In keeping with goal and style of the Handbook in Modern Biophysics series, the proposed book will maintain a chapter structure that contains two parts: concepts and biological application. The book also integrates all the chapters into a smooth, continuous discourse. The first and second chapters establish the mathematical methods and theoretical framework underpinning the different topics in the rest if the book. Other chapters will use the theoretical framework as a basis to discuss optical and NMR approaches. Each chapter will contain innovative didactic elements that facilitate teaching, self-study, and research preparation (key points, summary, exercise, references).

This book provides a premier resource on understanding the ribosome's essential nature and how it interacts with other proteins and nucleic acids to control protein synthesis. As one of the central foundations in our understanding of the biology at the molecular level, this topic appeals to a wide audience, from bench researcher to clinician. With the advent of atomic scale structures, methods to visualize and separate individual molecules, and the computational power to model the complex interactions of over a million atoms at once, our understanding of how gene expression is controlled at the level of protein translation is now deeply ensconced in the biophysical realm.

Themonographisdevotedtothetheoreticalstudiesofradiationeffectsonmammals. It summarizes the results obtained by the author over the past 30 years, most of them being of high priority. In the course of these studies, a single approach to the modeling of radiation effects on mammals has been elaborated. Speci?cally, in the framework of the developed deterministic mathematical models, the effects of both acute and chronic irradiation in a wide range of doses and dose rates on vital body systems (hematopoiesis, small intestine, and humoral immunity), as well as on the development of autoimmune diseases, are investigated. The radiation effects on the mortality dynamics in homogeneous and nonhomogeneous(in radiosensitivity) mammalian populations are also studied by making use of the developed stochastic models. The most appealing feature of these mortality models consists of the fact that they account for the intrinsic properties of the exposed organism. Namely, within these models the stochastic biometrical functions are calculated proceeding from statistical characteristics and dynamics of the respective critical body system (hematopoiesis or small intestine). The performed theoretical investigations contribute to the development of the system and quantitative approaches in radiation biology and ecology. These studies elucidate the major regulatory mechanisms of the damage and recovery processes running in the vital body systems of exposed mammals and reveal the key par- eters characterizing the processes.

Laser-based optical spectroscopies are powerful and versatile techniques that are continuing to evolve and find new applications. This book presents reviews of recent progress in our understanding of the spectra and dynamical processes of optically excited states of condensed matter, focusing on the advances made possible by the application of laser-based optical spectroscopies. Reviews are given of the optical properties of crystalline and amorphous semiconducting materials and structures, the properties of defect centers in insulators, two-photon nonlinear processes in insulators, optical energy diffusion in inorganic materials, and relaxation in organic materials. The individual chapters emphasize the methodology common to the various investigations. The volume is designed to be suitable as an introduction to applied laser spectroscopy of solids, as well as providing an update on the status of the field.

Signaling through antigen receptor initiates a complex series of events resulting in the activation of genes that regulate the development, proliferation and differentiation of lymphocytes. During the past few years, rapid progress has been made in understanding the molecular basis of signaling pathways mediated by antigen and cytokine receptors. These pathways involve protein tyrosine kinases which are coupled to downstream regulatory molecules, including small guanine nucleotide binding proteins (e. g. p21'OS), serine threonine kinases (e. g. , members of the ERK family), and a large group of transcription factors. More recently, there have been breakthroughs in elucidating the genetic defects underlying three X-linked primary immunodeficiency diseases in humans. This volume surveys aspects of these rapidly developing areas of research. The book is divided into 5 different sections. Section I deals with signaling pathways in B lymphocytes. It includes a contemporary assessment of B cell antigen receptor structures, and discussion of the role of Ig-a/lg-B polypeptides in linking the antigen receptor to intracellular signal transduction pathways. The role of accessory molecules in the regulation of signaling by the B cell antigen receptor is also considered. Section II adopts a similar approach to the analysis of the antigen receptor on T lymphocytes. The importance of specialized signaling motifs in the CD3 polypeptides, mechanisms whereby these motifs may interact with the lymphocyte-specific protein tyrosine kinases, and the downstream consequences of these interactions are reviewed. In addition, the role of antigen-induced apoptosis in the generation of immunological tolerance is discussed.

Proteins are still gaining importance in the pharmaceutical world, where they are used to improve our arsenal of therapeutic drugs and vaccines and as diagnostic tools. Proteins are different from "traditional" low-molecular-weight drugs. As a group, they exhibit a number of biopharmaceutical and formulation problems. These problems have drawn considerable interest from both industrial and aca demic environments, forcing pharmaceutical scientists to explore a domain previ ously examined only by peptide and protein chemists. Biopharmaceutical aspects of proteins, e.g., low oral bioavailability, have been extensively investigated. Although all possible conventional routes of ad ministration have been examined for proteins, no real, generally applicable alter native to parenteral administration in order to achieve systemic effects has yet been discovered. Several of these biopharmaceutical options have been discussed in Volume 4 of this series, Biological Barriers to Protein Delivery. Proteins are composed of many amino acids, several of which are notorious for their chemical instability. Rational design of formulations that optimize the native structure and/or bioactivity of a protein is therefore of great importance when long shelf life is required, as it is for pharmaceutical products. This issue has also been examined in two prior volumes of this series: Volume 2: Stability of Protein Pharmaceuticals (Part A) and Volume 5: Stability and Characterization of Protein and Peptide Drugs.

This volume represents the fIrst of a series of proceedings of the EL.B.A. Forum on Bioelectronics, a scientifIc discipline at the frontiers of Advanced Electronics and Biotechnology. The name for these forums derives not only from the place (the Isle of Elba in Italy), where the conferences have been held every 6 months since 1991, but also from an acronym: Electronics and Biotechnology Advanced. Bioelectronics is intended as "the use of biological materials and biological architectures for information processing and sensing systems and devices down to molecular level" and focuses its attention on three major areas: I New hardware architectures borrowed from the thorough study of brain and sensory systems down to the molecular level, utilizing existing semiconductor inorganic materials (both GaAs and Si) and giga-scale integration; II Protein Engineering, especially of systems involved in electron transfer and molecular recognition, integrated with Metabolism and Chemical Engineering, to develop new biomaterials by learning basic rules of macromolecular folding and self-assembly; m Sensors, thin film and electronic devices utilizing organic compounds and biopolymers, and by implementing nanotechnology bottom up through manufacturing and characterization at the atomic level.

Small-angle scattering of X rays and neutrons is a widely used diffraction method for studying the structure of matter. This method of elastic scattering is used in various branches of science and technology, includ ing condensed matter physics, molecular biology and biophysics, polymer science, and metallurgy. Many small-angle scattering studies are of value for pure science and practical applications. It is well known that the most general and informative method for investigating the spatial structure of matter is based on wave-diffraction phenomena. In diffraction experiments a primary beam of radiation influences a studied object, and the scattering pattern is analyzed. In principle, this analysis allows one to obtain information on the structure of a substance with a spatial resolution determined by the wavelength of the radiation. Diffraction methods are used for studying matter on all scales, from elementary particles to macro-objects. The use of X rays, neutrons, and electron beams, with wavelengths of about 1 A, permits the study of the condensed state of matter, solids and liquids, down to atomic resolution. Determination of the atomic structure of crystals, i.e., the arrangement of atoms in a unit cell, is an important example of this line of investigation."

Mechanical stress is vital to the functioning of the body, especially for tissues such as bone, muscle, heart, and vessels. It is well known that astronauts and bedridden patients suffer muscle and bone loss from lack of use. Even the heart, in pumping blood, causes mechanical stress to itself and to vascular tissue. With the loss of mechanical stress, homeostasis becomes impaired and leads to pathological conditions such as osteopenia, muscle atrophy, and vascular tissue dysfunction. In elderly populations, such mechanical pathophysiology, as well as the mechanical activities of locomotor and cardiovascular systems, is important because skeletal and heart functions decline and cause diseases in other organs. In this monograph, mechanical stress is discussed by experts in the field with respect to molecular, cellular, and tissue aspects in relation to medicine. Covering topics such as gravity and tissues and disuse osteoporosis, the book provides the most up-to-date information on cutting-edge advancements in the field of mechanobiology and is a timely contribution to research into locomotor and circulatory diseases that are major problems in contemporary society.

As we approach the twenty-first century the problems of industrialization are evident: we find there is a greenhouse effect, the ozone layer is being depleted, the rain is acidified, and there is a terrible problem of increasing C0 concentrations in the atmo 2 sphere. The carbonic anhydrases are a unique family of enzymes that solve these problems in the human body: they are responsible for converting C0 (a gas) to 2 HC0-, which is the biggest intracellular buffer, with a concomitant decrease in a 3 hydroxyl ion. Globally, the functions of the carbonic anhydrases in photosynthesis in rain forests and in the algae and plankton that cover our oceans indicate that they are also of utmost importance in the maintenance of the acid-base balance on our planet. Although the whole field of C0 metabolism is enormous and still rapidly 2 expanding, because of the research interests of the editors this book is mainly concerned with mammalian carbonic anhydrases. However, if the interested reader intends to purify carbonic anhydrases from nonmammalian sources, Dr. Cheg widden has provided the necessary information in Chapter 7. The carbonic anhydrases were first discovered in 1933; until1976 there were thought to be only two isozymes. Since then CA ill, IY, V, VI, and Vll have been discovered and well characterized. There is, of course, no reason to believe that we have found them all."

This volume contains the contributions from the speakers at the NATO Advanced Research Workshop on "Structure of the Photosynthetic Bacterial Reaction Center X-ray Crystallography and Optical Spectroscopy with Polarized Light" which was held at the "Maison d'Hotes" of the Centre d'Etudes Nucleaires de Cadarache in the South of France, 20-25 September, 1987. This meeting continued in the spirit of a previous workshop which took place in Feldafing (FRG), March 1985. Photosynthetic reaction centers are intrinsic membrane proteins which, by performing a photoinduced transmembrane charge separation, are responsible for the conversion and storage of solar energy. Since the pioneering work of Reed and Clayton (1968) on the isolation of the reaction center from photosynthetic bacteria, optical spectroscopy with polarized light has been one of the main tools used to investigate the geometrical arrangement of the various chromophores in these systems. The recent elucidation by X-ray crystallography of the structure of several bacterial reaction centers, a breakthrough initiated by Michel and Deisenhofer, has provided us with the atomic coordinates of the pigments and some details about their interactions with neighboring aminoacid residues. This essential step has given a large impetus both to experimentalists and to theoreticians who are now attempting to relate the X-ray structural model to the optical properties of the reaction center and ultimately to its primary biological function.

The predecessor to this book was A Guide to the Laboratory Use of the Squid Loligo pealei published by the Marine Biological Laboratory, Woods Hole, Massachusetts in 1974. The revision of this long out of date guide, with the approval of the Marine Biological Laboratory, is an attempt to introduce students and researchers to the cephalopods and particularly the squid as an object of biological research. Therefore, we have decided to expand on its original theme, which was to present important practical aspects for using the squid as experimental animals. There are twenty two chapters instead of the original eight. The material in the original eight chapters has been completely revised. Since more than one method can be used for accomplishing a given task, some duplication of methods was considered desirable in the various chapters. Thus, the methodology can be chosen which is best suited for each reader's requirements. Each subject also contains a mini-review which can serve as an introduction to the various topics. Thus, the volume is not just a laboratory manual, but can also be used as an introduction to squid biology. The book is intended for laboratory technicians, advanced undergraduate students, graduate students, researchers, and all others who want to learn the purpose, methods, and techniques of using squid as experimental animals. This is the reason why the name has been changed to its present title. Preceding the chapters is a list of many of the abbreviations, prefixes, and suffixes used in this volume.

Advanced Methods of Pharmacokinetic and Pharmocodynamic Systems Analysis Volume 3 is vital to professionals and academicians working in drug development and bioengineering. Both basic and clinical scientists will benefit from this work.This book contains chapters by leading researchers in pharmacokinetic/pharmacodynamic modeling and will be of interest to anyone involved with the application of pharmacokinetic and pharmacodynamics to drug development. The use of mathematical modeling and associated computational methods is central to the study of the absorption, distribution and elimination of therapeutic drugs (pharmacokinetics) and to understanding how drugs produce their effects (pharmacodynamics). From its inception, the field of pharmacokinetics and pharmacodynamics has incorporated methods of mathematical modeling, simulation and computation in an effort to better understand and quantify the processes of uptake, disposition and action of therapeutic drugs. These methods for pharmacokinetic/pharmacodynamic systems analysis impact all aspects of drug development. In vitro, animal and human testing, as well as drug therapy are all influenced by these methods. Modeling methodologies developed for studying pharmacokinetic/ pharmacodynamic processes confront many challenges. This is related in part to the severe restrictions on the number and type of measurements that are available from laboratory experiments and clinical trials, as well as the variability in the experiments and the uncertainty associated with the processes themselves. The contributions are organized in three main areas: Mechanism-Based PK/PD, Pharmacometrics and Pharmacotherapy. Both professionals and academics will profit from this extensive work.

This volume is compiled based on the proceedings of the 5th International Plant Cold Hardiness Seminar, which was held at Oregon State University, Corvallis, Oregon, USA, August 5 to 8, 1996. Participants representing 16 nations and 22 U. S. states attended the seminar. Researchers came from major laboratories around the world involving plant cold hardiness research. The information compiled in this volume represents the state-of the-art research and our understanding of plant cold hardiness in terms of molecular biol ogy, biochemistry, and physiology. The 1996 International Plant Cold Hardiness Seminar was the fifth of the series; it was first held in 1977 at the University of Minnesota, St. Paul, MN, and since then has met every 5 years. The overall goal of this seminar series is to foster the exchange of ideas and research findings among the diverse groups of scientists studying freezing and chilling stresses from a wide variety of perspectives. This is the only international conference focus ing its programs entirely on low temperature stress in plants. In accordance with the tradi tion, the fifth conference focused on freezing and chilling stress of plants and covered various aspects of plant cold hardiness, including molecular genetics, biochemistry, physi ology, and agricultural applications. All contributors to this volume are eminent researchers who have had significant contributions to the knowledge of plant cold hardiness."

There are many human cancers which actively synthesize specific characteristic proteins such as melanomas, thyroid cancer and squamous cell carcinoma. Many cancer researchers have of course tried to utilize this specific activity as a key for the selective treatment of cancers. In the past for example, the molecular hybrid compound of DOPA, a substrate of melanin, and nitrogen mustard N-oxide hydrochloride, a ctyotoxic anti-tumor drug, was synthesized as Melphalan and used to treat malignant melanoma. A major problem arose though in that it was soon found to be highly suppressive toward bone marrow and quite toxic while not being remarkably effective. Thus, malignant melanoma could not be cured by it. Such failure led us to develop a novel bimodal therapeutic system which includes the use of non-toxic potentially cytocidal chemicals which selectively accumulate within the cancer cells and which are converted by a controllable modality into an actively cytocidal element in situ. We can now non-surgically cure malignant melanoma and glioblastoma with our selective cancer treatment, neutron capture therapy (NCT); as can be found in this volume. Included are 124 papers on the latest breaking developments discussed at the Sixth International Symposium on NCT for Cancer held in Kobe during the late autumn of 1994.

What are the relations between the shape of a system of cities and that of fish school? Which events should happen in a cell in order that it participates to one of the finger of our hands? How to interpret the shape of a sand dune? This collective book written for the non-specialist addresses these questions and more generally, the fundamental issue of the emergence of forms and patterns in physical and living systems. It is a single book gathering the different aspects of morphogenesis and approaches developed in different disciplines on shape and pattern formation. Relying on the seminal works of D'Arcy Thompson, Alan Turing and Rene Thom, it confronts major examples like plant growth and shape, intra-cellular organization, evolution of living forms or motifs generated by crystals. A book essential to understand universal principles at work in the shapes and patterns surrounding us but also to avoid spurious analogies.

How does the brain code and process incoming information, how does it recog nize a certain object, how does a certain Gestalt come into our awareness? One of the key issues to conscious realization of an object, of a Gestalt is the attention de voted to the corresponding sensory input which evokes the neural pattern underly ing the Gestalt. This requires that the attention be devoted to one set of objects at a time. However, the attention may be switched quickly between different objects or ongoing input processes. It is to be expected that such mechanisms are reflected in the neural dynamics: Neurons or neuronal assemblies which pertain to one object may fire, possibly in rapid bursts at a time. Such firing bursts may enhance the synaptic strength in the corresponding cell assembly and thereby form the substrate of short-term memory. However, we may well become aware of two different objects at a time. How can we avoid that the firing patterns which may relate to say a certain type of move ment (columns in V5) or to a color (V 4) of one object do not become mixed with those of another object? Such a blend may only happen if the presentation times be come very short (below 20-30 ms). One possibility is that neurons pertaining to one cell assembly fire syn chronously. Then different cell assemblies firing at different rates may code different information."

In the past few years, the scientific community has witnessed significant progress in the study of ion channels. Technological advancement in biophysics, molecular biology, and immunology has been greatly ac celerated, making it possible to conduct experiments which were deemed very difficult if not impossible in the past. For example, patch-clamp techniques can now be used to measure ionic currents generated by almost every type of cell, thereby allowing us to analyze whole-cell and single channel events. It is now possible to incorporate purified ion channel components into lipid bilayers to reconstitute an "excitable membrane." Gene cloning and monoclonal antibody techniques provide us with new approaches to the study of the molecular structure of ion channels. A variety of chemicals have now been found to interact with ion channels. One of the classical examples is represented by tetrodotoxin, a puffer fish poison, which was shown in the early 1960s to block the voltage-activated sodium channel in a highly specific and potent manner.

It was just over ten years ago, at Aspeniisgarden near Gothenburg, Sweden, that Pro fessor Alexandr Sergeevich Davydov presented his soliton theory for the storage and transport of biological energy in protein to scientists from Europe, North America and Japan. Since then, his ideas have been vigorously studied and investigated throughout the world. Many feel that Davydov's theory is an important contribution to biomolecu lar dynamics, but others caution that neglected dispersive effects may destroy the energy localization that arises ill his theory. It was to discuss these differences of opinion that we organized a NATO Advanced Research Workshop on "Self-trapping of Vibrational Energy in Protein" from July 30 to August 5, 1989 at Hanstholm, Denmark. In addition to substantial financial support from the Special Programme on "Chaos; Order and Patterns" of the NATO Scientific Affairs Division, we received it generous grant from the Danish Natural Science Research Council. We also acknowledge invalu able assistance provided by the interdepartmental center of nonlinear studies ("MIDIT" is the Danish acronym) as well as the Laboratory of Applied Mathematical Physics, both at the Technical University of Denmark. It is a particular pleasure to thank Lise Gudmandsen and Dorthe Thcentsgersen for many forms of assistance before, during, and after the workshop."

Nutrients have been recognized as essential for maximum growth, successful reproduction, and infection prevention since the 1940s; since that time, the lion's share of nutrient research has focused on defining their role in these processes. Around 1990, however, a major shift began in the way that researchers viewed some nutrients particularly the vitamins. This shift was motivated by the discovery that modest declines in vitamin nutritional status are associated with an increased risk of ill-health and disease (such as neural tube defects, heart disease, and cancer), especially in those populations or individuals who are genetically predisposed. In an effort to expand upon this new understanding of nutrient action, nutritionists are increasingly turning their focus to the mathematical modeling of nutrient kinetic data. The availability of suitably-tagged (isotope) nutrients (such as B-carotene, vitamin A, folate, among others), sensitive analytical methods to trace them in humans (mass spectrometry and accelerator mass spectrometry), and powerful software (capable of solving and manipulating differential equations efficiently and accurately), has allowed researchers to construct mathematical models aimed at characterizing the dynamic and kinetic behavior of key nutrients in vivo in humans at an unparalleled level of detail."

Although there is general agreement that exogenous electric and electromagnetic fields influence and modulate the properties of biological systems. there is no concensus regarding the mechanisms by which such fields operate. It is the purpose of this volume to bring together and examine critically the mechanistic models and concepts that have been proposed. We have chosen to arrange the papers in terms of the level of biological organization emphasized by the contributors. Some papers overlap categories. but the progression from ions and membrane surfaces. through macromolecules and the membrane matrix to integrated systems. establishes a mechanistic chain of causality that links the basic interactions in the relatively well understood simple systems to the complex living systems. where all effects occur simultaneously. The backgrounds of the invited contributors include biochemistry. biophysics. cell biology. electrical engineering. electrochemistry. electrophysiology. medicine and physical chemistry. As a result of this diversity. the mechanistic models reflect the differing approaches used by these disciplines to explain the same phenomena. Areas of agreement define the common ground. while the areas of divergence provide opportunities for refining our ideas through further experimentation. To facilitate the interaction between the different points of view, the authors have clearly indicated those published observations that they are trying to explain. i.e. the experiments that have been critical in their thinking. This should establish a concensus regarding important observations. In the discussion of theories.

William P. Cooney III, R. A. Berger, and K. N. An Orthopedic Biomechanics Laboratory Department of Orthopedic Surgery Mayo Clinic and Mayo Foundation Rochester, MN 55905, U. S. A. As surgeons struggle to find new insights into the complex diseases and deformities that involve the wrist and hand, new insights are being provided by applied anatomy, physiology and biomechanics to these important areas. Indeed, a fresh new interaction of disciplines has immersed in which anatomists, bioengineers and surgeons examine together basic functions and principles that can provide a strong foundation for future growth. Clinical interest in the hand and wrist are now at a peak on an international level. Economic implications of disability affecting the hand and wrist are recognized that have international scope crossing oceans, cultures, languages and political philosophies. As with any struggle, a common ground for understanding is essential. NATO conferences such as this symposium on Biomechanics of the Hand and Wrist provides such a basis upon which to build discernment of fundamental postulates. As a start, basic research directed at studies of anatomy, pathology and pathophysiology and mechanical modeling is essential. To take these important steps further forward, funding from government and industry are needed to consider fundamental principles within the material sciences, biomechanical disciplines, applied anatomy and physiology and concepts of engineering modeling that have been applied to other areas of the musculoskeletal system.

In recent years experimental and numerical studies have shown that chaos is a widespread phenomenon throughout the biological hierarchy ranging from simple enzyme reactions to ecosystems. Although a coherent picture of the fundamental mechanisms responsible for chaotic dynamics has started to appear it is not yet clear what the implications of such dynamics are for biological systems in general. In some systems it appears that chaotic dynamics are associated with a pathological condi tion. In other systems the pathological condition has regular periodic dynamics whilst the normal non-pathological condition has chaotic dyna mics. Since chaotic behaviour is so ubiquitous in nature and since the phenomenon raises some fundamental questions about its implications for biology it seemed timely to organize an interdisciplinary meeting at which leading scientists could meet to exchange ideas, to evaluate the current state of the field and to stipulate the guidelines along which future research should be directed. The present volume contains the contributions to the NATO Advanced Research Workshop on "Chaos in Biological Systems" held at Dyffryn House, St. Nicholas, Cardiff, U. K., December 8-12, 1986. At this meeting 38 researchers with highly different backgrounds met to present their latest results through lectures and posters and to discuss the applica tions of non-linear techniques to problems of common interest. . In spite of their involvement in the study of chaotic dynamics for several years many of the participants met here for the first time."

I have been asked to write a brief foreword to this volume honoring Hisako Ikeda, providing a review of the accomplishments in our field over the past four decades, when Hisako was an active participant. This I am delighted to do. It has been a most exciting time in vision research and Hisako has been right in the middle of much of the excitement, publishing on a wide variety of topics and providing much new data and many new insights. Hisako's research career can be divided by decades into four quite distinct areas of inquiry. In the 1950s, as a student in Japan, her research interests were psychophysical in nature, and she was concerned with visual illusions, figural aftereffects, and motion detec tion. In the 1960s, after her move to London, she began electrophysiological studies. Much of her work in the 1960s was concerned with the electroretinogram (ERG), its components, and the use of this electrical response for evaluating spectral sensitivities of the eye and retinal degenerations. This work represented the beginning of her electrodiagnostic clinical work, which continued until her retirement."