RNA technologies are the driving forces of modern medicine and biotechnology. They combine the fields of biochemistry, chemistry, molecular biology, cell biology, physics, nanotechnology and bioinformatics. The combination of these topics is set to revolutionize the medicine of tomorrow. After more than 15 years of extensive research in the field of RNA technologies, the first therapeutics are ready to reach the first patients. Thus we are witnessing the birth of a very exciting time in the development of molecular medicine, which will be based on the methods of RNA technologies. This volume is the first of a series. It covers various aspects of RNA interference and microRNAs, although antisense RNA applications, hammerhead ribozyme structure and function as well as non-coding RNAs are also discussed. The authors are internationally highly respected experts in the field of RNA technologies.

and made insignificant in practice, by selecting for study simple kinds of ex periences which are devoid of emotional content and which can be tested for reliability. A simple somatosensory ''raw feel" fulfills these characteristics (see papers nos. 2,5). In any case, if we fail to find ways to use introspective reports in convincingly acceptable studies we would give up the ability to investigate the relation between conscious experience and neural activity, something warned against by William James (Krech, 1969). Another factor in the dearth of direct experimental studies is, of course, the comparative inaccessibility of the human brain for such purposes. Meaningful investigations of the issue in question requires simultaneous study of brain events and introspective reports of experiences in an awake, cooperative human subject. Analysis by neuropsychologists of pathological lesions in the brain and the related disturbances of conscious functions have contributed much to mapping the pos sible representations of these functions. The non-invasive recording of electrical activity with electrodes on the scalp, starting from Berger's initial EEG record ings in 1929, has contributed much to the problems of states of consciousness and to various cognitive features associated with sensory inputs, but not as much to the specific issue of conscious experience."

More than 70 years have elapsed since U. S. von Euler and I. H. Gaddum dis- covered an unidentified depressor substance in the brain and gut. The effects of the powdery extracts were marked as 'P' on the kymograph tracings, and the nondescript name of 'substance P' still carries the breath of this adventurous period. In the 1960s, substance P returned in another disguise, staging as a hypothalamic peptide that causes copious salivary secretion (see chapter by F. Lembeck and I. Donnerer). This time, though, the mysterious substance was tracked down by S. E. Leeman and her collaborators as an undecapeptide, after it had eluded its identification for some 40 years. Substance P turned out to be the mammalian counterpart of a family of peptides which had been extracted from amphibian and nonvertebrate species and which had been given the name 'tachykinins' by V. Erspamer. Soon novel members of this peptide family were discovered, and in mammals substance P was joined by neurokinin A and neu- rokinin B. The presence of tachykinins in frog skin as well as in venoms and toxins of microbes and arachnids raises the possibility that these peptides re- present an old system of biological weapons that have been transformed to a particular messenger system in mammals.

Proceedings of an International Workshop held in Sheffield, UK, September 1-4, 1997

TheobservationthatabloodclotspontaneouslydissolveswasfirstdescribedbyDenys in1889. Subsequently,thebloodclottingsystemwasshowntobeinvolvedintumor growth. Forexample,asearlyas1925,Fisherreportedthataviantissueexplantstrans- formedtomalignancybyvirusesgeneratedhighlevelsoffibrinolyticactivityundercon- ditionsinwhichculturesofnormalcellsdidnot. In1958,theconceptthatan equilibriumexistedbetweenthetendencyofbloodtoclotandtoremainfluidwaspro- posedbyAstrup. Atthattime,itwasbelievedthatthishemostaticbalancewasexplained bytheabilityofpolymerizingfibrintoorchestrateitsownclearancebystimulatingfib- rinolyticactivity. Sincethesepioneeringstudies,considerableinformationhasaccumu- latedthathasdefinedthecomponentsofthecoagulationandfibrinolyticsystemsand howtheyareinvolvedinphysiologicalandpathophysiologicalprocesses. Plasminogen: Structure, activation, and regulationfocusesonthebasicprinciplesandrecentdevelop- mentsintheplasminogen/plasminresearchfieldandhowtheseresultsprovideacon- ceptualframeworkforanunderstandingofthephysiologicalroleofplasminogenin healthanddisease. Theenzymaticcascadetriggeredbyactivationofplasminogenhasbeenimplicated inavarietyofnormalandpathologicaleventssuchasfibrinolysis,woundhealing,tis- sueremodeling,embryogenesis,angiogenesis,andtheinvasionandmetastasisoftumor cells. Thisimpressivelistofphysiologicalfunctionsforplasminogenreinforcesthewide diversityofrolesthatplasminogenplaysinvariousphysiologicalprocesses. Productive plasmingenerationrequirestheassemblyofbothplasminogenactivatorsandplasmino- genonasolidsupportsuchasthefibrinpolymerorthecellsurface. Theregulationof plasminproductioninvolvesacomplexinterplaybetweentheseplasminogenactivators, plasminogenactivatorinhibitors,andplasmininhibitors. Clearly,theexplosivegrowth inthisresearchfieldandthemanyexcitingdiscoveriessuggeststhattheresearchefforts inthenextdecadewillrevealthemechanismsbywhichthecomponentsoftheplas- minogensysteminteractandregulatebothplasminactivationandfunctionatacellular level. Plasminogen: Structure, activation, and regulationisdividedintotwosections. Thefirstsectiondealswiththestructureandregulationofplasminogen. Thechapters inthissectionrangefromdiscussionsofthestructureofplasminogenandtheregulation oftheplasminogengenetodiscussionsofthestructureandregulationofplasminogen activatorsandplasminogenactivatorinhibitors. Alsoexaminedistherelativelynewdata concerningthegenerationofanti-angiogenicmoleculesfromplasminogen. Thesecond sectiondealswiththephysiologicalandpathophysiologicalrolesofplasminogenaswell astheconsequencesofplasminogengeneknockout. Discussionsinthissectioninclude examinationoftheroleofplasminogeninhematopoieticmalignancies,tumorcell progression,angiogenesis,mammaryglandinvolution,woundhealing,andbone readsorption. xi xii Preface Inclosing,Iwouldliketothankmyadministrativeassistant,Ms. ViSommerfeld,for herinvaluableassistanceandtimelesseffortswiththeorganizationandeditingofthebook. Lastly,Iwouldliketoacknowledgetheeffortsoftheauthorsoftheindividualchapters, whoareauthorities inthisfield,foragreeingtotaketimefrombusyschedulestoprovide thesechaptersinatimelyfashion. DavidMortonWaisman Contents Part I. Plasminogen: Structure and Regulation 1. Human Plasminogen: Structure, Activation, and Function FrancisJ. Castellino and Victoria A. Ploplis 1. Introduction 3 2. StructureofHumanPlasminogen...3 2. 1. PrimaryProteinStructure...3 2. 2. GeneOrganization 5 3. ActivationofHumanPlasminogen...6 3. 1. ActivationbyPhysiologicalActivators 7 3. 1. 1. Urokinase-typePlasminogenActivator...7 3. 1. 2. Tissue-typePlasminogenActivator...8 3. 2. ActivationbyBacterial-derivedPlasminogenActivators...9 3. 2. 1. Streptokinase 9 3. 2. 2. Staphylokinase...9 4. TargetsforPlasminActivity...9 5. DysplasminogenemiasandPhenotypicManifestations 10 6. Conclusions 11 References...11 2. Plasminogen Activators: Structure and Function Vincent Ellis 1. Introduction ...19 2. SerineProteases...20 3. UrokinasePlasminogenActivator,uPA...21 3. 1. SerineProteaseDomain 22 3. 2. N-terminalDomains...24 3. 2. 1. KRModule 24 3. 2. 2. EGModule 24 4. MechanismsRegulatinguPAFunction...25 4. 1. ZymogenActivation...25 4. 2. ZymogenActivity...26 4. 3. ReciprocalZymogenActivation 27 4. 4. uPARStimulationofPlasminogenActivation...27 4. 4. 1. uPAandtheTemplateMechanism 28 4. 4. 2. PlasminogenandtheTemplateMechanism 29 4. 5. AvianuPA,aSpecialCase? 30 xiii xiv Contents 5. TissuePlasminogenActivator,tPA...30 5. 1. SerineProteaseDomain 31 5. 2. N-terminalDomains ,...33 5. 2. 1. KRModules ,. . ,. . ,...33 5. 2. 2. F1-EGSupermodule 33 6.

This monograph evolved from years of research into the auditory pathway and hearing of many species of marsupials. Its function is to give biologists, in par ticular neurobiologists, a broad description and review of what is known of the auditory sensory capacities and processing mechanisms in this large order of mammals. My initial interest in marsupials developed from collaborative work with Dr. Richard Gates at Monash and Melbourne Universities in the 1970s and by curiosity as to whether concepts about the auditory system was stimulated stemming from experiments mainly on domestic cats could be extended to mam mals of other orders. My subsequent interest in Australian marsupials, aroused by collaboration with Dr. John Nelson at Monash University in the 1980s and 1990s, concerned their auditory systems and behavior per se and not as primitive cousins of eutherians. More recently, I have collaborated with Dr. Bruce Masterton at Florida State University in studies of New World marsupials. His sad death in 1996 has robbed neurobiologists of one of our most provocative thinkers and hypothesis testers. I would like to thank the Department of Physiology at Monash University for making many facilities available to me, the National Health and Medical Research of Australia and the Australian Research Council for providing funds for Council research, and Jill Poynton and Michelle Mulholland, who illustrated this volume."

This drug is a landmark discovery, which consequently has become the definitive therapy for the treatment of erectile dysfunction (ED). Following the major breakthrough in the field of nitric oxide (NO)-physiology and pharmacology leading to sildenafil being marketed, the most current information is presented in this reference book, including ongoing research from several disparate groups about NO as endothelium-derived relaxing factor (EDRF) and also as a neurotransmitter for nerves innervating erectile tissue in mammals.

The development of sildenafil as an oral phosphodiesterase-5 (PDE5) inhibitor drug for the treatment of ED resulted in one of the first products, which made its way successfully from basic NO research to routine clinical therapy.

This volume addresses all fields of sildenafil application in both men and women. In a highly competitive research environment with a critical medical need for drug improvements the reader will learn more about clinical resistance to sildenafil treatment and the modalities to overcome the failure rates.

The individual chapters cover clinical use, pharmacokinetics, pharmacodynamics, biochemistry, and cultural aspects. They are written by leading experts in their respective fields. Therefore, readers whether professionals in the pharmaceutical industry, physicians treating ED, biochemists, chemists or pharmacologists will find a detailed and up-to-date knowledge base about current research activities and an excellent overview for further research on this compound class and its cultural impact."

Recent research suggests that adult growth hormone (GH) deficiency, whether of pathological or physiological origin, is associated with a dis tinct syndrome that includes alterations in body composition, endocrine metabolic function, immune competence, and physical and psychosocial well-being. Not surprisingly, substantial investigative effort is currently focused on validating the above hypothesis and on determining whether restoration of a normal GH-IGF-I axis in various states of adult GH deficiency is clinically useful, safe, and cost-beneficial. This book contains the proceedings from the Symposium on GHRH, GH, and IGF-I: Basic and Clinical Advances, held December 9 to 12, 1993, in San Diego, California, and sponsored by Serono Symposia USA, Inc. The conference was meant to highlight selected novel and exciting clinical research developments related to possible therapeutic uses of recombinant human GH and IGF-I, GHRH, GH releasing peptides, and related GH secretagogues. This meeting occurred only one year after a similar Serono symposium that was somewhat more oriented to novel basic science discoveries, thus attesting to the current scientific and clinical interest in this area.

Chronic obstructive pulmonary disease (COPD) ranges amongst the commonest diseases in the world. The relentless progression of the disease causes a pressing need for a better understanding of and therapies for COPD. This volume provides state-of-the-art information on the pathophysiology of COPD including an outlook on new therapies. It is of interest to researchers and clinicians in academia as well as in the pharmaceutical industry.

Electric currents and electromagnetic fields have been applied to biological systems, particularly humans, with both therapeutic and pathological results. This text discusses biological responses to electric currents and electromagnetic fields, including medical applications and shock hazards. It covers fundamental physical and engineering principles of responses to short-term electrical exposure and emphasises human reactions, although animal responses are considered as well, and the treatment covers reactions from the just-detectable to the clearly detrimental. An important new chapter discusses standards for human exposure to electromagnetic fields and electric current and demonstrates how these standards have been developed using the principles treated in earlier chapters.

"Nitric Oxide and Free Radicals in Peripheral Neurotransmission" is a welcome addition to the literature and describes current research into the role of nitric oxide in the peripheral nervous system and its associated organs. Topics covered range from general consideration of nitrergic transmission, in its broadest sense, to elaboration of our current understanding of the role of nitric oxide in transmission in individual peripheral organs, including its role as a backup, or alternate as well as chief transmitter. The influence of nitric oxide and related compounds on the more conventional modes of autonomic transmission are also considered. Aimed at students and researchers in the areas of neuroscience and physiology, "Nitric Oxide and Free Radicals in Peripheral Neurotransmission" also covers the emerging role of abnormal nitric oxide function in disease states and, where appropriate, as potential avenues of therapy.

The field of neural control of breathing has advanced rapidly in the past two decades, with the emergence of many new and promising research directions of increasing sophistication. The complexity and diversity of the current methodologies signify its remarkable vivacity, albeit at the price of much confusion. Captured in this book are the broad and intricate nature of the field and its multifaceted frontiers, including aspects of genetics, cell and molecular biology, comparative biology, neurophysiology, neurochemistry, neuroanatomy, imaging, human physiology in health and disease, and influence of environmental factors. Major topics include chemosensitivity, respiratory sensation, respiratory neurons, rhythmogenesis, plasticity, development, chemoreflex and exercise, respiratory instability and variability with behavioral and sleep states, etc., which are systematically laid out in the book for easy referencing.

The Taurine Symposium- "Taurine: Beginning the 21'' Century"- was held September 20-23, 2002, on the beautiful island of Kauai in Hawaii. The headquarters of the meeting was the Radisson Kauai Beach Resort. This international meeting was attending by approximately 80 individuals from 23 nations and 4 continents. Seventy-five papers were presented either as platform presentations or poster presentations. Taurine, first isolated from ox bile in 1827 by Tiedemann and Gmelin and named in 1838 by Demarcay, became of significant scientific interest in 1968 when the first extensive review article was published by Jacobsen and Smith. Interest in taurine grew exponentially after 1975 when the first taurine symposium was organized by Ryan Huxtable in Tucson, Arizona. Since that date, taurine symposia have been held approximately every two years held in various cities and resort areas around the world. Taurine investigators have had the privilege of attending these scientific meetings on three continents - Asia, Europe, and North America. Since the initial meeting in 1975, a central question addressed during many of the symposia has been: "What is physiological, pharmacological, nutritional, and pathological role of taurine?". Although taurine has been established as an important osmolyte, it appears to affect many other biological processes. However, the exact mechanism(s) by "which taurine acts" has not yet been definitively answered. In Kauai, the patticipants discussed many topics and asked many questions regarding the role and actions of taurine.

Skeletal muscle consumes significant amounts of oxygen, and its oxygen flux increases significantly under conditions of exercise and muscle contraction. This makes the muscle vulnerable to oxidative stress since concomitantly with the increase of oxygen flow there is an increase of free oxygen radicals which are a byproduct of muscle respiration. A number of studies in the last decade have documented the involvement of free oxygen radicals in exercising muscles. The consequences of muscle oxidative stress have resulted mainly in increased muscle protein oxidation, elevation of lipid peroxidation, and depletion of muscle antioxidants. The mechanisms of this oxidative stress are under extensive investigation in laboratories around the world and are topics of the chapters in this volume. This book is intended for professionals who are interested in muscle function, physiology, pathophysiology and well-being, such as therapists, trainers and medical professionals as well as for researchers in the field of muscle physiology.

Despite major efforts by the scientific community over the years, our understanding of the pathogenesis or the mechanisms of injury of multiple sclerosis is still limited. Consequently, the current strategies for treatment and management of patients are limited in their efficacy. The mechanisms of tissue protection and repair are probably even less understood. One reason for these limitations is the enormous complexity of the disease and every facet of its pathogenesis, the mechanisms of tissue injury, the diagnostic procedures and finally the efficacy of treatments and their side effects. The aim of this book is to review the most recent advances made in this highly complex field.

Physiological, pharmacological and molecular biological data generated over the past three decades have demonstrated the existence of two major families of extracellular receptors, the P1, a family of four G-protein coupled receptors and the P2, a family of at least 12 receptors responsive to purine (ATP, ADP) and pyrimidine (UTP) nucleotides through which adenosine and ATP can function as extracellular messengers. The present two-part volume represents an integrated compendium of invited chapters by leading researchers in the area focusing on advances in the understanding of purinergic and pyrimidinergic signaling systems, their role(s) in tissue function and pathophysiology and advances in developing potential new medications based on the modulation of P1 and P2 receptor signaling processes. The volumes will thus provide the reader with a topical, comprehensive and integrated overview of this important area.

Antisense technology may result in dramatic changes in the therapy of many diseases and may provide tools to dissect pharmacological processes and to confirm the roles of various genes. In this volume, progress in the understanding of antisense technology and its use in creating new drugs is discussed. Potential caveats, pitfalls and limitations of the technology are also presented. In the next few years the pace at which new molecular targets will be identified will increase exponentially as the sequencing of the human genome and of other genomes proceeds.

After a little more than 20 years since the original discovery of neuropeptide Y (NPY) by Tatemoto and colleagues, the field of NPY research has made remarkable progress and is coming of age.The present volume addresses all major topics in connection with NPY and related peptides by established leaders in their respective areas. Experienced NPY-aficionados will certainly find new and useful additional information in this volume and newcomers to the field will hopefully discover how much exciting research this still has to offer.

A succinct review of hundreds of studies on the regulation of protein mass and protein turnover in the human body. The book summarizes the biochemistry of protein synthesis and breakdown, and explains the methods that are used to examine protein metabolism in humans, together with their limitations. Chapters review the effects of nutrition, hormones, metabolic substrates, and physical activity, while various topics of clinical interest include cancer, diabetes, tissue injury, pregnancy, renal disease, muscular dystrophies, and other conditions. Normal values are presented for turnover of proteins in the whole body and individual organs, and for turnover of many individual proteins. This is thus a valuable resource for physiologists, nutritionists, and clinicians interested in the regulation of body protein stores in health and disease. For scientists primarily interested in the basic aspects of protein metabolism, it shows how the basic knowledge is being applied to the study of humans.

First published in 1986, Professor Tonomura's book explains at the molecular level how cells use energy harnessed as adenosine triphosphate to perform the fundamental physiological functions such as muscle contraction and the active transport of cations. In all cases, ATPases enzymes are involved and the detailed reaction mechanisms are carefully described. Young collaborators helped Professor Tonomura to put together the first draft of the book, for he was particularly anxious that the text should be accessible to students who were less familiar with the intricacies of the field than he himself, and should reflect their needs. After his sudden, untimely death, Professor Ebashi and his colleagues at the National Institute of Physiological Sciences, Okazaki, updated and completed the text. The result is a well-written, interesting account of the field and this volume forms a worthy memorial to one of the foremost workers in this area of biochemical research.

Cells maintain uneven distribution of Na, K and Ca ions across the cell membrane and membranes of intracellular organellae. Cells exert their functions by allowing for some ion to cross the membrane through ion channels which either produces an electrical effect across the membrane or switches on a series of chemical or physicochemical reactions. This is a comprehensive book about these vitally important ion channels with detailed description of the molecular structure and function and especially of activators and inhibitors. All chapters are written by renowned specialists in their field.

Since oxygen is mainly transported by diffusion within tissue, the oxygen pressure field reflects the local balance between oxygen supply and oxygen consumption and characterizes the state of oxygen supply. Despite large physiological varia- tions (e. g. , hypo-and hyperoxia, hypo-and hypertension, change of energy de- mand), this oxygen pressure field can remain remarkably constant, demonstrating that very effective mechanisms must exist that guarantee the adequacy of oxygen supply. Today, it is possible to describe in detail the responsible effector mecha- nisms that produce such a stable state of oxygen supply, but our knowledge of the reactions that sense tissue oxygen supply and trigger the regulatory responses is still incomplete. Since such knowledge is essential for understanding the system of oxygen supply and the way in which it has developed during evolution, even small progress is important. In this book the important O sensor reactions are discussed as they occur in 2 cells, organs, and organ systems. This broad approach gives an excellent picture of the actual state of knowledge in this field. Professor Dr. D. W. Lubbers Contributors Acker, H. Max-Planck-Institut fUr Systemphysiologie, Rheinlanddamm 201, 4600 Dortmund 1, FRG Bassenge, E. Institut fUr Angewandte Physiologie der Universitat Freiburg, Hermann-Herder-Stral3e 7, 7800 Freiburg, FRG Bingmann, D. Poliklinik fUr zahnarztliche Chirurgie, Universitat Mainz, Augustusplatz 2, 6500 Mainz, FRG Bauer, C. Physiologisches Institut, Universitat Zurich, Winterthurerstral3e 190, 8057 Zurich, Switzerland Busse, R. Institut fUr Angewandte Physiologie, Universitat Freiburg, Hermann-Herder-Stral3e 7, 7800 Freiburg, FRG Delpiano, M. A.

In this unique book, Sir Donald Harrison draws on his wide-ranging experience as a surgeon and comparative anatomist to produce an authoritative and detailed account of the anatomy and physiology of the mammalian larynx. His investigation of the larynx has involved the study of over 1400 specimens of mammalian larynges from around the world, as well as using data from his own clinical experiences. The comparative morphology of the larynx is discussed from a developmental and functional perspective and the involvement of the larynx in respiration, locomotion and vocalisation is highlighted. Throughout the book the relationship of structure to function is drawn out and the clinical relevance of features of the human larynx is emphasised. This book will be an invaluable reference for all researchers and clinicians involved in laryngology as well as for anatomists, zoologists and anaesthesiologists.

First published in 1989, this volume presents a detailed series of scientific reviews concerned with most of the key areas of dog and cat nutrition; for example, the volume surveys and provides data on protein and energy requirements, calcium metabolism and essential fatty acids. It shows the substantial developments in knowledge that have occurred in the subject and discusses potential trends. The volume is an expanded, updated and edited version of papers originally presented at the Seventh Waltham Symposium on advances in dog and cat nutrition, held at Queens' College Cambridge in 1985. This is a comprehensively reference volume in a subject which is scientifically challenging and of immense practical importance. The volume will provide an essential source of reference and information for practitioners and students of veterinary medicine and for nutritionists and food research scientists in academia and industry.