The primary question is what effect routine N2O anesthesia has on metabolic and clinical status related to subclinical cobalamin deficiency. It will also resolve whether or not the combination of N2O and the deficiency can explain the increased rate of postoperative cognitive problems in the elderly, and thus if preoperative or postoperative attention to cobalamin is needed in the elderly. A secondary goal is to extensively study cobalamin-related and homocysteine-related metabolism in these patients and their conditions, particularly as changes evolve after N2O use and later improvement. The clinical study provides a unique opportunity to establish these metabolic details and to compare their interactions with common genetic mutations in the patients that affect enzymes relevant to cobalamin deficiency, N2O effects, and their contribution to the clinical outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
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
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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 •
Project Title: SYNERGISTIC NUTRACEUTICAL EFFECTS OF DLPC AND SAME Principal Investigator & Institution: Lieber, Charles S.; Professor of Medicine & Pathology; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Our long-term objective is to develop effective prevention and therapy for liver cirrhosis. One of its nutritional consequences is decreased enzymatic transformation of essential nutrients to their active form, including defective activation of methionine to s-adenosylmethionine (SAMe), with loss of many of methionine's vital functions. This deficiency responds only partially to SAMe supplementation because optimal [cellular function] also requires integrity of the membranes, which are injured by free radical attack on their phosphatidylcholine (PC) infrastructure. This can be overcome through phospholipid replenishment with dilinoleoylphosphatidylcholine (DLPC), a highly bioavailable PC, but SAMe is also required because it is a crucial co-factor in the regeneration of PC through methylation of phosphatidylethanolamine. A major cause of oxidative stress and liver injury is cytochrome P4502E1 (CYP2E1) when induced by either ethanol (in alcoholic liver disease), lipids (in obesity) and ketones (in diabetes). Available CYP2E1 inhibitors are too toxic for clinical use, except for DLPC recently discovered to inhibit CYP2E1. Our immediate aim is to test the synergistic effects of the administration of SAMe + DLPC, using rodent models of precirrhotic alcoholic and nonalcoholic steatohepatitis and CCI4induced cirrhosis. Mechanisms of the beneficial interaction between SAMe and DLPC will be studied in vivo and also in vitro in cultured rodent hepatic stellate cells, Kupffer cells and macrophages, with focus on the preservation of the physiologic anti-oxidant glutathione, the restoration of phosphatidylethanolamine methyltransferase activity, the attenuation of oxidative stress and the resulting NF-?B activation, with lipid peroxidation and rise in the pathogenic cytokines TNF-?, TGF-?1, IL-1? and IL-6. Decreased fibrosis may be achieved through diminished stellate cell activation, enhanced collagenase activity and lowered leptin production. In summary, the synergistic effects of SAMe and DLPC, two innocuous and hepatoprotective nutraceuticals, will be tested against key modalities of experimental liver injury, including non-alcoholic and alcoholic steatohepatitis and CCI4 induced cirrhosis, thereby providing preclinical data needed to ultimately verify, in a clinical trial, the effectiveness of this nutraceutical combination in the prevention and treatment of liver cirrhosis, a common cause of mortality for which effective therapy is presently not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETS OF AMINO ACID RESTRICTION IN PROSTATE CANCER Principal Investigator & Institution: Meadows, Gary G.; Dorothy O. Kennedy Professor & Director,; Pharmaceutical Sciences; Washington State University 423 Neill Hall Pullman, Wa 99164 Timing: Fiscal Year 2004; Project Start 02-JUN-2004; Project End 31-MAY-2009 Summary: (provided by applicant) The objective of this application is to identify the molecular target(s) by which specific amino acid dependency modulates the viability and invasiveness of human androgen-independent prostate cancer calls. We hypothesize that specific amino acid-regulated invasion is dependent on the inhibition of FAK and its binding partners. We further hypothesize that specific amino acidregulated induction of apoptosis is due to the modulation and/or interference in cross talk between the MEKJERK survival pathway and the Akt pathway leading to loss of mitochondrial integrity with consequent activation of effector caspases. The specific aims are: 1) Identify if FAK/Cas/Crk or Rho/Ras pathway is the molecular target(s) of specific amino acid restriction in integrin-mediated attachment/invasion. 2) Determine how specific amino acid restriction modulates and/or interferes with the cross talk between the MEK/ERK and Akt survival pathways. 3) Determine the role(s) of BH123 and/or BH3 proteins of the Bcl-2 protein family on mitochondrial outer membrane permeabilization (MOMP), mitochondrial release of cytochrome c, and apoptosisinducing factor (AIF), and subsequent activation of caspases, and 4) Determine if dietary tyrosine and phenylalanine restriction and methionine restriction will inhibit growth and metastasis of prostate cancer xenografts. Specialized techniques utilized in the application involve cell attachment, migration/invasion, and wounding assays and immunoprecipitation and Western blot analysis. The cellular location of various signaling molecules will be examined with confocal immunofluorescence microscopy. Gene transfection experiments will be used to determine the role of certain cell signaling molecules. Intracellular amino acids will be determined by high pressure liquid chromatography and apoptosis will be measured by flow cytometry. A major benefit from the proposed research proposed is that it will expand knowledge into newer pathways of apoptosis research specific for prostate cancer cells as well as enhance understanding of the mechanisms underlying the anticancer activity of tyrosine/phenylalanine and methionine restriction. This is especially important research since there still is no satisfactory drug for treatment of androgen-independent, metastatic human prostate cancer. This research could serve as the basis for future development of more specific antimetastatic, anti-invasive, apoptosis-based therapies for human prostate cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE RELATIONSHIP OF PROTEIN DYNAMICS TO ENZYME CATALYSIS Principal Investigator & Institution: Reich, Norbert O.; Professor; Chemistry and Biochemistry; University of California Santa Barbara 3227 Cheadle Hall Santa Barbara, Ca 93106 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (provided by the applicant): The principal investigator and his collaborators propose to investigate the importance of protein dynamics on the catalytic rate enhancement of enzymatic methyl transfer. While much attention in the field of enzymatic catalysis is given to transition state stabilization or to entropic arguments, evidence in support of the importance of protein dynamics to catalysis is scant. Proteins
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are certainly known to undergo various types of conformational changes; for example, evidence in support of correlated motions contributing to ligand binding is available. Similar correlated motions have been identified for several enzyme-catalyzed reactions using molecular dynamic simulations. The investigators propose to apply a combination of x-ray crystallography, MD simulations, and functional analyses to provide an experimental and theoretical basis for relating protein dynamics and enzyme reaction rates. They propose to investigate M.HhaI, a bacterial S-adenosyl methionine-dependent DNA cytosine C5 methyltransferase. S-adenosyl methionine-dependent enzymes are widespread in biology and modify nucleic acids, proteins, lipids, carbohydrates, as well as drugs. Mammalian and bacterial DNA methyltransferases are important drug targets for anticancer and antibiotic drugs, respectively. M.HhaI is the best understood Sadenosyl methionine-dependent methyltransferase of any type, since numerous highresolution cocrystal structures are available and both the kinetic and chemical mechanisms are well known. The principal investigator and his collaborators identified structural elements that appear to be important for protein dynamics through inspection of both the M.HhaI-DNA cocrystal structure and MD analysis of the same structure. Several mutants have been prepared and are undergoing crystallographic, multiple conformer (MCA), and MD analyses. They propose to compare this structural and dynamic information with measurements of the methyl transfer rate. Data analysis will focus on correlations between methylation and 1) protein flexibility, 2) interatomic distances, 3) correlated motions, 4) frequency of near attack conformations (NACs), and 5) distribution if conformers. Multiple conformer analysis of the WT M.HhaI-DNA and mutant cocrystal structures will be used to design additional mutants to test the relationship between methylation and correlated motions. An extract-based screen will follow random mutagenesis of segments implicated in correlated motions; candidate mutants will be submitted to the structural and functional analyses. The combination of structural, molecular dynamic, and functional analyses should provide unique insights with potentially broad impact, into how correlated conformational changes contribute to catalysis. M.HhaI represents a class of enzymes with significant medical applications, and a better mechanistic property. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF H2-M3 IN T CELL DEVELOPMENT AND IMMUNITY Principal Investigator & Institution: Wang, Chyung-Ru; Associate Professor; Pathology; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-JUL-1996; Project End 31-MAY-2006 Summary: (provided by applicant): H2-M3 is an MHC class Ib molecule which preferentially binds N-Formylated peptides. Since all prokaryotes initiate protein synthesis with N-formylated methionine, the peptide binding specificity of M3 is especially suited for presenting these unique microbial antigens to T cells. Consistent with this notion, mice infected with Listeria monocytogenes, generate CD8+ CTLs that recognize N-formylated Listeria peptides presented by M3. Recent studies have shown that M3-restricted T cells expand rapidly during primary Listeria infection, prior to the expansion of class Ia-restricted T cells. However, the expansion of M3-restricted T cells following secondary Listeria infection was rather limited compared with the vigorous recall response of class Ia-restricted T cells. The mechanisms underlying the distinct kinetics of the M3-restricted response are not clear and the significance of M3-restricted T cells in bacterial infection remains to be defined. This application seeks to understand how M3 presents bacterial antigens and how M3 contributes to shaping the T cell repertoire during bacterial infections. First, we will use biochemical and cell biology
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approaches to examine the structural requirements for controlling intracellular trafficking of M3 and to elucidate the pathway for presentation of both endogenous and exogenous listerial antigens by M3. Secondly, we will compare T cell development in the M3-deficient and control mice to determine whether M3 is responsible for selecting unique subset(s) of T cells. Adoptive transfer of naive and memory T cells from D7 transgenic mice, expressing TCR specific for M3/LemA complexes, will be performed to investigate whether M3-restricted T cells have requirements similar to class Ia-restricted T cells for the maintenance of the periphery T cell pools. Thirdly, we will infect M3deficient, class Ia-deficient and control mice with Listeria to examine the relative contribution of class Ia-restricted and M3-restricted responses during Listeria infection, and to determine whether lack of an early M3 response could alter the kinetics and magnitude of class Ia-restricted response. Finally, we will extend our study to explore the functional role of M3-restricted T cells in immunity against Mycobaterium tuberculosis. Study of M3-restricted T cells responses against two distinct groups of intracellular bacteria would shed light on whether early and potent M3-restricted T cell response is unique to Listeria infection or is a general host defense mechanism against intracellular bacterial infection. Understanding the inter-relationship between class Iarestricted and class Ib-restricted responses during the generation of specific immunity may facilitate the development of more effective vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSCRIPTOME OF METASTATIC PROSTATE CANCER Principal Investigator & Institution: Glinsky, Gennadi V.; Associate Professor; Sidney Kimmel Cancer Center San Diego, Ca 921211181 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (Investigator's Abstract): The goal of this project is to discover genes that are differentially expressed during metastasis of prostate cancer. Potentially such transcripts and their products will be useful in detection, prognosis and ultimately, understanding and treatment of the disease. Because metastasis is a transient and rare event, it is difficult to study. We will concentrate on systems that reveal stark and potentially relevant phenotypic differences among cells of differing metastatic potential in vitro or which appear to model parts of the process in vivo. We have found that cell lines from a variety of different tumor types that differ in their metastatic potential generally demonstrated (i) differential clonogenic growth potential, (ii) strikingly different survival in serum starvation experiments, and (iii) phenotypic reversal of the metastatic phenotypein vitro and in vivo aft treatment with synthetic glycoamines, which are potential anti-metastatic drugs. We have shown that prostate cancer cell lines that differ in metastatic ability are also transcriptionally distinct, monitored on cDNA array. Remarkably, when cells selected for high metastatic ability are serum-starved and treated with glycoamines most of the transcriptional changes that would otherwise occur upon serum removal do not occur. These observations suggest that we can reveal functionally relevant differences in mode1 systems of the process of metastasis. We will study gene expression in an orthotopic human prostate cancer model in nude mice. Gene expression will also be measured during efficacy experiments of the leading clinic drug candidate, the Lac-L-Leu glycosarnine analog. To model one stage of metastasis we will inject cells of differing metastatic potential into the circulation of rabbits, recover cells by magnetic cell sorting base on an epithelial surface antigen, and then monitor changes in gene expression. We will also study leukapheresis-enriched disseminated cancer cells from human volunteers with advanced disease. To determine which, if any, of the gene status changes are likely to be diagnostic, prognostic, or of potential
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mechanistic or therapeutic value, we will examine a selected subset of genes in fresh pathology samples and in the blood-borne human prostate cancer cells using mRNA and protein expression-based assays. A set of 20-30 of the most relevant gene will be selected from the differential gene expression list and the levels of the corresponding proteins will be evaluated in time-course S35-methionine labeling and Western blot experiments. Subsequently the expression profile of these protein products will be studied in human prostate tumor samples by immunofluorescence analysis and immunohistochemistry to better correlate gene expression changes with phenotype. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSLATIONAL REGULATION IN SENDAI VIRUS Principal Investigator & Institution: Peeples, Mark E.; Professor; Rush University Medical Center Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The long-term goal of this proposal is to understand the regulation of protein synthesis in mammalian viruses. Our laboratory has focused on the role of mRNA structure on translation. The P/C mRNA of Sendai virus provides an excellent model to dissect translation machinery. It uses five translation start sites to express five proteins (P, C, C', Yl and Y2) in differential amounts. Expression of these proteins is not in accordance with the tenets of ribosome scanning, internal ribosome entry, or the ribosome shunting model. Our studies indicated that the C-AUG must occur in +1 orientation in relation to the P-AUG for the efficient synthesis of C protein. Importantly, all the known viral bicistronic mRNAs with overlapping reading frames have their second AUG in +1 orientation. Thus, one aim of the proposal is to test the hypothesis that the +1 orientation of the downstream reading frame in a bicistronic mRNA is crucial for its efficient initiation. This concept will be examined by constructing mRNAs with three overlapping open reading frames. Appropriate placement of AUG start sites will test the validity of this hypothesis. Second, non-AUG start sites are used efficiently in the P/C mRNA. The 5' UTR of the mRNA appears to be important for translation initiation at non-AUG codons. Third, the Y2 start site (fourth AUG) locus has a high propensity for translation initiation. Chimeric mRNAs will be constructed to define the loci that enhance translation of C' and Y2 proteins. Preliminary results have indicated that long-range interactions in the mRNA play a role in the initiation of all P/C mRNA encoded proteins. To test this, secondary structure of the entire P/C mRNA will be analyzed using both secondary and higher order structureprobing reagents to establish structure-function relationships. Creating deletions within the coding regions of P and C proteins will localize internal regulatory sequences. Fourth, synthesis of C' and certain cellular proteins is resistant to cycloheximide inhibition. Elements and mechanism that allow cycloheximide resistance will be defined. Finally, P/C mRNA binding proteins that are involved in translation regulation will be identified and characterized. Recent studies have shown that the internal initiation can occur on the A site of the ribosome without the initiator methionine tRNA, eIF2 or GTP hydrolysis. This initiation mechanism can explain some of our results. We will test this model for the P/C mRNA. In essence, the proposed studies will define the mechanisms that allow the regulated expression of the polycistronic P/C mRNA. Moreover, these studies will provide insights as to how mRNA structure and its interacting proteins regulate the protein synthesis machinery in mammalian cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSMISSION OF PRIONS WITHIN AND BETWEEN SPECIES Principal Investigator & Institution: Harrington, Robert D.; Vet Microbiology and Pathology; Washington State University 423 Neill Hall Pullman, Wa 99164 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 31-MAR-2007 Summary: (provided by applicant): Research Proposal: Transmissible Spongiform Encephalopathies (TSE) are a group of chronic invariably fatal neurodegenerative diseases. Chronic Wasting Disease (CWD) is a form of TSE in wild and captive elk, mule deer, and white tail deer. Oral transmission has been documented in many TSE's, and has been experimentally reproduced in deer given CWD infectious material. The oral transmissibility of CWD to other species remains uncertain. Potential hosts for CWD includehumans that consume venison, wild carnivores, and agriculturally important ruminants. Genetic polymorphismsthat effect TSE susceptibility have been identified for some species and may effect transmission of CWD. I will test the oral infectivityof CWD in a transgenic model to determine the effect of an amino acid polymorphism on disease susceptibility. I will test oral infectivity in a natural TSE host to further define the host range of TSE between species. Such studies are timely and topical due to the geographic spread of CWD positive animals and evidence that Bovine Spongiform Encephalopathy, the TSE affecting cattle, has zoonotic potential. The Candidate: The candidate is a veterinarian who has recently completed a residency in Comparative Medicine at the University of Washington School of Medicine. He has matriculated into the Washington State University Department of Veterinary Microbiology and Pathology for additional research training to culminate in the Doctor of Philosophy degree. The continuation of mentored training in biomedical research, with particular emphasis on continued investigation into the pathogenesis of TSE's, is necessary for development as an independent and collaborative investigator. The Environment: The research project will create a unique collaborative opportunity drawing on the resources and relevant expertise of both Washington State University and the University of Washington. Washington State University will provide interaction with internationally recognized faculty who have expertise in the study of Transmissible Spongiform Encephalopathies. The University of Washington and associated Comparative Medicine Transgenic Resource Laboratory will provide interaction with faculty and staff who have extensive experience in transgenic technology and the use of mutant mice in modern biomedical research. Both universities have established educational programs with a productive history of training veterinarians in biomedical research. Activities include weekly literature review, clinical-pathologic conferences, and research seminars. Participation in educational and training opportunities from these multiple sources will provide Dr. Harrington with a well rounded scientific background and allow specific research training pertinent to his area of research interest. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: X-RAY STRUCTURES OF EUKARYOTIC TRANSLATION FACTORS Principal Investigator & Institution: Bonanno, Jeffrey B.; Lab/Molecular Biophysics; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2002; Project Start 01-MAR-2000; Project End 31-DEC-2002 Summary: The long-term goal of the proposed research is a detailed structural and mechanistic understanding of the enormously complex macromolecular machine that controls translation initiation in eukaryotes. The proposed work builds on our structural and functional studies of mRNA selection by the cap-binding protein, eukaryotic initiation factor 4E or eIF4E. X-ray crystallography will be combined with chemical
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methods to study the structures and mechanisms of action of an important subset of the remaining translation initiation factors [eIF4G, eIF4A, eIF2, IF2, eIF3, eIF1A, eIF2B, eIF5, the poly (A)-binding protein (PABP), and a PABP-interacting protein]. These translation factors participate in the following biochemical steps: (a) resolving secondary structural features in the 5' untranslated region of the mRNA, (b) delivering the methionyl initiator tRNA to the 40S subunit, (d) recycling the G protein that loads the methionyl initiator tRNA onto the 40S subunit, (d) recruitment of the 40S subunit, the methionyl initiator tRNA and various accessory factors to the 5' untranslated region of cellular mRNAs bearing 5' 7-methyl-G caps, (e) recruitment of the same components to the 5' untranslated region of an uncapped viral RNA, (f) 60S ribosomal subunit joining, and (g) synergy of transcription initiation via mRNA circularization by the PABP. The specific aims of the research are as follows: Specific Aim 1. Determine X-ray structures of the RNA helicase eIF4A, and its complexes with ADP, a non-hydrolyzable ATP analog, and single-stranded RNA. Specific Aim 2. Determine X-ray structures of eIF2, and its complexes with GDP, a non-hydrolyzable GTP analog, and methionyl initiator tRNA. Specific Aim 3. Determine the X-ray structure of eukaryotic IF2. Specific Aim 4. Determine X-ray structures of a C-terminal fragment of eIF4G, and its complex with a picornavirus internal ribosome entry site. Specific Aim 5. Determine X-ray structures of eIF5 and eIF2Bepsilon, and their complexes with eIF2beta. Specific Aim 6. Determine Xray structures of PABP recognizing poly (A) RNA, and various binary and ternary complexes with a PABP-interacting protein and eIF4G. 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 “methionine” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for methionine in the PubMed Central database: •
A Gene Controlling Variation in Arabidopsis Glucosinolate Composition Is Part of the Methionine Chain Elongation Pathway. by Kroymann J, Textor S, Tokuhisa JG, Falk KL, Bartram S, Gershenzon J, Mitchell-Olds T.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129277
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A homologue of elongation factor 1[gamma] regulates methionine sulfoxide reductase A gene expression in Saccharomyces cerevisiae. by Hanbauer I, Boja ES, Moskovitz J.; 2003 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166206
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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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A new methionine locus, metR, that encodes a trans-acting protein required for activation of metE and metH in Escherichia coli and Salmonella typhimurium. by Urbanowski ML, Stauffer LT, Plamann LS, Stauffer GV.; 1987 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=211958
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A Test of the ``Jigsaw Puzzle" Model for Protein Folding by Multiple Methionine Substitutions within the Core of T4 Lysozyme. by Gassner NC, Baase WA, Matthews BW.; 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=37959
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Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor --induced lethal hepatitis. by Mari M, Colell A, Morales A, Paneda C, Varela-Nieto I, Garcia-Ruiz C, Fernandez-Checa JC.; 2004 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=362116
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Altered regulation of the glnRA operon in a Bacillus subtilis mutant that produces methionine sulfoximine-tolerant glutamine synthetase. by Schreier HJ, Rostkowski CA, Kellner EM.; 1993 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=196239
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Aminoacylation Identity Switch of Turnip Yellow Mosaic Virus RNA from Valine to Methionine Results in an Infectious Virus. by Dreher TW, Tsai C, Skuzeski JM.; 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=37969
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An anticodon change switches the identity of E. coli tRNA(mMet) from methionine to threonine. by Schulman LH, Pelka H.; 1990 Jan 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=330265
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Antisense Inhibition of Threonine Synthase Leads to High Methionine Content in Transgenic Potato Plants. by Zeh M, Casazza AP, Kreft O, Roessner U, Bieberich K, Willmitzer L, Hoefgen R, Hesse H.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129252
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Aromatic Amino Acid Transamination and Methionine Recycling in Trypanosomatids. by Berger BJ, Dai WW, Wang H, Stark RE, Cerami A.; 1996 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39498
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Bacterial variations on the methionine salvage pathway. by Sekowska A, Denervaud V, Ashida H, Michoud K, Haas D, Yokota A, Danchin A.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=395828
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Biochemical and regulatory effects of methionine analogues in Saccharomyces cerevisiae. by Colombani F, Cherest H, de Robichon-Szulmajster H.; 1975 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=246067
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Carbon dioxide stimulates peroxynitrite-mediated nitration of tyrosine residues and inhibits oxidation of methionine residues of glutamine synthetase: Both
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modifications mimic effects of adenylylation. by Berlett BS, Levine RL, Stadtman ER.; 1998 Mar 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19646 •
Characterization of Salmonella typhimurium Strains Sensitive and Resistant to Methionine Sulfoximine. by Steimer-Veale K, Brenchley JE.; 1974 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245690
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Cobalamin inactivation decreases purine and methionine synthesis in cultured lymphoblasts. by Boss GR.; 1985 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=423748
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Constitutive Overexpression of Cystathionine [gamma]-Synthase in Arabidopsis Leads to Accumulation of Soluble Methionine and S-Methylmethionine. by Kim J, Lee M, Chalam R, Martin MN, Leustek T, Boerjan W.; 2002 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148947
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Control of protein life-span by N-terminal methionine excision. by Giglione C, Vallon O, Meinnel T.; 2003 Jan 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140049
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Corynebacterium glutamicum Utilizes both Transsulfuration and Direct Sulfhydrylation Pathways for Methionine Biosynthesis. by Hwang BJ, Yeom HJ, Kim Y, Lee HS.; 2002 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134843
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Decreased methionine synthesis in purine nucleoside-treated T and B lymphoblasts and reversal by homocysteine. by Boss GR, Pilz RB.; 1984 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=425293
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Dimethylsulfoniopropionate and Methanethiol Are Important Precursors of Methionine and Protein-Sulfur in Marine Bacterioplankton. by Kiene RP, Linn LJ, Gonzalez J, Moran MA, Bruton JA.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91606
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Direct Sulfhydrylation for Methionine Biosynthesis in Leptospira meyeri. by Belfaiza J, Martel A, Margarita D, Saint Girons I.; 1998 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106879
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DNA binding of CPF1 is required for optimal centromere function but not for maintaining methionine prototrophy in yeast. by Mellor J, Rathjen J, Jiang W, Barnes CA, Dowell SJ.; 1991 Jun 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=328258
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Effects of methionine on the cytoplasmic distribution of actin and tubulin during neural tube closure in rat embryos. by Moephuli SR, Klein NW, Baldwin MT, Krider HM.; 1997 Jan 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19549
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Effects of Regulatory Mutations upon Methionine Biosynthesis in Saccharomyces cerevisiae: Loci eth2-eth3-eth10. by Cherest H, Surdin-Kerjan Y, Antoniewski J, de Robichon-Szulmajster H.; 1973 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=246357
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Enhanced methionine levels and increased nutritive value of seeds of transgenic lupins (Lupinus angustifolius L.) expressing a sunflower seed albumin gene. by Molvig L, Tabe LM, Eggum BO, Moore AE, Craig S, Spencer D, Higgins TJ.; 1997 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22931
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Enzymatic reduction of protein-bound methionine sulfoxide. by Brot N, Weissbach L, Werth J, Weissbach H.; 1981 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=319302
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Escherichia coli peptide methionine sulfoxide reductase gene: regulation of expression and role in protecting against oxidative damage. by Moskovitz J, Rahman MA, Strassman J, Yancey SO, Kushner SR, Brot N, Weissbach H.; 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=176620
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Existence of two levels of repression in the biosynthesis of methionine in Saccharomyces cerevisiae: effect of lomofungin on enzyme synthesis. by SurdinKerjan Y, de Robichon-Szulmajster H.; 1975 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=246066
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Exogenous methionine increases levels of mRNAs transcribed from pcbAB, pcbC, and cefEF genes, encoding enzymes of the cephalosporin biosynthetic pathway, in Acremonium chrysogenum. by Velasco J, Gutierrez S, Fernandez FJ, Marcos AT, Arenos C, Martin JF.; 1994 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=205148
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Extracting biological information from DNA arrays: an unexpected link between arginine and methionine metabolism in Bacillus subtilis. by Sekowska A, Robin S, Daudin JJ, Henaut A, Danchin A.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33395
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Factors Affecting Virulence of Shigella flexneri: Defective Methionine Synthesis in an Escherichia coli-Shigella Hybrid. by Rothman SW, Corwin LM.; 1972 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=251393
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Factors modulating conformational equilibria in large modular proteins: A case study with cobalamin-dependent methionine synthase. by Bandarian V, Ludwig ML, Matthews RG.; 2003 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166199
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Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig. by Halsted CH, Villanueva JA, Devlin AM, Niemela O, Parkkila S, Garrow TA, Wallock LM, Shigenaga MK, Melnyk S, James SJ.; 2002 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126626
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High in vivo rates of methionine biosynthesis in transformed human and malignant rat cells auxotrophic for methionine. by Hoffman RM, Erbe RW.; 1976 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=430329
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Homoserine O-acetyltransferase, involved in the Leptospira meyeri methionine biosynthetic pathway, is not feedback inhibited. by Bourhy P, Martel A, Margarita D, Saint Girons I, Belfaiza J.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179265
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Identification of L-Methionine-S-Sulfoximine as the Convulsant Isomer of Methionine Sulfoximine. by Rowe WB, Meister A.; 1970 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=283073
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In Vitro and In Vivo Oxidation of Methionine Residues in Small, Acid-Soluble Spore Proteins from Bacillus Species. by Hayes CS, Illades-Aguiar B, Casillas-Martinez L, Setlow P.; 1998 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107222
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In vivo growth characteristics of leucine and methionine auxotrophic mutants of Mycobacterium bovis BCG generated by transposon mutagenesis. by McAdam RA, Weisbrod TR, Martin J, Scuderi JD, Brown AM, Cirillo JD, Bloom BR, Jacobs WR Jr.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173102
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Induction and Repression in the S-Adenosylmethionine and Methionine Biosynthetic Systems of Saccharomyces cerevisiae. by Ferro AJ, Spence KD.; 1973 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=285450
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Insertional Inactivation of the Methionine S-Methyltransferase Gene Eliminates the S-Methylmethionine Cycle and Increases the Methylation Ratio. by Kocsis MG, Ranocha P, Gage DA, Simon ES, Rhodes D, Peel GJ, Mellema S, Saito K, Awazuhara M, Li C, Meeley RB, Tarczynski MC, Wagner C, Hanson AD.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166937
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Interference by methionine on valine uptake in Acremonium chrysogenum. by Alonso MJ, Luengo JM.; 1987 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=174728
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Involvement of folic acid and methionine in the synthesis of certain membraneassociated nucleotide sugars by Enterococcus hirae. by Wood RC.; 1994 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=196834
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Mapping the interactions between flavodoxin and its physiological partners flavodoxin reductase and cobalamin-dependent methionine synthase. by Hall DA, Vander Kooi CW, Stasik CN, Stevens SY, Zuiderweg ER, Matthews RG.; 2001 Aug 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55485
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Methionine sulfoxide is transported by high-affinity methionine and glutamine transport systems in Salmonella typhimurium. by Ayling PD.; 1981 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=216234
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Modification of protein surface hydrophobicity and methionine oxidation by oxidative systems. by Chao CC, Ma YS, Stadtman ER.; 1997 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20306
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Modulation of potassium channel function by methionine oxidation and reduction. by Ciorba MA, Heinemann SH, Weissbach H, Brot N, Hoshi T.; 1997 Sep 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23300
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Molecular Characterization and Sequence of a Methionine Biosynthetic Locus from Pseudomonas syringae. by Andersen GL, Beattie GA, Lindow SE.; 1998 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107460
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Molecular mechanisms of an inborn error of methionine pathway. Methionine adenosyltransferase deficiency. by Ubagai T, Lei KJ, Huang S, Mudd SH, Levy HL, Chou JY.; 1995 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185831
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MtaR, a Regulator of Methionine Transport, Is Critical for Survival of Group B Streptococcus In Vivo. by Shelver D, Rajagopal L, Harris TO, Rubens CE.; 2003 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=262094
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Mutation in the Threonine Synthase Gene Results in an Over-Accumulation of Soluble Methionine in Arabidopsis. by Bartlem D, Lambein I, Okamoto T, Itaya A, Uda Y, Kijima F, Tamaki Y, Nambara E, Naito S.; 2000 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58986
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Mutations affecting regulation of methionine biosynthetic genes isolated by use of met-lac fusions. by Mulligan JT, Margolin W, Krueger JH, Walker GC.; 1982 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=220301
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Myeloperoxidase-Mediated Oxidation of Methionine and Amino Acid Decarboxylation. by Tsan MF.; 1982 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351195
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N-terminal RAG1 frameshift mutations in Omenn's syndrome: Internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains. by Santagata S, Gomez CA, Sobacchi C, Bozzi F, Abinun M, Pasic S, Cortes P, Vezzoni P, Villa A.; 2000 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18960
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One- and two-electron oxidations of methionine by peroxynitrite. by Pryor WA, Jin X, Squadrito GL.; 1994 Nov 8; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45189
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Oxidation of methionine residues in proteins of activated human neutrophils. by Fliss H, Weissbach H, Brot N.; 1983 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=390013
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Partial purification and some properties of homoserine O-acetyltransferase of a methionine auxotroph of Saccharomyces cerevisiae. by Yamagata S.; 1987 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=212417
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Peptide methionine sulfoxide reductase from Escherichia coli and Mycobacterium tuberculosis protects bacteria against oxidative damage from reactive nitrogen intermediates. by John GS, Brot N, Ruan J, Erdjument-Bromage H, Tempst P, Weissbach H, Nathan C.; 2001 Aug 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55550
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Peroxynitrite-mediated modification of proteins at physiological carbon dioxide concentration: pH dependence of carbonyl formation, tyrosine nitration, and methionine oxidation. by Tien M, Berlett BS, Levine RL, Chock PB, Stadtman ER.; 1999 Jul 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22143
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Physical mapping of the scattered methionine genes on the Escherichia coli chromosome. by Old IG, Saint Girons I, Richaud C.; 1993 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=204776
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Probing the molecular mechanism of action of co-repressor in the E. coli methionine repressor-operator complex using surface plasmon resonance (SPR). by Parsons ID, Persson B, Mekhalfia A, Blackburn GM, Stockley PG.; 1995 Jan 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=306656
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Processing of the initiation methionine from proteins: properties of the Escherichia coli methionine aminopeptidase and its gene structure. by Ben-Bassat A, Bauer K, Chang SY, Myambo K, Boosman A, Chang S.; 1987 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=211843
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Properties of Mutant SHV-5 [beta]-Lactamases Constructed by Substitution of Isoleucine or Valine for Methionine at Position 69. by Giakkoupi P, Miriagou V, Gazouli M, Tzelepi E, Legakis NJ, Tzouvelekis LS.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105805
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Reduced availability of endogenously synthesized methionine for Sadenosylmethionine formation in methionine-dependent cancer cells. by Coalson DW, Mecham JO, Stern PH, Hoffman RM.; 1982 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=346647
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Reduction of methionine sulfoxide to methionine by Escherichia coli. by Ejiri SI, Weissbach H, Brot N.; 1979 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=216841
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Regulation of methionine transport activity in Escherichia coli. by Kadner RJ.; 1975 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=235647
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Regulation of the Methionine Feedback-Sensitive Enzyme in Mutants of Salmonella typhimurium. by Lawrence DA.; 1972 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=247244
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Repression of the tyrosine, lysine, and methionine biosynthetic pathways in a hisT mutant of Salmonella typhimurium. by Brown BA, Lax SR, Liang L, Dabney BJ, Spremulli LL, Ravel JM.; 1977 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=235064
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Role of methionine and formylation of initiator tRNA in initiation of protein synthesis in Escherichia coli. by Varshney U, RajBhandary UL.; 1992 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=207498
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Role of methionine in bacterial chemotaxis: requirement for tumbling and involvement in information processing. by Springer MS, Kort EN, Larsen SH, Ordal GW, Reader RW, Adler J.; 1975 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=388779
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Role of Methionine in Biosynthesis of Prodigiosin by Serratia marcescens. by Qadri SM, Williams RP.; 1973 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=246475
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S-Adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. [ISRCTN36233495]. by Najm WI, Reinsch S, Hoehler F, Tobis JS, Harvey PW.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=387830
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S-adenosyl methionine alters the DNA contacts of the EcoKI methyltransferase. by Powell LM, Murray NE.; 1995 Mar 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=306793
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S-Adenosyl Methionine-Mediated Repression of Methionine Biosynthetic Enzymes in Saccharomyces cerevisiae. by Cherest H, Surdin-Kerjan Y, Antoniewski J, De Robichon-Szulmajster H.; 1973 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=285346
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Selenoprotein R is a zinc-containing stereo-specific methionine sulfoxide reductase. by Kryukov GV, Kumar RA, Koc A, Sun Z, Gladyshev VN.; 2002 Apr 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123633
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Sinorhizobium meliloti Cells Require Biotin and either Cobalt or Methionine for Growth. by Watson RJ, Heys R, Martin T, Savard M.; 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93089
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Structure of Mycobacterium tuberculosis Methionine Sulfoxide Reductase A in Complex with Protein-Bound Methionine. by Taylor AB, Benglis, Jr. DM, Dhandayuthapani S, Hart PJ.; 2003 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164888
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Synergistic activity of 5-trifluoromethylthioribose and inhibitors of methionine synthesis against Klebsiella pneumoniae. by Tower PA, Johnson LL, Ferro AJ, Fitchen JH, Riscoe MK.; 1991 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245218
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Targeted Disruption of the Methionine Synthase Gene in Mice. by Swanson DA, Liu ML, Baker PJ, Garrett L, Stitzel M, Wu J, Harris M, Banerjee R, Shane B, Brody LC.; 2001 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=99560
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Targeted Inactivation of the mecB Gene, Encoding Cystathionine-[gamma]-Lyase, Shows that the Reverse Transsulfuration Pathway Is Required for High-Level Cephalosporin Biosynthesis in Acremonium chrysogenum C10 but Not for Methionine Induction of the Cephalosporin Genes. by Liu G, Casqueiro J, Banuelos O, Cardoza RE, Gutierrez S, Martin JF.; 2001 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95063
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The Abundance of Met30p Limits SCFMet30p Complex Activity and Is Regulated by Methionine Availability. by Smothers DB, Kozubowski L, Dixon C, Goebl MG, Mathias N.; 2000 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86396
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The anticodon triplet is not sufficient to confer methionine acceptance to a transfer RNA. by Senger B, Despons L, Walter P, Fasiolo F.; 1992 Nov 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=50423
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The atherogenic effect of excess methionine intake. by Troen AM, Lutgens E, Smith DE, Rosenberg IH, Selhub J.; 2003 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=299913
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The effect on endothelial function of vitamin C during methionine induced hyperhomocysteinaemia. by Hanratty CG, McGrath LT, McAuley DF, Young IS, Johnston DG.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34516
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The Folate Branch of the Methionine Biosynthesis Pathway in Streptomyces lividans: Disruption of the 5,10-Methylenetetrahydrofolate Reductase Gene Leads to Methionine Auxotrophy. by Blanco J, Coque JJ, Martin JF.; 1998 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107064
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The methionine salvage pathway in Bacillus subtilis. by Sekowska A, Danchin A.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113757
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The N-Terminal Region of Arabidopsis Cystathionine [gamma]-Synthase Plays an Important Regulatory Role in Methionine Metabolism. by Hacham Y, Avraham T, Amir R.; 2002 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148908
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The specific features of methionine biosynthesis and metabolism in plants. by Ravanel S, Gakiere B, Job D, Douce R.; 1998 Jun 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22764
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The UL3 Protein of Herpes Simplex Virus 1 Is Translated Predominantly from the Second In-Frame Methionine Codon and Is Subject to at Least Two Posttranslational Modifications. by Markovitz NS, Filatov F, Roizman B.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112816
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Transport and utilization of D-methionine and other methionine sources in Escherichia coli. by Kadner RJ.; 1977 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=234917
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Trifluoromethionine, a Prodrug Designed against Methionine [gamma]-LyaseContaining Pathogens, Has Efficacy In Vitro and In Vivo against Trichomonas vaginalis. by Coombs GH, Mottram JC.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90540
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Tyrosine Aminotransferase Catalyzes the Final Step of Methionine Recycling in Klebsiella pneumoniae. by Heilbronn J, Wilson J, Berger BJ.; 1999 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93571
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Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years. by Boers GH, Smals AG, Trijbels FJ, Leermakers AI, Kloppenborg PW.; 1983 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=437037
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Use of 13C Nuclear Magnetic Resonance and Gas Chromatography To Examine Methionine Catabolism by Lactococci. by Gao S, Mooberry ES, Steele JL.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90907
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Yeast mitochondrial methionine initiator tRNA: characterization and nucleotide sequence. by Canaday J, Dirheimer G, Martin RP.; 1980 Apr 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324008
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. To generate your own bibliography of studies dealing with methionine, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “methionine” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for methionine (hyperlinks lead to article summaries): •
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A 2-step strategy to reduce the need for methionine-loading tests to diagnose hyperhomocysteinemia. Author(s): van de Laak MF, Grobbee DE, van der Griend R, de Valk HW, Algra A, Banga JD, van der Graaf Y; Smart study group. Source: The Journal of Laboratory and Clinical Medicine. 2003 August; 142(2): 121-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12960959
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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A critical role of water in the specific cleavage of the anticodon loop of some eukaryotic methionine initiator tRNAs. Author(s): Perbandt M, Barciszewska MZ, Betzel C, Erdmann VA, Barciszewski J. Source: Molecular Biology Reports. 2003 March; 30(1): 27-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12688532
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A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Author(s): Pancheri P, Scapicchio P, Chiaie RD. Source: The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (Cinp). 2002 December; 5(4): 287-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12466028
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A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis. Author(s): Bernier SG, Lazarus DD, Clark E, Doyle B, Labenski MT, Thompson CD, Westlin WF, Hannig G. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 July 20; 101(29): 10768-73. Epub 2004 Jul 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15249666
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A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening: neonatal intrahepatic cholestasis caused by citrin deficiency. Author(s): Ohura T, Kobayashi K, Abukawa D, Tazawa Y, Aikawa J, Sakamoto O, Saheki T, Iinuma K. Source: European Journal of Pediatrics. 2003 May; 162(5): 317-22. Epub 2003 February 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692712
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A novel methionine-based signaling mechanism regulating the expression of thymidylate synthase. Author(s): Chu E. Source: Cancer Biology & Therapy. 2003 July-August; 2(4): 370-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14508107
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A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. Author(s): Roncaglia N, Locatelli A, Arreghini A, Assi F, Cameroni I, Pezzullo JC, Ghidini A. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2004 January; 111(1): 17-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687046
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A single amino acid residue defines the difference in ovalicin sensitivity between type I and II methionine aminopeptidases. Author(s): Brdlik CM, Crews CM. Source: The Journal of Biological Chemistry. 2004 March 5; 279(10): 9475-80. Epub 2003 December 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14676204
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A valine to methionine polymorphism at codon 83 in the 8-oxo-dGTPase gene MTH1 is not associated with sporadic Parkinson's disease. Author(s): Satoh J, Kuroda Y. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2000 November; 7(6): 673-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11136354
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Activity of Se-allylselenocysteine in the presence of methionine gamma-lyase on cell growth, DNA integrity, apoptosis, and cell-cycle regulatory molecules. Author(s): Zhu Z, Jiang W, Ganther HE, Ip C, Thompson HJ. Source: Molecular Carcinogenesis. 2000 December; 29(4): 191-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11170256
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Activity, tissue distribution and site-directed mutagenesis of a human peptide methionine sulfoxide reductase of type B: hCBS1. Author(s): Jung S, Hansel A, Kasperczyk H, Hoshi T, Heinemann SH. Source: Febs Letters. 2002 September 11; 527(1-3): 91-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12220640
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Acute methionine loading does not alter arterial stiffness in humans. Author(s): Wilkinson IB, Megson IL, MacCallum T, Rooijmans DF, Johnson SM, Boyd JL, Cockcroft JR, Webb DJ. Source: Journal of Cardiovascular Pharmacology. 2001 January; 37(1): 1-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11152366
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Alcohol, folate, methionine, and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Author(s): Feigelson HS, Jonas CR, Robertson AS, McCullough ML, Thun MJ, Calle EE. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 February; 12(2): 161-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12582027
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Alzheimer's amyloid beta-peptide (1-42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide. Author(s): Butterfield DA, Bush AI. Source: Neurobiology of Aging. 2004 May-June; 25(5): 563-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15172731
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An unusual peptide deformylase features in the human mitochondrial N-terminal methionine excision pathway. Author(s): Serero A, Giglione C, Sardini A, Martinez-Sanz J, Meinnel T. Source: The Journal of Biological Chemistry. 2003 December 26; 278(52): 52953-63. Epub 2003 October 07. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14532271
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Arterial stiffness is rapidly induced by raising the plasma homocysteine concentration with methionine. Author(s): Nestel PJ, Chronopoulos A, Cehun M. Source: Atherosclerosis. 2003 November; 171(1): 83-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642409
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Association of IL-1 RN*2 allele and methionine synthase 2756 AA genotype with dementia severity of sporadic Alzheimer's disease. Author(s): Bosco P, Gueant-Rodriguez RM, Anello G, Romano A, Namour B, Spada RS, Caraci F, Tringali G, Ferri R, Gueant JL. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2004 July; 75(7): 1036-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15201366
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Asymmetric dimethylarginine and total homocysteine in plasma after oral methionine loading. Author(s): Wanby P, Brattstrom L, Brudin L, Hultberg B, Teerlink T. Source: Scandinavian Journal of Clinical and Laboratory Investigation. 2003; 63(5): 34753. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14599157
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Basal and post-methionine serum homocysteine and lipoprotein abnormalities in patients with chronic liver disease. Author(s): Ben-Ari Z, Tur-Kaspa R, Schafer Z, Baruch Y, Sulkes J, Atzmon O, Greenberg A, Levi N, Fainaru M. Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 2001 July; 49(4): 325-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11478408
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Beneficial effect of S-adenosyl-L-methionine in lead intoxication. Another approach to clinical therapy. Author(s): Paredes SR, Juknat de Geralnik AA, Batlle AM, Conti HA. Source: Int J Biochem. 1985; 17(5): 625-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2863186
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Beta adrenergic modulation of formyl-methionine-leucine-phenylalanine-stimulated secretion of eosinophil peroxidase and leukotriene C4. Author(s): Munoz NM, Vita AJ, Neeley SP, McAllister K, Spaethe SM, White SR, Leff AR. Source: The Journal of Pharmacology and Experimental Therapeutics. 1994 January; 268(1): 139-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8301549
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Beta-endorphin-, leucine enkephalinand methionine enkephalin-like immunoreactivity in human cerebrospinal fluid. Simultaneous determination and relation to neurological disorders. Author(s): Neuser D, Lesch KP, Stasch JP, Przuntek H. Source: European Neurology. 1984; 23(2): 73-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6327313
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Binding of alpha-hydroxy-beta-amino acid inhibitors to methionine aminopeptidase. The performance of two types of scoring functions. Author(s): Jorgensen AT, Sorensen MD, Bjorkling F, Liljefors T. Source: Journal of Computer-Aided Molecular Design. 2003 May-June; 17(5-6): 383-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14635729
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Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells. Author(s): Judde JG, Ellis M, Frost P. Source: Cancer Research. 1989 September 1; 49(17): 4859-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2503245
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Biochemical aspect of dimethyl sulfide breath test in the studies on methionine metabolism. Author(s): Kaji H, Hisamura M, Saito N, Murao M. Source: Res Commun Chem Pathol Pharmacol. 1981 June; 32(3): 515-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7268195
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Biochemical basis for the dominant inheritance of hypermethioninemia associated with the R264H mutation of the MAT1A gene. A monomeric methionine adenosyltransferase with tripolyphosphatase activity. Author(s): Perez Mato I, Sanchez del Pino MM, Chamberlin ME, Mudd SH, Mato JM, Corrales FJ. Source: The Journal of Biological Chemistry. 2001 April 27; 276(17): 13803-9. Epub 2001 January 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11278456
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Biochemical marker in familial amyloidotic polyneuropathy, Portuguese type. Family studies on the transthyretin (prealbumin)-methionine-30 variant. Author(s): Saraiva MJ, Costa PP, Goodman DS. Source: The Journal of Clinical Investigation. 1985 December; 76(6): 2171-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3908483
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Biochemistry and pharmacology of S-adenosyl-L-methionine and rationale for its use in liver disease. Author(s): Chawla RK, Bonkovsky HL, Galambos JT. Source: Drugs. 1990; 40 Suppl 3: 98-110. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2081485
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Blood S-adenosyl-L-methionine levels in psychiatric disorders. Author(s): Cohen BM, Lipinski JF, Vuckovic A, Prosser E. Source: The American Journal of Psychiatry. 1982 February; 139(2): 229-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7055296
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Blood viscosity and red cell morphology in subjects suffering from cirrhosis before and after treatment with S-adenosyl-L-methionine (SAM). Author(s): Turchetti V, Bellini MA, Leoncini F, Petri F, Trabalzini L, Guerrini M, Forconi S. Source: Clinical Hemorheology and Microcirculation. 2000; 22(3): 215-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10976715
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Brady-tachycardia syndrome after radiotherapy for lung cancer. Assessment by computed tomography and carbon-11 methionine positron emission tomography. Author(s): Watanabe T, Okazaki O, Izumo K, Michihata T, Katagiri T, Harumi K. Source: Japanese Heart Journal. 1999 September; 40(5): 677-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10888388
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Brain ATP:L-methionine S-adenosyltransferase (MAT), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH): regional distribution and age-related changes. Author(s): Trolin CG, Lofberg C, Trolin G, Oreland L. Source: European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 1994 December; 4(4): 469-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7894257
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Brain methionine- and leucine-enkephalin receptors in patients with dementia. Author(s): Rinne JO, Lonnberg P, Marjamaki P, Molsa P, Sako E, Paljarvi L. Source: Neuroscience Letters. 1993 October 14; 161(1): 77-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8255552
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Brain tumor imaging using C-11-labeled L-methionine and D-methionine. Author(s): Schober O, Meyer GJ, Stolke D, Hundeshagen H. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1985 January; 26(1): 98-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3965661
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Brain tumor protein synthesis and histological grades: a study by positron emission tomography (PET) with C11-L-Methionine. Author(s): Bustany P, Chatel M, Derlon JM, Darcel F, Sgouropoulos P, Soussaline F, Syrota A. Source: Journal of Neuro-Oncology. 1986; 3(4): 397-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3485705
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Brain uptake of 11C-methionine in phenylketonuria. Author(s): Comar D, Saudubray JM, Duthilleul A, Delforge J, Maziere M, Berger G, Charpentier C, Todd-Pokropek A. Source: European Journal of Pediatrics. 1981 March; 136(1): 13-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7215387
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Brittle and sparse hair with normal cystine content caused by methionine deficiency? Author(s): Goerz G, Behrens W, Megahed M, Kuester W, Fohles J, Tsambaos D, Nikiforidis G, Balas C. Source: Acta Dermato-Venereologica. 1996 January; 76(1): 62-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8721497
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C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Author(s): Hanson NQ, Aras O, Yang F, Tsai MY. Source: Clinical Chemistry. 2001 April; 47(4): 661-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11274015
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Can dietary methionine restriction increase the effectiveness of chemotherapy in treatment of advanced cancer? Author(s): Epner DE. Source: Journal of the American College of Nutrition. 2001 October; 20(5 Suppl): 443S449S; Discussion 473S-475S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11603655
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CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families. Author(s): Zavadakova P, Fowler B, Zeman J, Suormala T, Pristoupilova K, Kozich V, Zavad'akova P. Source: Journal of Inherited Metabolic Disease. 2002 October; 25(6): 461-76. Erratum In: J Inherit Metab Dis. 2003; 26(1): 95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12555939
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Certain metals trigger fibrillation of methionine-oxidized alpha-synuclein. Author(s): Yamin G, Glaser CB, Uversky VN, Fink AL. Source: The Journal of Biological Chemistry. 2003 July 25; 278(30): 27630-5. Epub 2003 May 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12754258
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Changes in pulmonary vascular function after acute methionine loading in normal men. Author(s): O'Dochartaigh C, Ong H, Lovell S, Donnelly R, Hanratty C, Riley M, Frenneaux M, Young I, Nicholls P. Source: Clinical Science (London, England : 1979). 2004 April; 106(4): 413-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709159
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Chemoprevention of hepatocarcinogenesis: S-adenosyl-L-methionine. Author(s): Pascale RM, Simile MM, De Miglio MR, Feo F. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 193-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163149
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Clinical application of (11)C-methionine positron emission tomography for evaluation of pancreatic function. Author(s): Kono T, Okazumi S, Mochizuki R, Ootsuki K, Shinotou K, Matsuzaki H, Natsume T, Kenmochi T, Nakagohri T, Asano T, Ochiai T. Source: Pancreas. 2002 July; 25(1): 20-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131766
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Clinical relevance of the methionine loading test for assessment of hyperhomocysteinaemia. Author(s): van der Griend R, Biesma DH, Banga JD. Source: The Netherlands Journal of Medicine. 2000 October; 57(4): 174-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11185483
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Cobalamin deficiency with and without neurologic abnormalities: differences in homocysteine and methionine metabolism. Author(s): Carmel R, Melnyk S, James SJ. Source: Blood. 2003 April 15; 101(8): 3302-8. Epub 2002 December 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12515717
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Coexpression of proteins with methionine aminopeptidase and/or Nmyristoyltransferase in Escherichia coli to increase acylation and homogeneity of protein preparations. Author(s): Van Valkenburgh HA, Kahn RA. Source: Methods Enzymol. 2002; 344: 186-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11771383
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Combined 18F-FDG and 11C-methionine PET scans in patients with newly progressive metastatic prostate cancer. Author(s): Nunez R, Macapinlac HA, Yeung HW, Akhurst T, Cai S, Osman I, Gonen M, Riedel E, Scher HI, Larson SM. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2002 January; 43(1): 46-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11801702
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Comment: the methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. Author(s): Peral B, San Millan JL, Castello R, Moghetti P, Escobar-Morreale HF. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 August; 87(8): 3977-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12161545
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Comorbidity of 5,10-methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms and risk for neural tube defects. Author(s): Johanning GL, Tamura T, Johnston KE, Wenstrom KD. Source: Journal of Medical Genetics. 2000 December; 37(12): 949-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11186937
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Convenient synthesis of human calcitonin and its methionine sulfoxide derivative. Author(s): Shi T, Rabenstein DL. Source: Bioorganic & Medicinal Chemistry Letters. 2002 August 19; 12(16): 2237-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12127546
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Cranial neuronavigation with direct integration of (11)C methionine positron emission tomography (PET) data -- results of a pilot study in 32 surgical cases. Author(s): Braun V, Dempf S, Weller R, Reske SN, Schachenmayr W, Richter HP. Source: Acta Neurochirurgica. 2002 August; 144(8): 777-82; Discussion 782. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12181686
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CSF-methionine is elevated in psychotic patients. Author(s): Regland B, Abrahamsson L, Blennow K, Grenfeldt B, Gottfries CG. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2004 May; 111(5): 63140. Epub 2004 March 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15088156
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Cyclic oxidation and reduction of methionine residues of proteins in antioxidant defense and cellular regulation. Author(s): Stadtman ER. Source: Archives of Biochemistry and Biophysics. 2004 March 1; 423(1): 2-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14989257
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Cyclic oxidation and reduction of protein methionine residues is an important antioxidant mechanism. Author(s): Stadtman ER, Moskovitz J, Berlett BS, Levine RL. Source: Molecular and Cellular Biochemistry. 2002 May-June; 234-235(1-2): 3-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12162447
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Cystatin C is an independent predictor of fasting and post-methionine load total homocysteine concentrations among stable renal transplant recipients. Author(s): Aras O, Tsai MY, Hanson NQ, Bailey R, Rao G, Hunninghake DB. Source: Clinical Chemistry. 2001; 47(7): 1263-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11427458
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D919G polymorphism of methionine synthase gene is associated with blood pressure response to benazepril in Chinese hypertensive patients. Author(s): Zhang Y, Zhang M, Niu T, Xu X, Zhu G, Huo Y, Chen C, Wang X, Xing H, Peng S, Huang A, Hong X, Xu X. Source: Journal of Human Genetics. 2004; 49(6): 296-301. Epub 2004 May 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15148588
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Daily methionine requirements of healthy Indian men, measured by a 24-h indicator amino acid oxidation and balance technique. Author(s): Kurpad AV, Regan MM, Varalakshmi S, Vasudevan J, Gnanou J, Raj T, Young VR. Source: The American Journal of Clinical Nutrition. 2003 May; 77(5): 1198-205. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716672
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Deaths from low dose paracetamol poisoning. Use of oral methionine for overdose below threshold for acetylcysteine. Author(s): Wright B, Crowe M. Source: Bmj (Clinical Research Ed.). 1998 December 12; 317(7173): 1656-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9917155
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Decrease in peptide methionine sulfoxide reductase in Alzheimer's disease brain. Author(s): Gabbita SP, Aksenov MY, Lovell MA, Markesbery WR. Source: Journal of Neurochemistry. 1999 October; 73(4): 1660-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10501213
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Defects in auxiliary redox proteins lead to functional methionine synthase deficiency. Author(s): Gulati S, Chen Z, Brody LC, Rosenblatt DS, Banerjee R. Source: The Journal of Biological Chemistry. 1997 August 1; 272(31): 19171-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9235907
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Defects in methylthioadenosine phosphorylase are associated with but not responsible for methionine-dependent tumor cell growth. Author(s): Tang B, Li YN, Kruger WD. Source: Cancer Research. 2000 October 1; 60(19): 5543-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11034100
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Deficiencies of folate and vitamin B(6) exert distinct effects on homocysteine, serine, and methionine kinetics. Author(s): Cuskelly GJ, Stacpoole PW, Williamson J, Baumgartner TG, Gregory JF 3rd. Source: American Journal of Physiology. Endocrinology and Metabolism. 2001 December; 281(6): E1182-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11701432
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Delayed cerebral radionecrosis with a high uptake of 11C-methionine on positron emission tomography and 201Tl-chloride on single-photon emission computed tomography. Author(s): Tashima T, Morioka T, Nishio S, Hachisuga S, Fukui M, Sasaki M. Source: Neuroradiology. 1998 July; 40(7): 435-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9730342
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Depletion of methionine aminopeptidase 2 does not alter cell response to fumagillin or bengamides. Author(s): Kim S, LaMontagne K, Sabio M, Sharma S, Versace RW, Yusuff N, Phillips PE. Source: Cancer Research. 2004 May 1; 64(9): 2984-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15126329
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Determinants of fasting and post-methionine homocysteine levels in families predisposed to hyperhomocysteinemia and premature vascular disease. Author(s): de Jong SC, Stehouwer CD, van den Berg M, Kostense PJ, Alders D, Jakobs C, Pals G, Rauwerda JA. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 1999 May; 19(5): 1316-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10323785
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Dietary cysteine reduces the methionine requirement in men. Author(s): Di Buono M, Wykes LJ, Ball RO, Pencharz PB. Source: The American Journal of Clinical Nutrition. 2001 December; 74(6): 761-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11722957
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Dietary treatment of tyrosinemia type I: importance of methionine restriction. Author(s): Michals K, Matolon R, Wong PW. Source: Journal of the American Dietetic Association. 1978 November; 73(5): 507-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=701680
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Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Author(s): Olteanu H, Munson T, Banerjee R. Source: Biochemistry. 2002 November 12; 41(45): 13378-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12416982
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Differential diagnosis of thymic tumors using a combination of 11C-methionine PET and FDG PET. Author(s): Sasaki M, Kuwabara Y, Ichiya Y, Akashi Y, Yoshida T, Nakagawa M, Murayama S, Masuda K. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1999 October; 40(10): 1595-601. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10520697
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Differential effects of leucine and methionine enkephalin on morphine-induced analgesia, acute tolerance and dependence. Author(s): Vaught JL, Takemori AE. Source: The Journal of Pharmacology and Experimental Therapeutics. 1979 January; 208(1): 86-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=569699
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Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. Author(s): Cai J, Mao Z, Hwang JJ, Lu SC. Source: Cancer Research. 1998 April 1; 58(7): 1444-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9537246
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Differential regulation of methionine adenosyltransferase in superantigen and mitogen stimulated human T lymphocytes. Author(s): LeGros HL Jr, Geller AM, Kotb M. Source: The Journal of Biological Chemistry. 1997 June 20; 272(25): 16040-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9188509
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Diseases of sulphur metabolism: implications for the methionine-homocysteine cycle, and vitamin responsiveness. Author(s): Mudd SH. Source: Ciba Found Symp. 1979; (72): 239-58. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=398765
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Disruption of a regulatory system involving cobalamin distribution and function in a methionine-dependent human glioma cell line. Author(s): Fiskerstrand T, Riedel B, Ueland PM, Seetharam B, Pezacka EH, Gulati S, Bose S, Banerjee R, Berge RK, Refsum H. Source: The Journal of Biological Chemistry. 1998 August 7; 273(32): 20180-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9685364
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Early response to chemotherapy in hypopharyngeal cancer: assessment with (11)Cmethionine PET, correlation with morphologic response, and clinical outcome. Author(s): Chesnay E, Babin E, Constans JM, Agostini D, Bequignon A, Regeasse A, Sobrio F, Moreau S. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2003 April; 44(4): 526-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679395
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EEG and clinical profile of a synthetic analogue of methionine-enkephalin - FK 33824. Author(s): Krebs E, Roubicek J. Source: Pharmakopsychiatr Neuropsychopharmakol. 1979 January; 12(1): 86-93. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=368820
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Effect of heterozygosity for the methionine synthase 2756 A-->G mutation on the risk for recurrent cardiovascular events. Author(s): Hyndman ME, Bridge PJ, Warnica JW, Fick G, Parsons HG. Source: The American Journal of Cardiology. 2000 November 15; 86(10): 1144-6, A9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11074217
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Effect of intravenous injection of CDP-choline, S-adenosyl-methionine and citiolone in subjects with hyperlipemia. Author(s): Galeone F, Salvadorini F, Guarguaglini M, Saba P. Source: Artery. 1979 February; 5(2): 157-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=231953
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Effect of opioid peptide methionine-enkephalin in long-term cultures of human bone marrow. Author(s): Janda SS, Boranic M, Skodlar J, Petrovecki M, Nemet D, Labar B. Source: Acta Med Croatica. 2000; 54(3): 99-105. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11268793
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Effect of protein and methionine intakes on plasma homocysteine concentrations: a 6mo randomized controlled trial in overweight subjects. Author(s): Haulrik N, Toubro S, Dyerberg J, Stender S, Skov AR, Astrup A. Source: The American Journal of Clinical Nutrition. 2002 December; 76(6): 1202-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12450883
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Effects of acute methionine loading and vitamin C on endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation. Author(s): Labinjoh C, Newby DE, Wilkinson IB, Megson IL, MacCallum H, Melville V, Boon NA, Webb DJ. Source: Clinical Science (London, England : 1979). 2001 February; 100(2): 127-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11171280
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Effects of polymorphisms of methionine synthase and methionine synthase reductase on total plasma homocysteine in the NHLBI Family Heart Study. Author(s): Jacques PF, Bostom AG, Selhub J, Rich S, Ellison RC, Eckfeldt JH, Gravel RA, Rozen R; National Heart, Lung and Blood Institute, National Institutes of Health. Source: Atherosclerosis. 2003 January; 166(1): 49-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12482550
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Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Author(s): Delle Chiaie R, Pancheri P, Scapicchio P. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1172S-6S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12418499
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Electron transfer in human methionine synthase reductase studied by stopped-flow spectrophotometry. Author(s): Wolthers KR, Scrutton NS. Source: Biochemistry. 2004 January 20; 43(2): 490-500. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14717604
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Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency. Author(s): Stabler SP, Steegborn C, Wahl MC, Oliveriusova J, Kraus JP, Allen RH, Wagner C, Mudd SH. Source: Metabolism: Clinical and Experimental. 2002 August; 51(8): 981-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145770
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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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Essential role of methionine residues in calmodulin binding to Bordetella pertussis adenylate cyclase, as probed by selective oxidation and repair by the peptide methionine sulfoxide reductases. Author(s): Vougier S, Mary J, Dautin N, Vinh J, Friguet B, Ladant D. Source: The Journal of Biological Chemistry. 2004 July 16; 279(29): 30210-8. Epub 2004 May 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15148319
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Evaluation of the effect of high-energy proton irradiation treatment on meningiomas by means of 11C-L-methionine PET. Author(s): Gudjonsson O, Blomquist E, Lilja A, Ericson H, Bergstrom M, Nyberg G. Source: European Journal of Nuclear Medicine. 2000 December; 27(12): 1793-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11189942
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Evaluation of treatment effects in brain abscess with positron emission tomography: comparison of fluorine-18-fluorodeoxyglucose and carbon-11-methionine. Author(s): Tsuyuguchi N, Sunada I, Ohata K, Takami T, Nishio A, Hara M, Kawabe J, Okamura T, Ochi H. Source: Ann Nucl Med. 2003 February; 17(1): 47-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12691130
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Evidence against oxidative stress as mechanism of endothelial dysfunction in methionine loading model. Author(s): Nightingale AK, James PP, Morris-Thurgood J, Harrold F, Tong R, Jackson SK, Cockcroft JR, Frenneaux MP. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2001 March; 280(3): H1334-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11179081
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False-positive parathyroid scan leading to sternotomy: incidental detection of a thymoma by C-11 methionine positron emission tomography. Author(s): Adler LP, Akhrass R, Ma D, Bloom AD. Source: Surgery. 1997 July; 122(1): 116-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9225925
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Fast atom bombardment mass spectrometric quantitative analysis of methionineenkephalin in human pituitary tissues. Author(s): Kusmierz JJ, Sumrada R, Desiderio DM. Source: Analytical Chemistry. 1990 November 1; 62(21): 2395-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2291485
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Fasting and post-methionine homocyst(e)ine levels in a healthy Australian population. Author(s): Silberberg J, Crooks R, Fryer J, Wlodarczyk J, Nair B, Finucane P, Guo XW, Xie LJ, Dudman N. Source: Aust N Z J Med. 1997 February; 27(1): 35-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9079251
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Fasting and post-methionine homocysteine levels in NIDDM. Determinants and correlations with retinopathy, albuminuria, and cardiovascular disease. Author(s): Smulders YM, Rakic M, Slaats EH, Treskes M, Sijbrands EJ, Odekerken DA, Stehouwer CD, Silberbusch J. Source: Diabetes Care. 1999 January; 22(1): 125-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10333913
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Fasting and post-methionine load homocyst(e)ine values are correlated with microalbuminuria and could contribute to worsening vascular damage in noninsulin-dependent diabetes mellitus patients. Author(s): Lanfredini M, Fiorina P, Peca MG, Veronelli A, Mello A, Astorri E, Dall'Aglio P, Craveri A. Source: Metabolism: Clinical and Experimental. 1998 August; 47(8): 915-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9711985
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Fasting and post-methionine loading concentrations of homocysteine, vitamin B2, and vitamin B6 in patients on antiepileptic drugs. Author(s): Apeland T, Mansoor MA, Pentieva K, McNulty H, Strandjord RE. Source: Clinical Chemistry. 2003 June; 49(6 Pt 1): 1005-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766014
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Fasting, postprandial, and post-methionine-load homocysteinaemia and methylenetetrahydrofolate reductase polymorphism in vascular disease. Author(s): Candito M, Bedoucha P, Gibelin P, Jambou D, de Franchis R, Sadoul JL, Chatel M, Van Obberghen E. Source: Journal of Inherited Metabolic Disease. 1999 June; 22(5): 588-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10399090
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Fatal submassive hepatic necrosis associated with tyrosine-methionine-aspartateaspartate-motif mutation of hepatitis B virus after long-term lamivudine therapy. Author(s): Kim JW, Lee HS, Woo GH, Yoon JH, Jang JJ, Chi JG, Kim CY. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 August 1; 33(3): 403-5. Epub 2001 July 07. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11438912
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Fluctuations in dietary methionine intake do not alter plasma homocysteine concentration in healthy men. Author(s): Ward M, McNulty H, Pentieva K, McPartlin J, Strain JJ, Weir DG, Scott JM. Source: The Journal of Nutrition. 2000 November; 130(11): 2653-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11053502
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Fluorine-18-fluorodeoxyglucose and carbon-11-methionine evaluation of lymphadenopathy in sarcoidosis. Author(s): Yamada Y, Uchida Y, Tatsumi K, Yamaguchi T, Kimura H, Kitahara H, Kuriyama T. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1998 July; 39(7): 1160-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9669387
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fMLP-OMe analogs substituted at the methionine residue: an insight into the receptor properties. Author(s): Cavicchioni G, Monesi LG, Ferretti ME, Fabbri E, Rizzuti O, Spisani S. Source: Archiv Der Pharmazie. 1998 November; 331(11): 368-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9881061
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Folate deficiency, methionine metabolism, and alcoholic liver disease. Author(s): Halsted CH, Villanueva JA, Devlin AM. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 169-72. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163145
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Folate depletion induced by methotrexate affects methionine synthase activity and its susceptibility to inactivation by nitrous oxide. Author(s): Fiskerstrand T, Ueland PM, Refsum H. Source: The Journal of Pharmacology and Experimental Therapeutics. 1997 September; 282(3): 1305-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9316839
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Folate, homocysteine and methionine loading in patients on carbamazepine. Author(s): Apeland T, Mansoor MA, Strandjord RE, Vefring H, Kristensen O. Source: Acta Neurologica Scandinavica. 2001 May; 103(5): 294-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11328204
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Folate, methionine, alcohol, and colorectal cancer in a prospective study of women in the United States. Author(s): Flood A, Caprario L, Chaterjee N, Lacey JV Jr, Schairer C, Schatzkin A. Source: Cancer Causes & Control : Ccc. 2002 August; 13(6): 551-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12195645
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Folate, methionine, and alcohol intake and risk of colorectal adenoma. Author(s): Giovannucci E, Stampfer MJ, Colditz GA, Rimm EB, Trichopoulos D, Rosner BA, Speizer FE, Willett WC. Source: Journal of the National Cancer Institute. 1993 June 2; 85(11): 875-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8492316
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Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease). Author(s): Fowler B, Schutgens RB, Rosenblatt DS, Smit GP, Lindemans J. Source: Journal of Inherited Metabolic Disease. 1997 November; 20(6): 731-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9427140
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Functional expression of human methionine aminopeptidase type 1 in Saccharomyces cerevisiae. Author(s): Dummitt B, Fei Y, Chang YH. Source: Protein and Peptide Letters. 2002 August; 9(4): 295-303. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12144506
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Functional methionine synthase deficiency due to cblG disorder: a report of two patients and a review. Author(s): Harding CO, Arnold G, Barness LA, Wolff JA, Rosenblatt DS. Source: American Journal of Medical Genetics. 1997 September 5; 71(4): 384-90. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9286442
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Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency. Author(s): Wilson A, Leclerc D, Saberi F, Campeau E, Hwang HY, Shane B, Phillips JA 3rd, Rosenblatt DS, Gravel RA. Source: American Journal of Human Genetics. 1998 August; 63(2): 409-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9683607
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Gas chromatographic and gas chromatographic--mass spectrometric studies on alphaketo-gamma-methylthiobutyric acid in urine following ingestion of optical isomers of methionine. Author(s): Kaji H, Saito N, Murao M, Ishimoto M, Kondo H, Gasa S, Saito K. Source: Journal of Chromatography. 1980 November 14; 221(1): 145-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7451616
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Gas chromatographic-sensory parallel chracterisation of methionine-glucose reaction products and their relation to meat aroma. Author(s): Barylko-Pikielna N, Daniewski M, Mielniczuk Z. Source: Die Nahrung. 1974; 18(2): 125-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4838297
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Gender differences and other determinants of the rise in plasma homocysteine after L-methionine loading. Author(s): Silberberg J, Crooks R, Fryer J, Wlodarczyk J, Nair B, Guo XW, Xie LJ, Dudman N. Source: Atherosclerosis. 1997 August; 133(1): 105-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9258413
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Gene cloning and characterization of Pseudomonas putida L-methionine-alphadeamino-gamma-mercaptomethane-lyase. Author(s): Hori H, Takabayashi K, Orvis L, Carson DA, Nobori T. Source: Cancer Research. 1996 May 1; 56(9): 2116-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8616859
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Genetic basis of neural tube defects. II. Genes correlated with folate and methionine metabolism. Author(s): Gos M Jr, Szpecht-Potocka A. Source: Journal of Applied Genetics. 2002; 43(4): 511-24. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12441636
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Genetic determinants of fasting and post-methionine hyperhomocysteinemia in patients with retinal vein occlusion. Author(s): Marcucci R, Giusti B, Betti I, Evangelisti L, Fedi S, Sodi A, Cappelli S, Menchini U, Abbate R, Prisco D. Source: Thrombosis Research. 2003 April 15; 110(1): 7-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12877902
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Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Author(s): Christensen B, Arbour L, Tran P, Leclerc D, Sabbaghian N, Platt R, Gilfix BM, Rosenblatt DS, Gravel RA, Forbes P, Rozen R. Source: American Journal of Medical Genetics. 1999 May 21; 84(2): 151-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10323741
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Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A. Author(s): Rady PL, Szucs S, Grady J, Hudnall SD, Kellner LH, Nitowsky H, Tyring SK, Matalon RK. Source: American Journal of Medical Genetics. 2002 January 15; 107(2): 162-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11807892
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Germ-line mosaicism for a valine-to-methionine substitution at residue 553 in the glycoprotein Ib-binding domain of von Willebrand factor, causing type IIB von Willebrand disease. Author(s): Murray EW, Giles AR, Lillicrap D. Source: American Journal of Human Genetics. 1992 January; 50(1): 199-207. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1729889
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Gerstmann-Straussler-Scheinker disease with mutation at codon 102 and methionine at codon 129 of PRNP in previously unreported patients. Author(s): Young K, Jones CK, Piccardo P, Lazzarini A, Golbe LI, Zimmerman TR Jr, Dickson DW, McLachlan DC, St George-Hyslop P, Lennox A, et al. Source: Neurology. 1995 June; 45(6): 1127-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7783876
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Globin-methionine complexes formed during labelling studies. Author(s): Beutler E, Gelbart T. Source: Clinical and Laboratory Haematology. 1984; 6(3): 257-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6518729
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Glucose and methionine uptake and proliferative activity in meningiomas. Author(s): Iuchi T, Iwadate Y, Namba H, Osato K, Saeki N, Yamaura A, Uchida Y. Source: Neurological Research. 1999 October; 21(7): 640-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10555183
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Glucose consumption and methionine uptake in low-grade gliomas after iodine-125 brachytherapy. Author(s): Wurker M, Herholz K, Voges J, Pietrzyk U, Treuer H, Bauer B, Sturm V, Heiss WD. Source: European Journal of Nuclear Medicine. 1996 May; 23(5): 583-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8698067
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Growth of methionine-dependent human prostate cancer (PC-3) is inhibited by ethionine combined with methionine starvation. Author(s): Poirson-Bichat F, Gonfalone G, Bras-Goncalves RA, Dutrillaux B, Poupon MF. Source: British Journal of Cancer. 1997; 75(11): 1605-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9184175
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Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency. Author(s): Labrune P, Zittoun J, Duvaltier I, Trioche P, Marquet J, Niaudet P, Odievre M. Source: European Journal of Pediatrics. 1999 September; 158(9): 734-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10485306
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High expression of methionine aminopeptidase type 2 in germinal center B cells and their neoplastic counterparts. Author(s): Kanno T, Endo H, Takeuchi K, Morishita Y, Fukayama M, Mori S. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2002 July; 82(7): 893-901. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12118091
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High uptake on 11C-methionine positron emission tomographic scan of basal ganglia germinoma with cerebral hemiatrophy. Author(s): Sudo A, Shiga T, Okajima M, Takano K, Terae S, Sawamura Y, Ohnishi A, Nagashima K, Saitoh S. Source: Ajnr. American Journal of Neuroradiology. 2003 October; 24(9): 1909-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14561627
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High-performance liquid chromatography determination of methionine adenosyltransferase activity using catechol-O-methyltransferase-coupled fluorometric detection. Author(s): Wang SH, Kuo SC, Chen SC. Source: Analytical Biochemistry. 2003 August 1; 319(1): 13-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842102
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Histamine chloramine reactivity with thiol compounds, ascorbate, and methionine and with intracellular glutathione. Author(s): Peskin AV, Winterbourn CC. Source: Free Radical Biology & Medicine. 2003 November 15; 35(10): 1252-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14607524
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HIV-2 protease is inactivated after oxidation at the dimer interface and activity can be partly restored with methionine sulphoxide reductase. Author(s): Davis DA, Newcomb FM, Moskovitz J, Wingfield PT, Stahl SJ, Kaufman J, Fales HM, Levine RL, Yarchoan R. Source: The Biochemical Journal. 2000 March 1; 346 Pt 2: 305-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10677347
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Homocysteine concentrations and methionine loading in patients on antiepileptic drugs. Author(s): Apeland T, Mansoor MA, Strandjord RE, Kristensen O. Source: Acta Neurologica Scandinavica. 2000 April; 101(4): 217-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10770516
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Homocysteine levels during fasting and after methionine loading in adolescents with diabetic retinopathy and nephropathy. Author(s): Chiarelli F, Pomilio M, Mohn A, Tumini S, Vanelli M, Morgese G, Spagnoli A, Verrotti A. Source: The Journal of Pediatrics. 2000 September; 137(3): 386-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10969265
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Homocysteinemia and endothelial damage after methionine load. Author(s): Hladovec J, Sommerova Z, Pisarikova A. Source: Thrombosis Research. 1997 November 15; 88(4): 361-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9526959
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Homology modeling and calculation of the cobalt cluster charges of the Encephazlitozoon cuniculi methionine aminopeptidase, a potential target for drug design. Author(s): Bontems F, le Floch P, Duffieux F, Biderre C, Peyret P, Lallemand JY. Source: Biophysical Chemistry. 2003 August 1; 105(1): 29-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12932577
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Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Author(s): Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M, Eydoux P, Rosenblatt DS, Rozen R, Gravel RA. Source: Human Molecular Genetics. 1996 December; 5(12): 1867-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8968737
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Hydrogen peroxide for disulfide bridge formation in methionine-containing peptides. Author(s): Kudryavtseva EV, Sidorova MV, Ovchinnikov MV, Bespalova ZD. Source: Journal of Peptide Science : an Official Publication of the European Peptide Society. 2000 May; 6(5): 208-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10823489
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Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Author(s): Bellamy MF, McDowell IF, Ramsey MW, Brownlee M, Bones C, Newcombe RG, Lewis MJ. Source: Circulation. 1998 November 3; 98(18): 1848-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9799203
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Hyperhomocysteinemia following oral methionine load is associated with increased lipid peroxidation. Author(s): Domagala TB, Libura M, Szczeklik A. Source: Thrombosis Research. 1997 August 15; 87(4): 411-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9271819
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Identification of conserved amino acid residues in rat liver carnitine palmitoyltransferase I critical for malonyl-CoA inhibition. Mutation of methionine 593 abolishes malonyl-CoA inhibition. Author(s): Morillas M, Gomez-Puertas P, Bentebibel A, Selles E, Casals N, Valencia A, Hegardt FG, Asins G, Serra D. Source: The Journal of Biological Chemistry. 2003 March 14; 278(11): 9058-63. Epub 2002 December 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12499375
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Identification of methionine-rich clusters that regulate copper-stimulated endocytosis of the human Ctr1 copper transporter. Author(s): Guo Y, Smith K, Lee J, Thiele DJ, Petris MJ. Source: The Journal of Biological Chemistry. 2004 April 23; 279(17): 17428-33. Epub 2004 February 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14976198
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Identification of the authentic varicella-zoster virus gB (gene 31) initiating methionine overlapping the 3' end of gene 30. Author(s): Maresova L, Pasieka T, Wagenaar T, Jackson W, Grose C. Source: Journal of Medical Virology. 2003; 70 Suppl 1: S64-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12627491
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Identification, expression and chromosome localization of a human gene encoding a novel protein with similarity to the pilB family of transcriptional factors (pilin) and to bacterial peptide methionine sulfoxide reductases. Author(s): Huang W, Escribano J, Sarfarazi M, Coca-Prados M. Source: Gene. 1999 June 11; 233(1-2): 233-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10375640
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Impaired hepatic mitochondrial oxidation using the 13C-methionine breath test in patients with macrovesicular steatosis and patients with cirrhosis. Author(s): Spahr L, Negro F, Leandro G, Marinescu O, Goodman KJ, Rubbia-Brandt L, Jordan M, Hadengue A. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 January; 9(1): Cr6-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12552242
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Impairment of cerebrovascular reactivity by methionine-induced hyperhomocysteinemia and amelioration by quinapril treatment. Author(s): Chao CL, Lee YT. Source: Stroke; a Journal of Cerebral Circulation. 2000 December; 31(12): 2907-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11108747
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Importance of a deficiency in S-adenosyl-L-methionine synthesis in the pathogenesis of liver injury. Author(s): Martinez-Chantar ML, Garcia-Trevijano ER, Latasa MU, Perez-Mato I, Sanchez del Pino MM, Corrales FJ, Avila MA, Mato JM. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1177S-82S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12418501
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Increased plasma homocysteine and S-adenosylhomocysteine and decreased methionine is associated with altered phosphatidylcholine and phosphatidylethanolamine in cystic fibrosis. Author(s): Innis SM, Davidson AG, Chen A, Dyer R, Melnyk S, James SJ. Source: The Journal of Pediatrics. 2003 September; 143(3): 351-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517519
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Increased susceptibility to Kuru of carriers of the PRNP 129 methionine/methionine genotype. Author(s): Lee HS, Brown P, Cervenakova L, Garruto RM, Alpers MP, Gajdusek DC, Goldfarb LG. Source: The Journal of Infectious Diseases. 2001 January 15; 183(2): 192-196. Epub 2000 December 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11120925
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Increased viability of PC12 cells exposed to amyloid-beta peptide by transduction with human TAT-methionine sulfoxide reductase. Author(s): Jung B, Lee EH, Chung WS, Lee SJ, Shin SH, Joo SH, Kim SK, Lee JH. Source: Neuroreport. 2003 December 19; 14(18): 2349-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14663189
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Induction of caspase-dependent and -independent apoptosis in response to methionine restriction. Author(s): Lu S, Hoestje SM, Choo E, Epner DE. Source: International Journal of Oncology. 2003 February; 22(2): 415-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12527942
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Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction. Author(s): Chen J, Stampfer MJ, Ma J, Selhub J, Malinow MR, Hennekens CH, Hunter DJ. Source: Atherosclerosis. 2001 February 15; 154(3): 667-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11257268
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Influence of age, sex and vitamin status on fasting and post-methionine load plasma homocysteine levels. Author(s): Sassi S, Cosmi B, Palareti G, Legnani C, Grossi G, Musolesi S, Coccheri S. Source: Haematologica. 2002 September; 87(9): 957-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12217808
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Interaction between dietary methionine and methyl donor intake on rat liver betainehomocysteine methyltransferase gene expression and organization of the human gene. Author(s): Park EI, Garrow TA. Source: The Journal of Biological Chemistry. 1999 March 19; 274(12): 7816-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10075673
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Investigation of methionine metabolism in peripheral blood mononuclear cells of Irish hyperhomocysteinemic subjects. Author(s): Betts V, Collins PB, Meleady R, Graham I. Source: Biochemical Society Transactions. 1998 February; 26(1): S10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10909768
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Investigation of the metal binding site in methionine aminopeptidase by density functional theory. Author(s): Jorgensen AT, Norrby PO, Liljefors T. Source: Journal of Computer-Aided Molecular Design. 2002 March; 16(3): 167-79. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12363216
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Kinetic and thermodynamic characterization of the common polymorphic variants of human methionine synthase reductase. Author(s): Olteanu H, Wolthers KR, Munro AW, Scrutton NS, Banerjee R. Source: Biochemistry. 2004 February 24; 43(7): 1988-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14967039
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Kinetic evidence for decreased methionine adenosyltransferase activity in erythrocytes from schizophrenics. Author(s): Kelsoe JR Jr, Tolbert LC, Crews EL, Smythies JR. Source: Journal of Neuroscience Research. 1982; 8(1): 99-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7175980
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Kinetics of methionine transport and metabolism by Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense. Author(s): Goldberg B, Rattendi D, Lloyd D, Yarlett N, Bacchi CJ. Source: Archives of Biochemistry and Biophysics. 2000 May 1; 377(1): 49-57. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10775440
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Lack of effect of L-methionine ingestion on 14CO2 excretion from L-histidine (imidazole-2-14C) in folic acid and vitamin B12 deficient humans. Author(s): Stahelin HB, Winchell HS, Kusubov N. Source: Blood. 1970 January; 35(1): 86-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5412678
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Large-scale expression, purification and characterization of small fragments of thrombomodulin: the roles of the sixth domain and of methionine 388. Author(s): White CE, Hunter MJ, Meininger DP, White LR, Komives EA. Source: Protein Engineering. 1995 November; 8(11): 1177-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8819984
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Leukocyte 12-lipoxygenase: expression, purification, and investigation of the role of methionine residues in turnover-dependent inactivation and 5,8,11,14eicosatetraynoic acid inhibition. Author(s): Richards KM, Marnett LJ. Source: Biochemistry. 1997 June 3; 36(22): 6692-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9184149
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Levels of L-methionine S-adenosyltransferase activity in erythrocytes and concentrations of S-adenosylmethionine and S-adenosylhomocysteine in whole blood of patients with Parkinson's disease. Author(s): Cheng H, Gomes-Trolin C, Aquilonius SM, Steinberg A, Lofberg C, Ekblom J, Oreland L. Source: Experimental Neurology. 1997 June; 145(2 Pt 1): 580-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9217094
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L-methionine uptake by human cerebral cortex: maturation from infancy to old age. Author(s): O'Tuama LA, Phillips PC, Smith QR, Uno Y, Dannals RF, Wilson AA, Ravert HT, Loats S, Loats HA, Wagner HN Jr. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1991 January; 32(1): 16-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1988624
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Loss of the oncogene from human H-ras-1-transfected NIH/3T3 cells grown in the presence of excess methionine. Author(s): Hillova J, Hill M, Belehradek J Jr, Mariage-Samson R, Brada Z. Source: Journal of the National Cancer Institute. 1986 September; 77(3): 721-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3462412
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Low concentrations of folate in serum and erythrocytes of smokers: methionine loading decreases folate concentrations in serum of smokers and nonsmokers. Author(s): Mansoor MA, Kristensen O, Hervig T, Drablos PA, Stakkestad JA, Woie L, Hetland O, Osland A. Source: Clinical Chemistry. 1997 November; 43(11): 2192-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9365412
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Low diagnostic value of fasting and post-methionine load homocysteine tests. A study in Dutch subjects with homocysteine test indications. Author(s): Fokkema MR, Dijck-Brouwer DA, van Doormaal JJ, Reijngoud DJ, Muskiet FA. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003 May; 331(1-2): 153-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12691876
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Low methionine diet treatment of homocystinuria. Author(s): Schimke RN. Source: Annals of Internal Medicine. 1969 March; 70(3): 642-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5775042
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Lung tumor imaging by positron emission tomography using C-11 L-methionine. Author(s): Kubota K, Matsuzawa T, Ito M, Ito K, Fujiwara T, Abe Y, Yoshioka S, Fukuda H, Hatazawa J, Iwata R, et al. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1985 January; 26(1): 37-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2981300
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Maternal methionine adenosyltransferase I/III deficiency: reproductive outcomes in a woman with four pregnancies. Author(s): Mudd SH, Tangerman A, Stabler SP, Allen RH, Wagner C, Zeisel SH, Levy HL. Source: Journal of Inherited Metabolic Disease. 2003; 26(5): 443-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14518826
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Methionine adenosyltransferase as a useful molecular systematics tool revealed by phylogenetic and structural analyses. Author(s): Sanchez-Perez GF, Bautista JM, Pajares MA. Source: Journal of Molecular Biology. 2004 January 16; 335(3): 693-706. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687567
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Methionine catabolism and production of volatile sulphur compounds by OEnococcus oeni. Author(s): Pripis-Nicolau L, de Revel G, Bertrand A, Lonvaud-Funel A. Source: Journal of Applied Microbiology. 2004; 96(5): 1176-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15078536
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Methionine dependency and cancer treatment. Author(s): Cellarier E, Durando X, Vasson MP, Farges MC, Demiden A, Maurizis JC, Madelmont JC, Chollet P. Source: Cancer Treatment Reviews. 2003 December; 29(6): 489-99. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14585259
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Methionine enkephalin suppresses metabolic activity of a leukemic cell line (NALM1) and enhances CD10 expression. Author(s): Martin-Kleiner I, Gabrilovac J, Kusec R, Boranic M. Source: International Immunopharmacology. 2003 May; 3(5): 707-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12757739
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Methionine positron emission tomography of recurrent metastatic brain tumor and radiation necrosis after stereotactic radiosurgery: is a differential diagnosis possible? Author(s): Tsuyuguchi N, Sunada I, Iwai Y, Yamanaka K, Tanaka K, Takami T, Otsuka Y, Sakamoto S, Ohata K, Goto T, Hara M. Source: Journal of Neurosurgery. 2003 May; 98(5): 1056-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12744366
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Methionine restriction selectively targets thymidylate synthase in prostate cancer cells. Author(s): Lu S, Chen GL, Ren C, Kwabi-Addo B, Epner DE. Source: Biochemical Pharmacology. 2003 September 1; 66(5): 791-800. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12948860
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Methionine sulfoxide reductase A is important for lens cell viability and resistance to oxidative stress. Author(s): Kantorow M, Hawse JR, Cowell TL, Benhamed S, Pizarro GO, Reddy VN, Hejtmancik JF. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 June 29; 101(26): 9654-9. Epub 2004 Jun 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15199188
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Methionine synthase (MTR) 2756 (A --> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Author(s): Bosco P, Gueant-Rodriguez RM, Anello G, Barone C, Namour F, Caraci F, Romano A, Romano C, Gueant JL. Source: American Journal of Medical Genetics. 2003 September 1; 121A(3): 219-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12923861
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Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. Author(s): Goode EL, Potter JD, Bigler J, Ulrich CM. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2004 January; 13(1): 157-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14744749
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Methionine synthase polymorphism is a risk factor for Alzheimer disease. Author(s): Beyer K, Lao JI, Latorre P, Riutort N, Matute B, Fernandez-Figueras MT, Mate JL, Ariza A. Source: Neuroreport. 2003 July 18; 14(10): 1391-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12876480
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Methylenetetrahydrofolate reductase (MTHFR) 677C>T and methionine synthase reductase (MTRR) 66A>G polymorphisms: association with serum homocysteine and angiographic coronary artery disease in the era of flour products fortified with folic acid. Author(s): Brilakis ES, Berger PB, Ballman KV, Rozen R. Source: Atherosclerosis. 2003 June; 168(2): 315-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801615
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Monitoring the effect of chemotherapy in a mixed glioma by C-11-methionine PET. Author(s): Herholz K, Kracht LW, Heiss WD. Source: Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging. 2003 July; 13(3): 269-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12889176
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MtaR, a regulator of methionine transport, is critical for survival of group B streptococcus in vivo. Author(s): Shelver D, Rajagopal L, Harris TO, Rubens CE. Source: Journal of Bacteriology. 2003 November; 185(22): 6592-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14594832
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Mutations at the S1 sites of methionine aminopeptidases from Escherichia coli and Homo sapiens reveal the residues critical for substrate specificity. Author(s): Li JY, Cui YM, Chen LL, Gu M, Li J, Nan FJ, Ye QZ. Source: The Journal of Biological Chemistry. 2004 May 14; 279(20): 21128-34. Epub 2004 February 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14976199
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N-Acetylcysteine improves the disturbed thiol redox balance after methionine loading. Author(s): Raijmakers MT, Schilders GW, Roes EM, van Tits LJ, Hak-Lemmers HL, Steegers EA, Peters WH. Source: Clinical Science (London, England : 1979). 2003 August; 105(2): 173-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12708964
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Neuritogenesis induced by vasoactive intestinal peptide, pituitary adenylate cyclaseactivating polypeptide, and peptide histidine methionine in SH-SY5y cells is associated with regulated expression of cytoskeleton mRNAs and proteins. Author(s): Heraud C, Hilairet S, Muller JM, Leterrier JF, Chadeneau C. Source: Journal of Neuroscience Research. 2004 February 1; 75(3): 320-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14743445
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Nitric oxide inhibits methionine synthase activity in vivo and disrupts carbon flow through the folate pathway. Author(s): Danishpajooh IO, Gudi T, Chen Y, Kharitonov VG, Sharma VS, Boss GR. Source: The Journal of Biological Chemistry. 2001 July 20; 276(29): 27296-303. Epub 2001 May 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11371572
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Non-Invasive assessment of human hepatic mitochondrial function through the 13Cmethionine breath test. Author(s): Armuzzi A, Marcoccia S, Zocco MA, De Lorenzo A, Grieco A, Tondi P, Pola P, Gasbarrini G, Gasbarrini A. Source: Scandinavian Journal of Gastroenterology. 2000 June; 35(6): 650-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10912667
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Normal human lymphocytes exhibit a wide range of methionine-dependency which is related to altered cell division but not micronucleus frequency. Author(s): Crott J, Thomas P, Fenech M. Source: Mutagenesis. 2001 July; 16(4): 317-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11420399
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Normal variants, artefacts and interpretative pitfalls in PET imaging with 18-fluoro-2deoxyglucose and carbon-11 methionine. Author(s): Cook GJ, Maisey MN, Fogelman I. Source: European Journal of Nuclear Medicine. 1999 October; 26(10): 1363-78. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10541839
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N-terminal methionine removal and methionine metabolism in Saccharomyces cerevisiae. Author(s): Dummitt B, Micka WS, Chang YH. Source: Journal of Cellular Biochemistry. 2003 August 1; 89(5): 964-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12874831
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N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains. Author(s): Santagata S, Gomez CA, Sobacchi C, Bozzi F, Abinun M, Pasic S, Cortes P, Vezzoni P, Villa A. Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 December 19; 97(26): 14572-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11121059
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Nutrient intake and nutritional indexes in adults with metastatic cancer on a phase I clinical trial of dietary methionine restriction. Author(s): Epner DE, Morrow S, Wilcox M, Houghton JL. Source: Nutrition and Cancer. 2002; 42(2): 158-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12416254
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Oral methionine loading as a cause of acute serum folate deficiency: its relevance to parenteral nutrition. Author(s): Connor H, Newton DJ, Preston FE, Woods HF. Source: Postgraduate Medical Journal. 1978 May; 54(631): 318-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=97644
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Oxidation of either methionine 351 or methionine 358 in alpha 1-antitrypsin causes loss of anti-neutrophil elastase activity. Author(s): Taggart C, Cervantes-Laurean D, Kim G, McElvaney NG, Wehr N, Moss J, Levine RL. Source: The Journal of Biological Chemistry. 2000 September 1; 275(35): 27258-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10867014
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Oxidation of Ikappa Balpha at methionine 45 is one cause of taurine chloramineinduced inhibition of NF-kappa B activation. Author(s): Kanayama A, Inoue J, Sugita-Konishi Y, Shimizu M, Miyamoto Y. Source: The Journal of Biological Chemistry. 2002 July 5; 277(27): 24049-56. Epub 2002 April 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11983684
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Oxidation of methionine 35 attenuates formation of amyloid beta -peptide 1-40 oligomers. Author(s): Palmblad M, Westlind-Danielsson A, Bergquist J. Source: The Journal of Biological Chemistry. 2002 May 31; 277(22): 19506-10. Epub 2002 March 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11912198
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Oxidation of methionine in proteins: roles in antioxidant defense and cellular regulation. Author(s): Levine RL, Moskovitz J, Stadtman ER. Source: Iubmb Life. 2000 October-November; 50(4-5): 301-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11327324
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Oxidation of methionine residues affects the structure and stability of apolipoprotein A-I in reconstituted high density lipoprotein particles. Author(s): Sigalov AB, Stern LJ. Source: Chemistry and Physics of Lipids. 2001 November; 113(1-2): 133-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11687233
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Oxidation of methionine residues in antithrombin. Effects on biological activity and heparin binding. Author(s): Van Patten SM, Hanson E, Bernasconi R, Zhang K, Manavalan P, Cole ES, McPherson JM, Edmunds T. Source: The Journal of Biological Chemistry. 1999 April 9; 274(15): 10268-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10187813
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Oxidation of methionine residues of proteins: biological consequences. Author(s): Stadtman ER, Moskovitz J, Levine RL. Source: Antioxidants & Redox Signalling. 2003 October; 5(5): 577-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14580313
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Oxidation of methionine residues to methionine sulfoxides does not decrease potential antiatherogenic properties of apolipoprotein A-I. Author(s): Panzenbock U, Kritharides L, Raftery M, Rye KA, Stocker R. Source: The Journal of Biological Chemistry. 2000 June 30; 275(26): 19536-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10751387
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Oxidative stress and an altered methionine metabolism in alcoholism. Author(s): Bleich S, Spilker K, Kurth C, Degner D, Quintela-Schneider M, Javaheripour K, Ruther E, Kornhuber J, Wiltfang J. Source: Neuroscience Letters. 2000 November 3; 293(3): 171-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11036188
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Peptide methionine sulfoxide reductase: biochemistry and physiological role. Author(s): Brot N, Weissbach H. Source: Biopolymers. 2000; 55(4): 288-96. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11169920
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Peptidyl hydroxamic acids as methionine aminopeptidase inhibitors. Author(s): Hu X, Zhu J, Srivathsan S, Pei D. Source: Bioorganic & Medicinal Chemistry Letters. 2004 January 5; 14(1): 77-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684302
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Physiologically relevant metal cofactor for methionine aminopeptidase-2 is manganese. Author(s): Wang J, Sheppard GS, Lou P, Kawai M, Park C, Egan DA, Schneider A, Bouska J, Lesniewski R, Henkin J. Source: Biochemistry. 2003 May 6; 42(17): 5035-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12718546
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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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Polymorphism of methionine synthase gene in nuclear families of congenital heart disease. Author(s): Zhu WL, Cheng J, Dao JJ, Zhao RB, Yan LY, Li SQ, Li Y. Source: Biomed Environ Sci. 2004 March; 17(1): 57-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15202865
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Polymorphisms of the 5,10-methylenetetrahydrofolate and the methionine synthase reductase genes as independent risk factors for spina bifida. Author(s): Pietrzyk JJ, Bik-Multanowski M, Sanak M, Twardowska M. Source: Journal of Applied Genetics. 2003; 44(1): 111-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12590188
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Potential role of methionine sulfoxide in the inactivation of the chaperone GroEL by hypochlorous acid (HOCl) and peroxynitrite (ONOO-). Author(s): Khor HK, Fisher MT, Schoneich C. Source: The Journal of Biological Chemistry. 2004 May 7; 279(19): 19486-93. Epub 2004 February 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14757771
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Protein N-terminal methionine excision. Author(s): Giglione C, Boularot A, Meinnel T. Source: Cellular and Molecular Life Sciences : Cmls. 2004 June; 61(12): 1455-74. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15197470
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Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors. Author(s): Towbin H, Bair KW, DeCaprio JA, Eck MJ, Kim S, Kinder FR, Morollo A, Mueller DR, Schindler P, Song HK, van Oostrum J, Versace RW, Voshol H, Wood J, Zabludoff S, Phillips PE. Source: The Journal of Biological Chemistry. 2003 December 26; 278(52): 52964-71. Epub 2003 October 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14534293
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Putrescine or a combination of methionine and arginine restores virulence gene expression in a tRNA modification-deficient mutant of Shigella flexneri: a possible role in adaptation of virulence. Author(s): Durand JM, Bjork GR. Source: Molecular Microbiology. 2003 January; 47(2): 519-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12519201
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Quantification of erythrocyte S-adenosyl-L-methionine levels and its application in enzyme studies. Author(s): Lagendijk J, Ubbink JB, Vermaak WJ. Source: Journal of Chromatography. 1992 April 15; 576(1): 95-101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1500462
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Quantitation of total homocysteine, total cysteine, and methionine in normal serum and urine using capillary gas chromatography-mass spectrometry. Author(s): Stabler SP, Marcell PD, Podell ER, Allen RH. Source: Analytical Biochemistry. 1987 April; 162(1): 185-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3605587
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Quantitative analysis of methionine enkephalin and beta-endorphin in the pituitary by liquid secondary ion mass spectrometry and tandem mass spectrometry. Author(s): Desiderio DM, Zhu X. Source: J Chromatogr A. 1998 January 23; 794(1-2): 85-96. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9491558
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Quantitative evaluation of liver function by the methionine and aminopyrine breath tests in the early stages of liver transplantation. Author(s): Di Campli C, Angelini G, Armuzzi A, Nardo B, Zocco MA, Candelli M, Santoliquido A, Cavallari A, Bernardi M, Gasbarrini A. Source: European Journal of Gastroenterology & Hepatology. 2003 July; 15(7): 727-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12811302
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Reaction mechanism, evolutionary analysis, and role of zinc in Drosophila methionine-R-sulfoxide reductase. Author(s): Kumar RA, Koc A, Cerny RL, Gladyshev VN. Source: The Journal of Biological Chemistry. 2002 October 4; 277(40): 37527-35. Epub 2002 July 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145281
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Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. Author(s): Avila MA, Berasain C, Torres L, Martin-Duce A, Corrales FJ, Yang H, Prieto J, Lu SC, Caballeria J, Rodes J, Mato JM. Source: Journal of Hepatology. 2000 December; 33(6): 907-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11131452
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Redundancy in the pathway for redox regulation of mammalian methionine synthase: reductive activation by the dual flavoprotein, novel reductase 1. Author(s): Olteanu H, Banerjee R. Source: The Journal of Biological Chemistry. 2003 October 3; 278(40): 38310-4. Epub 2003 July 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871938
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Regulation of the human MAT2A gene encoding the catalytic alpha 2 subunit of methionine adenosyltransferase, MAT II: gene organization, promoter characterization, and identification of a site in the proximal promoter that is essential for its activity. Author(s): Halim AB, LeGros L, Chamberlin ME, Geller A, Kotb M. Source: The Journal of Biological Chemistry. 2001 March 30; 276(13): 9784-91. Epub 2000 December 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11124935
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Relationship of folate, vitamin B-6, vitamin B-12, and methionine intake to incidence of colorectal cancers. Author(s): Harnack L, Jacobs DR Jr, Nicodemus K, Lazovich D, Anderson K, Folsom AR. Source: Nutrition and Cancer. 2002; 43(2): 152-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12588695
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Response to "genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A". Author(s): Isotalo PA, Donnelly JG. Source: American Journal of Medical Genetics. 2002 June 15; 110(2): 191-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12116261
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Role of abnormal methionine metabolism in alcoholic liver injury. Author(s): Lu SC, Tsukamoto H, Mato JM. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 155-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163143
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Role of individual methionines in the fibrillation of methionine-oxidized alphasynuclein. Author(s): Hokenson MJ, Uversky VN, Goers J, Yamin G, Munishkina LA, Fink AL. Source: Biochemistry. 2004 April 20; 43(15): 4621-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15078109
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Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Author(s): Mischoulon D, Fava M. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1158S-61S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12420702
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S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Author(s): Baric I, Fumic K, Glenn B, Cuk M, Schulze A, Finkelstein JD, James SJ, Mejaski-Bosnjak V, Pazanin L, Pogribny IP, Rados M, Sarnavka V, Scukanec-Spoljar M, Allen RH, Stabler S, Uzelac L, Vugrek O, Wagner C, Zeisel S, Mudd SH. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 March 23; 101(12): 4234-9. Epub 2004 Mar 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15024124
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S-adenosyl-L-methionine is able to reverse micronucleus formation induced by sodium arsenite and other cytoskeleton disrupting agents in cultured human cells. Author(s): Ramirez T, Garcia-Montalvo V, Wise C, Cea-Olivares R, Poirier LA, Herrera LA. Source: Mutation Research. 2003 July 25; 528(1-2): 61-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12873724
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S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. Author(s): Di Rocco A, Rogers JD, Brown R, Werner P, Bottiglieri T. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2000 November; 15(6): 1225-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11104210
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S-adenosyl-methionine in depression: a comprehensive review of the literature. Author(s): Papakostas GI, Alpert JE, Fava M. Source: Current Psychiatry Reports. 2003 December; 5(6): 460-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609501
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Selective solid-phase isolation of methionine-containing peptides and subsequent matrix-assisted laser desorption/ionisation mass spectrometric detection of methionine- and of methionine-sulfoxide-containing peptides. Author(s): Grunert T, Pock K, Buchacher A, Allmaier G. Source: Rapid Communications in Mass Spectrometry : Rcm. 2003; 17(16): 1815-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12876681
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Severe methylenetetrahydrofolate reductase deficiency, methionine synthase, and nitrous oxide--a cautionary tale. Author(s): Erbe RW, Salis RJ. Source: The New England Journal of Medicine. 2003 July 3; 349(1): 5-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12840086
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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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Structure of Mycobacterium tuberculosis methionine sulfoxide reductase A in complex with protein-bound methionine. Author(s): Taylor AB, Benglis DM Jr, Dhandayuthapani S, Hart PJ. Source: Journal of Bacteriology. 2003 July; 185(14): 4119-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12837786
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Synthesis of glutathione in response to methionine load in control subjects and in patients with cirrhosis. Author(s): Bianchi G, Brizi M, Rossi B, Ronchi M, Grossi G, Marchesini G. Source: Metabolism: Clinical and Experimental. 2000 November; 49(11): 1434-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11092507
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Targeted disruption of the methionine synthase gene in mice. Author(s): Swanson DA, Liu ML, Baker PJ, Garrett L, Stitzel M, Wu J, Harris M, Banerjee R, Shane B, Brody LC. Source: Molecular and Cellular Biology. 2001 February; 21(4): 1058-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11158293
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The 2756A>G variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case-control study. Author(s): Klerk M, Lievers KJ, Kluijtmans LA, Blom HJ, den Heijer M, Schouten EG, Kok FJ, Verhoef P. Source: Thrombosis Research. 2003 May 1; 110(2-3): 87-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893022
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The additional methionine residue at the N-terminus of bacterially expressed human interleukin-2 affects the interaction between the N- and C-termini. Author(s): Endo S, Yamamoto Y, Sugawara T, Nishimura O, Fujino M. Source: Biochemistry. 2001 January 30; 40(4): 914-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11170412
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The impact of supplemental dietary methionine sources on volatile compound concentrations in broiler excreta. Author(s): Chavez C, Coufal CD, Carey JB, Lacey RE, Beier RC, Zahn JA. Source: Poultry Science. 2004 June; 83(6): 901-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15206616
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The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma. Author(s): Linnebank M, Schmidt S, Kolsch H, Linnebank A, Heun R, Schmidt-Wolf IG, Glasmacher A, Fliessbach K, Klockgether T, Schlegel U, Pels H. Source: British Journal of Cancer. 2004 May 17; 90(10): 1969-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15138479
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The peptide methionine sulfoxide reductases, MsrA and MsrB (hCBS-1), are downregulated during replicative senescence of human WI-38 fibroblasts. Author(s): Picot CR, Perichon M, Cintrat JC, Friguet B, Petropoulos I. Source: Febs Letters. 2004 January 30; 558(1-3): 74-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14759519
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The role of c-Myb in the up-regulation of methionine adenosyltransferase 2A expression in activated Jurkat cells. Author(s): Zeng Z, Yang H, Huang ZZ, Chen C, Wang J, Lu SC. Source: The Biochemical Journal. 2001 January 1; 353(Pt 1): 163-168. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11115410
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The role of methionine in ethylmalonic encephalopathy with petechiae. Author(s): McGowan KA, Nyhan WL, Barshop BA, Naviaux RK, Yu A, Haas RH, Townsend JJ. Source: Archives of Neurology. 2004 April; 61(4): 570-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15096407
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Tumor suppression by a rationally designed reversible inhibitor of methionine aminopeptidase-2. Author(s): Wang J, Sheppard GS, Lou P, Kawai M, BaMaung N, Erickson SA, TuckerGarcia L, Park C, Bouska J, Wang YC, Frost D, Tapang P, Albert DH, Morgan SJ, Morowitz M, Shusterman S, Maris JM, Lesniewski R, Henkin J. Source: Cancer Research. 2003 November 15; 63(22): 7861-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633714
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Unchecked DNA synthesis and blocked cell division induced by methionine deprivation in a human prostate cancer cell line. Author(s): Guo HY, Hoffman RM, Herrera H. Source: In Vitro Cellular & Developmental Biology. Animal. 1993 May; 29A(5): 359-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8314730
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Understanding the selectivity of fumagillin for the methionine aminopeptidase type II. Author(s): Klein CD, Folkers G. Source: Oncology Research. 2003; 13(12): 513-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899241
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Up-regulation of integrin alpha5 by a C-terminus four-amino-acid sequence of substance P (phenylalanine-glycine-leucine-methionine- amide) synergistically with insulin-like growth factor-1 in SV-40 transformed human corneal epithelial cells. Author(s): Chikama T, Nakamura M, Nishida T. Source: Biochemical and Biophysical Research Communications. 1999 February 24; 255(3): 692-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10049772
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Uptake of 11C-methionine in breast cancer studied by PET. An association with the size of S-phase fraction. Author(s): Leskinen-Kallio S, Nagren K, Lehikoinen P, Ruotsalainen U, Joensuu H. Source: British Journal of Cancer. 1991 December; 64(6): 1121-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1662533
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Uptake of positron emission tomography tracers in experimental bacterial infections: a comparative biodistribution study of radiolabeled FDG, thymidine, L-methionine, 67Ga-citrate, and 125I-HSA. Author(s): Sugawara Y, Gutowski TD, Fisher SJ, Brown RS, Wahl RL. Source: European Journal of Nuclear Medicine. 1999 April; 26(4): 333-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10199938
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Uptake of tritiated thymidine, deoxyglucose and methionine in three lung cancer cell lines: deoxyglucose uptake mirrors tritiated thymidine uptake. Author(s): Nerini-Molteni S, Seregni E, Crippa F, Maffioli L, Botti C, Bombardieri E. Source: Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine. 2001 March-April; 22(2): 92-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11125281
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Use of carbon-11 methionine positron emission tomography to assess malignancy grade and predict survival in patients with lymphomas. Author(s): Nuutinen J, Leskinen S, Lindholm P, Soderstrom KO, Nagren K, Huhtala S, Minn H. Source: European Journal of Nuclear Medicine. 1998 July; 25(7): 729-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9662595
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Use of co-registered 11C-methionine PET and computed tomography for the localisation of parathyroid adenomas. Author(s): Beggs AD, Hain SF. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2003 November; 30(11): 1602. Epub 2003 August 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14579103
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Usefulness of 11C-methionine PET in the evaluation of brain lesions that are hypo- or isometabolic on 18F-FDG PET. Author(s): Chung JK, Kim YK, Kim SK, Lee YJ, Paek S, Yeo JS, Jeong JM, Lee DS, Jung HW, Lee MC. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2002 February; 29(2): 176-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11926379
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Usefulness of PET with 11C-methionine for the detection of hilar and mediastinal lymph node metastasis in lung cancer. Author(s): Yasukawa T, Yoshikawa K, Aoyagi H, Yamamoto N, Tamura K, Suzuki K, Tsujii H, Murata H, Sasaki Y, Fujisawa T. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2000 February; 41(2): 283-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10688112
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Validation of a method for automatic image fusion (BrainLAB System) of CT data and 11C-methionine-PET data for stereotactic radiotherapy using a LINAC: first clinical experience. Author(s): Grosu AL, Lachner R, Wiedenmann N, Stark S, Thamm R, Kneschaurek P, Schwaiger M, Molls M, Weber WA. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 August 1; 56(5): 1450-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12873691
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Validation of abbreviated oral methionine-loading test. Author(s): Bostom AG, Roubenoff R, Dellaripa P, Nadeau MR, Sutherland P, Wilson PW, Jacques PF, Selhub J, Rosenberg IH. Source: Clinical Chemistry. 1995 June; 41(6 Pt 1): 948-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7768022
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Valine, not methionine, is amino acid 106 in human cytosolic thymidine kinase (TK1). Impact on oligomerization, stability, and kinetic properties. Author(s): Berenstein D, Christensen JF, Kristensen T, Hofbauer R, Munch-Petersen B. Source: The Journal of Biological Chemistry. 2000 October 13; 275(41): 32187-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10924519
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Variability of fasting and post-methionine plasma homocysteine levels in normo- and hyperhomocysteinaemic individuals. Author(s): van den Berg M, de Jong SC, Deville W, Rauwerda JA, Jakobs C, Pals G, Boers GH, Stehouwer CD. Source: The Netherlands Journal of Medicine. 1999 July; 55(1): 29-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10431553
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Variability of post-methionine load plasma homocysteine assays. Author(s): Ubbink JB, Becker PJ, Delport R, Bester M, Riezler R, Vermaak WJ. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003 April; 330(1-2): 111-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12636929
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Variability of the methionine loading test: no effect of a low protein diet. Author(s): den Heijer M, Bos GM, Brouwer IA, Gerrits WB, Blom HJ. Source: Annals of Clinical Biochemistry. 1996 November; 33 ( Pt 6): 551-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8937588
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Variation in plasma cystathionine and its relation to changes in plasma concentrations of homocysteine and methionine in healthy subjects during a 24-h observation period. Author(s): Guttormsen AB, Solheim E, Refsum H. Source: The American Journal of Clinical Nutrition. 2004 January; 79(1): 76-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684400
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Vasoactive intestinal polypeptide and peptide histidine methionine. Presence in human follicular fluid and effects on DNA synthesis and steroid secretion in cultured human granulosa/lutein cells. Author(s): Gras S, Ovesen P, Andersen AN, Sorensen S, Fahrenkrug J, Ottesen B. Source: Human Reproduction (Oxford, England). 1994 June; 9(6): 1053-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7962375
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Vibrational spectroscopic study of DL-methionine dihydrogen phosphate. Author(s): Rajkumar BJ, Ramakrishnan V. Source: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy. 2001 February; 57(2): 247-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11206558
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Whole brain methionine-enkephalin of ethanol-avoiding and ethanol-preferring c57BL mice. Author(s): Blum K, Briggs AH, DeLallo L, Elston SF, Ochoa R. Source: Experientia. 1982 December 15; 38(12): 1469-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6891340
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Whole-serum assay of L-methionine using a chloramphenicol resistant strain of Pediococcus acidilactici. Author(s): Tennant GB. Source: The Journal of Applied Bacteriology. 1979 December; 47(3): 395-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=541304
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Why not add methionine to paracetamol tablets? Author(s): Neuvonen PJ, Simell O, Tokola O. Source: British Medical Journal (Clinical Research Ed.). 1986 October 11; 293(6552): 958. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3094739
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X-linked dominant Charcot-Marie-Tooth neuropathy: valine-38-methionine substitution of connexin32. Author(s): Orth U, Fairweather N, Exler MC, Schwinger E, Gal A. Source: Human Molecular Genetics. 1994 September; 3(9): 1699-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7833935
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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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CHAPTER 2. NUTRITION AND METHIONINE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and methionine.
Finding Nutrition Studies on Methionine 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 “methionine” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
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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 “methionine” (or a synonym): •
Composition and properties of the milk in sheep from newly created dairy breed in Bulgaria. Author(s): Agricultural Institute, Shumen (Bulgaria) Source: Boikovski, S. Stancheva, N. Stefanova, G. Dimitrov, D. Bulgarian-Journal-ofAgricultural-Science. (2002). volume 8(2-3) page 289-293.
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Effect of enzyme lysis on the digestibility of brewer's yeasts included in the diets of chicken broilers. Author(s): Bulgarian Academy of Science, Plovdiv (Bulgaria). Inst. of Microbiology Source: Pavlova, K. Grigorova, D. Czech-Journal-of-Animal-Science-UZPI (Czech Republic). (September 2001). volume 46(9) page 408-412.
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Effect of partial dietary amino acid deductions on growth rate and nitrogen balance in growing chicks. Source: Gruber, K. Roth, F.X. Kirchgessner, M. Archiv-fuer-Gefluegelkunde (Germany). (2000). volume 64(6) page 244-250.
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Reducing the risk of urinary tract infections in breeding sows. Source: Hoehler, D. Lindermeayer, H. Wolffram, S. Kraftfutter (Germany). (2000). (no. 78) page 293-296.
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Requirement of lysine and total sulfur amino acid for force moulted WL layers. Source: Rama Rao, S.V. Praharaj, N.K. Shyam Sunder, G. Raju, M.V.L.N. Reddy, M.R. Panda, A.K. Archiv-fuer-Gefluegelkunde (Germany). (2000). volume 64(5) page 214-218.
Additional physician-oriented references include: •
5-demethylovalicin, as a methionine aminopeptidase-2 inhibitor produced by Chrysosporium. Author(s): Korea Research Institute of Bioscience and Biotechnology, 52-Eundong, Yusong, 305-333, Taejon, Republic of Korea.
[email protected] Source: Son, Kwang Hee Kwon, Ju Young Jeong, Ha Won Kim, Hyae Kyeong Kim, Chang Jin Chang, Yie Hwa Choi, Jung Do Kwon, Byoung Mog Bioorg-Med-Chem. 2002 January; 10(1): 185-8 0968-0896
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A single-nucleotide mutation in a gene encoding S-adenosylmethionine synthetase is associated with methionine over-accumulation phenotype in Arabidopsis thaliana. Author(s): Laboratory of Molecular Biology, Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Japan. Source: Goto, D B Ogi, M Kijima, F Kumagai, T van Werven, F Onouchi, H Naito, S Genes-Genet-Syst. 2002 April; 77(2): 89-95 1341-7568
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Catabolism of methionine and threonine in vitro by mixed ruminal bacteria and protozoa. Author(s): Laboratory of Animal Nutrition and Biochemistry, Division of Animal Science, Faculty of Agriculture, Miyazaki University, Japan.
[email protected] Source: Or Rashid, M M Onodera, R Wadud, S Oshiro, S Okada, T Amino-Acids. 2001 December; 21(4): 383-91 0939-4451
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Cystathionine gamma-synthase and threonine synthase operate in concert to regulate carbon flow towards methionine in plants. Author(s): Plant Science Laboratory, Migal Galilee Technological Center, PO Box 90000, Rosh Pina 12100, Israel.
[email protected]
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Source: Amir, Rachel Hacham, Yael Galili, Gad Trends-Plant-Sci. 2002 April; 7(4): 153-6 1360-1385 •
Dihydrolipoic acid as an effective cofactor for peptide methionine sulfoxide reductase in enzymatic repair of oxidative damage to both lipid-free and lipid-bound apolipoprotein a-I. Author(s): Biomedical Department, AMW Biomed, 22-1-11 Tarusskaya Street, Moscow 117588, Russia.
[email protected] Source: Sigalov, A B Stern, L J Antioxid-Redox-Signal. 2002 June; 4(3): 553-7 1523-0864
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Effect of maternal methionine pre-treatment on alcohol-induced exencephaly and axial skeletal dysmorphogenesis in mouse fetuses. Author(s): Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, PO Box 17666, Al Ain, United Arab Emirates.
[email protected] Source: Padmanabhan, R Ibrahim, Ahmad Bener, Abulbari Drug-Alcohol-Depend. 2002 February 1; 65(3): 263-81 0376-8716
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Effects of dietary methionine and ethanol on acetaminophen hepatotoxicity in mice. Source: Reicks, M M Hathcock, J N Drug-Nutr-Interact. 1984; 3(1): 43-51 0272-3530
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Functional modeling of cobalamine-independent methionine synthase with pyrazolylborate-zinc-thiolate complexes. Author(s): Institut fur Anorganische und Analytische Chemie der Universitat Freiburg, Albertstrasse 21, D-79104 Freiburg, Germany. Source: Brand, U Rombach, M Seebacher, J Vahrenkamp, H Inorg-Chem. 2001 November 19; 40(24): 6151-7 0020-1669
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High dietary folate supplementation: effects on diet utilization and methionine metabolism in aged rats. Author(s): Seccion de Nutricion y Bromatologia, Departamento de Ciencias Biomedicas I, Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo-CEU, 28668 Boadilla del Monte, Madrid, Spain.
[email protected] Source: Achon, M Alonso Aperts, E Varela Moreiras, G J-Nutr-Health-Aging. 2002; 6(1): 51-4 1279-7707
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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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Microsporidian methionine aminopeptidase type 2. Author(s): Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
[email protected] Source: Weiss, L M Costa, S F Zhang, H J-Eukaryot-Microbiol. 2001; Suppl: 88S-90S 1066-5234
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Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism. Author(s): Department of Biochemistry, Medical Center Vanderbilt University, 620 Light Hall, Nashville, TN 37232, USA. Source: Luka, Zigmund Cerone, Roberto Phillips, John A 3rd Mudd, Harvey S Wagner, Conrad Hum-Genet. 2002 January; 110(1): 68-74 0340-6717
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Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. Author(s): Division of Hepatology and Gene Therapy, Department of Medicine, School of Medicine, University of Navarra, Pamplona, Spain. Source: Martinez Chantar, Maria L Corrales, Fernando J Martinez Cruz, L Alfonso Garcia Trevijano, Elena R Huang, Zong Zhi Chen, Lixin Kanel, Gary Avila, Matias A Mato, Jose M Lu, Shelly C FASEB-J. 2002 August; 16(10): 1292-4 1530-6860
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Synthesis of optically active homocysteine from methionine and its use in preparing four stereoisomers of cystathionine. Author(s): Unit of Chemistry, Faculty of Engineering and High Technology Research Center, Kansai University, Osaka, Japan.
[email protected] Source: Shiraiwa, T Nakagawa, K Kanemoto, N Kinda, T Yamamoto, H Chem-PharmBull-(Tokyo). 2002 August; 50(8): 1081-5 0009-2363
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Tolerance of point substitution of methionine for isoleucine in hen egg white lysozyme. Author(s): Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Source: Ohmura, T Ueda, T Hashimoto, Y Imoto, T Protein-Eng. 2001 June; 14(6): 421-5 0269-2139
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/
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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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WebMDHealth: 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 methionine; 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 Vitamin B12 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B12 Source: Prima Communications, Inc.www.personalhealthzone.com
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Minerals Creatine Source: Prima Communications, Inc.www.personalhealthzone.com Gabapentin Source: Healthnotes, Inc.; www.healthnotes.com L-Carnitine Source: Healthnotes, Inc.; www.healthnotes.com Lecithin and Choline Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10040,00.html
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Selenium Source: Healthnotes, Inc.; www.healthnotes.com Selenium Source: Prima Communications, Inc.www.personalhealthzone.com Sulfur Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Integrative Medicine Communications; www.drkoop.com Zinc Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10071,00.html •
Food and Diet Betaine (Trimethylglycine) Source: Healthnotes, Inc.; www.healthnotes.com Spinach Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,35,00.html
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CHAPTER 3. ALTERNATIVE MEDICINE AND METHIONINE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to methionine. At the conclusion of this chapter, we will provide additional sources.
The Combined Health Information Database The Combined Health Information Database (CHID) is a bibliographic database produced by health-related agencies of the U.S. federal government (mostly from the National Institutes of Health) that can offer concise information for a targeted search. The CHID database is updated four times a year at the end of January, April, July, and October. Check the titles, summaries, and availability of CAM-related information by using the “Simple Search” option at the following Web site: http://chid.nih.gov/simple/simple.html. In the drop box at the top, select “Complementary and Alternative Medicine.” Then type “methionine” (or synonyms) in the second search box. We recommend that you select 100 “documents per page” and to check the “whole records” options. The following was extracted using this technique: •
S-Adenosyl-L-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease Source: Rockville, MD: Agency for Healthcare Research and Quality. 2002. 6 p. Contact: Available from National Center for Complementary and Alternative Medicine Clearinghouse. P.O. Box 7923, Gaithersburg, MD 20898. (888) 644-6226; INTERNATIONAL PHONE: (301) 519-3153; TTY: (866) 464-3615; FAX: (866) 464-3616; EMAIL:
[email protected]. PRICE: Free. Publication Number: D175. Summary: This evidence report/technology assessment summary from the Agency for Healthcare Research and Quality (AHRQ) provides a review of the published literature on the use of S-adenosyl-L-methionine (SAMe) for the treatment of osteoarthritis, depression, and liver disease (cholestasis of pregnancy). The literature review is used to evaluate evidence for the efficacy of SAMe. The summary includes a description of the methodology, including the search strategy; selection criteria; and data collection and
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analysis. The findings are then discussed followed by an overview of future research on the topic. Information is also given on when and where the full report will be available. 1 reference.
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 methionine 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 “methionine” (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 methionine: •
Abnormal hepatic methionine and glutathione metabolism in patients with alcoholic hepatitis. Author(s): Lee TD, Sadda MR, Mendler MH, Bottiglieri T, Kanel G, Mato JM, Lu SC. Source: Alcoholism, Clinical and Experimental Research. 2004 January; 28(1): 173-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14745316
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Analysis of cell-cycle kinetics and sulfur amino acid metabolism in methioninedependent tumor cell lines; the effect of homocysteine supplementation. Author(s): Pavillard V, Drbal AA, Swaine DJ, Phillips RM, Double JA, Nicolaou A. Source: Biochemical Pharmacology. 2004 April 15; 67(8): 1587-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15041476
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Antioxidant effects of alpha tocopherol, ascorbic acid and L-methionine on lead induced oxidative stress to the liver, kidney and brain in rats. Author(s): Patra RC, Swarup D, Dwivedi SK. Source: Toxicology. 2001 May 11; 162(2): 81-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11337108
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Antioxidant properties of S-adenosyl-L-methionine in Fe(2+)-initiated oxidations. Author(s): Caro AA, Cederbaum AI. Source: Free Radical Biology & Medicine. 2004 May 15; 36(10): 1303-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15110395
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Betaine as a determinant of postmethionine load total plasma homocysteine before and after B-vitamin supplementation. Author(s): Holm PI, Bleie O, Ueland PM, Lien EA, Refsum H, Nordrehaug JE, Nygard O.
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Betaine supplementation decreases post-methionine hyperhomocysteinemia in chronic renal failure. Author(s): McGregor DO, Dellow WJ, Robson RA, Lever M, George PM, Chambers ST. Source: Kidney International. 2002 March; 61(3): 1040-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11849459
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Capillary gas chromatography inductively coupled plasma mass spectrometry (CGCICPMS) for the enantiomeric analysis of D,L-selenomethionine in food supplements and urine. Author(s): Devos C, Sandra K, Sandra P. Source: Journal of Pharmaceutical and Biomedical Analysis. 2002 January 15; 27(3-4): 507-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11755752
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cDNA cloning and biochemical characterization of S-adenosyl-L-methionine: 2,7,4'trihydroxyisoflavanone 4'-O-methyltransferase, a critical enzyme of the legume isoflavonoid phytoalexin pathway. Author(s): Akashi T, Sawada Y, Shimada N, Sakurai N, Aoki T, Ayabe S. Source: Plant & Cell Physiology. 2003 February; 44(2): 103-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12610212
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Comparison of the in situ and in vivo intestinal disappearance of ruminally protected methionine. Author(s): Berthiaume R, Lapierre H, Stevenson M, Cote N, McBride BW. Source: Journal of Dairy Science. 2000 September; 83(9): 2049-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11003238
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Complementary responses between feather meal and poultry by-product meal with or without ruminally protected methionine and lysine in growing calves. Author(s): Klemesrud MJ, Klopfenstein TJ, Lewis AJ. Source: Journal of Animal Science. 1998 July; 76(7): 1970-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9690654
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Correlation of carnitine levels to methionine and lysine intake. Author(s): Krajcovicova-Kudlackova M, Simoncic R, Bederova A, Babinska K, Beder I. Source: Physiological Research / Academia Scientiarum Bohemoslovaca. 2000; 49(3): 399-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11043928
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C-terminal extension of phaseolin with a short methionine-rich sequence can inhibit trimerisation and result in high instability. Author(s): Nuttall J, Vitale A, Frigerio L. Source: Plant Molecular Biology. 2003 April; 51(6): 885-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777049
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Dietary supplementation of selenomethionine reduces metastasis of melanoma cells in mice. Author(s): Yan L, Yee JA, Li D, McGuire MH, Graef GL. Source: Anticancer Res. 1999 March-April; 19(2A): 1337-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10368696
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Dietary supplementation with L-methionine impairs the utilization of urea-nitrogen and increases 5-L-oxoprolinuria in normal women consuming a low protein diet. Author(s): Meakins TS, Persaud C, Jackson AA. Source: The Journal of Nutrition. 1998 April; 128(4): 720-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9521634
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Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Author(s): Zhou J, Moller J, Danielsen CC, Bentzon J, Ravn HB, Austin RC, Falk E. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2001 September; 21(9): 14706. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11557674
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DL-methionine supplementation of rice-and-bean diets affects gammaglutamyltranspeptidase activity and glutathione content in livers of growing rats. Author(s): De-Oliveira IM, Fujimori E, Pereira VG, De-Castro VD. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 1999 April; 32(4): 483-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10347814
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Doxorubicin and vincristine with methionine depletion contributed to survival in the Yoshida sarcoma bearing rats. Author(s): Nagahama T, Goseki N, Endo M. Source: Anticancer Res. 1998 January-February; 18(1A): 25-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9568051
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Effect of a methionine-supplemented diet on the blood pressure of Sprague-Dawley and deoxycorticosterone acetate-salt hypertensive rats. Author(s): Robin S, Maupoil V, Laurant P, Jacqueson A, Berthelot A.
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Source: The British Journal of Nutrition. 2004 June; 91(6): 857-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15182389 •
Effect of a methionine-supplemented diet on the blood pressure of Wistar-Kyoto and spontaneously hypertensive rats. Author(s): Robin S, Maupoil V, Groubatch F, Laurant P, Jacqueson A, Berthelot A. Source: The British Journal of Nutrition. 2003 April; 89(4): 539-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12654173
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Effect of dietary chromium-L-methionine on glucose metabolism of beef steers. Author(s): Kegley EB, Galloway DL, Fakler TM. Source: Journal of Animal Science. 2000 December; 78(12): 3177-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11132832
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Effect of methionine supplementation on endothelial function, plasma homocysteine, and lipid peroxidation. Author(s): McAuley DF, Hanratty CG, McGurk C, Nugent AG, Johnston GD. Source: Journal of Toxicology. Clinical Toxicology. 1999; 37(4): 435-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10465239
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Effect of rumen protected methionine supplementation on early lactational responses of dairy cows fed a grass silage and cereals diet. Author(s): Iwanska S, Strusinska D, Pysera B. Source: Acta Vet Hung. 1999; 47(2): 191-206. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10344080
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Effect of supplemental methionine on plasma homocysteine concentrations in healthy men: a preliminary study. Author(s): Ward M, McNulty H, McPartlin J, Strain JJ, Weir DG, Scott JM. Source: Int J Vitam Nutr Res. 2001 January; 71(1): 82-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11276928
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Effect of supplemental methionine, choline and their combinations on the performance and immune response of broilers. Author(s): Swain BK, Johri TS. Source: British Poultry Science. 2000 March; 41(1): 83-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10821528
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Effect of supplementation of dry cat food with D,L-methionine and ammonium chloride on struvite activity product and sediment in urine. Author(s): Funaba M, Yamate T, Narukawa Y, Gotoh K, Iriki T, Hatano Y, Abe M.
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Source: The Journal of Veterinary Medical Science / the Japanese Society of Veterinary Science. 2001 March; 63(3): 337-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11307939 •
Effect of two levels of crude protein and methionine supplementation on performance of dairy cows. Author(s): Leonardi C, Stevenson M, Armentano LE. Source: Journal of Dairy Science. 2003 December; 86(12): 4033-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14740841
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Effect of vitamin A supplementation on rhodopsin mutants threonine-17 --> methionine and proline-347 --> serine in transgenic mice and in cell cultures. Author(s): Li T, Sandberg MA, Pawlyk BS, Rosner B, Hayes KC, Dryja TP, Berson EL. Source: Proceedings of the National Academy of Sciences of the United States of America. 1998 September 29; 95(20): 11933-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9751768
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Effects of dietary supplements of zinc-methionine on milk production, udder health and zinc metabolism in dairy goats. Author(s): Salama AA, Caja G, Albanell E, Such X, Casals R, Plaixats J. Source: The Journal of Dairy Research. 2003 February; 70(1): 9-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12617388
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Effects of methionine loading on plasma and erythrocyte sulphur amino acids and sulph-hydryls before and after co-factor supplementation in haemodialysis patients. Author(s): Suliman ME, Filho JC, Barany P, Anderstam B, Lindholm B, Bergstrom J. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2001 January; 16(1): 102-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11209001
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Effects of methionine supplement on methionine incorporation in rat embryos cultured in vitro. Author(s): Pugarelli JE, Brent RL, Lloyd JB. Source: Teratology. 1999 July; 60(1): 6-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10413332
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Effects of replacing fish meal with soy protein concentrate and of DL-methionine supplementation in high-energy, extruded diets on the growth and nutrient utilization of rainbow trout, Oncorhynchus mykiss. Author(s): Mambrini M, Roem AJ, Carvedi JP, Lalles JP, Kaushik SJ.
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Source: Journal of Animal Science. 1999 November; 77(11): 2990-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10568469 •
Efficacy of the dietary supplement S-adenosyl-L-methionine. Author(s): Fetrow CW, Avila JR. Source: The Annals of Pharmacotherapy. 2001 November; 35(11): 1414-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11724095
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Electrophysiological neuroimaging of the central effects of S-adenosyl-L-methionine by mapping of electroencephalograms and event-related potentials and lowresolution brain electromagnetic tomography. Author(s): Saletu B, Anderer P, Di Padova C, Assandri A, Saletu-Zyhlarz GM. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1162S-71S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12418497
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Elucidation of solvent exposure, side-chain reactivity, and steric demands of the trifluoromethionine residue in a recombinant protein. Author(s): Duewel HS, Daub E, Robinson V, Honek JF. Source: Biochemistry. 2001 November 6; 40(44): 13167-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11683625
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Excess dietary methionine markedly increases the vitamin B-6 requirement of young chicks. Author(s): Scherer CS, Baker DH. Source: The Journal of Nutrition. 2000 December; 130(12): 3055-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11110868
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Free methionine supplementation limits alcohol-induced liver damage in rats. Author(s): Parlesak A, Bode C, Bode JC. Source: Alcoholism, Clinical and Experimental Research. 1998 April; 22(2): 352-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9581640
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Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine. Author(s): Santamaria E, Avila MA, Latasa MU, Rubio A, Martin-Duce A, Lu SC, Mato JM, Corrales FJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 March 18; 100(6): 3065-70. Epub 2003 Mar 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12631701
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Genetic engineering for high methionine grain legumes. Author(s): Muntz K, Christov V, Saalbach G, Saalbach I, Waddell D, Pickardt T, Schieder O, Wustenhagen T.
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Source: Die Nahrung. 1998 August; 42(3-4): 125-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9739551 •
Growth stimulation of intestinal tumours in Apc(Min/+) mice by dietary Lmethionine supplementation. Author(s): Paulsen JE, Alexander J. Source: Anticancer Res. 2001 September-October; 21(5): 3281-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11848484
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High dietary folate supplementation: effects on diet utilization and methionine metabolism in aged rats. Author(s): Achon M, Alonso-Aperts E, Varela-Moreiras G. Source: J Nutr Health Aging. 2002; 6(1): 51-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11813082
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High-dose folic acid supplementation in rats: effects on gestation and the methionine cycle. Author(s): Achon M, Alonso-Aperte E, Reyes L, Ubeda N, Varela-Moreiras G. Source: The British Journal of Nutrition. 2000 February; 83(2): 177-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10743497
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Identification of limiting amino acids in methionine- and lysine-supplemented lowprotein diets for turkeys. Author(s): Waibel PE, Carlson CW, Brannon JA, Noll SL. Source: Poultry Science. 2000 September; 79(9): 1299-305. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11020075
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Induction of human methionine adenosyltransferase 2A expression by tumor necrosis factor alpha. Role of NF-kappa B and AP-1. Author(s): Yang H, Sadda MR, Yu V, Zeng Y, Lee TD, Ou X, Chen L, Lu SC. Source: The Journal of Biological Chemistry. 2003 December 19; 278(51): 50887-96. Epub 2003 October 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14530285
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Influence of dietary protein level on the broiler chicken's response to methionine and betaine supplements. Author(s): Garcia Neto M, Pesti GM, Bakalli RI. Source: Poultry Science. 2000 October; 79(10): 1478-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11055856
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Influence of postruminal supplementation of methionine and lysine, isoleucine, or all three amino acids on intake and chewing behavior, ruminal fermentation, and milk and milk component production.
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Author(s): Robinson PH, Chalupa W, Sniffen CJ, Julien WE, Sato H, Fujieda T, Watanabe K, Suzuki H. Source: Journal of Animal Science. 1999 October; 77(10): 2781-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10521041 •
Interaction between genotype and dietary concentrations of methionine for immune function in commercial broilers. Author(s): Rama Rao SV, Praharaj NK, Ramasubba Reddy V, Panda AK. Source: British Poultry Science. 2003 March; 44(1): 104-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12737232
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L- and D- methionine provide equivalent long term protection against CDDPinduced ototoxicity in vivo, with partial in vitro and in vivo retention of antineoplastic activity. Author(s): Reser D, Rho M, Dewan D, Herbst L, Li G, Stupak H, Zur K, Romaine J, Frenz D, Goldbloom L, Kopke R, Arezzo J, Van De Water T. Source: Neurotoxicology. 1999 October; 20(5): 731-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10591510
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Limiting amino acids after methionine and lysine with growing turkeys fed lowprotein diets. Author(s): Waibel PE, Carlson CW, Brannon JA, Noll SL. Source: Poultry Science. 2000 September; 79(9): 1290-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11020074
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Liquid chromatographic determination of S-adenosyl-L-methionine in dietary supplement tablets. Author(s): Zhou JZ, Waszkuc T, Garbis S, Mohammed F. Source: J Aoac Int. 2002 July-August; 85(4): 901-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12180685
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L-methionine availability regulates expression of the methionine adenosyltransferase 2A gene in human hepatocarcinoma cells: role of S-adenosylmethionine. Author(s): Martinez-Chantar ML, Latasa MU, Varela-Rey M, Lu SC, Garcia-Trevijano ER, Mato JM, Avila MA. Source: The Journal of Biological Chemistry. 2003 May 30; 278(22): 19885-90. Epub 2003 March 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12660248
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L-methionine supplementation accelerates tumour growth and shifts the phospholipid derivative pattern in a murine model of malignant melanoma. A proton HRMAS NMR spectroscopy study. Author(s): Demidem A, Morvan D, Papon J, Madelmont JC.
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Low-dose folic acid supplementation does not influence plasma methionine concentrations in young non-pregnant women. Author(s): Brouwer IA, van Dusseldorp M, Duran M, Thomas CM, Hautvast JG, Eskes TK, Steegers-Theunissen RP. Source: The British Journal of Nutrition. 1999 August; 82(2): 85-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10743479
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Lymphocyte proliferation response of lactating dairy cows fed varying concentrations of rumen-protected methionine. Author(s): Soder KJ, Holden LA. Source: Journal of Dairy Science. 1999 September; 82(9): 1935-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10509252
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Methionine and somatotropin supplementation in growing beef cattle. Author(s): Tripp MW, Hoagland TA, Dahl GE, Kimrey AS, Zinn SA. Source: Journal of Animal Science. 1998 April; 76(4): 1197-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9581945
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Methionine depletion enhances the antitumoral efficacy of cytotoxic agents in drugresistant human tumor xenografts. Author(s): Poirson-Bichat F, Goncalves RA, Miccoli L, Dutrillaux B, Poupon MF. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 February; 6(2): 643-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10690550
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Methionine supplementation of soya products: effects on nitrogen balance parameters. Author(s): de Oliveira JE, de Souza N, Jordao Junior AA, Marchin JS. Source: Arch Latinoam Nutr. 1998 March; 48(1): 35-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9754403
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Methionine-induced hyperhomocysteinemia promotes superoxide anion generation and NFkappaB activation in peritoneal macrophages of C57BL/6 mice. Author(s): Song YS, Rosenfeld ME. Source: Journal of Medicinal Food. 2004 Summer; 7(2): 229-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15298772
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Methionine-induced phytoalexin production in rice leaves. Author(s): Nakazato Y, Tamogami S, Kawai H, Hasegawa M, Kodama O.
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Source: Bioscience, Biotechnology, and Biochemistry. 2000 March; 64(3): 577-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10803956 •
Nitrogen metabolism of beef steers fed endophyte-free tall fescue hay: effects of ruminally protected methionine supplementation. Author(s): Archibeque SL, Burns JC, Huntington GB. Source: Journal of Animal Science. 2002 May; 80(5): 1344-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12019624
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NMR regulatory analysis: determination and characterization of S-adenosyl-Lmethionine in dietary supplements. Author(s): Hanna GM. Source: Pharmazie. 2004 April; 59(4): 251-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15125566
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Nutritional and technological evaluation of an enzymatically methionine-enriched soy protein for infant enteral formulas. Author(s): de Regil LM, de la Barca AM. Source: International Journal of Food Sciences and Nutrition. 2004 March; 55(2): 91-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14985181
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Part II: surface-enhanced Raman spectroscopy investigation of methionine containing heterodipeptides adsorbed on colloidal silver. Author(s): Podstawka E, Ozaki Y, Proniewicz LM. Source: Applied Spectroscopy. 2004 May; 58(5): 581-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15165335
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Production of hydrogen peroxide and methionine sulfoxide by epigallocatechin gallate and antioxidants. Author(s): Sakagami H, Arakawa H, Maeda M, Satoh K, Kadofuku T, Fukuchi K, Gomi K. Source: Anticancer Res. 2001 July-August; 21(4A): 2633-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11724332
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Protective effect of methionine supplementation on arsenic-induced alteration of glucose homeostasis. Author(s): Pal S, Chatterjee AK. Source: Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. 2004 May; 42(5): 737-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15046819
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Purification and properties of a new S-adenosyl-L-methionine:flavonoid 4'-Omethyltransferase from carnation (Dianthus caryophyllus L.). Author(s): Curir P, Lanzotti V, Dolci M, Dolci P, Pasini C, Tollin G. Source: European Journal of Biochemistry / Febs. 2003 August; 270(16): 3422-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899699
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Radical production from free and peptide-bound methionine sulfoxide oxidation by peroxynitrite and hydrogen peroxide/iron(II). Author(s): Nakao LS, Iwai LK, Kalil J, Augusto O. Source: Febs Letters. 2003 July 17; 547(1-3): 87-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12860391
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Response of nitrogen metabolism in preparturient dairy cows to methionine supplementation. Author(s): Bach A, Huntington GB, Stern MD. Source: Journal of Animal Science. 2000 March; 78(3): 742-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10764083
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Role of S-adenosyl-L-methionine in the treatment of alcoholic liver disease: introduction and summary of the symposium. Author(s): Purohit V, Russo D. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 151-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163142
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Rumen degradation and availability of various amounts of liquid methionine hydroxy analog in lactating dairy cows. Author(s): Koenig KM, Rode LM, Knight CD, Vazquez-Anon M. Source: Journal of Dairy Science. 2002 April; 85(4): 930-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12018438
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Rumen-protected methionine or lysine supplementation of Comisana ewes' diets: effects on milk fatty acid composition. Author(s): Sevi A, Rotunno T, Di Caterina R, Muscio A. Source: The Journal of Dairy Research. 1998 August; 65(3): 413-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9718494
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Ruminal escape, gastrointestinal absorption, and response of serum methionine to supplementation of liquid methionine hydroxy analog in dairy cows. Author(s): Koenig KM, Rode LM, Knight CD, McCullough PR. Source: Journal of Dairy Science. 1999 February; 82(2): 355-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10068957
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S-adenosyl-L-methionine: effects on brain bioenergetic status and transverse relaxation time in healthy subjects. Author(s): Silveri MM, Parow AM, Villafuerte RA, Damico KE, Goren J, Stoll AL, Cohen BM, Renshaw PF. Source: Biological Psychiatry. 2003 October 15; 54(8): 833-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14550683
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S-adenosylmethionine (AdoMet) supplementation for treatment of chemotherapyinduced liver injury. Author(s): Santini D, Vincenzi B, Massacesi C, Picardi A, Gentilucci UV, Esposito V, Liuzzi G, La Cesa A, Rocci L, Marcucci F, Montesarchio V, Groeger AM, Bonsignori M, Tonini G. Source: Anticancer Res. 2003 November-December; 23(6D): 5173-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14981985
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S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x(S). Author(s): Yang H, Sadda MR, Li M, Zeng Y, Chen L, Bae W, Ou X, Runnegar MT, Mato JM, Lu SC. Source: Hepatology (Baltimore, Md.). 2004 July; 40(1): 221-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15239106
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Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. Author(s): Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM. Source: The Journal of Family Practice. 2002 May; 51(5): 425-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12019049
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Selenomethionine content of candidate reference materials. Author(s): Wolf WR, Zainal H, Yager B. Source: Fresenius' Journal of Analytical Chemistry. 2001 June; 370(2-3): 286-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11451253
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Site-directed mutagenesis of Glu-297 from the alpha-polypeptide of Phaseolus vulgaris glutamine synthetase alters kinetic and structural properties and confers resistance to L-methionine sulfoximine. Author(s): Clemente MT, Marquez AJ. Source: Plant Molecular Biology. 1999 July; 40(5): 835-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10487218
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S-methylmethionine plays a major role in phloem sulfur transport and is synthesized by a novel type of methyltransferase. Author(s): Bourgis F, Roje S, Nuccio ML, Fisher DB, Tarczynski MC, Li C, Herschbach C, Rennenberg H, Pimenta MJ, Shen TL, Gage DA, Hanson AD.
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Source: The Plant Cell. 1999 August; 11(8): 1485-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10449582 •
Structure and function of the methionine aminopeptidases. Author(s): Lowther WT, Matthews BW. Source: Biochimica Et Biophysica Acta. 2000 March 7; 1477(1-2): 157-67. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10708856
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Supplemental protein plus ruminally protected methionine and lysine for primiparous beef cattle consuming annual rye hay. Author(s): Hess BW, Scholljegerdes EJ, Coleman SA, Williams JE. Source: Journal of Animal Science. 1998 July; 76(7): 1767-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9690631
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Supplementation of methionine and selection of highly digestible rumen undegradable protein to improve nitrogen efficiency for milk production. Author(s): Noftsger S, St-Pierre NR. Source: Journal of Dairy Science. 2003 March; 86(3): 958-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12703633
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Supplementation of milk replacers containing soy protein with threonine, methionine, and lysine in the diets of calves. Author(s): Kanjanapruthipong J. Source: Journal of Dairy Science. 1998 November; 81(11): 2912-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9839234
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Suppression of rat hepatic cytochrome P450s by protein-calorie malnutrition: complete or partial restoration by cysteine or methionine supplementation. Author(s): Cho MK, Kim YG, Lee MG, Kim SG. Source: Archives of Biochemistry and Biophysics. 1999 December 1; 372(1): 150-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10562428
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The canonical methionine 392 of matrix metalloproteinase 2 (gelatinase A) is not required for catalytic efficiency or structural integrity: probing the role of the methionine-turn in the metzincin metalloprotease superfamily. Author(s): Butler GS, Tam EM, Overall CM. Source: The Journal of Biological Chemistry. 2004 April 9; 279(15): 15615-20. Epub 2004 January 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14732714
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The effect of graded levels of dietary casein, with or without methionine supplementation, on glutathione concentration in unstressed and endotoxin-treated
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rats. Author(s): Alhamdan AA, Grimble RF. Source: Int J Vitam Nutr Res. 2003 November; 73(6): 468-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14743552 •
The effect of tryptophan plus methionine, 5-azacytidine, and methotrexate on adjuvant arthritis of rat. Author(s): Kroger H, Dietrich A, Gratz R, Wild A, Ehrlich W. Source: General Pharmacology. 1999 August; 33(2): 195-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10461858
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The effects of dietary selenomethionine on polyamines and azoxymethane-induced aberrant crypts. Author(s): Baines AT, Holubec H, Basye JL, Thorne P, Bhattacharyya AK, Spallholz J, Shriver B, Cui H, Roe D, Clark LC, Earnest DL, Nelson MA. Source: Cancer Letters. 2000 November 28; 160(2): 193-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11053649
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The metal-catalyzed oxidation of methionine in peptides by Fenton systems involves two consecutive one-electron oxidation processes. Author(s): Hong J, Schoneich C. Source: Free Radical Biology & Medicine. 2001 December 1; 31(11): 1432-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11728815
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The methionine-homocysteine cycle and its effects on cognitive diseases. Author(s): Miller AL. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2003 February; 8(1): 7-19. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12611557
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The nutritional significance, metabolism and toxicology of selenomethionine. Author(s): Schrauzer GN. Source: Adv Food Nutr Res. 2003; 47: 73-112. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14639782
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The Pneumocystis carinii drug target S-adenosyl-L-methionine:sterol C-24 methyl transferase has a unique substrate preference. Author(s): Kaneshiro ES, Rosenfeld JA, Basselin-Eiweida M, Stringer JR, Keely SP, Smulian AG, Giner JL. Source: Molecular Microbiology. 2002 May; 44(4): 989-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12010494
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The purification and characterization of a Bacillus stearothermophilus methionine aminopeptidase (MetAP). Author(s): Chung JM, Chung IY, Lee YS. Source: J Biochem Mol Biol. 2002 March 31; 35(2): 228-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12297034
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The Rhizobium etli metZ gene is essential for methionine biosynthesis and nodulation of Phaseolus vulgaris. Author(s): Tate R, Riccio A, Caputo E, Iaccarino M, Patriarca EJ. Source: Mol Plant Microbe Interact. 1999 January; 12(1): 24-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9885190
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Thymoquinone and Nigella sativa oil protection against methionine-induced hyperhomocysteinemia in rats. Author(s): El-Saleh SC, Al-Sagair OA, Al-Khalaf MI. Source: International Journal of Cardiology. 2004 January; 93(1): 19-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14729430
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Visualizing central effects of S-adenosyl-L-methionine (SAMe), a natural molecule with antidepressant properties, by pharmaco-EEG mapping. Author(s): Saletu-Zyhlarz GM, Anderer P, Linzmayer L, Semlitsch HV, Assandri A, Prause W, Hassan Abu-Bakr M, Lindeck-Pozza E, Saletu B. Source: The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (Cinp). 2002 September; 5(3): 199-215. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12366873
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What is SAMe? S-Adenosylmethionine. Author(s): Cowley G, Underwood A. Source: Newsweek. 1999 July 5; 134(1): 46-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10538206
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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WebMDHealth: 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 methionine; 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 Alzheimer's Disease Source: Integrative Medicine Communications; www.drkoop.com Arthritis Source: Integrative Medicine Communications; www.drkoop.com Bipolar Disorder Source: Healthnotes, Inc.; www.healthnotes.com Bladder Infection Alternative names: Urinary Tract Infection [UTI] Source: Prima Communications, Inc.www.personalhealthzone.com Brain Cancer Source: Integrative Medicine Communications; www.drkoop.com Cancer Prevention (Reducing the Risk) Source: Prima Communications, Inc.www.personalhealthzone.com Cirrhosis Source: Integrative Medicine Communications; www.drkoop.com Colon Cancer Source: Healthnotes, Inc.; www.healthnotes.com Congestive Heart Failure Source: Healthnotes, Inc.; www.healthnotes.com Dementia Source: Integrative Medicine Communications; www.drkoop.com
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Depression Source: Healthnotes, Inc.; www.healthnotes.com Depression Source: Integrative Medicine Communications; www.drkoop.com Depression (Mild to Moderate) Source: Prima Communications, Inc.www.personalhealthzone.com Fibromyalgia Source: Healthnotes, Inc.; www.healthnotes.com Fibromyalgia Source: Integrative Medicine Communications; www.drkoop.com Hepatitis Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com High Homocysteine Source: Healthnotes, Inc.; www.healthnotes.com HIV and AIDS Support Source: Healthnotes, Inc.; www.healthnotes.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Liver Disease Source: Integrative Medicine Communications; www.drkoop.com Liver Disorders Source: Integrative Medicine Communications; www.drkoop.com Male Infertility Source: Healthnotes, Inc.; www.healthnotes.com Memory Loss Source: Integrative Medicine Communications; www.drkoop.com Migraine Headaches Source: Healthnotes, Inc.; www.healthnotes.com Miscarriage Source: Integrative Medicine Communications; www.drkoop.com
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Osteoarthritis Source: Healthnotes, Inc.; www.healthnotes.com Osteoarthritis Source: Integrative Medicine Communications; www.drkoop.com Osteoarthritis Source: Prima Communications, Inc.www.personalhealthzone.com Pancreatic Insufficiency Source: Healthnotes, Inc.; www.healthnotes.com Pancreatitis Source: Integrative Medicine Communications; www.drkoop.com Parkinson's Disease Source: Healthnotes, Inc.; www.healthnotes.com Phenylketonuria Source: Healthnotes, Inc.; www.healthnotes.com Pregnancy and Postpartum Support Source: Healthnotes, Inc.; www.healthnotes.com Psychological Conditions and Disorders Source: Integrative Medicine Communications; www.drkoop.com Serum Sickness Source: Integrative Medicine Communications; www.drkoop.com Skin Cancer Source: Integrative Medicine Communications; www.drkoop.com Spontaneous Abortion Source: Integrative Medicine Communications; www.drkoop.com •
Herbs and Supplements Acetaminophen Alternative names: Acephen, Aceta, Amaphen, Anoquan, Apacet, Arthritis Foundation Aspirin Free, Arthritis Foundation Nighttime, Aspirin Free Anacin, Aspirin Free Excedrin, Bayer Select, Dapacin, Dynafed, Endolor, Esgic, Excedrin P.M., Fem-Etts, Femcet, Feverall, Fioricet, Fiorpap, Genapap, Genebs, Halenol, Isocet, Liquiprin, Mapap, Maranox, Meda, Medigesic, Midol, Multi-Symptom Pamprin, Neopap, Nighttime Pamprin, Oraphen-PD, Panadol, Phrenilin, Repan, Ridenol, Sedapap, Silapap, Sominex Pain Relief, Tapanol, Tempra, Tylenol, Uni-Ace, Unisom with Pain Relief Source: Prima Communications, Inc.www.personalhealthzone.com Amino Acids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com
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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10003,00.html Amino Acids Overview Source: Healthnotes, Inc.; www.healthnotes.com Anticonvulsants Source: Healthnotes, Inc.; www.healthnotes.com Astragalus Sp Alternative names: Vetch, Rattlepod, Locoweed; Astragalus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Betaine Alternative names: Trimethylglycine Source: Integrative Medicine Communications; www.drkoop.com Calendula Alternative names: Calendula officinalis L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Cysteine Source: Healthnotes, Inc.; www.healthnotes.com Dandelion Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10021,00.html Dryopteris Alternative names: Male Fern; Dryopteris sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Glucosamine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,790,00.html Glutathione Source: Healthnotes, Inc.; www.healthnotes.com Lecithin Source: Prima Communications, Inc.www.personalhealthzone.com Levodopa/Carbidopa Alternative names: Sinemet Source: Prima Communications, Inc.www.personalhealthzone.com Lipotropic Combination Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,861,00.html
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MAO Inhibitors Source: Prima Communications, Inc.www.personalhealthzone.com Methionine Source: Healthnotes, Inc.; www.healthnotes.com Methionine Source: Prima Communications, Inc.www.personalhealthzone.com Methionine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10084,00.html Milk Thistle Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10044,00.html Phosphatidylserine (PS) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,813,00.html S-Adenosylmethionine (SAMe) Alternative names: SAMe Source: Integrative Medicine Communications; www.drkoop.com SAMe Source: Healthnotes, Inc.; www.healthnotes.com SAMe Alternative names: S-Adenosylmethionine (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: Prima Communications, Inc.www.personalhealthzone.com Tmg (trimethylglycine) Source: Prima Communications, Inc.www.personalhealthzone.com Tramadol Alternative names: Ultram Source: Prima Communications, Inc.www.personalhealthzone.com
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Tricyclic Antidepressants Source: Healthnotes, Inc.; www.healthnotes.com Tricyclic Antidepressants Source: Prima Communications, Inc.www.personalhealthzone.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 METHIONINE Overview In this chapter, we will give you a bibliography on recent dissertations relating to methionine. 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 “methionine” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on methionine, we have not necessarily excluded nonmedical dissertations in this bibliography.
Dissertations on Methionine 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 methionine. 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: •
Biochemical studies of human methionine synthase reductase by Olteanu, Horatiu, PhD from THE UNIVERSITY OF NEBRASKA - LINCOLN, 2003, 126 pages http://wwwlib.umi.com/dissertations/fullcit/3092583
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Effects of dietary supplemental methionine sources on odor volatiles in broiler excreta by Chavez, Cesar, PhD from TEXAS A&M UNIVERSITY, 2003, 124 pages http://wwwlib.umi.com/dissertations/fullcit/3115023
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Mapping the interactions between Escherichia coli flavodoxin and its physiological partners, flavodoxin reductase and cobalamin-dependent methionine synthase by Hall, Diane Anita, PhD from UNIVERSITY OF MICHIGAN, 2003, 134 pages http://wwwlib.umi.com/dissertations/fullcit/3079454
•
Part I. Enantioselectivity of hydroxy methionine (HMB) incorporation in short chain peptides. Part II. Development of an enzymatic process for isolation of enantio enriched HMB on a preparative scale. Part III. Synthesis and characterization of
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tailored s by Roy, Arindam, PhD from UNIVERSITY OF MISSOURI - ROLLA, 2003, 156 pages http://wwwlib.umi.com/dissertations/fullcit/3115170 •
Structures of two zinc-dependent homocysteine S-methyltransferases: Betainehomocysteine methyltransferase and cobalamin-dependent methionine synthase by Evans, John Charles, PhD from UNIVERSITY OF MICHIGAN, 2004, 191 pages http://wwwlib.umi.com/dissertations/fullcit/3121925
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Studies of methionine oxidation in abductin, a rubber-like protein by Xu, Jihong , MS from THE TEXAS A&M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER, 2003, 52 pages http://wwwlib.umi.com/dissertations/fullcit/1416265
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The effects of age and folate intake on the activities of four methionine cycle enzymes and plasma homocysteine levels in the rat by Keith, Roger Howard, MS from UNIVERSITY OF NEVADA, RENO, 2003, 78 pages http://wwwlib.umi.com/dissertations/fullcit/1414488
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The role of homoserine kinase and substrate availability on the regulation of methionine biosynthesis in Arabidopsis thaliana by Lee, Minsang, PhD from RUTGERS THE STATE UNIVERSITY OF NEW JERSEY - NEW BRUNSWICK, 2003, 176 pages http://wwwlib.umi.com/dissertations/fullcit/3092959
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 METHIONINE 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 “methionine” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on methionine, we have not necessarily excluded nonmedical patents in this bibliography.
Patents on Methionine By performing a patent search focusing on methionine, 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 will tell you how to obtain this information later in the chapter. The following is an 8Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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example of the type of information that you can expect to obtain from a patent search on methionine: •
Amidase Inventor(s): Murphy; Dennis (Paoli, PA), Reid; John (Bryn Mawr, PA), Robertson; Dan (Haddonfield, NJ) Assignee(s): Diversa Corporation (San Diego, CA) Patent Number: 6,465,204 Date filed: June 30, 2000 Abstract: A purified thermostable enzyme is derived from the archael bacterium Thermococcus GU5L5. The enzyme has a molecular weight of about 68.5 kilodaltons and has cellulase activity. The enzyme can be produced from native or recombinant host cells and can be used for the removal of arginine, phenylalanine, or methionine amino acids from the N-terminal end of peptides in peptide or peptidomimetic synthesis. The enzyme is selective for the L, or `natural` enantiomer of the amino acid derivatives and is therefore useful for the production of optically active compounds. These reactions can be performed in the presence of the chemically more reactive ester functionally, a step which is very difficult to achieve with nonenzymatic methods. Excerpt(s): This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production and isolation of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention has been identified as an amidase and in particular an enzyme having activity in the removal of arginine, phenylalanine or methionine from the N-terminal end of peptides in peptide or peptidomimetic synthesis. Thermophilic bacteria have received considerable attention as sources of highly active and thermostable enzymes (Bronneomeier, K. and Staudenbauer, W. L., D. R. Woods (Ed.), The Clostridia and Biotechnology, Butterworth Publishers, Stoneham, Mass. (1993). Recently, the most extremely thermophilic organotrophic eubacteria presently known have been isolated and characterized. These bacteria, which belong to the genus Thermotoga, are fermentative microorganisms metabolizing a variety of carbohydrates (Huber, R. and Stetter, K. O., in Ballows, et al., (Ed.), The Procaryotes, 2nd Ed., Springer-Verlaz, New York, pgs. 3809-3819 (1992)). Because to date most organisms identified from the archaeal domain are thermophiles or hyperthermophiles, archaeal bacteria are also considered a fertile source of thermophilic enzymes. Web site: http://www.delphion.com/details?pn=US06465204__
•
Chelated feed additive and method of preparation Inventor(s): Ciribolla; Antonio (Reggio Emilia, IT) Assignee(s): Agristudio S. r. L. (Reggio Emilia, IT) Patent Number: 6,461,664 Date filed: April 26, 2001 Abstract: Feed additive for agro-zootechnical use, in particular for alimentary use in the zootechnical sector, consisting of a chelate obtained by the reaction of methionine hydroxy analogue with the carbonate of a bivalent metal. The reaction is free from
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undesirable by-products, and the product is stable and effective in improving the main growth factors of the animal. Excerpt(s): The present invention relates to a chelated additive for agro-zootechnical use in the broad sense, and in particular for alimentary use in the zootechnical sector, and the associated method for obtaining said additive. A chelate is a compound which is obtained from an organic molecule (in the case in question an amino acid or a peptide chain) and a metal ion by means of strong co-ordination bonds. These compounds are widely used both in the agronomic field and in the zootechnical field since their usefulness is derived from the biological action of the metal involved, which acts as activator in a great number of enzymatic reactions and as regulator in various metabolic functions in all living organisms. The presence of the bond with an amino acid material favours the absorption, availability and use of the metal since it is transported by the organic component to all areas of the organism. Web site: http://www.delphion.com/details?pn=US06461664__ •
Compositions for protecting a plant from a disease and using method thereof Inventor(s): Kase; Rieko (9-1, Koishikawa 3-chome, Bunkyo-ku, Tokyo 112-0002, JP), Kawai; Hiroshi (409-5, Yabata Chigasaki-shi, Kanagawa 253-0085, JP) Assignee(s): none reported Patent Number: 6,492,303 Date filed: April 9, 2001 Abstract: An object of the present invention is to provide a composition for protecting a plant from a disease that is safe, at low cost, environment friendly, and improves the natural resistance of plant itself by inducing production of a phytoalexin, an antibacterial substance inherent to plant, and a using method thereof. For the above purpose the present invention employs said composition for protecting a plant from a disease comprised of at least one sulfur-containing amino acid selected from the group comprising methionine, cysteine, and cystine, and D-glucose in a mixed form. In a preferred embodiment of the present invention, it is sprayed on the aboveground part of a plant either undiluted or after dilution with water by 100,000 times, directly mixed with soil, or irrigated on a plant after dilution with water by 1-1,000,000 times. Excerpt(s): This invention relates to a composition for protecting a plant from a disease and a using method thereof. More particularly, it relates to a composition for protecting a plant from a disease that induces production of a phytoalexin by application to a plant and suppresses pathogenic plant bacteria, and further a method of applying said composition to a plant in order to induce production of a phytoalexin and suppress various pathogenic plant bacteria resulting in protection of a disease of plant. The present inventors have already found out that treatment of methionine to a rice plant is capable of inducing production of a phytoalexin that donates resistance to various diseases (Japanese Patent Application H09-44206). Treatment of methionine to a rice plant induces accumulation of phytoalexins such as Sakuranetin and Momilactone, and resultantly donates resistance to rice blight (Pyricularia oryzae) that is a representative disease of rice plants. However, the effect of using methionine alone has proved to be insufficient and occasionally led to an inability to exhibit a desired effect. The primary object of the present invention is to provide a composition for protecting a plant from a disease that induces production of a phytoalexin by application to a plant and suppresses plant bacteria more effectively than using methionine alone, and can be
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used throughout the year. The secondary object of the present invention is to provide a method of applying said protecting composition to a plant in order to induce production of a phytoalexin, suppress plant bacteria, and resultantly protect a plant from plant diseases. Web site: http://www.delphion.com/details?pn=US06492303__ •
Compositions for the protection of plants against the stress of oxidation Inventor(s): De Mil; Christophe (7, Rue Mechain, 75014 Paris, FR), Lauzanne; Eliane (57, Avenue de la Republique, 75011 Paris, FR), Morelle; Jean (170, Avenue Parmentier, 75010 Paris, FR), Rothfuss; Jacqueline (14, Rue du Faubourg, 67630 Lauterbourg, FR) Assignee(s): none reported Patent Number: 6,492,302 Date filed: June 20, 2001 Abstract: This invention concerns making compounds destined for the protection of plants against oxidative stress, characterized by lipo-amino acids enriched with methionine during a process of acylation with hydrolysates of proteins or of amino acids taken individually or combined; or after acylation and lipo-amino acids partially or totally salified by basic amino acids which gives them antioxidant and anti-free radical properties. This invention extends to the total or partial salification of this type of lipo-amino acids with oligoelements. Excerpt(s): It is well-known that many plants are sensitive to drops in temperature, even above the freezing point. This is the case for most fruit-bearing trees. It has been determined that frost and other fluctuations in temperature, including dryness and excessive heat, are aggressive to plant life, generating a phenomenon defined as "oxidative stress", defined as an accelerated and excessive generation of free radicals: alkoxy, peroxy, and oxygen singlets. These free radicals are produced by the interaction of lipooxygenase with the lipids of cell membranes. In the case of excessive dryness, the formation of super-oxidated anions (O.sub.2.degree.) among the plant chloroplasts has been observed. Web site: http://www.delphion.com/details?pn=US06492302__
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DAX-1 protein, methods for production and use thereof Inventor(s): Burris; Thomas P. (Woodland Hills, CA), Guo; Weiwen (Los Angeles, CA), McCabe; Edward R. B. (Pacific Palisades, CA), Vilain; Eric (Los Angeles, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,465,627 Date filed: July 26, 1996 Abstract: The invention provides a DAX-1 protein molecule having the amino acid sequence beginning with methionine at position 1 and ending with isoleucine at position 470 as shown in FIG. 12. The invention further provides the genomic nucleic acid sequence for DAX-1, including intron, exons and a promoter region. Additionally, the invention provides methods for using and making the DAX-1 protein and DAX-1 nucleic acid molecules.
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Excerpt(s): Throughout this application, various publications are referenced within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. Presently, there are no commercially effective tests to provide a rapid diagnostic approach to individuals with adrenocortical disorders of metabolism and development such as the X-linked cytomegalic form of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to mutations in DAX-1, a new member of the nuclear hormone receptor gene superfamily. Left untreated, the results of these disorders include failure to achieve pubertal growth, sexual maturity, and eventually death. Clinical signs and symptoms of infants with adrenal hypoplasia include poor feeding, failure to gain weight, hyperpigmentation, vomiting, diarrhea, vascular collapse, and sudden death. Dehydration, hyponatremia, hyperkalemia, acidosis, and hypoglycemia are common biochemical findings characteristic of combined glucocorticoid and mineralocorticoid deficiency. Web site: http://www.delphion.com/details?pn=US06465627__ •
Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for caspases and other enzymes and the use thereof Inventor(s): Cai; Sui Xiong (San Diego, CA), Drewe; John A. (Carlsbad, CA), Keana; John F. W. (Eugene, OR), Weber; Eckard (San Diego, CA), Zhang; Han-Zhong (Irvine, CA) Assignee(s): Cytovia, Inc. (San Diego, CA) Patent Number: 6,759,207 Date filed: September 7, 2001 Abstract: The present invention relates to novel fluorescent dyes, novel fluorogenic and fluorescent reporter molecules and new enzyme assay processes that can be used to detect the activity of caspases and other enzymes involved in apoptosis in whole cells, cell lines and tissue samples derived from any living organism or organ. The reporter molecules and assay processes can be used in drug screening procedures to identify compounds which act as inhibitors or inducers of the caspase cascade in whole cells or tissues. The reagents and assays described herein are also useful for determining the chemosensitivity of human cancer cells to treatment with chemotherapeutic drugs. The present invention also relates to novel fluorogenic and fluorescent reporter molecules and new enzyme assay processes that can be used to detect the activity of type 2 methionine aminopeptidase, dipeptidyl peptidase IV, calpain, aminopeptidase, HIV protease, adenovirus protease, HSV-1 protease, HCMV protease and HCV protease. Excerpt(s): This invention is in the field of intracellular detection of enzymes using fluorogenic or fluorescent probes. The invention relates to novel fluorescent dyes and application of these dyes for the preparation of novel fluorogenic or fluorescent peptide or amino acid derivatives which are substrates of proteases and peptidases. In particular, the invention relates to novel fluorogenic or fluorescent peptide derivatives which are substrates of enzymes involved in apoptosis, such as caspases and the lymphocyte-derived serine protease Granzyme B. The invention also relates to a process for measuring the activity of caspases and other enzymes involved in apoptosis in living or dead whole cells, cell lines or tissue samples derived from any healthy, diseased, infected or cancerous organ or tissue. The invention also relates to the use of the
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fluorogenic or fluorescent substrates in a novel assay system for discovering or detecting inhibitors or inducers of apoptosis in compound collections or compound libraries. Furthermore, the invention relates to the use of the fluorogenic or fluorescent substrates in determining the sensitivity of cancer cells to treatment with chemotherapeutic drugs. The invention also relates to novel fluorogenic or fluorescent peptide derivatives which are substrates of exopeptidases such as aminopeptidase A and N, methionine aminopeptidase and dipeptidyl-peptidase IV, endopetidases such as calpain, proteases such as HIV proteases, HCMV protease, HSV protease, HCV protease and adenovirus protease. Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-437 (1965); Ellis et al., Dev. 112:591-603 (1991); Vaux et al., Cell 76:777-779 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721). There are a number of morphological changes shared by cells experiencing regulated cell death, including plasma and nuclear membrane blebbing, cell shrinkage (condensation of nucleoplasm and cytoplasm), organelle relocalization and compaction, chromatin condensation and production of apoptotic bodies (membrane enclosed particles containing intracellular material) (Orrenius, S., J. Internal Medicine 23 7:529-536 (1995)). Web site: http://www.delphion.com/details?pn=US06759207__ •
Materials and methods for controlling pests Inventor(s): Cuda; James S. (Gainesville, FL), Long; Lewis S. (Gainesville, FL), Stevens; Bruce Russell (Gainesville, FL) Assignee(s): University of Florida Research Foundation, Inc. (Gainesville, FL) Patent Number: 6,766,613 Date filed: November 16, 2001 Abstract: The present invention provides materials and methods for pest control. The subject invention provides pesticidal compositions that contain one or more compounds that interact with organic solute transporter/ligand-gated ion channel multifunction polypeptides in the pest. Upon exposure to a target pest, these compositions either compromise pest growth and/or cause the death of the pest. In a preferred embodiment, the compositions of the subject invention contain one or more amino acids and/or amino acid analogs. In a particularly preferred embodiment, the methods of the subject invention involve exposing a pest to a composition that comprises methionine or leucine, or an analog thereof. Excerpt(s): A longstanding worldwide demand exists for new, effective, environmentally friendly, and safe means to control pests that damage agriculture or serve as disease vectors. Agriculture costs incurred by pests exceed billions of dollars annually in decreased crop yields, reduced crop quality, increased harvesting costs, pesticide application costs, and negative ecological impact. In addition to agriculture pests, many blood-feeding insects are vectors for pathogenic microorganisms that threaten human and animal health, or are annoying at the least. As in the case of agriculture pests, direct and intangible costs incurred by blood-feeding pests concern
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pesticide safety hazards to humans and animals, bioaccumulation and environmental incompatibility, and synthesis and application costs. Almost all field crops, nursery and horticulture plants, and commercial farming areas are susceptible to attack by one or more pests. Particularly problematic are Coleopteran and Lepidopteran pests. An example of a Lepidopteran pest is the hornworm larva of Manduca sexta, and an example of a Coleopteran pest is the Colorado potato beetle, Leptinotarsa decemlineata. Vegetable and cole crops, lentils, leafy vegetables, melons, peppers, potatoes and related tubers, tomatoes, cucumbers and related vine crops, as well as a variety of spices are sensitive to infestation by one or more pests including loopers, armyworms, moth larvae, budworms, webworms, earworms, leafeaters, borers, cloverworms, melonworms, leafrollers, various caterpillars, fruitworms, hornworms, and pinworms. Likewise, pasture and hay crops such as alfalfa, pasture and forage grasses and silage are often attacked by a variety of pests including armyworms, alfalfa caterpillars, European skipper, a variety of loopers and webworms, as well as yellowstriped armyworms. Fruit (including citrus), nut, and vine crops are susceptible to attack by a variety of pests, including sphinx moth larvae, cutworms, skippers, fireworms, leafrollers, cankerworms, fruitworms, girdlers, webworms, leaffolders, skeletonizers, shuckworms, hornworms, loopers, orangeworms, tortrix, twig borers, casebearers, spanworms, budworms, budmoths, and a variety of caterpillars and armyworms. Web site: http://www.delphion.com/details?pn=US06766613__ •
Methioninase gene therapy for tumor treatment Inventor(s): Tan; Yuying (San Diego, CA), Xu; Mingxu (San Diego, CA) Assignee(s): AntiCancer, Inc. (San Diego, CA) Patent Number: 6,524,571 Date filed: November 18, 1998 Abstract: A depletion method to inhibit tumor growth includes introducing a viral expression system capable of expressing methioninase or a fusion protein containing methioninase into a tumor contained in a vertebrate subject or cells thereof. The fusion protein may contain a fluorescent protein to permit monitoring of the completeness of the depletion method. The fusion protein can be used in vivo as well as in vitro screening protocols which employ the viral expression system. The expression system includes control sequences and means to integrate the nucleotide sequence into the genome of a host cell for expression. The method may also include treating the cells with isolated methioninase and/or with a therapeutic cell. The depletion method can be with other known therapies, such as maintaining the animal having the tumor on a methionine depleted diet. Excerpt(s): The invention relates to protocols for the treatment of tumors. More specifically, the invention concerns insertion of a methioninase gene into tumor cells, optionally in combination with administration of methioninase, methionine deprivation or administration of a chemotherapeutic agent. Various approaches to tumor treatment using gene replacement or other genetic therapy protocols have been suggested and verified in animal models. For example, since it is known that the p53 gene is a tumor suppressor (Harris, C. C., JNCI (1996) 88:1442-1445), the antitumor effects of p53 gene transfer have been explored. Successful results for tumors which contain defective p53 genes have been shown by Roth, J. A., et al., Nat Med (1996) 2:985-991 using retrovirusmediated gene transfer in patients with lung cancer. Adenoviral vectors encoding p53 for gene therapy have been described by Wills, K. N., et al., Hum Gene Ther (1994)
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5:1079-1088. An animal model of malignant human breast cancer in nude mice was shown to respond to adenoviral-mediated delivery of p53 by Lesoon-Wood, L. A., et al., Hum Gene Ther (1995) 6:395-405. Alternatively, the Herpes simplex virus thymidine kinase gene (HSV-tk) in combination with gancyclovir has been shown to inhibit tumor growth in melanoma mode by Vile, R., et al. Cancer Res Dec. 1 (1994); 54(23):6228-34. However, surrounding cells may also be killed using such protocols in a "bystander" effect. Web site: http://www.delphion.com/details?pn=US06524571__ •
Method of preparing ultrathin light-sensitive tabular grain emulsions rich in silver bromide Inventor(s): Elst; Kathy (Kessel, BE), Mans; Ilse (Herenthout, BE) Assignee(s): Agfa-Gevaert (Mortsel, BE) Patent Number: 6,558,892 Date filed: July 11, 2001 Abstract: A method has been described for preparing an ultrathin tabular grain emulsion rich in silver bromide, having {111} major faces, wherein tabular grains having a thickness of less than 0.08.mu.m exhibit an average aspect ratio of more than 5:1 and account for at least 75% by number of hexagonal grains and a coefficient of variation on average equivalent surface area of less than 0.50. The process is characterized in that during formation, (a) pH is maintained from 0.8 to 10; (b) a gelatino-peptizer is present in a concentration of 0 to 50 g per liter of dispersing medium, and (c) pBr having a value of at least 1.8 is maintained during grain nucleation and pBr is maintained at less than 2.4 during growth provided that a gelatin peptizer which is free from calcium ions and has a methionine content of less than 30 micromoles per gram of gelatino-peptizer is present. Excerpt(s): The present invention relates to a method of preparing light-sensitive ultrathin tabular grains rich in silver bromide, having {111} major faces. High aspect ratio tabular grains exhibit several pronounced photographic advantages as is wellknown since their introduction into photographic applications in the eighties. Thanks to their particular morphology greater amounts of spectral sensitizers can be adsorbed per mole of silver halide if compared with classical globular (e.g. cubic or octahedral) grains. As a consequence such spectrally sensitized tabular grains show an improved speedgranularity relationship and a wide separation between their blue speed and minus blue speed. Sharpness of photographic images can be improved using tabular grains thanks to their lower light scattering properties, again if compared with conventionally known globular emulsion grains. In color negative materials e.g. the conventional sequence of the light-sensitive layers can be altered and the yellow filter layer can be omitted. In developed black-and-white images high covering power is obtained even at high hardening levels. Alternatively reduced silver halide coverages can be achieved if desired, which again results in improved sharpness. In duplitized radiographic materials the presence of tabular grains reduces the so-called cross-over which is the main factor for sharpness in such materials. Moreover coating amounts of silver can be reduced, further in favor of production cost and ecology. An emulsion is generally understood to be a "tabular grain emulsion" when tabular grains account for at least 50 percent of total grain projected area. A grain is generally considered to be a tabular grain when the ratio of its equivalent circular diameter to its thickness is at least 2. The
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equivalent circular diameter of a grain is the diameter of a circle having an area equal to the projected area of the grain. Web site: http://www.delphion.com/details?pn=US06558892__ •
Method of producing biologically active human acidic fibroblast growth factor and its use in promoting angiogenesis Inventor(s): Chernykh; Svitlana I. (Kiev, UA), Kordyum; Vitaliy A. (Kiev, UA), Slavchenko; Iryna Yu. (Kiev, UA), Stegmann; Thomas J. (Petersberg, DE), Vozianov; Oleksandr F. (Kiev, UA) Assignee(s): Phage Biotechnology Corporation (Tustin, CA) Patent Number: 6,642,026 Date filed: August 15, 2001 Abstract: The gene of human acidic fibroblast growth factor 155 (haFGF 155) has been obtained by chemical synthesis. The nucleotide sequence of haFGF 155 gene has been deduced on the basis of haFGF 155 amino acid sequence as described in the literature. The amino acid sequence of the synthesized haFGF 155 does not differ from those described in the literature. The nucleotide sequence of haFGF gene differs from those described previously. For chemical synthesis of haFGF 155 gene, codons were used which are the ones most often used by E. coli in highly expressed E. coli proteins. A plasmid with haPGF 155 (phaFGF 155) gene was obtained and was used to transform E. coli. Production of haFGF 154 protein was achieved by cultivation of the producer strain under conditions which slow down the lytic development of lambda phage. The haFGF 154 protein accumulated in culture medium in a soluble condition as a result of the producer strain cells lysis by the lambda phage. The haFGF 154 protein constituted 20% of the soluble protein accumulated in the culture medium and its biological activity was demonstrated by its ability to generate new vessels (angiogenesis). The initiator methionine residue at position 1 of the FGF 155 protein was completely removed during protein synthesis resulting in an FGF 154 amino acid product. The use of the phage-dependent method to produce other forms of the haFGF protein is also disclosed. Excerpt(s): The field of the invention relates to methods of producing a recombinant fibroblast growth factor protein and its use in promoting angiogenesis. Fibroblast growth factors (FGF) are nine structurally related polypeptides, which are potent regulators of cell proliferation, differentiation and normal development. They also take part in pathological processes of tumorogenesis and metastasis (Galzie, et al. Biochem. Cell Biol. (1997) 75: 669-685). They are potent mitogens and differentiation factors for a broad range of mesoderm and neuroectoderm derived cells, including endothelial cells. The heparin proteoglycans, heparin or heparin sulfate, bind several FGF molecules together as a complex which are presented to the FGF receptors. FGF proteins bind to their receptors resulting in the activation of protein tyrosine kinases. The phosphorylation of these tyrosine kinases initiates multiple signals including the transcription of new mRNA's. Web site: http://www.delphion.com/details?pn=US06642026__
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Methods and compositions for a gender specific diet for puppies Inventor(s): Bebiak; David M. (Villa Ridge, MO), Kealy; Richard D. (Waterloo, IL) Assignee(s): Nestec, LTD (Vevey, CH) Patent Number: 6,582,752 Date filed: November 2, 2001 Abstract: A gender specific food for puppies is disclosed where the food includes at least about 0.25% methionine by weight and at least about 0.45% total sulfur amino acids. The food further includes a total dietary lipid level based on gender, and for maximizing body weight and length gains, lipid levels and the amounts of methionine are adjusted based upon the gender of the puppy. Excerpt(s): This invention relates generally to food products for pets, and, more particularly, to compositions relating to a gender specific diet for puppies. While pet care product customers presently have a host of suppliers and products to choose from, it may take significant time, effort, and investigation to determine a product that best suits a particular pet's needs among the available alternatives. This is particularly true in the case of pet foods. While veterinarians and other professionals may assist in recommending a given brand of pet food for a particular pet, pet foods are typically mass manufactured to meet the needs of an average pet within a selected range of pets that is typically based on pet age and/or size. Nutritional needs, however, vary from pet to pet, and an optimal regimen of appropriate nutrients for a particular pet or breed of pet would be beneficial. Nutritional requirements for young pets, such as puppies are especially important as the nutritional intake of a puppy will determine such things as health, size, and appearance as the puppy becomes an adult dog and matures into an older dog. In one aspect, a gender specific food for puppies is provided which comprises at least about 0.25% methionine, at least about 0.45% total sulfur amino acids, and a total dietary lipid level based on gender. Web site: http://www.delphion.com/details?pn=US06582752__
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Methods for identifying inhibitors of methionine aminopeptidases Inventor(s): Chang; Yie-Hwa (St. Louis, MO) Assignee(s): Saint Louis University (Saint Louis, MO) Patent Number: 6,593,454 Date filed: May 24, 2001 Abstract: Methods are provided for detecting methionine aminopeptidase (MAP) activity and for detecting inhibitors of MAP. The methods utilize a peptide comprising an N-terminal methionine which can be cleaved from the peptide by MAP, and a Cterminal detection moiety which is released by a second peptidase only if the N-terminal methionine has been cleaved from the peptide. When the peptide is combined with MAP and the second peptidase, the detection moiety is released, while the addition of a MAP inhibitor will inhibit the release of the detection moiety. Reaction mixes, peptides, and kits which are useful for practicing the methods are also provided. Excerpt(s): The present invention generally relates to assays for enzyme activity and for enzyme inhibitors. More specifically, the invention relates to assays for detecting methionine aminopeptidases and inhibitors of methionine aminopeptidases. In all living cells, protein synthesis is initiated with an AUG codon, specifying methionine as
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the N-terminal amino acid in nascent proteins. In both prokaryotes and eukaryotes, this N-terminal methionine will be removed by a methionine aminopeptidase (MAP) (EC 3.4.11.18) if the penultimate amino acid residue is small and uncharged, e.g., Gly, Ala, Ser, Cys, Thr, Pro, and Val, although methionine cleavage activity by MA is reduced when the N-terminal three amino acids are Met-Thr-Pro or Met-Val-Pro (Moerschell et al., 1990, J. Biol. Chem. 265, 19638-19643; Tsunasawa et al., 1985, J. Biol. Chem. 260, 53825391). Removal of the N-terminal methionine is essential for certain proteins to function normally in vivo. For example, the removal of the initiator methionine is often required for subsequent N-terminal modifications, such as N-myristoylation, which is essential for the normal function of various signal transduction proteins, cancer cells, protein targeting moieties, and enzymes (Gordon et al., 1991, J. Biol. Chem. 266, 8647-8650; Duronio et al., 1989, Science 243, 796-800). Methionine aminopeptidases have been isolated and cloned from several organisms, including E. coli and several other eubacteria, yeast, rat, and various archaea. Currently discovered MAPs have been categorized into two types, type 1 MAP and type 2 MAP, based on structural and sequence similarities. Eubacteria have type 1, archaea have type 2, and eukaryotes have both types. In eukaryotes, null mutants in either type are viable but slow growing, but null mutants of both MAP types are nonviable (Li and Chang, 1995, Proc. Natl. Acad. Sci. USA 92, 12357-12361; Li and Chang, 1996, Biochem. Biophys. Res. Commun. 227, 152-159; Bradshaw et al., 1998, Trends Biochem. Sci. 21, 285-286). Similarly, knockouts of the bacterial MAP1 gene are lethal (Ben-Bassat et al., 1987, H. Bacteriol. 169, 751-757). Thus, MAP activity is essential for normal functioning of prokaryotic and eukaryotic cells. Web site: http://www.delphion.com/details?pn=US06593454__ •
Methods of treating asthma with interleukin-9 receptor antibodies Inventor(s): Kari; U. Prasad (Hatfield, PA), Levitt; Roy Clifford (Ambler, PA), Maloy; W. Lee (Lansdale, PA), Nicolaides; Nicholas C. (Media, PA) Assignee(s): Genaera Corporation (Plymouth Meeting, PA) Patent Number: 6,645,492 Date filed: May 4, 2001 Abstract: A C to T DNA variation at position 3365 in exon 5 of the human Asthma Associated Factor 1 (AAF1) produces the predicted amino acid substitution of a methionine for a threonine at codon 117 of AAF1. When this substitution occurs in both alleles in one individual, it is associated with less evidence of atopic allergy including asthma, fewer abnormal skin test responses, and a lower serum total IgE. Thus, applicant has identified the existence of a non-asthmatic, non-atopic phenotype characterized by methionine at codon 117 when it occurs in both AAF1 gene products in one individual. Excerpt(s): This invention relates to regulating IL-9 activity and treating atopic allergies and related disorders like asthma, based upon the relationship between IL-9 and its receptor. Inflammation is a complex process in which the body's defense system combats foreign entities. While the battle against foreign entities may be necessary for the body's survival, some defense systems improperly respond to foreign entities, even innocuous ones, as dangerous and thereby damage surrounding tissue in the ensuing battle. Atopic allergy is an ecogenetic disorder, where genetic background dictates the response to environmental stimuli. The disorder is generally characterized by an increased ability of lymphocytes to produce IgE antibodies in response to ubiquitous
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antigens. Activation of the immune system by these antigens leads to allergic inflammation and may occur after ingestion, penetration through the skin, or after inhalation. When this immune activation occurs and pulmonary inflammation ensues this disorder is broadly characterized as asthma. Certain cells are critical to this inflammatory reaction and they include T cells and antigen presenting cells, B cells that produce IgE, and mast cells/basophils and eosinophils that bind IgE. These inflammatory cells accumulate at the site of allergic inflammation and the toxic products they release contribute to the tissue destruction related to the disorder. Web site: http://www.delphion.com/details?pn=US06645492__ •
Modulators of methylation for control of bacterial virulence Inventor(s): Han; Quinghong (San Diego, CA), Tan; Yuying (San Diego, CA), Xu; Mingxu (San Diego, CA) Assignee(s): AntiCancer, Inc. (San Diego, CA) Patent Number: 6,632,430 Date filed: December 30, 2002 Abstract: Compositions and methods which ameliorate the virulence of bacterial infection are described wherein the active ingredient modulates transmethylation reactions in bacterial cells. Particularly useful compounds are inhibitors of S-adenosyl methionine synthetase (SAMS), of S-adenosyl homocysteine hydrolase (SAHH) and of transmethylases. Excerpt(s): The invention relates to the control of bacterial infection in animals. More particularly, it relates to the use of inhibitors of bacterial transmethylation pathways to control such infection. The importance of transmethylation reactions in metabolism in general has gained considerable recognition. PCT application WO96/20010 and U.S. Pat. No. 5,872,104, incorporated herein by reference, describe the use of methylation inhibitors to reduce the resistance of microorganisms to antibiotics. Heithoff, D. M., et al,. Science (1999) 284:967-970 report the results of a study showing that Salmonella typhimurium which lacks DNA adenine methylase (Dam) were essentially avirulent and therefore could be used as live vaccines against murine typhoid fever. The authors concluded that Dam regulated the expression of at least 20 genes known to be induced during infection and noted that inhibitors of Dam were likely to be antimicrobials. It was earlier shown by Braaten, B. A., et al,. Cell (1994) 76:577-588 that the methylation patterns associated with pyelonephritis-associated pili (Pap) DNA controlled gene expression in E. coli. Thus, it is clear that in bacteria, methylation status is significant in controlling metabolism, and thus infectivity in general. The importance of S-adenosyl-Lmethionine (SAM) dependent transmethylation in viral infection has also been studied by Liu, S., et al., Antiviral Research (1992) 19:247-265. S-adenosyl-homocysteine hydrolase (SAHH) is significantly related to transmethylation by virtue of its ability to regulate the ratio of SAM to S-adenosylhomocysteine (SAH). SAHH catalyzes the equilibrium between SAH and its lysis products, adenosine and homocysteine. It is significant in regulating the levels of adenosine as well. SAHH has been used as a target for antiparasitic and antiviral chemotherapy as described by Minatto, et al,. Experimental Parasitol (1998) 175-180. SAM is the source of methyl groups for all transmethylation reactions and SAH constitutes a methylation inhibitor. Thus, if SAHH which controls the ratio of SAM to SAH is inhibited, this will result in modulating the transmethylation metabolism of the bacterium, and consequently, the virulence of the bacterium. Methylation processes are also affected by methionine levels, and agents
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that deplete methionine, such as methionine-.alpha.,.gamma.-lyase (methioninase) are effective to modulate methylation status as well. Web site: http://www.delphion.com/details?pn=US06632430__ •
Mutant.alpha.-amylases Inventor(s): Araki; Hiroyuki (Tochigi, JP), Hagihara; Hiroshi (Tochigi, JP), Hatada; Yuji (Tochigi, JP), Hayashi; Yasuhiro (Tochigi, JP), Igarashi; Kazuaki (Tochigi, JP), Ikawa; Kaori (Tochigi, JP), Ito; Susumu (Tochigi, JP), Ozaki; Katsuya (Tochigi, JP) Assignee(s): Kao Corporation (Tokyo, JP) Patent Number: 6,486,113 Date filed: September 23, 1999 Abstract: The invention relates to a mutant.alpha.-amylase having an amino acid sequence obtained by making deletion or replacement by another arbitrary amino acid residue of at least a methionine residue at the 202-position or a position homologous thereto among amino acid residues set forth in SEQ ID NO:1, which constitute a liquefying alkaline.alpha.-amylase, a gene thereof, and a detergent composition comprising the mutant.alpha.-amylase. The mutant.alpha.-amylase has the optimum pH in an alkaline range, an excellent.alpha.-amylase activity, and high and lasting resistance to oxidizing agents, and is hence particularly useful as a component of detergent compositions containing a bleaching agent and an oxidizing agent. Excerpt(s): The present invention relates to mutant liquefying.alpha.-amylases which have the optimum pH in an alkaline range and excellent resistance to oxidizing agents and are particularly useful as enzymes for detergents comprising an oxidizing agent, and genes thereof. Various enzymes are incorporated into detergents for the purpose of enhancing detergency, and it is considered to incorporate an.alpha.-amylase against, for example, starch smears. However, the.alpha.-amylase incorporated into a detergent must be an alkaline.alpha.-amylase, since the detergent comprises a surfactant, and the pH of a detergent solution is in an alkaline range. By the way, detergents, in which an oxidation bleaching component is incorporated to expect not only detergency against dirt, but also a bleaching action, have been recently marketed. It is considered that the.alpha.-amylase is also incorporated into such an oxidation bleaching agentcontaining detergent. However, the usual.alpha.-amylase is easy to inactivate in the presence of an oxidizing agent and has hence been unable to be incorporated into the oxidation bleaching agent-containing detergent. Web site: http://www.delphion.com/details?pn=US06486113__
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Mutant form of a cytotoxic ribonucleolytic protein which allows production by recombinant methods Inventor(s): Ardelt; Wojciech (New City, NY), Boix; Ester (Barcelona, ES), Vasandani; Veena M. (Rockville, MD), Wu; Yon-Neng (Bethesda, MD), Youle; Richard J. (Bethesda, MD) Assignee(s): The United States of America as represented by the Department of Health and (Washington, DC) Patent Number: 6,649,392 Date filed: April 4, 1996 Abstract: The present invention provides recombinant Onc (rOnc) compositions and methods. Recombinant Onc proteins of the invention have an amino terminal methionine and comprise an Onc polypeptide. The amino terminal methionine of the protein allows for recombinant production in a bacterial host cell. Cleaving the amino terminal methionine exposes the amino terminal glutamine of the polypeptide. The Onc polypeptide has an amino terminal glutamine. Cyclization of the amino terminal glutamine of the polypeptide to a pyroglutamyl residue provides rOnc polypeptides and proteins have anti-cancer and anti-viral activity. Excerpt(s): The invention relates to methods and compositions for the recombinant production of Onc, a cytotoxic ribonucleolytic protein having anti-tumor and anti-viral properties. In particular, the invention relates to a recombinant Onc protein having an amino terminal methionine and comprising an Onc polypeptide. Unfortunately, since Onc is isolated from oocytes, procurement of an adequate supply is uncertain. Recent concerns regarding the availability of the anti-cancer compound taxol illustrate some of the problems of obtaining natural products for use as pharmaceuticals. Similarly, availability of Onc is increasingly problematic in light of the declining population of R. pipiens and the seasonal variation in the supply of its oocytes. Accordingly, what is needed in the art is a means to produce Onc by recombinant methods so as to meet demand for this therapeutic and alleviate the impact on its native source. Further, what is needed is a means to derivatize and alter the sequence of Onc to provide more efficacious compounds. Quite surprisingly, the present invention provides these and other advantages. Web site: http://www.delphion.com/details?pn=US06649392__
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Nutritional composition containing methionine Inventor(s): Hageman; Robert Johan Joseph (Waddinxveen, NL) Assignee(s): N. V. Nutricia (Zoetermeer, NL) Patent Number: 6,544,547 Date filed: January 31, 2000 Abstract: An enteral food composition for clinical or dietary use, comprises, in addition to carbohydrates and proteins or their hydrolysates the following components or their nutritional equivalents, per daily dosage: methionine (0.6-7 g), cysteine (0.5-2.5 g), folic acid (0.4-8 mg), pyridoxal (vitamin B.sub.6) (3-20 mg), zinc (18-120 mg) and at least 400 kcal energy in the form of carbohydrates. These amounts are well above the Recommended Daily Allowance (RDA) values. Further preferred components include
Patents 167
lecithin, cyanocobalamine, betaine and magnesium, as well as transsulfuration metabolites, ATP enhancers and antioxidants. Excerpt(s): The present invention relates to a module of nutritional components which supports total methionine metabolism in man, for use in a universal medicinal food. The invention also relates to food products containing this module and to a method of producing food products by using selected amounts of the module. Methionine is metabolised in man via a multi-step pathway, the transsulfuration pathway. Several intermediate products are formed in this pathway, which play a dominant role in other biochemical pathways as well. For example, the reaction product S-adenosyl methionine is extensively used in many methylation reactions; homocysteine is the main methyl acceptor in folate metabolism and also the conversion of betaine to dimethylglycine (via methylation of homocysteine) strongly influences folate metabolism. Another intermediate in the transsulfuration pathway is cystathionine generated by reaction between homocysteine and serine, that may split into cysteine and 2-oxy-butyrate. The latter is involved in the metabolism of several other compounds (e.g. threonine). Cysteine is metabolised to various useful products such as taurine and sulphates. It is also an important precursor for glutathione in the liver and some other tissues. Glutathione that is produced in the liver has to be transported to cell compartments in some peripheral organs in order to exhibit its activity. Intracellular glutathione levels are in turn strongly influenced by the presence of reducing equivalents and amino acids in the cell. Web site: http://www.delphion.com/details?pn=US06544547__ •
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
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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 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 eliminating N-terminal methionine Inventor(s): Asano; Tsuneo (Hyogo, JP), Nishimura; Osamu (Ibaraki, JP), Ohmae; Hiroaki (Nara, JP), Okutani; Norio (Hyogo, JP), Suenaga; Masato (Hyogo, JP) Assignee(s): Takeda Chemical Industries, Ltd. (Osaka, JP) Patent Number: 6,774,221 Date filed: May 7, 2001 Abstract: A method for removing from a peptide the diketone of the methionine residue, and a method for manufacturing a peptide or salt thereof which does not possess an N-terminal methionine residue, characterized by having a peptide or salt thereof which possesses a diketone of the optionally oxidized N-terminal methionine residue react with 3,4-diaminobenzoic acid or a salt thereof in the presence of acetic acid and sodium formate, formic acid and sodium formate, or formic acid and sodium acetate. Excerpt(s): This invention relates to a method for the efficient removal, from peptides (including proteins) or salts thereof which possess an optionally oxidized N-terminal methionine residue or diketone of said methionine residue, of the N-terminal methionine residue or the diketone of said methionine residue, in the presence of acetic acid and sodium formate, formic acid and sodium formate, or formic acid and sodium acetate; and to a method for manufacturing peptides or salts thereof which do not possess an optionally oxidized N-terminal methionine residue or diketone of said methionine residue. When protein is biosynthesized within a cell, its N-terminal is known to start with methionine, which corresponds to the initiation codon AUG of the mRNA. However, as this methionine is removed by subsequent processing, it is usually no longer present in the completed mature protein molecule. With advancements in recombinant DNA techniques, it has become possible to produce useful proteins using microorganisms and/or animal cells, for example Escherichia coli. There have been instances wherein protein produced via this type of method was found to retain a residue comprised of the aforementioned methionine. For example, the retention rate of methionine was as high as approximately 100% in human growth hormone expressed in E. coli [Nature, 293, 408 (1981)], and 50% in interferon-.alpha. [J. Interferon Res., 1, 381 (1981)], while in nonglycosylated human interleukin-2 the presence of a molecular
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species with methionine retention on the amino-terminal (N-terminal methionine residue) (Met-rIL-2) has been noted in addition to the molecular species rIL-2 which, like naturally-occurring human interleukin-2, is initiated with alanine. Web site: http://www.delphion.com/details?pn=US06774221__ •
Process for the production of methionine Inventor(s): Gros; Georges (Antony, FR), Laval; Phillippe (Paris, FR), Ponceblanc; Herve (Villerubanne, FR), Rossi; Jean-Christophe (Villeneuve les Maguelone, FR) Assignee(s): Aventis Animal Nutrition, SA (Antony, FR) Patent Number: 6,545,179 Date filed: February 13, 2001 Abstract: A process for the production of methionine which comprises (a) hydrolysing the methionine amide in the presence of a catalyst comprising titanium to produce ammonium methioninate, said catalyst having a porosity of from 5 to 1000 nm, a total pore volume of from 0.2 to 0.55 cm.sup.3 /g and a surface area of from 30 to 150 m.sup.2 /g, and (b) a second step of recuperating methionine from the ammonium methioninate salt by removing ammonia. Also claimed is an industrial process for the production of methionine incorporating the aforementioned hydrolysis. Excerpt(s): The hydrolysis of the methionine amide to produce the methionine is a known process. In particular, European Patent Application No228938 discloses a process for the production of methionine by the hydrolysis of the methionine amide using a strong base. A problem with this process is that the acidification step uses a strong acid which results in the co-production of mineral salts such as carbonates, chlorides or sulphates. An additional purification step is generally required to remove the salt. French Patent Application No. 9814000 attempts to overcome the aforementioned problem through the use of a titanium catalyst in the hydrolysis reaction. The use of a titanium based catalyst is also disclosed in Japanese patent applications 03093753, 03093754, 03093755, 03093756. We have now found that methionine can be produced in high yields using a specific titanium catalyst. Accordingly, the present invention provides a process for the production of methionine which comprises (a) hydrolysing methionine amide in the presence of a catalyst comprising titanium to produce ammonium methioninate, said catalyst having a porosity of from 5 to 1000 nm, a total pore volume of from 0.2 to 0.55 cm.sup.3 /g and a surface area of from 30 to 150 m.sup.2 /g, and (b) a second step of recuperating methionine from the ammonium methioninate salt by removing ammonia. Web site: http://www.delphion.com/details?pn=US06545179__
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S-adenosyl methionine regulation of metabolic pathways and its use in diagnosis and therapy Inventor(s): O'Day; Christine L. (Mountlake Terrace, WA), Schwartz; Dennis E. (Redmond, WA), Vermeulen; Nicolaas M. J. (Woodinville, WA) Assignee(s): MediQuest Therapeutics, Inc. (Seattle, WA) Patent Number: 6,596,701 Date filed: March 16, 1998
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Abstract: A new paradigm of disease centers around the metabolic pathways of Sadenosyl-L-methionine (SAM), the intermediates of these pathways and other metabolic pathways influenced by the SAM pathways. Methods are provided to analyze and modulate SAM pathways associated with a disease or condition. Such methods permit identification and utilization of diagnostic and therapeutic protocols and agents for such disease states and conditions. Excerpt(s): The invention relates to a new paradigm of disease centering around the metabolic pathways of S-adenosyl-L-methionine (SAM), the intermediates of these pathways and other metabolic pathways influenced by the SAM pathways. Specifically, the invention relates to analyzing and regulating SAM pathways that exist in association with a disease or condition including cancer and a number of diseases or conditions connected with degeneration and aging. More specifically, the invention concerns designing analytical, diagnostic and therapeutic protocols and agents for such disease states and conditions through recognition of the central role of SAM and its metabolic pathways in controlling cell metabolism, cell growth and intercellular communication. It is commonly believed that an understanding of cellular metabolism and function, as well as the nature of biological degeneration and the creation of disease conditions, can be achieved by ascertaining the genetic information contained in eukaryotic cells and understanding how this genetic information is transcribed and translated into proteins which then control chemical conversions within the cell. The present conceptual frame work considers DNA as the core of life. Within this framework, the function of proteins is commonly assumed to be regulated in large part by phosphorylation and dephosphorylation of relevant proteins at appropriate times. The present invention was made in response to the absence of a greater unifying relationship between small molecule biochemistry and the macromolecules RNA, DNA and protein. Present-day molecular biology is focused completely on macromolecules and has provided essentially no connection with the small molecules which carry out the chemical reactions of life. In fact, the study of small molecules in the biological and biochemical sciences has not been in vogue for the last 20 years. Web site: http://www.delphion.com/details?pn=US06596701__ •
Type 2 methionine aminopeptidase (MetAP2) inhibitors and uses thereof Inventor(s): Griffith; Eric C. (Somerville, MA), Liu; Jun O. (Cambridge, MA), Su; Zhuang (Cambridge, MA) Assignee(s): Massachusetts Institute of Technology (Cambridge, MA) Patent Number: 6,566,541 Date filed: March 21, 2001 Abstract: Novel compounds that are anti-angiogenic or immunosuppressive are described. Also described are methods for determining if an animal is at risk for a disease involving abnormal angiogenesis or an immune reaction resulting in pathology comprising evaluating an aspect of MetAP2 metabolism or structure; methods for identifying agents that are anti-angiogenic or immunosuppressive comprising evaluating the effect of the agent on an aspect of MetAP2 metabolism; methods for treating a cell having an abnormality in metabolism or structure of MetAP2; and methods for treating abnormal angiogenesis or an immune reaction which results in pathology in an animal. Pharmaceutical compositions are also provided.
Patents 171
Excerpt(s): This invention relates to agents which inhibit type 2 methionine aminopeptidase (MetAP2), including novel ovalicin and fumagillin derivatives, and to the identification and use of such agents for treating and diagnosing diseases involving abnormal angiogenesis or immune reactions which result in pathology. Angiogenesis is the process of new blood vessel formation. It has been shown to play a pivotal role in certain normal physiological reactions, e.g., wound healing, corpus luteum formation and embryonic development. It has also been reported to play a pivotal role in a variety of pathological conditions, e.g., tumors, diabetic retinopathy, inflammatory diseases and arteriosclerosis. For example, it has been reported that without access to sufficient vasculature, tumor growth is restrained as a result of widespread cell death. Further, while immune reactions are required to protect animals from deleterious foreign antigens, certain immune reactions can result in pathological conditions, e.g., autoimmune diseases, allergies or tissue graft rejection. Web site: http://www.delphion.com/details?pn=US06566541__
Patent Applications on Methionine 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 methionine: •
Anti-microbial agents derived from methionine sulfoximine analogues Inventor(s): Griffith, Owen W.; (Milwaukee, WI), Harth, Gunter; (Los Angeles, CA), Horwitz, Marcus; (Los Angeles, CA) Correspondence: Stradling Yocco Carlson & Rauth; Suite 1600; 660 Newport Center Drive; P.O. Box 7680; Newport Beach; CA; 92660; US Patent Application Number: 20040157802 Date filed: November 17, 2003 Abstract: Novel antimicrobial compositions containing analogues of L-methionine-SRsulfoximine (MSO) that are effective in treating intracellular pathogen infections are provided. Specifically, the compostions provided are MSO analogues having superior antimicrobial activity with significantly less toxicity as compared to MSO. These MSO analogues are suitable for use in treating infection in animals including primates, cows, pigs, horses, rabbits, mice, rats, cats, and dogs. Moreover, the MSO analogues are ideally suited for treating infections caused by the genus Mycobacterium. Additionally, methods for using the novel MSO analogues are also provided. Excerpt(s): The present application claims priority to U.S. provisional patent application serial No. 60/426,502 filed Nov. 15, 2002, now abandoned and 60/430,407 filed Dec. 2, 2002, now abandoned both of which are incorporated herein in their entirety by reference. The present invention relates to anti-microbial agents useful in treating intracellular pathogen infections in animals. Specifically, the present invention relates to methionine sulfoximine (MSO) analogues and structurally similar compounds useful in treating intracellular pathogen infections. More specifically, the present invention relates to MSO analogues and structurally similar compounds useful in treating infections in
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This has been a common practice outside the United States prior to December 2000.
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animals caused by the genus Mycobacterium. Reference to numerous articles and publications are made through the text. For convenience, each reference is cited using numerical notations enclosed in parentheses. These numerical notations correspond to the complete citation found in the Literature Cited list immediately preceding the Claims. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Assay for nitrous oxide neurologic syndrome Inventor(s): Hogan, Kirk J.; (Madison, WI), Selzer, Rebecca M.R.; (Verona, WI) Correspondence: Quarles & Brady Llp; 411 E. Wisconsin Avenue, Suite 2040; Milwaukee; WI; 53202-4497; US Patent Application Number: 20030198985 Date filed: February 24, 2003 Abstract: A method for detection of susceptibility to nitrous oxide neurologic syndrome in a subject is disclosed. In one embodiment, the method comprises: (a) providing a sample from a subject, wherein said subject is a candidate for nitrous oxide anesthesia; and (b) detecting the presence or absence of folate, cobalamin, methionine and homocysteine pathway genetic polymorphisms in said sample, wherein the presence of a polymorphism indicates that the subject is susceptible to nitrous oxide neurologic syndrome. Excerpt(s): The present invention claims priority to U.S. Serial No. 60/358,781, incorporated by reference herein. 5,10-methylene tetrahydrofolate reductase (MTHFR) regulates the synthesis of 5-methyl tetrahydrofolate, the primary circulatory form of folate which acts as the methyl donor to methionine. Homocysteine is a sulphur amino acid formed by demethylation of the essential amino acid methionine. A methyltransferase enzyme known as methionine synthase (MTR) is responsible for converting homocysteine back to methionine, the body's sole methyl donor. Among many other reactions, methyl moieties are crucial for the synthesis of neurotransmitters, assembly of the myelin sheath, and DNA synthesis in proliferating tissues such as bone marrow and the developing brain. Genetic defects that cause deficiencies in either MTR or MTHFR are associated with high serum homocysteine levels and homocystinurea. Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B.sub.12, and thus inhibits the activity of the cobalamin-dependent enzyme MTR. Over twenty-four rare mutations in MTHFR have been described as associated with pronounced enzymatic deficiency and homocystinuria. In addition, two common single nucleotide polymorphisms have been identified that affect folate and homocysteine metabolism, both of which are implicated in the pathogenesis of cardiovascular disease, neural tube defects and developmental delay. One polymorphism is a missense mutation consisting of a C.fwdarw.T transition at position 677, which produces an alanine to valine amino acid substitution within the catalytic domain of MTHFR. The resulting enzyme has reduced catalytic activity. The second mutation is found at position 1298, an A.fwdarw.C transition which results in a glutamate to alanine substitution located in the presumed regulatory domain of MTHFR. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Asthma associated factors as targets for treating atopic allergies including asthma and related disorders Inventor(s): Kari, U. Prasad; (Hatfield, PA), Levitt, Roy Clifford; (Ambler, PA), Maloy, W. Lee; (Lansdale, PA), Nicolaides, Nicholas C.; (Media, PA) Correspondence: Morgan Lewis & Bockius Llp; 1111 Pennsylvania Avenue NW; Washington; DC; 20004; US Patent Application Number: 20040076607 Date filed: August 18, 2003 Abstract: A C to T DNA variation at position 3365 in exon 5 of the human Asthma Associated Factor 1 (AAF1) produces the predicted amino acid substitution of a methionine for a threonine at codon 117 of AAF1. When this substitution occurs in both alleles in one individual, it is associated with less evidence of atopic allergy including asthma, fewer abnormal skin test responses, and a lower serum total IgE. Thus, applicant has identified the existence of a non-asthmatic, non-atopic phenotype characterized by methionine at codon 117 when it occurs in both AAF1 gene products in one individual. Excerpt(s): This application is related to U.S. Provisional Application Serial No. 60/002,765 which was filed Aug. 24, 1995. This invention relates to regulating IL-9 activity and treating atopic allergies and related disorders like asthma, based upon the relationship between IL-9 and its receptor. Inflammation is a complex process in which the body's defense system combats foreign entities. While the battle against foreign entities may be necessary for the body's survival, some defense systems improperly respond to foreign entities, even innocuous ones, as dangerous and thereby damage surrounding tissue in the ensuing battle. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Catalytic antioxidants and methods of use Inventor(s): Brot, Nathan; (West Orange, NJ), Weissbach, Herbert; (Boynton Beach, FL) Correspondence: Stanley A. Kim, PH.D., ESQ.; Akerman Senterfitt; Suite 400; 222 Lakeview Avenue; West Palm Beach; FL; 33401-6183; US Patent Application Number: 20040143016 Date filed: November 26, 2003 Abstract: The invention provides small molecules that act as catalytic antioxidants and methods of use thereof. The compounds can repeatedly bind and destroy reactive oxygen species by serving as substates for enzymes of the methionine sulfoxide reductase (Msr) class. Some embodiments of the catalytic antioxidant compounds are derived from drugs with anti-inflammatory activity due to inhibition of cyclooxygenase enzymes. Excerpt(s): The present application claims the priority of U.S. provisional patent application No. 60/429,269 filed on Nov. 26, 2002. Not applicable. The invention relates to the fields of biochemistry, pharmacology, and medicine. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compounds and methods Inventor(s): Kallander, Lara S.; (King of Prussia, PA), Thompson, Scott; (King of Prussia, PA) Correspondence: Smithkline Beecham Corporation; Corporate Intellectual Property-Us, Uw2220; P. O. Box 1539; King OF Prussia; PA; 19406-0939; US Patent Application Number: 20030220371 Date filed: October 10, 2002 Abstract: Compounds of this invention are non-peptide, reversible inhibitors of type 2 methionine aminopeptidase, useful in treating conditions mediated by angiogenesis, such as cancer, haemangioma, proliferative retinophathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity. Excerpt(s): Compounds of this invention are non-peptide, reversible inhibitors of type 2 methionine aminopeptidase, useful in treating conditions mediated by angiogenesis, such as cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity. In 1974, Folkman proposed that for tumors to grow beyond a critical size and to spread to form metastases, they must recruit endothelial cells from the surrounding stroma to form their own endogenous microcirculation in a process termed angiogenesis (Folkman J. (1974) Adv Cancer Res. 19; 331). The new blood vessels induced by tumor cells as their life-line of oxygen and nutrients also provide exits for cancer cells to spread to other parts of the body. Inhibition of this process has been shown to effectively stop the proliferation and metastasis of solid tumors. A drug that specifically inhibits this process is known as an angiogenesis inhibitor. Having emerged as a promising new strategy for the treatment of cancer, the anti-angiogenesis therapy ("indirect attack") has several advantages over the "direct attack" strategies. All the "direct attack" approaches such as using DNA damaging drugs, antimetabolites, attacking the RAS pathway, restoring p53, activating death programs, using aggressive T-cells, injecting monoclonal antibodies and inhibiting telomerase, etc., inevitably result in the selection of resistant tumor cells. Targeting the endothelial compartment of tumors as in the "indirect attack", however, should avoid the resistance problem because endothelial cells do not exhibit the same degree of genomic instability as tumor cells. Moreover, anti-angiogenic therapy generally has low toxicity due to the fact that normal endothelial cells are relatively quiescent in the body and exhibit an extremely long turnover. Finally since the "indirect attack" and "direct attack" target different cell types, there is a great potential for a more effective combination therapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Expression and secretion vector for human interferon alpha and process for producing human interferon alpha by employing same Inventor(s): Bae, Sung-Min; (Seoul, KR), Choi, Ki-Doo; (Seoul, KR), Jung, Sung-Youb; (Seoul, KR), Kim, Cha-Soon; (Yongin-Shi, Gyonggi-do, KR), Kwon, Se-Chang Chang; (Seoul, KR), Lee, Gwan-Sun; (Seoul, KR) Correspondence: Anderson Kill & Olick; 1251 Avenue OF The Americas; New York; NY; 10020-1182; US Patent Application Number: 20040151695 Date filed: July 18, 2002
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Abstract: Disclosed in this invention are: an expression vector for the secretive production of human interferon alpha (hIFN.alpha.) comprising a polynucleotide encoding a modified E. coli thermostable enterotoxin II signal sequence and a polynucleotide encoding hIFN.alpha.) ligated to the 3'-end thereof; a microorganism transformed with the expression vector, and a process for secretively producing human interferon by culturing the microorganism, said process being capable of secreting a soluble form of active hIFN.alpha.), which does not contain an additional methionine residue at its N-terminal, into the periplasm of an E coli cell. Excerpt(s): The present invention relates to an expression vector for the secretive production of human interferon alpha (hIFN.alpha.) comprising a polynucleotide encoding a modified E.coli thermostable enterotoxin II signal sequence and a polynucleotide encoding hIFN.alpha. ligated to the 3'-end thereof; a microorganism transformed with the expression vector; and a process for secretively producing hIFN.alpha. having no methionine residue added at its N-terminal in the periplasm of E.coli cell. Isaacs and Lindenmann reported in 1957 that when chicken is infected with influenza virus A, a viral replication inhibitory factor designated interferon is produced (Isaacs, K and Lindenmann, J. Proc. R. Soc. Lond., B147:258-267, 1957). Human interferons are cytokine proteins which inhibit in vivo immune response or viral replication and they are classified as interferon alpha (IFN.alpha.), interferon beta (IFN.beta.) and interferon gamma (IFN.gamma.) according to cell types producing them (Kirchner, H. et al., Tex. Rep. Biol. Med., 41:89-93, 1981; Stanton, G. J. et al., Tex. Rep. Biol. Med., 41:84-88, 1981). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
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
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(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 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 •
Human methionine aminopeptidase type 3 Inventor(s): Aurora, Rajeev; (Glencoe, MO), Dotson, Stanton B.; (Chesterfield, MO), Frazier, Ronald B.; (Lake St. Louis, MO), Sympson, Carolyn J.; (Ballwin, MO), Woods, Cynthia L.; (St. Peters, MO), Zakeri, Hamideh; (Chesterfield, MO), Zhou, Xianzhi; (Chesterfield, MO) Correspondence: Pharmacia Corporation; Global Patent Department; Post Office Box 1027; ST. Louis; MO; 63006; US Patent Application Number: 20030203406 Date filed: November 19, 2002 Excerpt(s): The present application is a continuation-in-part of U.S. application Ser. No. 09/523,263, filed Mar. 10, 2000, pending, which claims priority under Title 35, United States Code.sctn.119, to U.S. Provisional Application Serial No. 60/125,139, filed Mar. 11, 1999. Methionine aminopeptidases catalyse the co-translational removal of amino terminal methionine residues from nascent polypeptide chains. A newly-discovered enzyme, designated methionine aminopeptidase type-3 (MetAP-3), has a substrate specificity which is similar to MetAP-1 and MetAP-2, although it is not inhibited by fumagillin, an irreversible inhibitor of MetAP-2. MetAP-3 also preferentially localizes to
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mitochondria, unlike MetAP-1 and MetAP-2, which accumulate in the cytoplasm. One embodiment of the present invention relates to human cDNAs encoding polypeptides comprising MetAP-3. Other embodiments of the invention relate to nucleic acid molecules derived from these cDNAs, including complements, homologues, and fragments thereof, and methods of using these nucleic acid molecules, to generate polypeptides and fragments thereof. Other embodiments of the invention relate to antibodies directed against polypeptides comprising MetAP-3, and methods to screen for compounds or compositions that preferentially or specifically effect the activity of polypeptides comprising MetAP-3. Angiogenesis, the process of new blood vessel formation, is essential for the exponential growth of solid tumors and tumor metastasis. Radiological and cytocidal treatments, combined with regimens involving selective inhibitors of angiogenesis should lead to dramatic reductions in tumor growth. One well-known angiogenesis inhibitor was first discovered as fungal contaminant in bovine endothelial cell cultures that inhibited cell proliferation (Ingber et al. Nature 348:555-557, 1990). The responsible organism was subsequently identified as A. fumagatus, and the product identified as fumagillin, a widely recognized amebicide and antibiotic (McCowen et al., Science 113:202-203 (1951)). Fumagillin was found to be a potent inhibitor of endothelial cell proliferation, but its therapeutic window was insufficient for further clinical advancement. TNP-470, a fumagillin-like derivative with 50-fold higher potency, was subsequently developed from a directed chemical approach (Ingber et al., Nature 348:555-557 (1990), Kusaka et al., Biochem. Biophys. Res. Commun. 174:10701076 (1991)). This compound's therapeutic use is limited, however, by its lack of oral availability and dose-limiting neurotoxicity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Human methionine synthase: cloning, and methods for evaluating risk of neural tube defects, cardiovascular disease, and cancer Inventor(s): Campeau, Eric; (Montreal, CA), Goyette, Philippe; (Montreal, CA), Gravel, Roy A.; (Westmont, CA), LeClerc, Daniel; (Montreal, CA), Rozen, Rima; (Montreal West, CA) Correspondence: Clark & Elbing Llp; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20040073018 Date filed: June 27, 2003 Abstract: The invention features a method for detecting an increased likelihood of hyperhomocysteinemia and, in turn, an increased or decreased likelihood of neural tube defects or cardiovascular disease. The invention also features therapeutic methods for reducing the risk of neural tube defects, colon cancers and related cancers. Also provided are the sequences of the human methionine synthase gene and protein and compounds and kits for performing the methods of the invention. Excerpt(s): This invention claims priority from U.S. Provisional Applications Serial Nos. 60/031,964 and 60/050,310, filed Nov. 27, 1996 and Jun. 20, 1997, respectively. The invention relates to the diagnosis and treatment of patients at risk for methionine synthase deficiency and associated altered risk for diseases such as neural tube defects, cardiovascular disease, and cancer. Methionine synthase (EC 2.1.1.13, 5methyltetrahydrofolate-homocyst- eine methyltransferase) catalyses the remethylation of homocysteine to methionine in a reaction in which methylcobalamin serves as an intermediate methyl carrier. This occurs by transfer of the methyl group of 5methyltetrahydrofolate to the enzyme-bound cob(I)alamin to form methylcobalamin
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with subsequent transfer of the methyl group to homocysteine to form methionine. Over time, cob(I)alamin may become oxidized to cob(II)alamin rendering the enzyme inactive. Regeneration of the functional enzyme occurs through the methionine synthase-mediated methylation of the cob(II)alamin in which S-adenosylmethionine is utilized as methyl donor. In E. coli, two flavodoxins have been implicated in the reductive activation of methionine synthase (Fujii, K. and Huennekens, F. M. (1974) J. Biol. Chem., 249, 6745-6753). A methionine synthase-linked reducing system has yet to be identified in mammalian cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Hydrazide and alkoxyamide angiogenesis inhibitors Inventor(s): Ba-Maung, Nwe; (Niles, IL), Craig, Richard A.; (Racine, WI), Kawai, Megumi; (Libertyville, IL), Lynch, Linda M.; (Pleasant Prairie, WI), Patel, Jyoti R.; (Libertyville, IL), Searle, Xenia Beebe; (Grayslake, IL), Sheppard, George S.; (Wilmette, IL), Wang, Jieyi; (Lake Bluff, IL), Yang, Fan; (Highwood, IL) Correspondence: Steven F. Weinstock; Abbott Laboratories; 100 Abbott Park Road; DEPT. 377/ap6a; Abbott Park; IL; 60064-6008; US Patent Application Number: 20040167126 Date filed: February 19, 2004 Abstract: Compounds having the formula 1are methionine aminopeptidase type 2 (MetAP2) inhibitors and are useful for inhibiting angiogenesis. Also disclosed are MetAP2-inhibiting compositions and methods of inhibiting angiogenesis in a mammal. Excerpt(s): This application is a continuation of U.S. patent application Ser. No. 09/833,917, filed Apr. 12, 2001, which claims priority to U.S. provisional patent application 60/197,262, filed Apr. 14, 2000. The present invention relates to substituted hydrazides and N-alkoxyamides which are useful for preventing angiogenesis, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds. Angiogenesis, the fundamental process by which new blood vessels are formed, is essential to a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e., one of no capillary growth) for prolonged periods which may last for as long as weeks or in some cases, decades. When necessary, however, (such as during wound repair), these same cells undergo rapid proliferation and turnover within a 5 day period. (The Journal of biological Chemistry, 267: 1093110934 (1987), Science, 235: 442-447 (1987)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Methionine salvage pathway in bacillus Inventor(s): Danchin, Antoine; (Pokfulam, HK), Sekowska, Agnieszka; (Pokfulam, HK) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20040019066 Date filed: May 6, 2003 Excerpt(s): This application claims benefit under 35 U.S.C.sctn.119(a) to Provisional Application Serial No. 60/377,622, filed on May 6, 2002, and incorporated herein by reference. The present invention relates to pathways for the synthesis and recycling of methylthioribose (MTR), applications in the fight against plant and vertebrate pathogens (including parasites and their vectors), application for the production of fine chemicals, and in fermentation industry. The present invention also relates to the identification of new drug targets in previously unknown metabolic pathways in living organisms, in particular in bacteria, yeasts, mold, parasites and plants. Polyamine synthesis produces methylthioadenosine, which has to be disposed of. The cell recycles it into methionine through methylthioribose (MTR). Very little was known about MTR recycling for methionine salvage in Bacilli, particularly Bacillus subtilis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for supplying bioavailable methionine to a cow Inventor(s): Bennett, Robert; (Antony, FR), Gros, Georges; (Antony, FR), Robert, JeanClaude; (Antony, FR) Correspondence: Connolly Bove Lodge & Hutz, Llp; P O Box 2207; Wilmington; DE; 19899; US Patent Application Number: 20040154549 Date filed: January 16, 2004 Abstract: The present invention relates to a method for supplying bioavailable methionine to a cow which comprises supplying to the cow an ester of methionine or methionine amide and/or an ester of the hydroxy analogue of methionine or a salt thereof. Excerpt(s): This application claims the benefit of foreign priority to French patent application no. 98 14249, filed Nov. 13, 1998, and French patent application no. 99 10050, filed Jul. 29, 1999. Both of these foreign priority documents are incorporated by reference herein. The present invention relates to a method for supplying bioavailable methionine to a cow which comprises administering to the cow an ester of methionine or methionine amide and/or an ester of the hydroxy analogue of methionine or a salt thereof. The present invention also relates to a method of improving milk obtained from dairy cows and in particular to a method which comprises supplying to the dairy cow an ester of methionine or methionine amide and/or an ester of the hydroxy analogue of methionine or a salt thereof. Protein is one of the major nutrients in the diets of lactating cows. The cows however do not actually require proteins but instead they require the specific amino acids, which are the building blocks that make up their own protein. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Novel fluorescence dyes and their applications for whole-cell fluorescence screening assays for caspases, peptidases, proteases and other enzymes and the use thereof Inventor(s): Cai, Sui Xiong; (San Diego, CA), Drewe, John A.; (Carlsbad, CA), Yang, Wu; (Irvine, CA), Zhang, Han-Zhong; (San Diego, CA) Correspondence: Sterne, Kessler, Goldstein & Fox Pllc; 1100 New York Avenue, N.W.; Washington; DC; 20005; US Patent Application Number: 20030208037 Date filed: May 6, 2002 Abstract: The present invention relates to novel fluorescent dyes, novel fluorogenic and fluorescent reporter molecules and new enzyme assay processes that can be used to detect the activity of caspases and other enzymes involved in apoptosis in whole cells, cell lines and tissue samples derived from any living organism or organ. The reporter molecules and assay processes can be used in drug screening procedures to identify compounds which act as inhibitors or inducers of the caspase cascade in whole cells or tissues. The reagents and assays described herein are also useful for determining the chemosensitivity of human cancer cells to treatment with chemotherapeutic drugs. The present invention also relates to novel fluorogenic and fluorescent reporter molecules and new enzyme assay processes that can be used to detect the activity of type 2 methionine aminopeptidase, HIV protease, adenovirus protease, HSV-1 protease, HCMV protease and HCV protease. Excerpt(s): This invention is in the field of intracellular detection of enzymes using fluorogenic or fluorescent probes. The invention relates to novel fluorescent dyes and application of these dyes for the preparation of novel fluorogenic or fluorescent peptide or amino acid derivatives which are substrates of proteases and peptidases. In particular, the invention relates to novel fluorogenic or fluorescent peptide derivatives which are substrates of enzymes involved in apoptosis, such as caspases and the lymphocyte-derived serine protease Granzyme B. The invention also relates to a process for measuring the activity of caspases and other enzymes involved in apoptosis in living or dead whole cells, cell lines or tissue samples derived from any healthy, diseased, infected or cancerous organ or tissue. The invention also relates to the use of the fluorogenic or fluorescent substrates in a novel assay system for discovering or detecting inhibitors or inducers of apoptosis in compound collections or compound libraries. Furthermore, the invention relates to the use of the fluorogenic or fluorescent substrates in determining the sensitivity of cancer cells to treatment with chemotherapeutic drugs. The invention also relates to novel fluorogenic or fluorescent peptide derivatives which are substrates of exopeptidases such as aminopeptidase A and N, methionine aminopeptidase and dipeptidyl-peptidase IV, endopetidases such as calpain, proteases such as HIV proteases, HCMV protease, HSV protease, HCV protease and adenovirus protease. Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-437 (1965); Ellis et al., Dev. 112:591-603 (1991); Vaux et al., Cell 76:777-779 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721). There are a number of morphological changes shared by cells
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experiencing regulated cell death, including plasma and nuclear membrane blebbing, cell shrinkage (condensation of nucleoplasm and cytoplasm), organelle relocalization and compaction, chromatin condensation and production of apoptotic bodies (membrane enclosed particles containing intracellular material) (Orrenius, S., J. Internal Medicine 237:529-536 (1995)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel gene controlling disease resistance reactions and use thereof Inventor(s): Hirochika, Hirohiko; (Ibaraki, JP), Miyao, Akio; (Ibaraki, JP), Onosato, Katsura; (Tokyo, JP) Correspondence: Perkins Coie Llp; P.O. Box 2168; Menlo Park; CA; 94026; US Patent Application Number: 20040003428 Date filed: November 26, 2002 Abstract: A polynucleotide encoding a plant gene capable of controlling disease resistance reactions in plants is provided which includes a polynucleotide having a nucleotide sequence encoding amino acid sequence from methionine at position 1 to Serine at position 361 of SEQ ID NO: 2 in the sequence listing, or having the amino acid sequence having one or several amino acid deletions, substitutions and/or additions, and being capable of controlling disease resistance reactions. Excerpt(s): The present invention relates to a novel gene. More particularly, the present invention relates to a novel gene encoding a protein capable of controlling disease resistance reactions in plants. A number of gene disruption strains of rice have been produced by the property of rice retrotransposon Tos17 that it is activated by cell/tissue culture to undergo transposition. Transposons are mutagenic genes which are ubiquitous in the genomes of animals, yeast, bacteria, and plants. Transposons are classified into two categories according to their transposition mechanism. Transposons of class II undergo transposition in the form of DNA without replication. Examples of class II transposons include Ac/Ds, Spm/dSpm and Mu elements of maize (Zea mays) (Fedoroff, 1989, Cell 56, 181-191; Fedoroff et al., 1983, Cell 35, 235-242; Schiefelbein et al., 1985, Proc. Natl. Acad. Sci. USA 82, 4783-4787), and Tam element of Antirrhinum (Antirrhinum majus) (Bonas et al., 1984, EMBO J, 3, 1015-1019). Class II transposons are widely used for gene isolation by means of transposon tagging. Such a technique utilizes a property of transposons, that is, a transposon transposes within a genome and enters a certain gene and, as a result, such a gene is physiologically and morphologically modified, whereby the phenotype controlled by the gene is changed. If such a phenotype change can be detected, the affected gene may be isolated (Bancroft et al., 1993, The Plant Cell, 5, 631-638; Colasanti et al., 1998, Cell, 93, 593-603; Gray et al., 1997, Cell, 89, 25-31; Keddie et al., 1998, The Plant Cell, 10, 877-887; and Whitham et al., 1994, Cell, 78, 1101-1115). Transposons of class I are also called retrotransposons. Retrotransposons undergo replicative transposition through RNA as an intermediate. A class I transposon was originally identified and characterized in Drosophila and yeast. A recent study has revealed that retrotransposons are ubiquitous and dominant in plant genomes (Bennetzen, 1996, Trends Microbiolo., 4, 347-353; Voytas, 1996, Science, 274, 737-738). It appears that most retrotransposons are an integratable but non-transposable unit. Recently, it has been reported that some retrotransposons of such a type are activated under stress conditions, such as injury, pathogen attack, and cell culture (Grandbastien, 1998, Trends in Plant Science, 3, 181-187; Wessler, 1996, Curr. Biol., 6, 959-961;Wessler et al., 1995, Curr. Opin. Genet. Devel., 5, 814-821). For example, such
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activation under stress conditions was found in retrotransposons of tobacco, Tnt1A and Tto1 (Pouteau et al., 1994, Plant J., 5, 535-542; Takeda et al., 1988, Plant Mol. Biol., 36, 365-376), and a retrotransposon of rice, Tos17 (Hirochika et al., 1996, Proc. Natl. Acad. Sci. USA, 93, 7783-7788). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel methionine aminopeptidase-2 and uses thereof Inventor(s): Henkin, Jack; (Highland Park, IL), Lou, PingPing; (Gurnee, IL), Sheppard, George S.; (Wilmette, IL), Wang, Jieyi; (Lake Bluff, IL) Correspondence: Steven F. Weinstock; Abbott Laboratories; 100 Abbott Park Road; DEPT. 377/ap6a; Abbott Park; IL; 60064-6008; US Patent Application Number: 20040077031 Date filed: October 17, 2002 Abstract: The present invention uses the manganese-dependent physiological form of the enzyme methionine aminopeptidase type 2 to assess inhibition by agents that might be used in the treatment of angiogenesis, cancer, malaria and leishmaniasis. This method has the advantage of using the manganese form of the enzyme and therefore, the advantage of identifying potent inhibitors that might not show activity in cellular systems because the wrong metal cofactor is used. Therefore it is a new tool for the development of agents useful in the therapy of cancer and other angiogenesis-related diseases and, several infectious diseases including malaria, leishmaniais and microsporidiosis. Excerpt(s): The present invention relates to a novel, methionine aminopeptidase-2 that uses manganese as the necessary stimulating divalent cation. Methionine aminopeptidase-2 inactivation is linked to anti-angiogenic, anti-tumor, anti-parasitic, anti-bacterial and anti-microsporidian effects. The novel manganese form of the enzyme represents a useful in vitro tool, for example in the discovery of inhibitory compounds that can be used in the treatment of cancer, angiogenesis, malaria and leishmaniasis. Methionine aminopeptidases (MetAPs) are cellular metalloproteases capable of removing the N-terminal initiator methionine residue of nascent proteins. The removal of the N-terminal methionine is a critical step for protein modifications that are important in controlling protein subcellular localization and/or protein degradation. Inhibition of MetAPs therefore affects regulation of cellular signal transduction and cell cycle progression. MetAP enzymes have a conserved C-terminal catalytic domain with a protease fold, termed the "pita bread" fold, that appears to be highly conserved in all MetAP enzymes and other related enzymes (Bazan et al., Proc. Nat'l Acad. Sci. USA, 91(7): 2473-77, 1993). The C-terminus of the human MetAP2 contains the catalytic domain showing high amino acid identity with MetAP sequences from prokaryotes and yeast, while the N-terminal region has two basic poly-lysine blocks and an acidic aspartic acid block. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Novel rice gene controlling tolerance to salt stress Inventor(s): Abe, Kiyomi; (Saitama, JP), Hirochika, Hirohiko; (Ibaraki, JP), Miyao, Akio; (Ibaraki, JP), Takeda, Makoto; (Saitama, JP) Correspondence: Richard M Klein; Fay Sharpe Fagan Minnich & Mckee; Seventh Floor; 1100 Superior Avenue; Cleveland; OH; 44114; US Patent Application Number: 20040016027 Date filed: May 16, 2003 Abstract: A gene encoding a protein capable of controlling salt stress tolerance is provided. A polynucleotide encoding a plant gene capable of controlling salt stress tolerance is provided. The polynucleotide includes a polynucleotide which has a nucleotide sequence encoding an amino acid sequence from methionine at position 1 to asparagine at position 243 of SEQ ID NO: 2 in the sequence listing, or which has a nucleotide sequence encoding the amino acid sequence having one or several amino acid deletions, substitutions and/or additions and is capable of controlling salt stress tolerance. Excerpt(s): The present invention relates to a novel gene. More particularly, the present invention relates to a novel gene encoding a protein having a function of controlling salt stress tolerance in plants. Plants constantly suffer from stresses even in a normal growth environment. Such stresses variously include salt, drying, high temperature, low temperature, intense light, air pollution, and the like. Salt stress has received attention in terms of agricultural production. When soils and stones are decomposed, salts are generated, and the generation of salts is constantly continued. When it rains, the salts may flow into the river or the sea. In desert areas of low rainfall, a lesser amount of salts flow out, so that the salt concentration is considerably higher in soil water. Plants draw salts (nutrients) along with water osmotically through roots. When the salt concentration is high, plants cannot draw water. Moreover, the growth of the plants is inhibited due to physiological actions specific to ions. It is known that responses of plants to a salt stress overlap responses to environmental stresses, such as drying, high osmotic pressure, low temperature, and the like. These stresses lead to considerably severe damage to agriculture. Recently, due to use of fertilizers in bulk or long-term sequential cropping, it is often observed that a high concentration of salt is accumulated in soil. Especially in greenhouse soil, detrimental salt accumulation frequently occurs. In areas near seashores, sea water or sea breeze causes damage. In arid or semiarid regions, salts are accumulated in the surface layer of soil due to excessive evaporation. These problems limit use of agricultural lands. In order to solve such problems, generally, the affected soil is exchanged or salts are removed by irrigation. However, these methods require huge expense or effort. The removal of salts by irrigation causes a large volume of salt water to flow into surrounding regions, leading to environmental pollution. Restriction of irrigation is now under consideration. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Nucleic acids encoding ranpirnase variants and methods of making them Inventor(s): Saxena, Shailendra K.; (West Orange, NJ) Correspondence: Mark H Jay; Post Office Box E; Short Hills; NJ; 07078 Patent Application Number: 20040126865 Date filed: December 30, 2002
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Abstract: Ribonuclease DNA coding for an amino acid sequence beginning with a residue of glutamine is introduced into a vector of pET22b(+) plasmid to form recombinant plasmid DNA that begins with a Pel B leader sequence. The recombinant plasmid DNA is used to transform an E.coli BL21(DE3) host. Signal peptidase enzyme present in the host cell cleaves the pelB leader sequence during signal processing and thereby allows the glutamine residue to autocyclize to pyroglutamic acid. In this way, the Ribonuclease can be produced directly, i.e. without a separate step of cleaving the initial N-terminal methionine residue. Excerpt(s): The invention relates to Ribonucleases (RNases), and more particularly relates to ranpirnase. In its most immediate sense, the invention relates to nucleic acids that encode proteins that produce ranpirnase and proteins closely related to ranpirnase (such closely related proteins being herein referred to as "variants" and "ranpirnase variants"). Ranpirnase is the generic name of an RNase that is produced by Alfacell Corporation (assignee herein) under the registered trademark ONCONASE. Ranpirnase is a protein 104 residues long, with a blocked N-terminal of pyroglutamic acid (
Overexpression of aminoacyl-tRNA synthetases for efficient production of engineered proteins containing amino acid analogues Inventor(s): Kiick, Kristi Lynn; (Altadena, CA), Tirrell, David A.; (Pasadena, CA) Correspondence: Lisa A. Haile, J.D., PH.D.; Gray Cary Ware & Freidenrich Llp; Suite 1100; 4365 Executive Drive; San Diego; CA; 92121-2133; US Patent Application Number: 20040058415 Date filed: July 1, 2003 Abstract: Methods for producing modified polypeptides containing amino acid analogues are disclosed.The invention further provides purified dihydrofolate reductase polypeptides, produced by the methods of the invention, in which the methionine residues have been replaced with homoallyglycine, homoproparglycine, norvaline, norleucine, cis-crotylglycine, trans-crotylglycine, 2-aminoheptanoic acid, 2butynylglycine and allylglycine. Excerpt(s): This application is based on and claims the priority of U.S. Serial No. 60/207,627 filed May 26, 2000, the contents of which are hereby incorporated by reference in their entirety. Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. The present invention relates to novel compositions and methods, for incorporating amino acid analogues into proteins in vivo, by overexpression of aminoacyl-tRNA synthetases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Oxidized collagen formulations for use with non-compatible pharmaceutical agents Inventor(s): Burke, David J.; (Oakland, CA), Kuan, Son I.; (San Jose, CA) Correspondence: Dorsey & Whitney Llp; Intellectual Property Department; 4 Embarcadero Center; Suite 3400; San Francisco; CA; 94111; US Patent Application Number: 20040043074 Date filed: September 4, 2003 Abstract: Disclosed are oxidized collagen compositions wherein the thiomethyl group of one or more of the methionine residues of the collagen have been replaced with methylsulfoxy and/or methylsulfonyl groups. Excerpt(s): This application is a continuation of U.S. Ser. No. 09/858,247, filed May 15,2001. This invention is directed to novel collagen compositions and to methods of using such compositions. In particular, the collagen compositions of this invention are directed to oxidized collagen compositions wherein the thiomethyl group of one or more of the methionine residues of the collagen has been replaced with methylsulfoxy and/or methylsulfonyl groups. Surprisingly, the oxidized collagen compositions described herein are compatible with pharmaceutical drugs which are otherwise noncompatible with non-oxidized collagen. Accordingly, the oxidized collagen compositions described herein provide for improved drug delivery, administration, clinical utility and/or therapeutic use of certain non-compatible pharmaceutical drugs, particularly cytotoxic drugs, when used in combination with the oxidized collagen. In addition, the oxidized collagen compositions described herein will provide for improved drug delivery when used with compatible pharmaceutical drugs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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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.
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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 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 •
Polynucleotide encoding a novel methionine aminopeptidase, protease-39 Inventor(s): Bassolino, Donna A.; (Hamilton, NJ), Chen, Jian; (Princeton, NJ), Feder, John N.; (Belle Mead, NJ), Krystek, Stanley R.; (Ringoes, NJ), Naglich, Joseph; (Yardley, PA), Nelson, Thomas C.; (Lawrenceville, NJ) Correspondence: Stephen B. Davis; Bristol-Myers Squibb Company; Patent Department; P O Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20030204070 Date filed: January 23, 2003 Abstract: The present invention provides novel polynucleotides encoding Protease-39 polypeptides, fragments and homologues thereof. Also provided are vectors, host cells, antibodies, and recombinant and synthetic methods for producing said polypeptides. The invention further relates to diagnostic and therapeutic methods for applying these novel Protease-39 polypeptides to the diagnosis, treatment, and/or prevention of various diseases and/or disorders related to these polypeptides. The invention further relates to screening methods for identifying agonists and antagonists of the polynucleotides and polypeptides of the present invention.
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Excerpt(s): This application claims benefit to provisional application U.S. Serial No. 60/351,251 filed Jan. 23, 2002; and to provisional application U.S. Serial No. 60/362,872, filed Mar. 8, 2002. The entire teachings of the referenced applications are incorporated herein by reference. Protein synthesis is typically initiated with an amino-terminal methionine in eukaryotes, or N-formylmethionine in prokaryotes, mitochondria, and chloroplasts. The resulting nascent peptides are subject to posttranslational modifications that occur through the actions of a variety of enzymes, including those from the Methionyl Aminopeptidase Gene Family (MAP). Two classes of MAPs are known and their gene products are methionine aminopeptidases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Silver-dispersing polypeptides Inventor(s): Bogels, Gertjan; (Tilburg, NL), Bouwstra, Jan Bastiaan; (Bilthoven, NL), Toda, Yuzo; (Goirle, NL) Correspondence: Anthony H. Handal; Kirkpatrick & Lockhart, Llp; 599 Lexington Avenue; 31st Floor; New York; NY; 10022-6030; US Patent Application Number: 20040048208 Date filed: June 26, 2003 Abstract: The invention pertains to silver halide emulsions for photographic uses. The emulsions contain a nucleation peptiser, said nucleation peptiser being a polypeptide comprising: at least one region A comprising up to 100 amino acids, either consisting of (i) at least two silver-binding amino acids and up to 98 amino acids between said two silver-binding amino acids, or consisting of (ii) a stretch of from 9 to 100 amino acids having a polarity corresponding to an average transfer free energy.delta.F equal to or higher than +1.0 kcal/mol, and at least one region B (separated from region A) comprising at least 50 amino acids and having a polarity corresponding to an average transfer free energy equal to or lower than -1.0 kcal/mol and not containing methionine residues. The emulsion may also contain a growth peptiser having similar characteristics as the nucleation peptiser, but having a longer A region and a greater overall length. Excerpt(s): The subject invention is directed to biopolymers having silver-dispersing properties and to emulsions containing these biopolymers suitable for use in improved photographic products. The process of manufacturing photographic paper or film consists of coating several layers on top of either a laminated paper or a transparent polymer support like triacetate cellulose film. These layers comprise emulsion layers which contain the photosensitive silver halide crystals as an essential component, and intermediate layers which do not contain these photosensitive components. The process of silver halide grain formation is controlled by the use of dispersing agents, usually referred to as peptisers. A nucleation peptiser is used during the precipitation of the silver halide grains to avoid uncontrolled coalescence. A growth peptiser is used during the growth process as dispersion stabiliser of the silver halide crystals, which functionality is also used between the different growth steps as well as after the end of the growth process when the crystals should remain stabilised under storage conditions. It is well known that tabular grains with high aspect ratio have several photographic advantages like increased sharpness, improved speed granularity relationships, more rapid developability and higher silver covering power (Research Disclosure Vol. 225 January 1983, Item 22534; EP-A-0.610.796). It has also been desired to produce tabular grains not only with high aspect ratio but also with a narrow grain size distribution, otherwise expressed as a desire for mono- or homodispersity.
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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Sulfonamides having antiangiogenic and anticancer activity Inventor(s): BaMaung, Nwe Y.; (Niles, IL), Comess, Kenneth M.; (Winnetka, IL), Erickson, Scott A.; (Zion, IL), Henkin, Jack; (Highland Park, IL), Kalvin, Douglas M.; (Buffalo Grove, IL), Kawai, Megumi; (Libertyville, IL), Kim, Ki Hwan; (Vista, CA), Park, Chang Hoon; (Libertyville, IL), Sheppard, George S.; (Wilmette, IL), Vasudevan, Anil; (Gurnee, IL), Wang, Jieyi; (Lake Bluff, IL) Correspondence: Steven F. Weinstock; Abbott Laboratories; 100 Abbott Park Road; DEPT. 377/ap6a; Abbott Park; IL; 60064-6008; US Patent Application Number: 20040068012 Date filed: October 8, 2002 Abstract: Compounds having methionine aminopeptidase-2 inhibitory (MetAP2) are described. Also described are pharmaceutical compositions comprising the compounds, methods of treatment using the compounds, methods of inhibiting angiogenesis, and methods of treating cancer. Excerpt(s): The present invention relates to compounds having methionine aminopeptidase-2 inhibitory (MetAP2) activity useful for treating cancer and other conditions which arise from or are exacerbated by angiogenesis, pharmaceutical compositions comprising the compounds, methods of treatment using the compounds, methods of inhibiting angiogenesis, and methods of treating cancer. Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities (such as reproduction, development, and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions these molecules appear to maintain the microvasculature in a quiescent state (i.e., one of no capillary growth) for prolonged periods that may last for weeks, or in some cases, decades. However, when necessary, such as during wound repair, these same cells can undergo rapid proliferation and turnover within as little as five days. Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as "angiogenic diseases") are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exacerbate an existing pathological condition. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
•
Therapeutic use of D-methionine to reduce the toxicity of radiation Inventor(s): Campbell, Kathleen C.M.; (Glenarm, IL) Correspondence: Senniger Powers Leavitt And Roedel; One Metropolitan Square; 16th Floor; ST Louis; MO; 63102; US Patent Application Number: 20040127568 Date filed: October 27, 2003 Abstract: Methods of preventing or treating ototoxicity, neurotoxicity, alopecia, gastrointestinal disorder, and reduced survival in patients who have been exposed to
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toxic levels of radiation are provided. These methods comprise administering an effective amount of a protective agent comprising a methionine or a methionine-like moiety to said patient prior to, simultaneously with, or subsequently to exposure to radiation. Combinations of these time periods can also be employed. Excerpt(s): This patent application is a continuation of pending U.S. patent application Ser. No. 09/911,195 filed Jul. 23, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09/057,065 filed Apr. 8, 1998 (issued as U.S. Pat. No. 6,265,386), which is a continuation-in-part of U.S. patent application Ser. No. 08/942,845 filed Oct. 2, 1997 (issued as U.S. Pat. No. 6,187,817), which claims priority from U.S. Provisional Application Serial No. 60/027,750 filed Oct. 3, 1996 (now abandoned). The entire texts of U.S. patent application Ser. Nos. 09/911,195, 09/057,065, 08/942,845, and U.S. Provisional Application Serial No. 60/027,750 are hereby incorporated herein by reference. The present invention relates to the use of protective agents in cancer chemotherapy in human and animal subjects. Protective agents are compounds that prevent, reduce, or otherwise ameliorate the toxic side effects of anti-cancer chemotherapeutic compounds in normal body cells while substantially preserving the anti-tumor properties of these compounds in vivo when administered prior to, concomitantly with, or subsequently to administration of such chemotherapeutic compounds. More specifically, the present invention relates to the use of D-methionine and structurally related compounds as protective agents having oto-protective, weight loss-protective, gastrointestinal-protective, neuro-protective, alopecia-protective, and survival-enhancing effects in conjunction with chemotherapy employing platinumcontaining anti-neoplastic agents, such as cisplatin. The present invention also relates to the use of D-methionine and structurally related compounds as protective agents having oto-protective effects against noise-induced, loop diuretic-induced, aminoglycoside antibiotic-induced, iron chelator-induced, quinidine-induced, and radiation-induced hearing loss, as well as protective effects in ameliorating other radiation-induced side effects such as neural damage, alopecia, gastrointestinal disorders, and reduced patient survival. Cisplatin (cis-diamminedichloroplatinum(II); CDDP) is a widely used antineoplastic agent. Cisplatin administration has increased both in the variety of cancer types for which it is employed and in the amount used in a given individual to achieve maximal therapeutic effect (Blumenreich et al., 1985; Forastiere et al., 1987; Gandara et al., 1989). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Topical composition and methods for treatment of aged or environmentally damaged skin Inventor(s): Burke-Colvin, Dawn Elizabeth; (Dallas, TX), Majmudar, Gopa; (Irving, TX), Schiltz, John Raymond; (Coppell, TX) Correspondence: Fulbright & Jaworski L.L.P.; 600 Congress AVE.; Suite 2400; Austin; TX; 78701; US Patent Application Number: 20040126449 Date filed: December 30, 2002 Abstract: The invention describes a unique composition of ingredients for improving the skin's visual appearance, function, and biophysical properties that has been changed by factors such as chronological age, chronic sun exposure, adverse environmental pollutants, household chemicals, disease pathologies, smoking, and malnutrition. In particular, the present invention relates to the composition of topically-applied
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cosmetics formulas that effectively treat aged and environmentally-damaged skin. These formulas may comprise various combinations of cosmetically compatible plant lectins, a high energy source for skin cell metabolism such as lactobacillus ferment, hydrolyzed wheat protein, glycine, arginine, and methionine and.beta.-Glucans, which are formulated into different types of cosmetic vehicles. The invention provides for an effective alternative to the use of mono- and polyhydroxy acids, retinoid compounds, vitamins, nutraceuticals, physical corneum desquamating devices, and various plant and animal extracts. Excerpt(s): The invention describes a unique composition of ingredients for improving the skin's visual appearance, function, and biophysical properties that have been changed by factors such as chronological age, chronic sun exposure, adverse environmental pollutants, household chemicals, disease pathologies, smoking, and malnutrition. In particular, the present invention relates to the composition of topically applied cosmetics formulas that effectively treat aged and environmentally damaged skin. These formulas contain various combinations of cosmetically compatible plant lectins, a high energy source for skin cell metabolism (such as lactobacillus ferment, hydrolyzed wheat protein, glycine, arginine, and methionine) and.beta.-Glucans, which are formulated into different types of cosmetic vehicles. The invention provides for an effective alternative to the use of mono- and polyhydroxy acids, retinoid compounds, vitamins, nutraceuticals, physical corneum desquamating devices, and various plant and animal extracts and ferments. With chronological age and chronic exposure to adverse environmental factors, the visual appearance and feel, physical properties, and physiological functions of skin change in ways that are considered cosmetically undesirable. The most notable and obvious changes include the development of fine line and wrinkles, loss of elasticity and firmness, increased sagging, loss of color evenness (tone), coarse surface texture, and mottled pigmentation. Less obvious, but measurable changes that occur as skin ages or endures chronic environmental insult include a general reduction in cellular and tissue vitality, reduction in cell replication rates, reduced cutaneous blood flow, reduced moisture content, accumulated errors in structure and function, and a reduction in the skin's ability to remodel and repair itself. Many of the above alterations in appearance and function are caused by changes in the outer epidermal layer of the skin, while others are caused by changes in the dermis. When the epidermis is injured, the epidermal basal cells respond to the injury by dividing at a more frequent rate. This increase in replication rate results in a more rapid replacement of the damaged epidermis with a new epidermis and stratum corneum, a process referred to as "epidermal cell renewal." Common examples of injuries that can increase epidermal cell renewal rates include abrasion, chemical damage, pH extremes, excessive sun exposure, or allergic or non-allergic contact irritation. If the injury is too severe, the increased replication will result in a "hyperplastic" epidermis and a thickened, poorly-functioning stratum corneum which is manifested as dry, rough scales. Other common stimuli which induce epidermal cell renewal include physical removal of the stratum corneum (i.e., an example of which is tape stripping, a process where tape is applied to the skin and pulled off, removing the top layer of the stratum corneum with it) and friction (i.e., on the soles and heels of the feet), all processes which result in epidermal hyperplasia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Keeping Current In order to stay informed about patents and patent applications dealing with methionine, 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 “methionine” (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 methionine. You can also use this procedure to view pending patent applications concerning methionine. 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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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
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
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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
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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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
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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
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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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
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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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
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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/
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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
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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
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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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
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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 “methionine” (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 54484 76 747 105 425 55837
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 “methionine” (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/.
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Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
The Genome Project and Methionine In the following section, we will discuss databases and references which relate to the Genome Project and methionine. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).21 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 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. 21 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.
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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “methionine” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for methionine: •
Peptide Methionine Sulfoxide Reductase Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601250
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Transfer RNA Methionine 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601433
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Transfer RNA Methionine Initiator 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=180620
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Transfer RNA Methionine Initiator 2 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=180621 Genes and Disease (NCBI - Map)
The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •
Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html
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Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html
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Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html
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Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html
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•
Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html
•
Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html
•
Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez
Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •
3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books
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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome
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NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/
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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide
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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset
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ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein
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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure
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Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy
To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “methionine” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database22 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database23 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “methionine” (or synonyms) into the search box, and
22
Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 23 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.
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review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).
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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 methionine 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 methionine. 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 methionine. 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 “methionine”:
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Gaucher's Disease http://www.nlm.nih.gov/medlineplus/gauchersdisease.html Genetic Brain Disorders http://www.nlm.nih.gov/medlineplus/geneticbraindisorders.html Leukodystrophies http://www.nlm.nih.gov/medlineplus/leukodystrophies.html Liver Diseases http://www.nlm.nih.gov/medlineplus/liverdiseases.html Metabolic Disorders http://www.nlm.nih.gov/medlineplus/metabolicdisorders.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 methionine. 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.
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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 methionine. 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 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
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Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
•
WebMDHealth: 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 methionine. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with methionine. 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 methionine. 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
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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/. Simply type in “methionine” (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 “methionine”. 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 “methionine” (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 “methionine” (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.24
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
24
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)25: •
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/
25
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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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/
•
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
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
•
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
•
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
•
Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
•
Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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METHIONINE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 2-Aminopurine: A purine that is an isomer of adenine (6-aminopurine). [NIH] 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] Ablation: The removal of an organ by surgery. [NIH] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] Abrasion: 1. The wearing away of a substance or structure (such as the skin or the teeth) through some unusual or abnormal mechanical process. 2. An area of body surface denuded of skin or mucous membrane by some unusual or abnormal mechanical process. [EU] Abscess: A localized, circumscribed collection of pus. [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] 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] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics,
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adhesives and synthetic rubber. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acylation: The addition of an organic acid radical into a molecule. [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] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenoma: A benign 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] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] 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 Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [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] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
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,
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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]
Aggressiveness: The quality of being aggressive (= characterized by aggression; militant; enterprising; spreading with vigour; chemically active; variable and adaptable). [EU] Agonists: Drugs that trigger an action from a cell or another drug. [NIH] Agoraphobia: Obsessive, persistent, intense fear of open places. [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 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] Albuminuria: More than normal amounts of a protein called albumin in the urine. Albuminuria may be a sign of kidney disease. [NIH] Alcohol Dehydrogenase: An enzyme that catalyzes reversibly the final step of alcoholic fermentation by reducing an aldehyde to an alcohol. In the case of ethanol, acetaldehyde is reduced to ethanol in the presence of NADH and hydrogen. The enzyme is a zinc protein which acts on primary and secondary alcohols or hemiacetals. EC 1.1.1.1. [NIH] Alfalfa: A deep-rooted European leguminous plant (Medicago sativa) widely grown for hay and forage. [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] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as
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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]
Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergens: Antigen-type substances (hypersensitivity, immediate). [NIH]
that
produce
immediate
hypersensitivity
Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Alloys: A mixture of metallic elements or compounds with other metallic or metalloid elements in varying proportions. [NIH] Allylglycine: An inhibitor of glutamate decarboxylase and an antagonist of GABA. It is used to induce convulsions in experimental animals. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha 1-Antitrypsin: Plasma glycoprotein member of the serpin superfamily which inhibits trypsin, neutrophil elastase, and other proteolytic enzymes. Commonly referred to as alpha 1-proteinase inhibitor (A1PI), it exists in over 30 different biochemical variant forms known collectively as the PI (protease inhibitor) system. Hereditary A1PI deficiency is associated with pulmonary emphysema. [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] 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] Ambulatory Care: Health care services provided to patients on an ambulatory basis, rather than by admission to a hospital or other health care facility. The services may be a part of a hospital, augmenting its inpatient services, or may be provided at a free-standing facility. [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: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration.
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Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] 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] 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] Ammonium Chloride: An acidifying agent that is used as an expectorant and a diuretic. [NIH]
Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amylase: An enzyme that helps the body digest starches. [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] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaemia: A reduction below normal in the number of erythrocytes per cu. mm., in the quantity of haemoglobin, or in the volume of packed red cells per 100 ml. of blood which occurs when the equilibrium between blood loss (through bleeding or destruction) and blood production is disturbed. [EU] 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]
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Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]
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] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] 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] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [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] 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] Anode: Electrode held at a positive potential with respect to a cathode. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH] Anthocyanins: Glycosidic pigments in blue, red, and purple flowers and also found as metabolic byproducts in blood and urine. [NIH] Antiangiogenic: Having to do with reducing the growth of new blood vessels. [NIH] 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]
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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] Anticarcinogenic: Pertaining to something that prevents or delays the development of cancer. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticodon: The sequential set of three nucleotides in transfer RNA that interacts with its complement in messenger RNA, the codon, during translation in the ribosome. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antiepileptic: An agent that combats epilepsy. [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 causes immune complex diseases. [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] Antimetastatic: Having to do with reducing inflammation. [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] 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] Antiparasitic Agents: Drugs used to treat or prevent parasitic infections. [NIH] Antiplasmin: A member of the serpin superfamily found in human plasma that inhibits the lysis of fibrin clots which are induced by plasminogen activator. It is a glycoprotein, molecular weight approximately 70,000 that migrates in the alpha 2 region in immunoelectrophoresis. It is the principal plasmin inactivator in blood, rapidly forming a very stable complex with plasmin. [NIH] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [EU]
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Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [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] 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] Arachidonate 12-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 12-hydroperoxyarachidonate (12-HPETE) which is itself rapidly converted by a peroxidase to 12-hydroxy-5,8,10,14-eicosatetraenoate (12-HETE). The 12-hydroperoxides are preferentially formed in platelets. EC 1.13.11.31. [NIH] Arachidonate 15-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in neutrophils and lymphocytes. EC 1.13.11.33. [NIH] Arachidonate Lipoxygenases: Enzymes catalyzing the oxidation of arachidonic acid to hydroperoxyarachidonates (HPETES). These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids (HETES). The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat 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] Archaea: One of the three domains of life (the others being bacteria and Eucarya), formerly called Archaebacteria under the taxon Bacteria, but now considered separate and distinct. They are characterized by: 1) the presence of characteristic tRNAs and ribosomal RNAs; 2) the absence of peptidoglycan cell walls; 3) the presence of ether-linked lipids built from branched-chain subunits; and 4) their occurrence in unusual habitats. While archaea resemble bacteria in morphology and genomic organization, they resemble eukarya in their method of genomic replication. The domain contains at least three kingdoms: crenarchaeota, euryarchaeota, and korarchaeota. [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]
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Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Asbestos: Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aspartate: A synthetic amino acid. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [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] Asphyxia: A pathological condition caused by lack of oxygen, manifested in impending or actual cessation of life. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astringent: Causing contraction, usually locally after topical application. [EU] 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] Asymptomatic: Having no signs or symptoms of disease. [NIH]
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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] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] Atopic allergy: A person with a type I allergic reaction, specifically with strong familiar tendencies, caused by allergens such as pollens, foods, etc. [NIH] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] 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] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [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] Azoxymethane: A potent carcinogen and neurotoxic compound. It is particularly effective in inducing colon carcinomas. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [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] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [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] Baroreflex: A negative feedback system which buffers short-term changes in blood pressure. Increased pressure stretches blood vessels which activates pressoreceptors (baroreceptors) in
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the vessel walls. The net response of the central nervous system is a reduction of central sympathetic outflow. This reduces blood pressure both by decreasing peripheral vascular resistance and by lowering cardiac output. Because the baroreceptors are tonically active, the baroreflex can compensate rapidly for both increases and decreases in blood pressure. [NIH]
Basal cells: Small, round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [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 Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [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-glucans: Polysaccharides made by several types of mushrooms. Beta-glucans have been used to treat patients with gastric cancer and colorectal cancer. They may be able to stimulate the immune system. [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] 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]
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Biofilms: Films of bacteria or other microbial organisms, usually embedded in extracellular polymers such as implanted medical devices, which adhere to surfaces submerged in, or subjected to, aquatic environments (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed). Biofilms consist of multilayers of microbial cells glued together to form microbial communities which are highly resistant to both phagocytes and antibiotics. [NIH] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH] Biological Markers: Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. [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] Bioluminescence: The emission of light by living organisms such as the firefly, certain mollusks, beetles, fish, bacteria, fungi and protozoa. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [NIH] Biophysics: The science of physical phenomena and processes in living organisms. [NIH] Biopolymers: Polymers, such as proteins, DNA, RNA, or polysaccharides formed by any living organism. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopterin: A natural product that has been considered as a growth factor for some insects. [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] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Bladder: The organ that stores urine. [NIH]
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Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [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 vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bone Cements: Adhesives used to fix prosthetic devices to bones and to cement bone to bone in difficult fractures. Synthetic resins are commonly used as cements. A mixture of monocalcium phosphate, monohydrate, alpha-tricalcium phosphate, and calcium carbonate with a sodium phosphate solution is also a useful bone paste. [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 metastases: Cancer that has spread from the original (primary) tumor to the bone. [NIH]
Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [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] Bradycardia: Excessive slowness in the action of the heart, usually with a heart rate below 60 beats per minute. [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] Breath Tests: Any tests done on exhaled air. [NIH]
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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] Buffers: A chemical system that functions to control the levels of specific ions in solution. When the level of hydrogen ion in solution is controlled the system is called a pH buffer. [NIH]
Butyric Acid: A four carbon acid, CH3CH2CH2COOH, with an unpleasant odor that occurs in butter and animal fat as the glycerol ester. [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 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] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcitonin: A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. [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] 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
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calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH] Canonical: A particular nucleotide sequence in which each position represents the base more often found when many actual sequences of a given class of genetic elements are compared. [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] Capping: A 7-methyl guanosine cap attached to the 5'-end of eucaryotic mRNAs by a phosphodiester linkage. The cap is believed to increase the stability of the message, since most nucleases require a 5'-3'or 3'-5'bond in order to cleave the RNA. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [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] 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] 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] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] 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] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH]
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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] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Caspase 1: A member of the caspase family that is highly specific for interleukin-1beta (interleukin-1). It plays a role in inflammation and mammalian apoptosis. Interleukin-1beta converting enzyme is frequently abbreviated ICE. EC 3.4.22.36 [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] 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] Catechol: A chemical originally isolated from a type of mimosa tree. Catechol is used as an astringent, an antiseptic, and in photography, electroplating, and making other chemicals. It can also be man-made. [NIH] Catecholamines: A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. [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] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cavernous Sinus: An irregularly shaped venous space in the dura mater at either side of the sphenoid bone. [NIH] Celecoxib: A drug that reduces pain. Celecoxib belongs to the family of drugs called
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nonsteroidal anti-inflammatory agents. It is being studied for cancer prevention. [NIH] 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 Aging: The decrease in the cell's ability to proliferate with the passing of time. Each cell is programmed for a certain number of cell divisions and at the end of that time proliferation halts. The cell enters a quiescent state after which it experiences cell death via the process of apoptosis. [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 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 motility: The ability of a cell to move. [NIH] Cell Physiology: Characteristics and physiological processes of cells from cell division to cell death. [NIH] 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 Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [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] Cellobiose: A disaccharide consisting of two glucose units in beta (1-4) glycosidic linkage. Obtained from the partial hydrolysis of cellulose. [NIH] Cellular metabolism: The sum of all chemical changes that take place in a cell through which energy and basic components are provided for essential processes, including the synthesis of new molecules and the breakdown and removal of others. [NIH] Cellulase: An enzyme isolated from fungi and bacteria. It catalyzes the endohydrolysis of 1,4-beta-glucosidic linkages in cellulose, lichenin, and cereal beta-glucans. EC 3.2.1.4. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Cerebellar: Pertaining to the cerebellum. [EU]
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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] 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] Chemotaxis: The movement of cells or organisms toward or away from a substance in response to its concentration gradient. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chlorides: Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. [NIH]
Chlorine: A greenish-yellow, diatomic gas that is a member of the halogen family of elements. It has the atomic symbol Cl, atomic number 17, and atomic weight 70.906. It is a powerful irritant that can cause fatal pulmonary edema. Chlorine is used in manufacturing, as a reagent in synthetic chemistry, for water purification, and in the production of chlorinated lime, which is used in fabric bleaching. [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] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [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,
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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] 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 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] 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] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [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 study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [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] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [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
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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] 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] Codon: A set of three nucleotides in a protein coding sequence that specifies individual 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] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [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] 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] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Colorectal Neoplasms: Tumors or cancer of the either the colon or rectum or both. The most frequent malignant tumor in the United States. Etiological factors which increase the risk of colorectal cancer include chronic ulcerative colitis, familial polyposis of the colon, exposure to asbestos, irradiation of the cervix. [NIH]
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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] 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] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray
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machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confidence Intervals: A range of values for a variable of interest, e.g., a rate, constructed so that this range has a specified probability of including the true value of the variable. [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] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constriction: The act of constricting. [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] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]
Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or
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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 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] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] 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] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Creatinine clearance: A test that measures how efficiently the kidneys remove creatinine and other wastes from the blood. Low creatinine clearance indicates impaired kidney function. [NIH] Crenarchaeota: A kingdom in the domain Archaea comprised of thermoacidophilic, sulfurdependent organisms. The two orders are Sulfolobales and Thermoproteales. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [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] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH]
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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] Cyclin: Molecule that regulates the cell cycle. [NIH] Cycloheximide: Antibiotic substance isolated from streptomycin-producing strains of Streptomyces griseus. It acts by inhibiting elongation during protein synthesis. [NIH] Cyst: A sac or capsule filled with fluid. [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] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [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 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] Cytochrome b: Cytochromes (electron-transporting proteins) with protoheme or a related heme as the prosthetic group. The prosthetic group is not covalently bound to the protein moiety. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [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] Cytoprotection: The process by which chemical compounds provide protection to cells against harmful agents. [NIH] 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]
Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH]
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Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [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] Dementia: An acquired organic mental disorder with loss of intellectual abilities of 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]
Demyelinating Diseases: Diseases characterized by loss or dysfunction of myelin in the central or peripheral nervous system. [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] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [NIH]
Deoxyglucose: 2-Deoxy-D-arabino-hexose. An antimetabolite of glucose with antiviral activity. [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] 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] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH]
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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 and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [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] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [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] Dihydrotestosterone: Anabolic agent. [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] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Dipeptidases: Exopeptidases that specifically act on dipeptides. EC 3.4.13. [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] 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] Disease Susceptibility: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the individual more than usually susceptible to certain diseases. [NIH] Disease Vectors: Invertebrates or non-human vertebrates which transmit infective organisms from one host to another. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] 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
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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] 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] Diuretic: A drug that increases the production of urine. [NIH] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] 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] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Evaluation: Any process by which toxicity, metabolism, absorption, elimination, preferred route of administration, safe dosage range, etc., for a drug or group of drugs is determined through clinical assessment in humans or veterinary animals. [NIH] Drug Evaluation, Preclinical: Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended
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effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [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] Dysphoric: A feeling of unpleasantness and discomfort. [NIH] 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] 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] Eicosanoids: A class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid compounds (HETE). They are hormone-like substances that act near the site of synthesis without altering functions throughout the body. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] 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] Electrolysis: Destruction by passage of a galvanic electric current, as in disintegration of a chemical compound in solution. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] 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] 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]
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Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [NIH] Encephalocele: Cerebral tissue herniation through a congenital or acquired defect in the skull. The majority of congenital encephaloceles occur in the occipital or frontal regions. Clinical features include a protuberant mass that may be pulsatile. The quantity and location of protruding neural tissue determines the type and degree of neurologic deficit. Visual defects, psychomotor developmental delay, and persistent motor deficits frequently occur. [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] 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, 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] Endotoxemia: A condition characterized by the presence of endotoxins in the blood. If endotoxemia is the result of gram-negative rod-shaped bacteria, shock may occur. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid
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and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enhancers: Transcriptional element in the virus genome. [NIH] Enkephalin: A natural opiate painkiller, in the hypothalamus. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [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]
Environmental Pollutants: Substances which pollute the environment. Use environmental pollutants in general or for which there is no specific heading. [NIH]
for
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [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] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] 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 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] 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] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH]
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Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [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] Ethionine: 2-Amino-4-(ethylthio)butyric acid. An antimetabolite and methionine antagonist that interferes with amino acid incorporation into proteins and with cellular ATP utilization. It also produces liver neoplasms. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Euryarchaeota: A kingdom of Archaea comprising the methanogens, extreme halophiles (Halobacteriales), sulfate-reducing species (Archaeoglobales), and the thermophiles (Thermococcales and Thermoplasmales). [NIH] Evaluation Studies: Studies determining the effectiveness or value of processes, personnel, and equipment, or the material on conducting such studies. For drugs and devices, clinical trials, drug evaluation, and drug evaluation, preclinical are available. [NIH] 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] Excrete: To get rid of waste from the body. [NIH] Exhaustion: The feeling of weariness of mind and body. [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;
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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] Expectorant: 1. Promoting the ejection, by spitting, of mucus or other fluids from the lungs and trachea. 2. An agent that promotes the ejection of mucus or exudate from the lungs, bronchi, and trachea; sometimes extended to all remedies that quiet cough (antitussives). [EU]
Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [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 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] 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] Familial polyposis: An inherited condition in which numerous polyps (tissue masses) develop on the inside walls of the colon and rectum. It increases the risk for colon cancer. [NIH]
Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [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 Development: Morphologic and physiologic growth and development of the mammalian embryo or fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibril: Most bacterial viruses have a hollow tail with specialized fibrils at its tip. The tail
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fibers attach to the cell wall of the host. [NIH] Fibrillation: A small, local, involuntary contraction of muscle, invisible under the skin, resulting from spontaneous activation of single muscle cells or muscle fibres. [EU] 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] Fibrinolysis: The natural enzymatic dissolution of fibrin. [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] Financial Management: The obtaining and management of funds for institutional needs and responsibility for fiscal affairs. [NIH] Flatus: Gas passed through the rectum. [NIH] Flavodoxin: A low-molecular-weight (16,000) iron-free flavoprotein containing one molecule of flavin mononucleotide (FMN) and isolated from bacteria grown on an irondeficient medium. It can replace ferredoxin in all the electron-transfer functions in which the latter is known to serve in bacterial cells. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [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] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorine: A nonmetallic, diatomic gas that is a trace element and member of the halogen family. It is used in dentistry as flouride to prevent dental caries. [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]
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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] Follicular Fluid: A fluid consisting of sex steroid hormones, plasma proteins, mucopolysaccharides, and electrolytes that is present in the vesicular ovarian follicle (Graafian follicle) surrounding the ovum. [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 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] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Gallate: Antioxidant present in tea. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory and antiviral activity. [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
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through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastritis: Inflammation of the stomach. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [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 Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Expression Profiling: The determination of the pattern of genes expressed i.e., transcribed, under specific circumstances or in a specific cell. [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 Library: A large collection of cloned DNA fragments from a given organism, tissue, organ, or cell type. It may contain complete genomic sequences (genomic library) or complementary DNA sequences, the latter being formed from messenger RNA and lacking intron sequences. [NIH] Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. [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 Complementation Test: A test used to determine whether or not complementation (compensation in the form of dominance) will occur in a cell with a given mutant phenotype when another mutant genome, encoding the same mutant phenotype, is introduced into that cell. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by
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such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Techniques: Chromosomal, biochemical, intracellular, and other methods used in the study of genetics. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genomic Library: A form of gene library containing the complete DNA sequences present in the genome of a given organism. It contrasts with a cDNA library which contains only sequences utilized in protein coding (lacking introns). [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [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] Germinoma: The most frequent type of germ-cell tumor in the brain. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [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] Gliosarcoma: A type of glioma. [NIH] Glomeruli: Plural of glomerulus. [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] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [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] 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
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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] 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] Glycoprotein: A protein that has sugar molecules attached to it. [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] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonads: The gamete-producing glands, ovary or testis. [NIH] 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]
Grade: The grade of a tumor depends on how abnormal the cancer cells look under a 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 Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a
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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] Granulosa Cells: Cells of the membrana granulosa lining the vesicular ovarian follicle which become luteal cells after ovulation. [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] Guinea Pigs: A common name used for the family Caviidae. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. [NIH]
Haemodialysis: The removal of certain elements from the blood by virtue of the difference in the rates of their diffusion through a semipermeable membrane, e.g., by means of a haemodialyzer. [EU] 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] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [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] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Helminths: Commonly known as parasitic worms, this group includes the acanthocephala, nematoda, and platyhelminths. Some authors consider certain species of leeches that can become temporarily parasitic as helminths. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH]
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Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemiatrophy: Progressive atrophy of all structures of one side of the face, including skin, subcutaneous tissue, muscle and bone. [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] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [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 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] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [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] Hepatocyte Growth Factor: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is proto-oncogene protein C-met. [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]
Heterotrophic: Pertaining to organisms that are consumers and dependent on other
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organisms for their source of energy (food). [NIH] Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Hirsutism: Excess hair in females and children with an adult male pattern of distribution. The concept does not include hypertrichosis, which is localized or generalized excess hair. [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] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [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]
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] Homozygotes: An individual having a homozygous gene pair. [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] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Housekeeping: The care and management of property. [NIH] Human Genome Project: A coordinated effort of researchers to map and sequence the human genome. [NIH] Human growth hormone: A protein hormone, secreted by the anterior lobe of the pituitary, which promotes growth of the whole body by stimulating protein synthesis. The human gene has already been cloned and successfully expressed in bacteria. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hydrochloric Acid: A strong corrosive acid that is commonly used as a laboratory reagent. It is formed by dissolving hydrogen chloride in water. Gastric acid is the hydrochloric acid component of gastric juice. [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
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isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [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] Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxamic Acids: A class of weak acids with the general formula R-conhoh. [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] Hyperandrogenism: A state characterized or caused by an excessive secretion of androgens by the adrenal cortex, ovaries, or testes. The clinical significance in males is negligible, so the term is used most commonly with reference to the female. The common manifestations in women are hirsutism and virilism. It is often caused by ovarian disease (particularly the polycystic ovary syndrome) and by adrenal diseases (particularly adrenal gland hyperfunction). [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] Hyperpigmentation: Excessive pigmentation of the skin, usually as a result of increased melanization of the epidermis rather than as a result of an increased number of melanocytes. Etiology is varied and the condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. [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]
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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] Hypochlorous Acid: HClO. An oxyacid of chlorine containing monovalent chlorine that acts as an oxidizing or reducing agent. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypogonadism: Condition resulting from or characterized by abnormally decreased functional activity of the gonads, with retardation of growth and sexual development. [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamic: Of or involving the hypothalamus. [EU] 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] Hypotonia: A condition of diminished tone of the skeletal muscles; diminished resistance of muscles to passive stretching. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Idiopathic: Describes a disease of unknown cause. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Imipramine: The prototypical tricyclic antidepressant. It has been used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. It has less sedative effect than some other members of this therapeutic group. [NIH]
Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [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] Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as western blot analysis (blotting, western). [NIH]
Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunoelectrophoresis: A technique that combines protein electrophoresis and double immunodiffusion. In this procedure proteins are first separated by gel electrophoresis (usually agarose), then made visible by immunodiffusion of specific antibodies. A distinct elliptical precipitin arc results for each protein detectable by the antisera. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using
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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] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [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] 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] Incidental: 1. Small and relatively unimportant, minor; 2. Accompanying, but not a major part of something; 3. (To something) Liable to occur because of something or in connection with something (said of risks, responsibilities, .) [EU] Incision: A cut made in the body during surgery. [NIH] Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [NIH] 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] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] 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,
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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]
Infestation: Parasitic attack or subsistence on the skin and/or its appendages, as by insects, mites, or ticks; sometimes used to denote parasitic invasion of the organs and tissues, as by helminths. [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]
Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [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] 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] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [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] Insulin-like: Muscular growth factor. [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]
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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] 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-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] Interleukin-9: Factor that is thought to be a regulator of hematopoiesis. It has been shown to enhance the growth of human mast cells and megakaryoblastic leukemic cells as well as murine helper t-cell clones. IL-9 is a glycoprotein with a molecular weight of 32-39 that is derived from T-cells, and maps to human chromosome 5. [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 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] Interneurons: Most generally any neurons which are not motor or sensory. Interneurons may also refer to neurons whose axons remain within a particular brain region as contrasted with projection neurons which have axons projecting to other brain regions. [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] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Introns: Non-coding, intervening sequences of DNA that are transcribed, but are removed from within the primary gene transcript and rapidly degraded during maturation of messenger RNA. Most genes in the nuclei of eukaryotes contain introns, as do mitochondrial and chloroplast genes. [NIH] 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.
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[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] 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] 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] Irrigation: The washing of a body cavity or surface by flowing solution which is inserted and then removed. Any drug in the irrigation solution may be absorbed. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoflurane: A stable, non-explosive inhalation anesthetic, relatively free from significant side effects. [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] Isoniazid: Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] 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] 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] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually
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by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Laboratory Personnel: Those health care professionals, technicians, and assistants staffing a research or health care facility where specimens are grown, tested, or evaluated and the results of such measures are recorded. [NIH] Lactobacillus: A genus of gram-positive, microaerophilic, rod-shaped bacteria occurring widely in nature. Its species are also part of the many normal flora of the mouth, intestinal tract, and vagina of many mammals, including humans. Pathogenicity from this genus is rare. [NIH] Lamivudine: A reverse transcriptase inhibitor and zalcitabine analog in which a sulfur atom replaces the 3' carbon of the pentose ring. It is used to treat HIV disease. [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] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [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] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or
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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] 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] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [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] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [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 Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [NIH] Liver Neoplasms: Tumors or cancer of the liver. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [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] Loss of Heterozygosity: The loss of one allele at a specific locus, caused by a deletion mutation; or loss of a chromosome from a chromosome pair. It is detected when heterozygous markers for a locus appear monomorphic because one of the alleles was deleted. When this occurs at a tumor suppressor gene locus where one of the alleles is already abnormal, it can result in neoplastic transformation. [NIH]
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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] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [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] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [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]
Lymphadenopathy: Disease or swelling of the lymph nodes. [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: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] 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] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] 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] 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]
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Malabsorption: Impaired intestinal absorption of nutrients. [EU] 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]
Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Man-made: Ionizing radiation emitted by artificial or concentrated natural, radioactive material or resulting from the operation of high voltage apparatus, such as X-ray apparatus or particle accelerators, of nuclear reactors, or from nuclear explosions. [NIH] Mastication: The act and process of chewing and grinding food in the mouth. [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 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] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical
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Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] 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] Membrane: A very thin layer of tissue that covers a surface. [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] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Health: The state wherein the person is well adjusted. [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] Mesoderm: The middle germ layer of the embryo. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metaphase: The second phase of cell division, in which the chromosomes line up across the equatorial plane of the spindle prior to separation. [NIH] 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] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH]
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Methylenetetrahydrofolate Dehydrogenase: Catalyzes the oxidation of methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate. Includes EC 1.5.1.15 which uses NAD+. EC 1.5.1.5. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: 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] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [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] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [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] Microsporidiosis: Infections with protozoa of the phylum Microspora. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] 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] Modeling: A treatment procedure whereby the therapist presents the target behavior which
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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] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] 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] 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] 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] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [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] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motility: The ability to move spontaneously. [EU] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [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] 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] Multicenter Studies: Controlled studies which are planned and carried out by several cooperating institutions to assess certain variables and outcomes in specific patient populations, for example, a multicenter study of congenital anomalies in children. [NIH]
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Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]
Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multienzyme Complexes: Systems of enzymes which function sequentially by catalyzing consecutive reactions linked by common metabolic intermediates; may involve simply a transfer of water molecules of hydrogen atoms or be associated with large supramolecular structures such as mitochondria or ribosomes. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [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] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [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] Myalgia: Pain in a muscle or muscles. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelin Sheath: The lipid-rich sheath investing many axons in both the central and peripheral nervous systems. The myelin sheath is an electrical insulator and allows faster and more energetically efficient conduction of impulses. The sheath is formed by the cell membranes of glial cells (Schwann cells in the peripheral and oligodendroglia in the central nervous system). Deterioration of the sheath in demyelinating diseases is a serious clinical problem. [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] 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] Myoglobin: A conjugated protein which is the oxygen-transporting pigment of muscle. It is made up of one globin polypeptide chain and one heme group. [NIH] 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] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be
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progressive. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [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] Neonatal: Pertaining to the first four weeks after birth. [EU] Neonatal Screening: The identification of selected parameters in newborn infants by various tests, examinations, or other procedures. Screening may be performed by clinical or laboratory measures. A screening test is designed to sort out healthy neonates from those not well, but the screening test is not intended as a diagnostic device, rather instead as epidemiologic. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [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 tube defects: These defects include problems stemming from fetal development of the spinal cord, spine, brain, and skull, and include birth defects such as spina bifida, anencephaly, and encephalocele. Neural tube defects occur early in pregnancy at about 4 to 6 weeks, usually before a woman knows she is pregnant. Many babies with neural tube defects have difficulty walking and with bladder and bowel control. [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] Neurologic: Having to do with nerves or the nervous system. [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,
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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. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [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] Neutrophil Infiltration: The diffusion or accumulation of neutrophils in tissues or cells in response to a wide variety of substances released at the sites of inflammatory reactions. [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] 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]
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 Oxides: Inorganic oxides that contain nitrogen. [NIH] Nitrous Oxide: Nitrogen oxide (N2O). A colorless, odorless gas that is used as an anesthetic and analgesic. High concentrations cause a narcotic effect and may replace oxygen, causing death by asphyxia. It is also used as a food aerosol in the preparation of whipping cream. [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]
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Nosocomial: Pertaining to or originating in the hospital, said of an infection not present or incubating prior to admittance to the hospital, but generally occurring 72 hours after admittance; the term is usually used to refer to patient disease, but hospital personnel may also acquire nosocomial infection. [EU] 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] Nuclear Medicine: A specialty field of radiology concerned with diagnostic, therapeutic, and investigative use of radioactive compounds in a pharmaceutical form. [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] Nucleolus: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleotidases: A class of enzymes that catalyze the conversion of a nucleotide and water to a nucleoside and orthophosphate. EC 3.1.3.-. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritive Value: An indication of the contribution of a food to the nutrient content of the diet. This value depends on the quantity of a food which is digested and absorbed and the amounts of the essential nutrients (protein, fat, carbohydrate, minerals, vitamins) which it contains. This value can be affected by soil and growing conditions, handling and storage, and processing. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Oligodendroglia: A class of neuroglial (macroglial) cells in the central nervous system. Oligodendroglia may be called interfascicular, perivascular, or perineuronal satellite cells according to their location. The most important recognized function of these cells is the formation of the insulating myelin sheaths of axons in the central nervous system. [NIH] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncology: The study of cancer. [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]
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Open Reading Frames: Reading frames where successive nucleotide triplets can be read as codons specifying amino acids and where the sequence of these triplets is not interrupted by stop codons. [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] Ophthalmic: Pertaining to the eye. [EU] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] 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 Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]
Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] 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] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [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] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH]
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Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovarian Follicle: Spheroidal cell aggregation in the ovary containing an ovum. It consists of an external fibro-vascular coat, an internal coat of nucleated cells, and a transparent, albuminous fluid in which the ovum is suspended. [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] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [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 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 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] Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [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]
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Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Panic Disorder: A type of anxiety disorder characterized by unexpected panic attacks that last minutes or, rarely, hours. Panic attacks begin with intense apprehension, fear or terror and, often, a feeling of impending doom. Symptoms experienced during a panic attack include dyspnea or sensations of being smothered; dizziness, loss of balance or faintness; choking sensations; palpitations or accelerated heart rate; shakiness; sweating; nausea or other form of abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest discomfort or pain; fear of dying and fear of not being in control of oneself or going crazy. Agoraphobia may also develop. Similar to other anxiety disorders, it may be inherited as an autosomal dominant trait. [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] 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] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [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] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]
Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (=
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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] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] 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] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: An ulceration of the mucous membrane of the esophagus, stomach or duodenum, caused by the action of the acid gastric juice. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make 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 T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Perennial: Lasting through the year of for several years. [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] Perioperative: Around the time of surgery; usually lasts from the time of going into the hospital or doctor's office for surgery until the time the patient goes home. [NIH] Peripheral blood: Blood circulating throughout the body. [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
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polyneuropathy." [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] Periplasm: The space between the inner and outer membranes of a cell that is shared with the cell wall. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] 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 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] 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] Pest Control: The reduction or regulation of the population of noxious, destructive, or dangerous insects or other animals. [NIH] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] 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] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmacokinetics: Dynamic and kinetic mechanisms of exogenous chemical and drug
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absorption, biotransformation, distribution, release, transport, uptake, and elimination as a function of dosage, and extent and rate of metabolic processes. It includes toxicokinetics, the pharmacokinetic mechanism of the toxic effects of a substance. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [NIH] 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] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenytoin: An anticonvulsant that is used in a wide variety of seizures. It is also an antiarrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [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] Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3. [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 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] Phosphorylase a: The phosphorylated and more active form of phosphorylase that functions as a regulatory enzyme during glycogen breakdown. The phosphate groups are hydrolytically removed by phosphorylase phosphatase to form phosphorylase B and orthophosphate. EC 2.4.1.-. [NIH] Phosphorylase Phosphatase: An enzyme that deactivates glycogen phosphorylase a by releasing inorganic phosphate and phosphorylase b, the inactive form. EC 3.1.3.17. [NIH] Phosphorylated: 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] Photoreceptor: Receptor capable of being activated by light stimuli, as a rod or cone cell of the eye. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase
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"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] Picornavirus: Any of a group of tiny RNA-containing viruses including the enteroviruses and rhinoviruses. [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] Pilot study: The initial study examining a new method or treatment. [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] Plant Diseases: Diseases of plants. [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] 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] 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: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [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] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain
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pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [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] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]
Pneumonia: Inflammation of the lungs. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This 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] 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] 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] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Porosity: Condition of having pores or open spaces. This often refers to bones, bone implants, or bone cements, but can refer to the porous state of any solid substance. [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] Postoperative: After surgery. [NIH]
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Postprandial: Occurring after dinner, or after a meal; postcibal. [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] 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] Prealbumin: A tetrameric protein, molecular weight between 50,000 and 70,000, consisting of 4 equal chains, and migrating on electrophoresis in 3 fractions more mobile than serum albumin. Its concentration ranges from 7 to 33 per cent in the serum, but levels decrease in liver disease. [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] Preclinical: Before a disease becomes clinically recognizable. [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] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Diagnosis: Determination of the nature of a pathological condition or disease in the postimplantation embryo, fetus, or pregnant female before birth. [NIH] Preoperative: Preceding an operation. [EU] Pressoreceptors: Receptors in the vascular system, particularly the aorta and carotid sinus, which are sensitive to stretch of the vessel walls. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary central nervous system lymphoma: Cancer that arises in the lymphoid tissue found in the central nervous system (CNS). The CNS includes the brain and spinal cord. [NIH]
Primary endpoint: The main result that is measured at the end of a study to see if a given
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treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Prion: Small proteinaceous infectious particles that resist inactivation by procedures modifying nucleic acids and contain an abnormal isoform of a cellular protein which is a major and necessary component. [NIH] 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] Procollagen: A biosynthetic precursor of collagen containing additional amino acid sequences at the amino-terminal ends of the three polypeptide chains. Protocollagen, a precursor of procollagen consists of procollagen peptide chains in which proline and lysine have not yet been hydroxylated. [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] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prokaryotic Cells: Cells, such as those of bacteria and the blue green algae, which lack a nuclear membrane so that the nuclear material is either scattered in the cytoplasm or collected in a nucleoid region. [NIH] Proliferative Retinopathy: A disease of the small blood vessels of the retina of the eye. [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] 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] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [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
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upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]
Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [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 Engineering: Procedures by which nonrandom single-site changes are introduced into structural genes (site-specific mutagenesis) in order to produce mutant genes which can be coupled to promoters that direct the synthesis of a specifically altered protein, which is then analyzed for structural and functional properties and then compared with the predicted and sought-after properties. The design of the protein may be assisted by computer graphic technology and other advanced molecular modeling techniques. [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 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 Splicing: Excision of in-frame internal protein sequences (inteins) of a precursor protein, coupled with ligation of the flanking sequences (exteins). Protein splicing is an autocatalytic reaction and results in the production of two proteins from a single primary translation product: the intein and the mature protein. [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] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [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]
Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [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]
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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] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] 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] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of 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]
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] Pyelonephritis: Inflammation of the kidney and its pelvis, beginning in the interstitium and rapidly extending to involve the tubules, glomeruli, and blood vessels; due to bacterial infection. [EU] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [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] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quiescent: Marked by a state of inactivity or repose. [EU]
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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 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] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiopharmaceuticals: Drugs containing a radioactive substance that are used in the diagnosis and treatment of cancer and in pain management of bone metastases. Also called radioactive drugs. [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] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and
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control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [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] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [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] Reading Frames: The sequence of codons by which translation may occur. A segment of mRNA 5'AUCCGA3' could be translated in three reading frames, 5'AUC. or 5'UCC. or 5'CCG., depending on the location of the start codon. [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] 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 cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive
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error (myopia, hyperopia, or astigmatism). [NIH] 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] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [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] Resection: Removal of tissue or part or all of an organ by surgery. [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 Burst: A large increase in oxygen uptake by neutrophils and most types of tissue macrophages through activation of an NADPH-cytochrome b-dependent oxidase that reduces oxygen to a superoxide. Individuals with an inherited defect in which the oxidase that reduces oxygen to superoxide is decreased or absent (granulomatous disease, chronic) often die as a result of recurrent bacterial infections. [NIH] Respiratory System: The tubular and cavernous organs and structures, by means of which pulmonary ventilation and gas exchange between ambient air and the blood are brought about. [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
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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] Retinal Vein: Central retinal vein and its tributaries. It runs a short course within the optic nerve and then leaves and empties into the superior ophthalmic vein or cavernous sinus. [NIH]
Retinal Vein Occlusion: Occlusion of the retinal vein. Those at high risk for this condition include patients with hypertension, diabetes mellitus, arteriosclerosis, and other cardiovascular diseases. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] 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] Retrotransposons: DNA sequence which is a copy of a RNA virus into a host's DNA and which can reinsert itself elsewhere in the genome. [NIH] 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] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [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] 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] Rickettsiae: One of a group of obligate intracellular parasitic microorganisms, once regarded as intermediate in their properties between bacteria and viruses but now classified as bacteria in the order Rickettsiales, which includes 17 genera and 3 families: Rickettsiace. [NIH]
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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] Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Ruminants: A suborder of the order Artiodactyla whose members have the distinguishing feature of a four-chambered stomach. Horns or antlers are usually present, at least in males. [NIH]
Ryanodine: Insecticidal alkaloid isolated from Ryania speciosa; proposed as a myocardial depressant. [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] 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] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Sarcoplasmic Reticulum: A network of tubules and sacs in the cytoplasm of skeletal muscles that assist with muscle contraction and relaxation by releasing and storing calcium ions. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [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]
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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] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] 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] SelenoSemen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sequela: Any lesion or affection following or caused by an attack of disease. [EU] Sequence Alignment: The arrangement of two or more amino acid or base sequences from an organism or organisms in such a way as to align areas of the sequences sharing common properties. The degree of relatedness or homology between the sequences is predicted computationally or statistically based on weights assigned to the elements aligned between the sequences. This in turn can serve as a potential indicator of the genetic relatedness between the organisms. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is
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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] Sessile: Attached directly by the base, denoting a tumor without penduncle or stalk; in zoology, attached so that it is not possible to move about. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sharpness: The apparent blurring of the border between two adjacent areas of a radiograph having different optical densities. [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]
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] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Sil: The arithmetical average of the octave band sound pressure levels of a noise, centered on the frequencies 425, 850 and 1700 Hz together with the frequency 212 of the SIL in this band exceeds the others by 10 dB or more. [NIH] Silage: Fodder converted into succulent feed for livestock through processes of anaerobic fermentation (as in a silo). [NIH] Sinoatrial Node: The small mass of modified cardiac muscle fibers located at the junction of the superior vena cava and right atrium. Contraction impulses probably start in this node, spread over the atrium and are then transmitted by the atrioventricular bundle to the ventricle. [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] Skin test: A test for an immune response to a compound by placing it on or under the skin. [NIH]
Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH]
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Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [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] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [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] Sodium Acetate: The trihydrate sodium salt of acetic acid, which is used as a source of sodium ions in solutions for dialysis and as a systemic and urinary alkalizer, diuretic, and expectorant. [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] 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] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatotropin: A small peptide hormone released by the anterior pituitary under hypothalamic control. Somatotropin, or growth hormone, stimulates mitosis, cell growth, and, for some cell types, differentiation in many tissues of the body. It has profound effects on many aspects of gene expression and metabolism. [NIH] Spasmodic: Of the nature of a spasm. [EU] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [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
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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] Spina bifida: A defect in development of the vertebral column in which there is a central deficiency of the vertebral lamina. [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] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] 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 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] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]
Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Steady state: Dynamic equilibrium. [EU] Steatosis: Fatty degeneration. [EU] Stellate: Star shaped. [NIH] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] Stereotactic radiosurgery: A radiation therapy technique involving a rigid head frame that is attached to the skull; high-dose radiation is administered through openings in the head frame to the tumor while decreasing the amount of radiation given to normal brain tissue. This procedure does not involve surgery. Also called stereotaxic radiosurgery and stereotactic radiation therapy. [NIH] Sterile: Unable to produce children. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this
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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] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Streptococcal: Caused by infection due to any species of streptococcus. [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] Streptomycin: O-2-Deoxy-2-(methylamino)-alpha-L-glucopyranosyl-(1-2)-O-5- deoxy-3-Cformyl-alpha-L-lyxofuranosyl-(1-4)-N,N'-bis(aminoiminomethyl)-D-streptamine. Antibiotic substance produced by the soil actinomycete Streptomyces griseus. It acts by inhibiting the initiation and elongation processes during protein synthesis. [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] 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] Struvite: A type of kidney stone caused by infection. [NIH] Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [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] 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]
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Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is somewhat misleading, because some patients survive. [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] Sulfur Compounds: Inorganic or organic compounds that contain sulfur as an integral part of the molecule. [NIH] Superior vena cava: Vein which returns blood from the head and neck, upper limbs, and thorax. It is formed by the union of the two brachiocephalic veins. [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] Suppositories: A small cone-shaped medicament having cocoa butter or gelatin at its basis and usually intended for the treatment of local conditions in the rectum. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Surface Plasmon Resonance: A biosensing technique in which biomolecules capable of binding to specific analytes or ligands are first immobilized on one side of a metallic film. Light is then focused on the opposite side of the film to excite the surface plasmons, that is, the oscillations of free electrons propagating along the film's surface. The refractive index of light reflecting off this surface is measured. When the immobilized biomolecules are bound by their ligands, an alteration in surface plasmons on the opposite side of the film is created which is directly proportional to the change in bound, or adsorbed, mass. Binding is measured by changes in the refractive index. The technique is used to study biomolecular interactions, such as antigen-antibody binding. [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]
Surgical Wound Infection: Infection occurring at the site of a surgical incision. [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] Symphysis: A secondary cartilaginous joint. [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] 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]
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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] 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] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] 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] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] 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] Theca Cells: The connective tissue cells of the ovarian follicle. [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]
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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] 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, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] 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] Thymoma: A tumor of the thymus, an organ that is part of the lymphatic system and is located in the chest, behind the breastbone. [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] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Thyrotropin: A peptide hormone secreted by the anterior pituitary. It promotes the growth
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of the thyroid gland and stimulates the synthesis of thyroid hormones and the release of thyroxine by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [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] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [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] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] 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] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [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] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] 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]
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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] 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] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [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] Transposons: Discrete genetic elements capable of inserting, in a non-permuted fashion, into the chromosomes of many bacteria. [NIH] Trans-Splicing: The joining of RNA from two different genes. One type of trans-splicing is the "spliced leader" type (primarily found in protozoans such as trypanosomes and in lower invertebrates such as nematodes) which results in the addition of a capped, noncoding, spliced leader sequence to the 5' end of mRNAs. Another type of trans-splicing is the "discontinuous group II introns" type (found in plant/algal chloroplasts and plant mitochondria) which results in the joining of two independently transcribed coding sequences. Both are mechanistically similar to conventional nuclear pre-mRNA cis-splicing. Mammalian cells are also capable of trans-splicing. [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] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] Trigeminal: Cranial nerve V. It is sensory for the eyeball, the conjunctiva, the eyebrow, the skin of face and scalp, the teeth, the mucous membranes in the mouth and nose, and is motor to the muscles of mastication. [NIH] 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] Tuberculostatic: Inhibiting the growth of Mycobacterium tuberculosis. [EU] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH]
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Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [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] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [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] Typhimurium: Microbial assay which measures his-his+ reversion by chemicals which cause base substitutions or frameshift mutations in the genome of this organism. [NIH] Typhoid fever: The most important member of the enteric group of fevers which also includes the paratyphoids. [NIH] Typhoid fever: The most important member of the enteric group of fevers which also includes the paratyphoids. [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] 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] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] 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] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [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]
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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] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]
Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagal: Pertaining to the vagus nerve. [EU] 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] Vagolytic: Having an effect resembling that produced by interruption of impulses transmitted by the vagus nerve; parasympatholytic. [EU] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic afferents (from skin in back of the ear and the external auditory meatus), visceral afferents (from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [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]
Varicella: Chicken pox. [EU] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoactive Intestinal Peptide: A highly basic, single-chain polypeptide isolated from the intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems. It is also found in several parts of the central and peripheral nervous systems and is a neurotransmitter. [NIH] Vasodilators: Any nerve or agent which induces dilatation of the blood vessels. [NIH] 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] 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] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinarians: Individuals with a degree in veterinary medicine that provides them with
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training and qualifications to treat diseases and injuries of animals. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virilism: Development of masculine traits in the female. [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] 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] Vitamin U: A vitamin found in green vegetables. It is used in the treatment of peptic ulcers, colitis, and gastritis and has an effect on secretory, acid-forming, and enzymatic functions of the intestinal tract. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH] 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]
Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] Warts: Benign epidermal proliferations or tumors; some are viral in origin. [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] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Wound Infection: Invasion of the site of trauma by pathogenic microorganisms. [NIH]
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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] Zalcitabine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication at low concentrations, acting as a chainterminator of viral DNA by binding to reverse transcriptase. Its principal toxic side effect is axonal degeneration resulting in peripheral neuropathy. [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]
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INDEX 2 2-Aminopurine, 29, 217 A Abdomen, 217, 229, 261, 264, 276, 277, 278, 294, 295, 302 Abdominal, 217, 218, 275, 276, 278, 301 Abdominal Pain, 217, 301 Aberrant, 29, 143, 217 Ablation, 30, 217 Abortion, 147, 217, 257 Abrasion, 190, 217 Abscess, 90, 217 Acatalasia, 217, 232 Acceptor, 167, 217, 264, 275, 298 Acetaminophen, 125, 147, 217 Acetylcholine, 41, 217, 234, 235, 272 Acetylcysteine, 43, 85, 107, 217 Acidity, 217, 278 Acidosis, 157, 217 Acrylonitrile, 217, 290 Actin, 68, 218, 270 Acylation, 20, 83, 156, 218 Adaptability, 218, 233 Adaptation, 112, 218, 270 Adduct, 29, 218 Adenine, 29, 164, 217, 218, 285 Adenocarcinoma, 186, 218, 255 Adenoma, 21, 22, 92, 106, 218 Adenosine, 5, 8, 46, 164, 218, 230, 279, 297 Adenovirus, 157, 158, 180, 218 Adenylate Cyclase, 89, 108, 218 Adipocytes, 218, 263 Adjustment, 218 Adjuvant, 143, 218, 251 Adrenal Cortex, 218, 239, 247, 257, 283 Adrenal Glands, 218, 221 Adrenergic, 79, 218, 243, 246, 286 Adverse Effect, 218, 279, 292 Aerobic, 218, 268 Aerosol, 43, 218, 272 Afferent, 218, 263 Affinity, 8, 9, 70, 218, 225, 293 Agar, 219, 280 Aggressiveness, 23, 219 Agonists, 37, 186, 219 Agoraphobia, 219, 258, 276 Alanine, 10, 14, 46, 47, 169, 172, 175, 219, 242
Albumin, 4, 69, 219, 280 Albuminuria, 91, 219 Alcohol Dehydrogenase, 22, 219 Alfalfa, 159, 219 Algorithms, 219, 228 Alimentary, 154, 155, 219, 276 Alkaline, 165, 217, 219, 221, 230, 275, 279, 297 Alkaloid, 219, 236, 269, 286, 290, 297 Alkylating Agents, 219, 301 Alleles, 46, 163, 173, 220, 256, 264 Allergens, 220, 226 Allogeneic, 220, 253 Allograft, 6, 220 Alloys, 220, 236 Allylglycine, 184, 220 Alopecia, 188, 189, 220 Alpha 1-Antitrypsin, 109, 220 Alpha Particles, 220, 286 Alpha-1, 220, 279 Alternative medicine, 10, 220 Alternative Splicing, 50, 220, 284 Ambulatory Care, 220 Ameliorating, 189, 220 Amenorrhea, 220, 281 Amino Acid Sequence, 156, 161, 165, 181, 183, 184, 221, 222, 227, 247, 251, 283 Amino Acid Substitution, 46, 163, 172, 173, 221 Aminopeptidases, 29, 33, 77, 107, 142, 162, 176, 182, 187, 221, 247 Amino-terminal, 169, 187, 221, 283 Ammonia, 169, 221, 253, 296, 301 Ammonium Chloride, 133, 221 Amplification, 11, 221 Ampulla, 221, 234 Amylase, 165, 221 Amyloid, 45, 46, 78, 100, 109, 221 Amyloidosis, 45, 221 Anaemia, 93, 221, 267 Anaerobic, 12, 221, 292 Anaesthesia, 221, 259 Anal, 221, 246 Analgesic, 217, 221, 245, 269, 272, 274, 286 Analog, 29, 33, 42, 63, 66, 140, 158, 221, 263 Analogous, 222, 243, 300 Analytes, 222, 296
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Methionine
Anaphylatoxins, 222, 237 Anatomical, 222, 226, 245, 259, 268, 290 Androgens, 218, 222, 257 Anemia, 4, 51, 201, 222, 236, 250, 266 Anesthesia, 58, 172, 222 Angiogenesis, 29, 161, 170, 171, 174, 177, 178, 182, 188, 222, 266 Angiogenesis inhibitor, 29, 174, 177, 178, 222 Animal model, 24, 28, 57, 159, 222 Anions, 10, 156, 219, 222, 262, 292, 296 Anode, 222 Anomalies, 222, 269 Anovulation, 222, 281 Anthocyanins, 175, 222 Antiangiogenic, 188, 222 Antibacterial, 20, 155, 222, 262, 294 Antibiotic, 42, 56, 62, 177, 189, 222, 240, 277, 294, 295 Antibodies, 5, 28, 38, 56, 163, 177, 186, 222, 223, 224, 254, 258, 259, 265, 269, 280, 286 Anticarcinogenic, 22, 223 Anticoagulant, 223, 284 Anticodon, 67, 74, 76, 223 Anticonvulsant, 9, 223, 231, 279 Antiepileptic, 91, 97, 223 Antigen-Antibody Complex, 223, 237 Anti-infective, 223, 257, 262 Anti-inflammatory, 5, 173, 217, 223, 233, 252 Anti-Inflammatory Agents, 223, 233 Antimetabolite, 223, 241, 247, 267 Antimetastatic, 61, 223 Antimicrobial, 43, 171, 223, 241 Antineoplastic, 137, 189, 220, 223, 250, 267, 303 Antioxidant, 24, 33, 57, 84, 110, 130, 156, 173, 223, 225, 250, 275 Antiparasitic Agents, 8, 223 Antiplasmin, 26, 223 Antipyretic, 217, 223, 286 Antiseptic, 223, 232 Antiserum, 25, 224 Antiviral, 164, 217, 224, 241, 250, 261, 277 Anus, 186, 221, 224, 236 Apolipoproteins, 224, 264 Apoptosis, 11, 15, 26, 31, 32, 56, 61, 77, 100, 141, 157, 180, 224, 232, 233, 240 Applicability, 53, 224 Aqueous, 185, 224, 240, 245, 257, 263 Arachidonate 12-Lipoxygenase, 224, 264 Arachidonate 15-Lipoxygenase, 224, 264
Arachidonate Lipoxygenases, 224, 264 Arachidonic Acid, 224, 244, 283 Archaea, 163, 224, 239, 247, 268 Arginine, 13, 16, 41, 46, 69, 83, 112, 154, 190, 222, 224, 242, 256, 272, 300 Arterial, 41, 47, 77, 78, 224, 225, 234, 257, 284, 297 Arteries, 224, 225, 226, 229, 239, 265, 268, 270, 285, 298 Arterioles, 225, 229, 231, 268, 302 Arteriolosclerosis, 225 Arteriosclerosis, 86, 131, 132, 171, 225, 289 Arteriovenous, 225, 268 Artery, 88, 107, 224, 225, 239, 276, 285, 288 Articular, 225, 274 Asbestos, 225, 236 Ascorbic Acid, 37, 130, 225, 257 Aspartate, 91, 167, 225, 253 Aspartic, 182, 225 Aspartic Acid, 182, 225 Asphyxia, 225, 272 Assay, 4, 31, 36, 38, 120, 157, 158, 172, 180, 225, 258, 301 Astringent, 225, 232 Astrocytes, 34, 225, 268 Asymptomatic, 58, 217, 225 Ataxia, 201, 226, 297 Atherogenic, 4, 74, 226 Atopic, 163, 173, 226 Atopic allergy, 163, 173, 226 Atrioventricular, 226, 292 Atrium, 226, 292, 302 Atrophy, 200, 201, 226, 255, 271 Attenuated, 25, 226, 242, 302 Attenuation, 60, 226 Autoimmune disease, 12, 171, 226 Autonomic, 30, 37, 217, 226, 272, 277 Autoradiography, 56, 226 Avian, 226, 239 Axons, 226, 261, 270, 273, 274 Azoxymethane, 143, 226 B Bacillus, 54, 67, 69, 70, 74, 144, 179, 226, 230 Bacterial Infections, 62, 118, 226, 288 Bacterial Physiology, 218, 226 Bactericidal, 24, 226, 247 Bacteriophage, 226, 280, 300 Bacterium, 25, 154, 164, 226, 238 Baroreflex, 31, 226 Basal cells, 190, 227 Basal Ganglia, 96, 226, 227, 250
307
Basal Ganglia Diseases, 226, 227 Base Sequence, 227, 250, 251, 291 Basophils, 164, 227, 263 Benign, 218, 225, 227, 250, 254, 271, 276, 286, 303 Beta-Endorphin, 112, 227 Beta-glucans, 227, 233 Beta-pleated, 221, 227 Bilateral, 227, 281 Bile, 227, 264, 295, 297 Bile Acids, 227, 295, 297 Biliary, 227, 234 Bilirubin, 219, 227 Binding Sites, 56, 227 Bioavailability, 41, 227 Bioavailable, 60, 179, 227 Biofilms, 56, 228 Biogenesis, 11, 228 Biological Markers, 9, 228 Biological therapy, 228, 254 Bioluminescence, 228, 265 Biomarkers, 21, 39, 77, 106, 228 Biomolecular, 13, 120, 228, 296 Biophysics, 12, 19, 30, 65, 84, 102, 142, 228 Biopolymers, 110, 187, 228 Biopsy, 50, 228 Biopterin, 18, 228 Biosynthesis, 12, 18, 20, 40, 53, 56, 68, 69, 73, 74, 89, 144, 152, 167, 224, 228, 240, 292 Biotechnology, 66, 75, 124, 139, 154, 161, 197, 199, 200, 201, 202, 228 Bioterrorism, 43, 228 Bivalent, 154, 228 Bladder, 145, 228, 237, 271, 283, 301 Blood Coagulation, 229, 230, 298 Blood Glucose, 229, 255, 260 Blood Platelets, 229, 292 Blood pressure, 84, 132, 133, 226, 229, 231, 257, 258, 269, 278, 285, 293 Blot, 28, 61, 64, 229, 258 Blotting, Western, 229, 258 Body Fluids, 228, 229, 244, 293, 301 Body Mass Index, 229, 275 Bone Cements, 229, 281 Bone Marrow, 88, 172, 229, 251, 265, 269, 293 Bone metastases, 229, 286 Bone scan, 229, 290 Bowel, 5, 221, 229, 260, 261, 271, 278, 295, 301 Brachytherapy, 95, 229, 261, 262, 286, 304
Bradycardia, 37, 229 Bradykinin, 229, 272, 280 Breath Tests, 112, 229 Breeding, 45, 124, 176, 230 Bronchiseptica, 230, 278 Buccal, 230, 257 Buffers, 226, 230 Butyric Acid, 230, 247 C Caffeine, 230, 285 Calcification, 52, 225, 230 Calcitonin, 84, 230 Calcium, 9, 15, 39, 53, 54, 58, 160, 225, 229, 230, 231, 237, 266, 268, 276, 284, 290, 297 Calcium Channels, 9, 53, 230 Calmodulin, 52, 55, 58, 89, 230 Calpain, 157, 158, 180, 230 Canonical, 142, 231 Capillary, 112, 131, 178, 188, 229, 231, 302 Capping, 8, 231 Capsules, 231, 251 Carbamazepine, 92, 231 Carbohydrate, 231, 252, 253, 273, 281 Carbon Dioxide, 72, 231, 241, 253, 280, 288 Carboxypeptidases, 231, 248 Carcinogen, 20, 29, 218, 226, 231 Carcinogenesis, 21, 29, 77, 231 Carcinogenic, 22, 29, 220, 231, 260, 283, 295, 301 Carcinoma, 22, 97, 185, 186, 231 Cardiac, 4, 37, 46, 227, 230, 231, 246, 247, 270, 286, 292, 295, 296 Cardiac Output, 227, 231 Cardiomyopathy, 45, 231 Cardiovascular, 6, 10, 19, 30, 41, 51, 53, 77, 88, 91, 172, 177, 206, 230, 231, 289, 292, 302 Cardiovascular disease, 6, 19, 41, 51, 53, 91, 172, 177, 206, 231, 289 Carnitine, 99, 127, 131, 231 Carotene, 232, 288 Carrier Proteins, 232, 280 Case report, 232, 235 Case series, 232, 235 Caspase, 12, 26, 31, 100, 157, 180, 232 Caspase 1, 26, 232 Catabolism, 12, 23, 75, 105, 124, 232, 301 Catalase, 24, 217, 232 Catalyse, 176, 232 Catalytic Domain, 172, 182, 232 Cataract, 59, 232 Catechol, 96, 232
308
Methionine
Catecholamines, 19, 232, 243 Cations, 232, 262 Caudal, 232, 242, 258, 281 Causal, 232, 246 Cause of Death, 43, 232 Cavernous Sinus, 232, 289 Celecoxib, 73, 232 Cell Aging, 52, 233 Cell Cycle, 15, 30, 39, 182, 233, 235, 240 Cell Death, 11, 31, 32, 158, 171, 180, 224, 233, 252, 271 Cell Division, 108, 117, 200, 226, 233, 254, 267, 268, 280, 283, 291 Cell membrane, 156, 230, 232, 233, 250, 270, 279, 303 Cell motility, 233, 255 Cell Physiology, 53, 131, 233 Cell proliferation, 15, 161, 177, 225, 233, 261 Cell Respiration, 233, 268, 288 Cell Size, 233, 249 Cell Survival, 233, 254 Cellobiose, 233 Cellular metabolism, 170, 233 Cellulase, 154, 233 Cellulose, 187, 233, 280 Centromere, 68, 233 Cerebellar, 226, 233, 287 Cerebral, 4, 85, 96, 100, 104, 226, 227, 234, 238, 245, 246, 266, 285, 297 Cerebral Cortex, 104, 226, 234 Cerebrospinal, 79, 234 Cerebrospinal fluid, 79, 234 Cerebrovascular, 6, 100, 227, 231, 234, 297 Cerebrum, 234, 297, 300 Cervical, 185, 186, 234 Cervix, 217, 234, 236 Chemotactic Factors, 234, 237 Chemotaxis, 42, 73, 234 Chemotherapeutic agent, 31, 33, 159, 234 Chemotherapy, 18, 32, 82, 87, 107, 141, 164, 189, 234 Chimeras, 48, 234 Chlorides, 169, 234 Chlorine, 234, 258 Chlorophyll, 234 Chloroplasts, 156, 187, 234, 300 Cholestasis, 76, 129, 234 Cholesterol, 146, 227, 234, 235, 239, 264, 265, 295 Cholesterol Esters, 234, 264 Choline, 15, 31, 38, 39, 88, 127, 133, 234
Cholinergic, 103, 235 Chondrocytes, 235, 249 Chromatin, 38, 158, 181, 224, 235 Chromium, 133, 235 Chromosomal, 221, 235, 252, 256, 269, 280, 289 Chromosome, 72, 99, 233, 235, 238, 254, 261, 264, 291 Chronic Disease, 22, 235 Chronic renal, 7, 131, 235, 281 Chylomicrons, 235, 264 Cirrhosis, 50, 60, 80, 99, 115, 145, 235 CIS, 32, 54, 184, 189, 235, 289, 300 Cisplatin, 189, 235 Clear cell carcinoma, 235, 241 Cleave, 33, 231, 235, 242 Clinical Medicine, 75, 235, 282 Clinical study, 59, 235, 238 Clinical trial, 5, 20, 30, 44, 46, 60, 109, 114, 184, 197, 235, 238, 243, 247, 270, 284, 287 Clone, 21, 38, 235 Cloning, 13, 24, 56, 94, 98, 131, 176, 177, 228, 235, 260 Clot Retraction, 236, 280 Cobalt, 33, 51, 73, 97, 172, 236 Codon, 13, 47, 74, 77, 95, 162, 163, 168, 173, 223, 236, 251, 287, 291 Coenzyme, 225, 236 Cofactor, 12, 26, 32, 51, 111, 125, 182, 236, 284, 298 Cohort Studies, 21, 22, 236, 246 Colchicine, 236, 301 Colitis, 236, 303 Collagen, 9, 185, 221, 236, 248, 249, 251, 266, 281, 283 Collapse, 157, 236 Colloidal, 139, 219, 236, 244, 278, 292 Colon, 14, 21, 22, 39, 42, 48, 145, 177, 200, 226, 236, 248, 260, 263, 301 Colorectal, 20, 22, 92, 106, 113, 227, 236 Colorectal Cancer, 20, 92, 113, 227, 236 Colorectal Neoplasms, 20, 236 Combinatorial, 28, 237 Complement, 24, 35, 222, 223, 237, 251, 265, 280 Complementary and alternative medicine, 129, 130, 150, 237 Complementary medicine, 130, 237 Complementation, 98, 237, 251 Compliance, 27, 237 Computational Biology, 197, 199, 237
309
Computed tomography, 14, 80, 85, 118, 237, 238, 290 Computerized axial tomography, 237, 238, 290 Computerized tomography, 237, 238 Conduction, 238, 270 Cones, 238, 289 Confidence Intervals, 26, 238 Congenita, 157, 238, 286 Conjugated, 238, 240, 270 Conjugation, 184, 238 Conjunctiva, 238, 260, 300 Connective Tissue, 225, 229, 236, 238, 241, 249, 250, 251, 265, 289, 290, 297 Consciousness, 221, 238, 241, 243 Constriction, 238, 262 Contraindications, ii, 238 Control group, 238, 283, 287 Controlled clinical trial, 6, 238 Controlled study, 17, 49, 238 Convulsions, 220, 223, 238 Coordination, 11, 44, 238 Cornea, 239, 295, 304 Corneum, 190, 239, 246 Coronary, 4, 6, 107, 111, 116, 231, 239, 257, 268, 270 Coronary heart disease, 4, 7, 111, 116, 231, 239 Coronary Thrombosis, 239, 268, 270 Corpus, 171, 239, 265, 277, 283, 303 Corpus Luteum, 171, 239, 265, 283 Cortex, 239, 287 Cortical, 239, 247, 291, 297 Cortisol, 219, 239 Creatinine, 6, 239 Creatinine clearance, 6, 239 Crenarchaeota, 224, 239 Crossing-over, 239, 287 Cross-Sectional Studies, 239, 246 Crystallins, 37, 59, 239 Crystallization, 6, 239 Cultured cells, 30, 239 Curative, 239, 272, 298 Cutaneous, 190, 239, 263 Cyclic, 84, 218, 230, 231, 240, 254, 272, 297 Cyclin, 15, 39, 240 Cycloheximide, 64, 240 Cyst, 16, 240 Cystathionine beta-Synthase, 240, 257 Cysteinyl, 16, 240 Cystine, 16, 81, 155, 240
Cytochrome, 10, 18, 22, 24, 60, 61, 142, 240, 288 Cytochrome b, 240, 288 Cytokine, 43, 175, 240 Cytoplasm, 158, 177, 181, 224, 227, 233, 240, 245, 246, 269, 270, 283, 289, 290 Cytoprotection, 44, 240 Cytosine, 29, 62, 240, 285 Cytoskeletal Proteins, 230, 240 Cytoskeleton, 108, 114, 240 Cytotoxic, 7, 138, 166, 185, 240, 286 Cytotoxicity, 43, 235, 240 D Data Collection, 129, 241 De novo, 6, 16, 34, 38, 53, 241 Deamination, 241, 301 Degenerative, 241, 255, 274, 289 Deletion, 29, 165, 224, 241, 251, 264 Dementia, 4, 27, 45, 78, 81, 145, 241 Demethylation, 172, 206, 241 Demyelinating Diseases, 241, 270 Denaturation, 37, 241 Dendrites, 241, 272 Density, 4, 55, 101, 110, 229, 241, 249, 264, 273 Dental Caries, 241, 249 Deoxyglucose, 108, 118, 241 Depressive Disorder, 17, 49, 76, 241 Deprivation, 117, 159, 241 Dermis, 190, 241, 296 DES, 115, 222, 241 Detergents, 165, 241 Deuterium, 242, 257 Diabetes Mellitus, 242, 255, 289 Diabetic Retinopathy, 97, 171, 242 Diagnostic procedure, 153, 242 Diarrhea, 157, 242 Diarrhoea, 242, 257 Diastolic, 242, 257 Diencephalon, 242, 258, 297 Diffusion, 242, 254, 260, 272 Digestion, 219, 227, 229, 242, 261, 264, 277, 295, 302 Digestive tract, 242, 293, 294 Dihydrotestosterone, 242, 287 Dilution, 102, 155, 242 Dimethyl, 79, 242 Dipeptidases, 242, 248 Dipeptidyl Peptidases, 242, 248 Diploid, 237, 242, 280
310
Methionine
Direct, iii, 10, 17, 25, 28, 29, 31, 49, 57, 68, 84, 158, 174, 235, 242, 243, 284, 286, 287, 296 Discrete, 12, 56, 242, 300, 304 Disease Susceptibility, 65, 242 Disease Vectors, 158, 242 Disinfectant, 242, 247 Dissection, 18, 242 Dissociation, 219, 242 Distal, 21, 243, 277 Diuretic, 189, 221, 243, 293 Dizziness, 9, 243, 276 Domesticated, 243, 254 Dominance, 243, 251 Dopamine, 243, 272, 279 Dose-limiting, 177, 243 Double-blind, 6, 17, 49, 50, 73, 76, 243 Drug Design, 97, 243 Drug Evaluation, 243, 247 Drug Evaluation, Preclinical, 243, 247 Drug Resistance, 32, 243 Drug Tolerance, 243, 299 Duct, 221, 244, 290, 296 Dyes, 157, 180, 221, 227, 244, 249 Dysphoric, 241, 244 Dysplasia, 38, 185, 201, 244 Dystrophy, 200, 244 E Edema, 234, 242, 244, 263 Effector, 43, 61, 217, 237, 244 Effector cell, 43, 244 Efficacy, 5, 10, 17, 28, 32, 42, 46, 49, 56, 63, 75, 76, 89, 129, 135, 138, 141, 243, 244 Eicosanoids, 5, 244 Elastic, 244, 296 Elasticity, 52, 190, 225, 244 Elastin, 236, 244, 248 Elective, 42, 59, 115, 244 Electrolysis, 222, 232, 244 Electrolyte, 244, 282, 293 Electrons, 223, 244, 262, 275, 286, 296 Electrophoresis, 52, 244, 258, 282 Electroplating, 232, 244 Embryo, 217, 244, 248, 259, 267, 282 Emphysema, 220, 244 Emulsion, 160, 187, 226, 245 Enamel, 56, 241, 245 Encephalocele, 245, 271 Encephalopathy, 65, 117, 245 Endemic, 18, 245, 266, 294 Endocytosis, 99, 245
Endogenous, 7, 45, 63, 88, 174, 227, 230, 243, 244, 245, 275, 284, 300 Endorphin, 79, 227, 245 Endothelial cell, 25, 30, 33, 41, 161, 174, 177, 178, 188, 245, 249, 298 Endothelium, 41, 52, 88, 245, 272, 280 Endothelium, Lymphatic, 245 Endothelium, Vascular, 245 Endothelium-derived, 245, 272 Endotoxemia, 43, 245 Endotoxins, 237, 245, 262 End-stage renal, 7, 235, 245, 281 Energy balance, 246, 263 Enhancers, 167, 246 Enkephalin, 79, 81, 87, 88, 90, 106, 112, 120, 227, 246 Environmental Exposure, 228, 246, 273 Environmental Health, 196, 198, 246 Environmental Pollutants, 29, 189, 190, 246 Enzyme Inhibitors, 11, 162, 246, 280 Eosinophil, 79, 246 Eosinophilic, 246 Epidemic, 246, 294 Epidemiologic Studies, 20, 228, 246 Epidermal, 190, 246, 267, 303 Epidermis, 190, 227, 239, 241, 246, 257 Epidermoid carcinoma, 246, 294 Epinephrine, 218, 243, 246, 272, 301 Epithelial, 7, 63, 117, 186, 218, 246, 255, 276 Epithelial Cells, 7, 117, 246, 255 Epithelium, 245, 246, 276, 304 Erectile, 247, 277 Erythrocytes, 23, 102, 103, 104, 221, 222, 229, 230, 247, 287 Essential Tremor, 201, 247 Estradiol, 24, 247 Estrogen, 36, 247 Estrogen receptor, 36, 247 Ethanol, 9, 26, 56, 60, 69, 120, 125, 219, 247, 248 Ether, 224, 247 Ethionine, 70, 95, 105, 106, 107, 138, 247 Ethnic Groups, 47, 247 Eukaryotic Cells, 163, 170, 240, 247, 259, 273, 274 Euryarchaeota, 224, 247 Evaluation Studies, 14, 247 Excitability, 34, 247, 286 Excitation, 30, 247, 249, 272 Excitatory, 34, 247, 253
311
Excrete, 6, 247, 262 Exhaustion, 247, 266 Exogenous, 38, 63, 69, 86, 245, 247, 278, 284 Exon, 47, 50, 83, 163, 173, 220, 247 Exopeptidases, 158, 180, 221, 242, 247, 277 Expectorant, 221, 248, 293 Extensor, 248, 285 External-beam radiation, 248, 262, 286, 304 Extracellular, 41, 221, 225, 228, 238, 245, 248, 249, 266, 268, 293, 297 Extracellular Matrix, 238, 248, 249, 266 Extracellular Matrix Proteins, 248, 266 Extracellular Space, 248, 268 Eye Infections, 218, 248 F Familial polyposis, 236, 248 Family Planning, 197, 248 Fat, 9, 15, 39, 218, 224, 229, 230, 232, 239, 248, 263, 264, 273, 275, 289, 293, 296 Fatty Liver, 26, 248 Fermentation, 136, 168, 179, 219, 248, 292 Fertilizers, 183, 248 Fetal Development, 248, 271 Fetus, 217, 248, 280, 282, 302 Fibril, 46, 248 Fibrillation, 82, 114, 249 Fibrinogen, 4, 249, 280, 298 Fibrinolysis, 26, 88, 249 Fibroblast Growth Factor, 161, 249 Fibroblasts, 116, 249 Fibrosis, 9, 60, 100, 201, 249, 290 Financial Management, 44, 249 Flatus, 249, 251 Flavodoxin, 12, 70, 151, 249 Flow Cytometry, 61, 249 Fluorescence, 28, 29, 157, 180, 249 Fluorescent Dyes, 157, 180, 249 Fluorine, 14, 90, 92, 249 Fold, 36, 177, 182, 249 Folic Acid, 6, 21, 27, 31, 46, 56, 70, 102, 107, 127, 136, 138, 166, 249, 250 Follicular Fluid, 120, 250 Forearm, 229, 250 Frameshift, 71, 109, 250, 301 Frameshift Mutation, 71, 109, 250, 301 Free Radicals, 156, 223, 243, 250 Friction, 190, 250 Fungi, 13, 228, 233, 238, 248, 250, 254, 268, 302, 304
G Gallate, 139, 250 Gamma Rays, 250, 286 Gamma-interferon, 25, 250 Ganglia, 217, 227, 250, 271, 277 Ganglion, 250, 274, 304 Gap Junctions, 250, 297 Gas, 51, 75, 93, 102, 112, 131, 221, 231, 234, 242, 249, 250, 256, 272, 288 Gastric, 227, 231, 251, 256, 277 Gastrin, 251, 256 Gastritis, 251, 303 Gastrointestinal, 140, 188, 189, 225, 229, 246, 247, 251, 266, 292, 295, 301, 302 Gastrointestinal tract, 247, 251, 292, 301 Gelatin, 160, 251, 253, 296, 298 Gene Deletion, 26, 251 Gene Expression, 13, 15, 27, 28, 30, 32, 39, 50, 55, 63, 66, 101, 112, 164, 201, 251, 293 Gene Expression Profiling, 40, 251 Gene Fusion, 35, 251 Gene Library, 251, 252 Gene Silencing, 176, 251 Gene Therapy, 126, 159, 218, 251 Genetic Code, 251, 273 Genetic Complementation Test, 16, 251 Genetic Engineering, 176, 228, 235, 251 Genetic Techniques, 51, 252 Genetic testing, 40, 252 Genetics, 40, 45, 83, 84, 93, 94, 95, 98, 101, 106, 111, 113, 120, 238, 243, 252 Genital, 24, 235, 252 Genomic Library, 48, 251, 252 Genotype, 23, 26, 48, 78, 98, 100, 137, 252, 279 Germ Cells, 252, 267, 273, 275, 297 Germinal Center, 96, 252 Germinoma, 96, 252 Gestation, 136, 252, 280 Gestational, 76, 252 Giant Cells, 252, 290 Gland, 218, 252, 257, 265, 275, 276, 280, 283, 290, 291, 295, 296, 298, 299 Glioma, 87, 107, 252 Gliosarcoma, 14, 252 Glomeruli, 252, 285 Glottis, 252, 278 Glucocorticoid, 157, 252 Gluconeogenesis, 12, 252 Glucuronic Acid, 252, 255 Glutamate, 34, 43, 172, 220, 253 Glutamate Decarboxylase, 220, 253
312
Methionine
Glutamic Acid, 250, 253, 272, 283 Glutamine, 34, 43, 67, 70, 141, 166, 184, 253 Glutathione Peroxidase, 253, 291 Glycine, 16, 21, 23, 117, 125, 167, 175, 185, 190, 220, 242, 253, 272, 292 Glycogen, 253, 279 Glycoprotein, 95, 220, 223, 249, 252, 253, 261, 269, 298, 301 Glycoside, 253, 257, 290 Glycosidic, 222, 233, 253, 279 Goats, 134, 253 Gonadal, 253, 295 Gonads, 253, 258 Governing Board, 253, 282 Gp120, 253, 277 Grade, 95, 118, 186, 253 Graft, 171, 253 Graft Rejection, 171, 253 Gram-negative, 54, 230, 245, 253 Gram-positive, 54, 254, 263, 295 Granule, 254, 289 Granulosa Cells, 254, 265 Grasses, 159, 250, 254 Growth factors, 155, 161, 254, 268 Guanine, 29, 254, 285 Guanylate Cyclase, 254, 272 Guinea Pigs, 43, 254 H Haemodialysis, 134, 254 Hair follicles, 241, 254, 303 Half-Life, 14, 254 Haploid, 254, 280 Haplotypes, 47, 48, 254 Haptens, 219, 254 Headache, 230, 254, 260 Heart attack, 4, 231, 254 Heartbeat, 254, 296 Helminths, 254, 260 Hematopoiesis, 254, 261 Heme, 10, 11, 41, 227, 240, 255, 270 Hemiatrophy, 96, 255 Hemoglobin, 10, 222, 247, 255, 262, 263 Hemoglobinopathies, 251, 255 Hemoglobinuria, 200, 255 Hemorrhage, 30, 254, 255, 295, 303 Hemostasis, 255, 292 Heparin, 110, 161, 255 Hepatic, 8, 27, 43, 50, 60, 69, 91, 99, 108, 130, 142, 219, 255, 264 Hepatitis, 44, 50, 67, 91, 103, 130, 146, 255 Hepatocellular, 87, 113, 255
Hepatocellular carcinoma, 87, 113, 255 Hepatocyte, 28, 48, 57, 234, 255 Hepatocyte Growth Factor, 28, 255 Hepatoma, 38, 255 Hepatotoxicity, 125, 255 Hereditary, 220, 255, 271, 278, 289 Heredity, 251, 252, 255 Heterogeneity, 58, 219, 255 Heterotrophic, 250, 255 Heterozygotes, 21, 243, 256 Hirsutism, 256, 257 Histamine, 96, 222, 256 Histidine, 4, 33, 102, 103, 104, 108, 120, 256 Histones, 235, 256 Homeostasis, 9, 15, 16, 19, 32, 57, 58, 139, 158, 180, 256 Homodimer, 57, 256 Homologous, 21, 48, 165, 220, 228, 239, 251, 256, 291, 296 Homozygotes, 21, 243, 256 Hormonal, 226, 256 Hormone Replacement Therapy, 9, 256 Housekeeping, 51, 256 Human Genome Project, 24, 49, 202, 256 Human growth hormone, 168, 256 Human papillomavirus, 185, 186, 256 Humoral, 253, 256 Hybrid, 69, 235, 256 Hydrochloric Acid, 234, 256 Hydrogen Peroxide, 41, 139, 140, 232, 253, 257, 264, 296 Hydrolases, 8, 257, 279 Hydrolysis, 64, 169, 225, 233, 235, 257, 277, 279, 281, 284, 300 Hydrophobic, 25, 59, 241, 257, 264 Hydroxamic Acids, 111, 257 Hydroxylation, 11, 257 Hydroxylysine, 236, 257 Hydroxyproline, 221, 236, 257 Hyperandrogenism, 83, 257 Hyperkeratosis, 185, 257 Hyperpigmentation, 157, 257 Hyperplasia, 190, 257 Hypersensitivity, 220, 246, 257, 289 Hypertension, 31, 52, 225, 231, 254, 257, 289 Hypertrophy, 257, 258 Hypochlorous Acid, 41, 111, 258 Hypoglycemia, 157, 258 Hypogonadism, 157, 258 Hypoplasia, 157, 258 Hypotension, 52, 238, 258
313
Hypothalamic, 258, 293 Hypothalamus, 30, 242, 246, 258, 280 Hypotonia, 47, 258 Hypoxia, 158, 180, 258, 297 I Idiopathic, 258, 290 Imaging procedures, 258, 299 Imidazole, 102, 256, 258 Imipramine, 76, 89, 258 Immune function, 42, 137, 258 Immune response, 133, 175, 218, 223, 226, 253, 254, 258, 259, 265, 292, 295, 303 Immune system, 52, 164, 227, 228, 244, 258, 259, 265, 278, 303 Immunoassay, 186, 258 Immunoblotting, 56, 258 Immunodeficiency, 200, 258 Immunoelectrophoresis, 219, 223, 258 Immunofluorescence, 61, 64, 258 Immunoglobulin, 222, 258, 269 Immunohistochemistry, 31, 64, 258 Immunologic, 234, 258, 259, 286 Immunology, 31, 218, 219, 249, 259 Immunosuppressant, 220, 259, 267 Immunosuppression, 259, 274 Immunosuppressive, 170, 252, 259 Impairment, 7, 19, 23, 100, 226, 234, 248, 259 Implant radiation, 259, 261, 262, 286, 304 In situ, 15, 23, 40, 131, 259 In Situ Hybridization, 23, 259 In vivo, 8, 9, 12, 13, 16, 18, 22, 23, 24, 25, 28, 29, 37, 41, 43, 45, 48, 51, 54, 60, 63, 69, 70, 71, 107, 108, 109, 131, 137, 159, 163, 175, 184, 189, 251, 255, 259, 268, 275, 298 Incidental, 90, 259 Incision, 259, 261, 296 Incubated, 56, 259 Incubation, 259, 278 Incubation period, 259, 278 Induction, 24, 31, 32, 38, 42, 48, 51, 61, 70, 74, 100, 136, 222, 259 Infancy, 104, 259 Infarction, 259, 288 Infection, 4, 18, 24, 25, 33, 62, 145, 164, 171, 226, 228, 234, 248, 258, 259, 260, 263, 265, 272, 273, 274, 277, 278, 285, 289, 295, 296, 303, 304 Infestation, 159, 260 Infiltration, 260, 304 Inflammatory bowel disease, 5, 260
Influenza, 175, 260 Ingestion, 4, 93, 102, 164, 257, 260, 281, 297 Inhalation, 164, 218, 225, 260, 262, 281 Initiation, 29, 46, 64, 65, 72, 73, 168, 260, 295, 300 Initiator, 29, 64, 66, 73, 75, 76, 161, 163, 182, 200, 260 Inorganic, 34, 234, 235, 260, 265, 269, 272, 279, 296 Insertional, 56, 70, 260 Insight, 92, 260 Insulator, 260, 270 Insulin, 24, 91, 117, 260 Insulin-dependent diabetes mellitus, 91, 260 Insulin-like, 24, 117, 260 Interferon, 168, 174, 175, 250, 260, 261, 265 Interferon-alpha, 260, 261 Interleukin-1, 232, 261 Interleukin-2, 116, 168, 261 Interleukin-9, 163, 261 Interleukins, 5, 261 Internal radiation, 261, 262, 286, 304 Interneurons, 34, 261 Interstitial, 229, 248, 261, 262, 304 Intestinal, 15, 25, 39, 120, 131, 136, 232, 261, 263, 266, 302, 303 Intestinal Mucosa, 261, 302 Intestine, 229, 236, 261, 263 Intoxication, 79, 261 Intracellular Membranes, 261, 267 Intraepithelial, 185, 261 Intrahepatic, 56, 76, 261 Intramuscular, 76, 89, 261, 276 Intravenous, 88, 261, 276 Intrinsic, 219, 261 Introns, 49, 252, 261, 300 Invasive, 28, 61, 108, 186, 261, 265 Invertebrates, 242, 262, 265, 300 Involuntary, 227, 247, 249, 262, 270, 293 Iodine, 95, 262 Ion Channels, 30, 225, 262, 279, 297 Ionizing, 220, 246, 262, 266, 286 Ions, 6, 33, 53, 160, 183, 217, 230, 243, 244, 256, 262, 269, 284, 290, 293 Irradiation, 32, 90, 236, 262, 304 Irrigation, 183, 262 Ischemia, 41, 158, 180, 226, 262, 288 Isoflurane, 42, 262 Isoleucine, 4, 41, 46, 72, 126, 136, 156, 167, 168, 262 Isoniazid, 43, 262
314
Methionine
Isozymes, 35, 38, 262 K Kb, 32, 196, 262 Keto, 93, 262 Kidney Disease, 97, 196, 201, 206, 219, 262 Kidney Failure, 245, 262 Kidney stone, 263, 295 Kinetic, 12, 16, 20, 29, 51, 52, 53, 62, 102, 105, 119, 141, 262, 263, 278 L Labile, 237, 263 Laboratory Personnel, 40, 263 Lactobacillus, 190, 263 Lamivudine, 91, 263 Large Intestine, 236, 242, 261, 263, 287, 293 Latent, 263, 282 Lectin, 263, 267 Leishmaniasis, 18, 182, 263 Lens, 59, 103, 106, 232, 238, 239, 263 Leptin, 30, 60, 263 Lesion, 263, 264, 291 Lethal, 29, 67, 163, 226, 263 Leucine, 4, 16, 41, 70, 79, 81, 87, 117, 158, 227, 263 Leucocyte, 220, 246, 263, 265 Leukapheresis, 63, 263 Leukemia, 200, 251, 263 Leukocytes, 227, 229, 234, 261, 263, 269, 278, 301 Life cycle, 18, 250, 263 Ligament, 264, 283 Ligands, 7, 10, 11, 57, 264, 296 Ligation, 264, 284 Linkage, 23, 27, 58, 231, 233, 264 Lipid, 43, 45, 56, 60, 98, 125, 133, 162, 224, 225, 235, 260, 262, 264, 270, 275 Lipid Peroxidation, 43, 45, 60, 98, 133, 264, 275 Lipoprotein, 4, 78, 110, 254, 264, 265 Lipoxygenase, 103, 224, 264 Liver Cirrhosis, 60, 113, 146, 264 Liver Neoplasms, 247, 264 Liver scan, 104, 264, 290 Liver Transplantation, 46, 112, 264 Lobe, 256, 264 Localization, 17, 18, 98, 99, 182, 258, 264 Localized, 23, 217, 221, 241, 256, 259, 264, 280 Locomotion, 264, 280 Loop, 76, 189, 264 Loss of Heterozygosity, 23, 264 Low-density lipoprotein, 264, 265
Luciferase, 48, 265 Luminescence, 28, 265 Lutein Cells, 120, 265 Lymph, 92, 118, 234, 245, 265, 290 Lymph node, 118, 234, 265, 290 Lymphadenopathy, 92, 265 Lymphatic, 245, 260, 265, 293, 294, 298 Lymphatic system, 265, 293, 294, 298 Lymphoblasts, 68, 265 Lymphocyte, 7, 32, 138, 157, 180, 223, 259, 265, 266 Lymphoid, 222, 252, 263, 265, 282 Lymphoma, 32, 200, 265 Lysine, 4, 73, 124, 131, 136, 137, 140, 142, 167, 175, 182, 242, 256, 257, 265, 283, 300 Lytic, 161, 265, 292 M Magnetic Resonance Imaging, 14, 265, 290 Major Histocompatibility Complex, 254, 265 Malabsorption, 200, 266 Malaria, 182, 266 Malaria, Falciparum, 266 Malaria, Vivax, 266 Malignancy, 118, 266, 276 Malignant, 14, 69, 137, 160, 185, 200, 218, 223, 225, 236, 266, 271, 286, 290, 297 Malignant tumor, 236, 266 Malnutrition, 142, 189, 190, 219, 226, 266, 270 Mammary, 31, 48, 266 Mammogram, 230, 266, 268 Manifest, 45, 46, 266 Man-made, 232, 266 Mastication, 266, 300 Matrix metalloproteinase, 142, 266 Meat, 3, 93, 266 Medial, 225, 266, 274 Mediate, 30, 45, 243, 266 Mediator, 261, 266, 292 MEDLINE, 197, 199, 201, 266 Megaloblastic, 51, 93, 250, 267 Meiosis, 228, 267, 296 Melanin, 267, 279, 301 Melanocytes, 257, 267 Melanoma, 132, 137, 160, 200, 267 Membrane Proteins, 6, 267 Memory, 25, 63, 146, 241, 252, 267 Meninges, 233, 267 Menopause, 267, 281, 282 Mental, iv, 5, 196, 198, 202, 234, 241, 243, 267, 285, 291
315
Mental Health, iv, 5, 196, 198, 267, 285 Mercury, 249, 267 Mesoderm, 161, 267 Metabolite, 141, 242, 267 Metaphase, 228, 267 Metastasis, 28, 48, 61, 63, 118, 132, 161, 174, 177, 266, 267 Metastatic, 48, 61, 63, 83, 106, 109, 267, 291 Metastatic cancer, 109, 267 Methotrexate, 5, 46, 92, 143, 267 Methylenetetrahydrofolate Dehydrogenase, 48, 268 Methyltransferase, 19, 38, 47, 60, 62, 70, 73, 96, 101, 125, 131, 140, 141, 152, 172, 177, 268 MI, 4, 144, 215, 268 Microbe, 144, 268, 299 Microbiology, 18, 31, 53, 65, 105, 112, 124, 143, 218, 228, 268 Microcalcifications, 230, 268 Microcirculation, 80, 174, 264, 268, 280 Microdialysis, 37, 268 Microglia, 225, 268 Micronutrients, 6, 268 Microorganism, 175, 236, 268, 276, 303 Microsporidiosis, 182, 268 Migration, 15, 42, 61, 268 Mitochondria, 21, 44, 48, 177, 187, 268, 270, 274, 300 Mitochondrial Swelling, 268, 271 Mitosis, 224, 268, 293 Modeling, 11, 60, 97, 125, 243, 268, 284 Modification, 20, 21, 37, 41, 42, 48, 52, 54, 56, 70, 72, 112, 221, 251, 269, 285, 304 Molecular Structure, 19, 269, 300 Monitor, 63, 99, 239, 269, 273 Monoclonal, 174, 258, 262, 269, 286, 304 Monoclonal antibodies, 174, 258, 269 Monocytes, 42, 261, 263, 269 Mononuclear, 101, 269, 301 Morphine, 87, 269, 271, 274 Morphological, 12, 158, 180, 244, 267, 269 Morphology, 56, 80, 160, 224, 232, 269 Mosaicism, 95, 269 Motility, 269, 292 Mucins, 269, 290 Mucocutaneous, 263, 269 Mucolytic, 217, 269 Mucositis, 269, 298 Mucus, 248, 269, 301 Multicenter Studies, 89, 269 Multicenter study, 269, 270
Multidrug resistance, 32, 270 Multienzyme Complexes, 32, 270 Muscle Contraction, 54, 270, 290 Muscle Fibers, 270, 292 Muscular Atrophy, 200, 270 Muscular Dystrophies, 244, 270 Mutagenesis, 19, 20, 33, 35, 54, 59, 62, 70, 77, 108, 141, 270, 284 Mutagenic, 181, 220, 270 Mutagens, 250, 270 Myalgia, 260, 270 Myelin, 172, 241, 270, 273 Myelin Sheath, 172, 270, 273 Myocardial infarction, 4, 101, 239, 268, 270 Myocardium, 268, 270 Myofibrils, 231, 270 Myoglobin, 10, 270 Myosin, 270 Myotonic Dystrophy, 200, 270 N Narcotic, 269, 271, 272 Nasal Mucosa, 260, 271 Natural selection, 228, 271 NCI, 1, 21, 22, 40, 195, 235, 271 Necrosis, 26, 56, 91, 106, 224, 259, 268, 270, 271, 288, 290 Neonatal, 36, 76, 271 Neonatal Screening, 36, 271 Neoplasia, 200, 271 Neoplasm, 271, 276, 290, 301 Neoplastic, 96, 189, 264, 265, 271 Nephropathy, 45, 97, 262, 271 Nerve, 218, 222, 226, 241, 250, 266, 271, 272, 274, 276, 277, 282, 289, 290, 295, 300, 302, 304 Nervous System, 9, 201, 217, 218, 219, 227, 230, 233, 250, 253, 254, 266, 268, 269, 270, 271, 272, 273, 274, 277, 282, 292, 297 Neural, 19, 22, 34, 68, 83, 84, 94, 172, 177, 189, 218, 221, 245, 256, 268, 271 Neural tube defects, 19, 22, 83, 94, 172, 177, 271 Neurodegenerative Diseases, 12, 65, 227, 271 Neurologic, 83, 172, 245, 271 Neuromuscular, 217, 271 Neuromuscular Junction, 217, 271 Neuronal, 4, 34, 230, 271, 272 Neurons, 5, 30, 34, 50, 241, 247, 250, 261, 271, 272, 296 Neuropathy, 120, 272, 277 Neuropeptides, 103, 230, 272
316
Methionine
Neurotoxic, 226, 272 Neurotoxicity, 78, 177, 188, 272 Neurotransmitter, 34, 217, 218, 221, 225, 229, 243, 253, 256, 262, 272, 295, 297, 302 Neutrons, 220, 262, 272, 286 Neutrophil, 42, 43, 109, 220, 272 Neutrophil Infiltration, 43, 272 Niacin, 272, 300 Nitric Oxide, 11, 37, 41, 54, 272 Nitrogen, 11, 16, 42, 51, 72, 124, 132, 138, 139, 140, 142, 219, 222, 248, 253, 272, 300 Nitrogen Oxides, 11, 51, 272 Nitrous Oxide, 11, 42, 58, 92, 115, 172, 272 Norepinephrine, 218, 243, 272 Nosocomial, 42, 273 Nuclear Medicine, 14, 81, 83, 86, 87, 90, 92, 95, 102, 104, 105, 108, 118, 273 Nuclei, 30, 220, 238, 244, 251, 252, 256, 261, 265, 268, 272, 273, 274, 284 Nucleolus, 273, 289 Nucleotidases, 257, 273 Nucleus, 224, 227, 235, 240, 242, 247, 250, 267, 269, 272, 273, 283, 284, 297 Nutritive Value, 69, 273 O Ocular, 174, 273 Odds Ratio, 273, 288 Oligodendroglia, 270, 273 Oligomenorrhea, 273, 281 Oncogene, 32, 104, 200, 255, 273 Oncology, 14, 77, 81, 100, 106, 117, 119, 273 Oocytes, 166, 273 Opacity, 232, 241, 273 Open Reading Frames, 64, 274 Operon, 67, 274, 288 Ophthalmic, 274, 289 Opiate, 227, 246, 269, 274 Opium, 269, 274 Opportunistic Infections, 17, 274 Opsin, 274, 289 Optic Chiasm, 258, 274 Optic Nerve, 274, 288, 289 Organ Culture, 274, 299 Organelles, 6, 52, 240, 267, 269, 274, 280 Osmosis, 274 Osmotic, 183, 219, 268, 274, 292 Osteoarthritis, 73, 129, 141, 147, 274 Osteoclasts, 230, 274 Outpatient, 275 Ovarian Follicle, 239, 250, 254, 275, 297 Ovaries, 257, 275, 281
Ovary, 239, 247, 253, 275 Overdose, 85, 275 Overexpress, 6, 275 Overweight, 88, 126, 275 Ovum, 239, 250, 252, 263, 275, 283, 304 Oxidants, 36, 275 Oxidation-Reduction, 31, 275 Oxidative Stress, 4, 11, 24, 35, 36, 43, 44, 45, 52, 56, 58, 60, 78, 90, 106, 126, 130, 156, 275 Oxides, 272, 275 P P53 gene, 159, 275 Palliative, 275, 298 Pancreas, 82, 217, 228, 260, 275, 276, 300, 301 Pancreatic, 40, 82, 147, 200, 231, 275, 276 Pancreatic cancer, 40, 200, 276 Panic, 258, 276 Panic Disorder, 258, 276 Papillary, 257, 276 Papilloma, 185, 186, 276 Papillomavirus, 186, 276 Parasite, 8, 18, 276 Parasitic, 182, 223, 254, 260, 276, 289 Parathyroid, 90, 118, 276, 297 Parathyroid Glands, 276 Parenteral, 17, 49, 109, 276 Parenteral Nutrition, 109, 276 Parotid, 276, 290 Paroxysmal, 200, 276, 278, 303 Partial remission, 276, 288 Particle, 266, 276, 300 Pathogen, 25, 171, 175, 181, 259, 276 Pathogenesis, 26, 41, 44, 45, 56, 65, 100, 172, 276 Pathologic, 65, 217, 224, 228, 239, 257, 276, 277, 285 Pathologic Processes, 224, 277 Pathologies, 37, 189, 190, 277 Pathophysiology, 45, 277 Patient Education, 206, 210, 212, 215, 277 Pelvic, 277, 283 Pelvis, 217, 263, 275, 277, 285, 302 Penicillin, 277, 302 Penis, 186, 277 Peptic, 277, 303 Peptic Ulcer, 277, 303 Peptide Hydrolases, 247, 257, 277 Peptide T, 168, 277 Perception, 52, 277 Perennial, 277, 300
317
Perfusion, 258, 277, 299 Perioperative, 42, 277 Peripheral blood, 21, 101, 261, 277 Peripheral Nervous System, 241, 270, 271, 272, 277, 295, 302 Peripheral Neuropathy, 45, 47, 277, 304 Peripheral Vascular Disease, 6, 278 Periplasm, 175, 278 Peritoneal, 138, 278 Peritoneum, 278 Peroxidase, 24, 79, 224, 264, 278 Peroxide, 98, 278 Pertussis, 89, 278, 303 Pest Control, 158, 278 Petechiae, 117, 278 Petrolatum, 245, 278 PH, 72, 85, 137, 278 Phagocyte, 275, 278 Pharmaceutical Preparations, 233, 247, 251, 278 Pharmacokinetics, 243, 278 Pharmacologic, 5, 222, 254, 279, 299 Pharynx, 260, 279, 302 Phenolphthalein, 245, 279 Phenotype, 17, 45, 48, 64, 124, 163, 173, 181, 228, 237, 251, 279 Phenylalanine, 4, 41, 61, 79, 117, 154, 279, 301 Phenytoin, 231, 279 Phospholipids, 248, 264, 279 Phosphoric Monoester Hydrolases, 257, 279 Phosphorus, 230, 276, 279 Phosphorylase, 85, 231, 279 Phosphorylase a, 85, 279 Phosphorylase Phosphatase, 279 Phosphorylated, 236, 279 Phosphorylation, 161, 170, 279 Photoreceptor, 279, 289 Physiologic, 7, 60, 228, 248, 254, 268, 279, 287 Physiology, 6, 34, 37, 55, 85, 90, 228, 280 Picornavirus, 66, 280 Pigment, 176, 227, 234, 267, 270, 280 Pigmentation, 190, 257, 280 Pilot study, 84, 280 Pituitary Gland, 249, 280 Placenta, 247, 280, 283 Plant Diseases, 156, 280 Plaque, 132, 226, 280 Plasma cells, 222, 280
Plasma protein, 4, 219, 245, 250, 280, 284, 292 Plasmid, 161, 184, 280, 302 Plasmin, 26, 223, 280 Plasminogen, 223, 280 Plasminogen Activators, 280 Plastids, 274, 280 Platelet Aggregation, 88, 222, 272, 281, 298 Platelets, 224, 230, 272, 281, 298 Platinum, 189, 235, 264, 281 Pneumonia, 42, 238, 281 Point Mutation, 39, 59, 281 Poisoning, 85, 261, 267, 281 Polycystic, 83, 201, 257, 281 Polycystic Ovary Syndrome, 83, 257, 281 Polymerase, 281, 288 Polymers, 42, 228, 281, 284, 295 Polymorphic, 25, 86, 94, 102, 113, 235, 281 Polymorphism, 21, 23, 27, 47, 65, 77, 83, 84, 91, 101, 106, 107, 111, 116, 172, 281 Polyposis, 236, 281 Polysaccharide, 223, 233, 281, 284 Porosity, 169, 281 Posterior, 221, 226, 275, 281 Postmenopausal, 9, 281 Postoperative, 42, 58, 281 Postprandial, 91, 282 Postsynaptic, 282, 297 Post-translational, 29, 52, 56, 282 Potassium, 71, 282, 286 Practice Guidelines, 198, 282 Prealbumin, 80, 282 Precancerous, 186, 282 Precipitation, 187, 282 Preclinical, 60, 243, 282 Precursor, 10, 16, 23, 45, 167, 224, 234, 243, 244, 246, 272, 279, 280, 282, 283, 284, 300, 301, 302 Predisposition, 38, 47, 282 Premalignant, 15, 38, 282 Premenopausal, 75, 282 Prenatal, 82, 244, 282 Prenatal Diagnosis, 82, 282 Preoperative, 59, 282 Pressoreceptors, 226, 282 Presynaptic, 272, 282, 297 Prevalence, 7, 17, 26, 40, 46, 49, 186, 273, 282 Primary central nervous system lymphoma, 116, 282 Primary endpoint, 15, 282 Prion, 11, 283
318
Methionine
Probe, 268, 283 Procollagen, 9, 283 Progeny, 238, 283 Progesterone, 283, 295 Progression, 30, 38, 46, 50, 58, 182, 222, 283 Progressive, 52, 83, 225, 235, 241, 243, 255, 270, 271, 274, 283, 301 Projection, 261, 272, 274, 283, 287 Prokaryotic Cells, 33, 283 Proliferative Retinopathy, 174, 283 Proline, 134, 236, 242, 257, 283 Promoter, 29, 32, 38, 113, 156, 283 Prophase, 228, 273, 283, 296 Prospective Studies, 4, 283 Prospective study, 92, 186, 283 Prostaglandins, 224, 244, 283 Prostate, 14, 23, 61, 63, 83, 95, 106, 117, 200, 228, 283, 301 Protease, 96, 157, 180, 182, 186, 220, 284 Protective Agents, 189, 284 Protein Binding, 37, 284, 299 Protein Conformation, 221, 284 Protein Engineering, 41, 103, 284 Protein Isoforms, 220, 284 Protein Splicing, 50, 284 Proteoglycans, 161, 248, 284 Proteolytic, 46, 220, 237, 249, 280, 284 Prothrombin, 26, 284, 298 Protocol, 23, 42, 284 Protons, 220, 256, 262, 284, 286 Protozoa, 124, 228, 238, 263, 268, 285, 302 Protozoan, 266, 285 Psoriasis, 174, 285 Psychiatric, 80, 228, 285 Psychiatry, 17, 49, 78, 80, 115, 141, 285 Psychic, 267, 285, 291 Psychomotor, 231, 245, 285 Public Health, 20, 21, 22, 37, 41, 43, 47, 48, 198, 285 Public Policy, 197, 285 Publishing, 66, 285 Pulmonary, 82, 96, 164, 220, 229, 234, 246, 263, 285, 288, 296, 302 Pulmonary Artery, 229, 285, 302 Pulmonary hypertension, 96, 285 Pulse, 56, 269, 285 Purines, 5, 21, 23, 53, 227, 285, 292 Pyelonephritis, 164, 285 Pyridoxal, 26, 166, 240, 253, 285 Pyrimidines, 227, 285, 292
Q Quality of Life, 4, 17, 49, 50, 285 Quiescent, 174, 178, 188, 233, 285 Quinidine, 189, 286 Quinine, 286 R Race, 26, 47, 268, 286 Radiation therapy, 248, 261, 262, 286, 294, 304 Radioactive, 226, 229, 254, 257, 259, 261, 262, 264, 266, 269, 273, 286, 290, 301, 304 Radioimmunotherapy, 286 Radioisotope, 286, 299 Radiolabeled, 118, 229, 262, 286, 304 Radiology, 13, 273, 286 Radiopharmaceuticals, 14, 286 Radiotherapy, 80, 119, 229, 262, 286, 294, 304 Random Allocation, 286, 287 Randomization, 6, 287 Randomized, 6, 17, 21, 26, 49, 50, 59, 76, 88, 244, 287 Randomized clinical trial, 17, 21, 49, 287 Reactive Oxygen Species, 24, 35, 54, 55, 173, 287 Reading Frames, 64, 287 Reagent, 234, 256, 265, 287 Receptors, Serotonin, 287, 292 Recombinant, 18, 46, 52, 125, 135, 154, 161, 166, 168, 184, 186, 287, 302 Recombinant Proteins, 18, 287 Recombination, 71, 109, 238, 251, 287 Rectum, 224, 236, 242, 248, 249, 251, 260, 263, 284, 287, 296 Red blood cells, 94, 247, 287, 290 Red Nucleus, 226, 287 Refer, 1, 230, 237, 243, 250, 261, 264, 272, 273, 281, 286, 287, 299 Refraction, 287, 293 Regeneration, 22, 41, 60, 178, 249, 288 Regimen, 59, 162, 244, 288 Relative risk, 15, 288 Remission, 5, 17, 49, 288 Reperfusion, 41, 288 Reperfusion Injury, 288 Repressor, 72, 274, 288 Resection, 42, 288 Respiration, 231, 269, 288 Respiratory Burst, 24, 288 Respiratory System, 288, 302 Retina, 238, 242, 263, 274, 283, 288, 289, 290
319
Retinal, 94, 242, 274, 288, 289 Retinal Vein, 94, 289 Retinal Vein Occlusion, 94, 289 Retinoblastoma, 200, 289 Retinoid, 57, 190, 289 Retinol, 57, 288, 289 Retinopathy, 91, 242, 289 Retrotransposons, 181, 289 Retroviral vector, 251, 289 Retrovirus, 159, 289 Reversion, 289, 301 Rheumatism, 289 Rheumatoid, 4, 76, 174, 275, 289 Rheumatoid arthritis, 4, 76, 174, 289 Rhodopsin, 134, 274, 289 Ribose, 218, 289 Ribosome, 13, 64, 66, 223, 289, 300 Rickettsiae, 289, 302 Risk factor, 4, 6, 23, 39, 40, 45, 47, 51, 53, 106, 107, 111, 246, 257, 283, 288, 290 Rod, 226, 245, 263, 279, 290 Rubber, 152, 218, 290 Ruminants, 65, 253, 290 Ryanodine, 54, 290 S Saliva, 56, 290 Salivary, 56, 276, 290 Salivary glands, 290 Saponins, 290, 295 Sarcoidosis, 92, 290 Sarcoma, 132, 290 Sarcoplasmic Reticulum, 54, 290 Scans, 83, 290 Scatter, 28, 290 Sclerosis, 201, 225, 290 Screening, 6, 18, 36, 42, 48, 76, 157, 159, 180, 186, 235, 271, 290 Sebaceous, 241, 290, 291, 303 Sebaceous gland, 241, 291, 303 Secondary tumor, 267, 291 Secretion, 79, 120, 174, 256, 257, 260, 261, 268, 269, 291, 302 Secretory, 291, 297, 303 Sedative, 258, 291 Sediment, 133, 291 Sedimentation, 291, 301 Segregation, 287, 291 Seizures, 47, 231, 276, 279, 291 Selenium, 35, 128, 291 Selenocysteine, 35, 291 Selenomethionine, 105, 131, 132, 141, 143 Semen, 283, 291
Senescence, 116, 291 Senile, 46, 291 Sequela, 44, 291 Sequence Alignment, 20, 291 Sequence Homology, 16, 277, 291 Sequencing, 32, 38, 47, 56, 291 Serine, 21, 23, 46, 85, 134, 157, 167, 180, 181, 231, 240, 291, 300 Serologic, 258, 292 Serotonin, 17, 49, 272, 287, 292, 300 Serous, 245, 292 Serum Albumin, 4, 282, 292 Sessile, 55, 292 Sex Determination, 201, 292 Sharpness, 160, 187, 292 Shock, 245, 292, 300 Side effect, 9, 17, 28, 46, 49, 189, 218, 228, 243, 262, 292, 299, 304 Signs and Symptoms, 157, 288, 292 Sil, 292 Silage, 133, 159, 292 Sinoatrial Node, 37, 292 Skeletal, 54, 125, 222, 258, 270, 286, 290, 292 Skeleton, 218, 292 Skin test, 163, 173, 292 Skull, 245, 271, 292, 294 Small intestine, 235, 256, 261, 293, 300 Smooth muscle, 222, 230, 256, 269, 293, 295 Sneezing, 278, 293 Social Environment, 285, 293 Sodium, 32, 114, 168, 229, 286, 293, 296 Sodium Acetate, 168, 293 Soft tissue, 229, 292, 293 Solid tumor, 14, 174, 177, 222, 293 Solvent, 46, 52, 135, 247, 274, 293 Somatic, 256, 267, 268, 277, 293, 297, 302 Somatotropin, 138, 293 Spasmodic, 278, 293 Spatial disorientation, 243, 293 Specialist, 207, 293 Specificity, 19, 56, 62, 219, 224, 230, 293, 299 Spectrophotometry, 89, 293 Spectroscopic, 32, 33, 51, 53, 58, 120, 293 Spectrum, 18, 268, 293 Sperm, 222, 235, 294, 301 Spina bifida, 111, 271, 294 Spinal cord, 225, 233, 234, 250, 267, 271, 272, 277, 282, 294 Spinous, 246, 294
320
Methionine
Spleen, 221, 265, 290, 294 Sporadic, 77, 78, 271, 289, 294 Squamous, 186, 246, 294 Squamous cell carcinoma, 186, 246, 294 Squamous cells, 294 Stabilization, 54, 61, 279, 294 Staging, 290, 294 Statistically significant, 42, 294 Steady state, 9, 294 Steatosis, 99, 248, 294 Stellate, 9, 60, 294 Stereotactic, 106, 119, 294 Stereotactic radiosurgery, 106, 294 Sterile, 276, 294 Steroid, 24, 120, 239, 250, 290, 294 Stimulant, 230, 256, 295, 302 Stimulus, 244, 247, 262, 295, 298 Stomach, 217, 242, 251, 256, 277, 279, 290, 293, 294, 295 Stool, 236, 263, 295 Streptococcal, 56, 295 Streptococcus, 71, 107, 295 Streptomycin, 240, 295 Stress, 4, 11, 26, 36, 44, 45, 52, 58, 60, 110, 156, 181, 183, 239, 275, 282, 289, 290, 295 Stroke, 4, 100, 121, 196, 231, 295 Stroma, 174, 295 Struvite, 133, 295 Styrene, 290, 295 Subacute, 260, 295 Subarachnoid, 30, 254, 295 Subclinical, 58, 260, 291, 295 Subcutaneous, 218, 244, 255, 276, 295 Subspecies, 293, 295 Substance P, 267, 291, 295 Substrate, 11, 12, 26, 29, 33, 35, 41, 53, 105, 107, 143, 152, 176, 232, 246, 257, 295 Substrate Specificity, 33, 35, 107, 176, 295 Sudden death, 157, 296 Sulfur, 12, 16, 32, 34, 59, 68, 124, 128, 130, 141, 155, 162, 167, 239, 248, 263, 296 Sulfur Compounds, 35, 296 Superior vena cava, 292, 296 Superoxide, 36, 44, 54, 138, 288, 296 Superoxide Dismutase, 36, 44, 296 Suppositories, 251, 296 Suppression, 117, 142, 176, 251, 296 Suppressive, 9, 296 Surface Plasmon Resonance, 72, 296 Surfactant, 165, 296 Surgical Wound Infection, 42, 296 Sweat, 241, 296
Sweat Glands, 241, 296 Symphysis, 283, 296 Synapse, 218, 271, 282, 296, 297, 300 Synaptic, 34, 272, 296, 297 Synaptic Transmission, 34, 297 Synergistic, 35, 38, 60, 73, 297 Systemic, 13, 45, 221, 229, 246, 260, 262, 286, 290, 293, 297, 302, 304 Systolic, 257, 297 T Tachycardia, 80, 297 Taurine, 27, 109, 111, 149, 167, 297 Telangiectasia, 201, 297 Telencephalon, 227, 234, 297 Telomerase, 174, 297 Testis, 247, 253, 297 Testosterone, 287, 297 Tetany, 276, 297 Thalamic, 226, 297 Thalamic Diseases, 226, 297 Theca Cells, 265, 297 Theophylline, 285, 297 Therapeutics, 28, 79, 87, 92, 169, 298 Thermal, 38, 225, 243, 272, 298 Threonine, 4, 33, 46, 67, 71, 124, 134, 142, 163, 167, 173, 277, 292, 298 Threshold, 32, 85, 247, 257, 298 Thrombin, 26, 249, 281, 284, 298 Thrombomodulin, 103, 284, 298 Thrombosis, 25, 86, 94, 97, 98, 116, 131, 132, 284, 295, 298 Thromboxanes, 224, 244, 298 Thrombus, 239, 259, 281, 298 Thylakoids, 234, 298 Thymidine, 118, 119, 160, 298 Thymidine Kinase, 119, 160, 298 Thymidylate Synthase, 76, 106, 298 Thymoma, 90, 298 Thymus, 7, 265, 298 Thyroid, 230, 262, 276, 298, 299, 301 Thyroid Gland, 276, 298, 299 Thyroid Hormones, 298, 299, 301 Thyrotropin, 103, 298 Thyroxine, 219, 279, 299 Ticks, 260, 299 Tissue Culture, 181, 299 Tissue Distribution, 77, 299 Tolerance, 87, 126, 183, 218, 299 Tomography, 14, 80, 81, 82, 84, 85, 90, 105, 106, 118, 135, 299 Tone, 31, 190, 258, 299 Tonus, 299
321
Tooth Preparation, 218, 299 Topical, 65, 189, 225, 247, 257, 278, 299 Toxic, iv, 8, 57, 60, 164, 189, 220, 238, 240, 243, 246, 254, 272, 279, 291, 295, 299, 304 Toxicity, 18, 43, 44, 46, 171, 174, 188, 243, 267, 299 Toxicology, 21, 22, 130, 133, 139, 143, 198, 299 Toxin, 299 Trace element, 235, 236, 249, 299 Tracer, 16, 26, 299 Transcriptase, 263, 289, 297, 299, 304 Transcription Factors, 176, 300 Transduction, 28, 33, 100, 163, 182, 300 Transfection, 38, 48, 61, 228, 251, 300 Translation, 13, 64, 65, 220, 223, 284, 287, 300 Translational, 13, 176, 251, 300 Transmitter, 34, 217, 225, 243, 262, 266, 272, 300 Transplantation, 134, 235, 265, 300 Transposons, 181, 300 Trans-Splicing, 8, 300 Trauma, 51, 227, 254, 271, 297, 300, 303 Trees, 156, 290, 300 Triad, 20, 300 Tricyclic, 17, 49, 150, 258, 300 Trigeminal, 30, 300 Trypsin, 220, 300 Tryptophan, 4, 143, 167, 185, 236, 292, 300 Tuberculosis, 43, 63, 72, 73, 115, 262, 300 Tuberculostatic, 262, 300 Tuberous Sclerosis, 201, 300 Tubulin, 68, 301 Tumor marker, 228, 301 Tumor Necrosis Factor, 67, 136, 301 Tumor suppressor gene, 30, 39, 264, 275, 301 Tumorigenic, 48, 301 Tumour, 118, 137, 250, 301 Typhimurium, 67, 68, 70, 72, 73, 164, 301 Typhoid fever, 164, 301 Tyrosine, 4, 28, 33, 46, 48, 53, 61, 67, 72, 73, 75, 91, 161, 232, 243, 301 U Ulcerative colitis, 5, 236, 260, 301 Uracil, 21, 285, 301 Urea, 132, 296, 301 Ureters, 263, 301 Urethra, 277, 283, 301 Urinary, 124, 145, 293, 301 Urinary tract, 124, 301
Urinary tract infection, 124, 301 Urine, 36, 93, 112, 131, 133, 219, 222, 228, 239, 243, 255, 263, 301 Uterus, 217, 234, 239, 275, 283, 302 V Vaccines, 18, 63, 164, 302, 303 Vacuoles, 245, 274, 302 Vagal, 37, 302 Vagina, 186, 234, 241, 263, 302 Vaginal, 186, 302 Vagolytic, 37, 302 Vagus Nerve, 302 Valine, 4, 47, 67, 70, 72, 77, 95, 119, 120, 172, 302 Varicella, 99, 302 Vascular, 4, 22, 25, 31, 52, 75, 81, 82, 86, 91, 131, 132, 157, 227, 241, 245, 257, 259, 260, 264, 268, 272, 275, 280, 282, 298, 302 Vascular Resistance, 227, 302 Vasoactive, 103, 108, 120, 302 Vasoactive Intestinal Peptide, 103, 108, 302 Vasodilators, 272, 302 Vector, 31, 174, 175, 184, 260, 300, 302 Vein, 225, 261, 273, 276, 289, 296, 302 Venous, 225, 232, 284, 302 Ventricle, 226, 258, 285, 292, 297, 302 Venules, 229, 231, 245, 268, 302 Vertebral, 294, 302 Vesicular, 250, 254, 302 Veterinarians, 65, 162, 302 Veterinary Medicine, 197, 302, 303 Vinblastine, 301, 303 Vinca Alkaloids, 303 Vincristine, 132, 301, 303 Viral, 33, 64, 66, 159, 164, 166, 175, 217, 252, 260, 289, 300, 301, 303, 304 Virilism, 257, 303 Virulence, 18, 69, 112, 164, 226, 299, 303 Virus, 64, 67, 74, 91, 99, 160, 175, 186, 226, 246, 252, 253, 256, 261, 280, 289, 300, 303, 304 Visceral, 263, 278, 302, 303 Viscosity, 80, 217, 303 Vitamin U, 12, 303 Vitreous, 242, 263, 288, 303 Vitreous Hemorrhage, 242, 303 Vitro, 7, 8, 9, 13, 14, 16, 18, 23, 24, 30, 32, 37, 41, 42, 43, 45, 46, 48, 51, 54, 58, 59, 60, 63, 70, 75, 117, 124, 134, 137, 159, 182, 243, 251, 255, 259, 299, 303
322
Methionine
Vivo, 9, 13, 14, 24, 28, 37, 41, 54, 63, 70, 71, 75, 137, 303 Voltage-gated, 9, 303 Vulgaris, 141, 144, 303 W Warts, 186, 256, 303 White blood cell, 223, 259, 263, 265, 269, 272, 280, 303 Whooping Cough, 278, 303 Wound Healing, 42, 171, 249, 266, 303 Wound Infection, 42, 303
X Xenograft, 222, 304 X-ray, 19, 33, 62, 65, 237, 238, 249, 250, 262, 266, 273, 286, 290, 294, 304 X-ray therapy, 262, 304 Y Yeasts, 124, 179, 250, 279, 304 Z Zalcitabine, 263, 304 Zoster, 99, 304 Zygote, 238, 269, 304 Zymogen, 12, 284, 304
323
324
Methionine
