Genome research will certainly be one of the most important and exciting sci- tific disciplines of the 21st century. Deciphering the structure of the human genome, as well as that of several model organisms, is the key to our understanding how genes fu- tion in health and disease. With the combined development of innovativetools, resources, scientific know-how, and an overall functional genomic strategy, the origins of human and other organisms'geneticdiseases can be traced. Scientificresearch groups and dev- opmental departments of several major pharmaceutical and biotechnological companies are using new, innovative strategies to unravel how genes function, elucidating the gene protein product, understanding how genes interact with others-both in health and in the disease state. Presently, the impact of the applications of genome research on our society in medicine, agriculture and nutrition will be comparable only to that of communication technologies. In fact, computational methods, including networking, have been playing a substantial role even in genomics and proteomics from the beginning. We can observe, however, a fundamental change of the paradigm in life sciences these days: research focused until now mostly on the study of single processes related to a few genes or gene products, but due to technical developments of the last years we can now potentially identify and analyze all genes and gene products of an organism and clarify their role in the network of lifeprocesses.

Virus Variability and Impact on Epidemiology and Control of Diseases E. Kurstak and A. Hossain I. INTRODUCTION An important number of virus infections and their epidemic developments demonstrate that ineffec tiveness of prevention measures is often due to the mutation rate and variability of viruses (Kurstak et al., 1984, 1987). The new human immunodeficiency retroviruses and old influenza viruses are only one among several examples of virus variation that prevent, or make very difficult. the production of reliable vaccines. It could be stated that the most important factor limiting the effectiveness of vaccines against virus infections is apparently virus variation. Not much is, how ever, known about the factors influencing and responsible for the dramatically diverse patterns of virus variability. II. MUTATION RATE AND VARIABILITY OF HUMAN AND ANIMAL VIRUSES Mutation is undoubtedly the primary source of variation, and several reports in the literature suggest that extreme variability of some viruses may be a consequence of an unusually high mutation rate (Holland et al., 1982; Domingo et al., 1985; Smith and Inglis, 1987). The mutation rate of a virus is defined as the probability that during a single replication of the virus genome a particular nucleotide position is altered through substitution, deletion, insertion. or recombination. Different techniques have been utilized to measure virus mutation rates, and these have been noted in the extent of application to different viruses."

Leading experts provide the only comprehensive book examining all aspects of immune response and immune-based treatments for HIV infection. Contributions, divided into three sections, discuss basic mechanisms, immunopathogenesis of HIV infection, and immune-based therapies. Researchers thoroughly review vaccine-including prospects of T cell vaccine-and gene therapy for HIV infection. Additional topics include organization of HIV genes, the role of co-receptors in signaling of lymphocytes, and biological response modifiers. This reference is designed for basic and clinical researchers, internists, pediatricians, infectious disease specialists, neuropathologists, oncologists, and rheumatologists.

The development of radioimmunoassay (RIA) by R.S. Yalow and S.A. Berson in 1959 opens up a new avenue in ultra sensitive analysis of trace substances in complex biological systems. In recognition of the enormous contributions of RIA to basic research in biology and to routine clinical tests in laboratory medicine, R.S. Yalow, the co-developer of RIA, was awarded, in 1977, the Nobel Prize for Medicine and Physiology. The basic principle of RIA is elegantly simple. It is based on a specific, competitive binding reaction between the analyte and the radio-labeled analog of the analyte for the specific antibody raised to the analyte. The combination of high specificity and affinity of an antibody molecule makes it a very versatile analytical reagent capable of reacting specifically with analytes at a very low concentration in a complex solution such as serum. The sensitivity of RIA is provided by using a radioactive tracer."

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.

Vaccination is one of the most efficient and cost effective methods of promoting human health and has been in clinical use for at least 200 years. Nevertheless, infectious diseases continue to constitute a constant threat to the well being of humanity. Common pathogens, once believed to be under control, acquire increased virulence and resistance to drugs, while exotic microorganisms emerged from hidden reservoirs to cause yet incurable diseases in humans. These changes, together with epidemic outbreaks related to political and socio-economic instabilities, increase the needs for the development of new, advanced vaccines. In this volume, devoted to the proceedings of the 39th OHOLO Conference, we present some of the recent strategies for the design and production of novel vaccines. The advent of recombinant DNA technology has stimulated the production of several subunit vaccines. In spite of the obvious advantages to this approach, the limited immuno genicity of many subunit candidates has hindered their development. Strategies to enhance the immunogenicity of subunit vaccines is therefore critical. Several approaches toward this goal, including design of novel adjuvants and delivery systems as well as design of advantageous carriers, are presented here. Among the carriers evaluated here are polypep tides (flagellin, HBV core antigen, J3-galactosidase), attenuated virions (Vaccinia, Sindbis), and nonpathogenic licensed bacteria (Salmonella)."

Volume 3 is devoted to the latest diagnostic technology for virus diseases, particularly molecular methodologies.

The fifth of the annual research conferences of the American Institute for Cancer Research was held September l-2, 1994, at the L'Enfant Plaza Hotel in Washington, DC. Appropriately, in view of current directions in research, the theme was "Diet and Cancer: Molecular Mechanisms of Interactions". This proceedings volume contains chapters from the platform presentations and abstracts from the poster session held on the end of the first day. The subtopics for the tl;rree sessions held were "Retinoids, Vitamins A and Din Cancer Prevention and Therapy," "Choline and Lipids: Signal Transduction, Gene Expression and Growth Regulation," and "Dietary Factors and Regulation of Oncogenes, Growth and Differentiation. " A general overview on vitamins A and D emphasized that A and D, in addition to their established roles in vision, reproduction, and bone mineral homeostasis, may play significant roles in regulating cell function. Vitamin A metabolites, trans-retinoic acid and 9-cis-retinoic acid, regulate growth and differentiation. Furthermore, vitamin A deprived animals were more susceptible to both spontaneous and carcinogen-induced tumors. Epidemiological studies showed a correlation between low A intake and higher incidences of certain types of human cancers. Conversely, all-trans retinoic acid is useful in treatment and control of certain types of cancer. Physiologically, Vitamin D is converted to the active form, l ,25-dihydroxyvitamin D (VD). VD regulates hormone production and secretion, myocardial contractility, vascu 3 3 3 lar tone, and growth inhibition and differentiation.

Experts in microbiology and autoimmunity examine the association between microorganisms and the development of specific categories of autoimmune diseases. The opening chapters explore the bacterial induction of diseases considered autoimmune in nature. Subsequent chapters describe the role of viruses in the induction of these diseases and of diseases with an autoimmune component. Specific topics include: the role of streptococcal infection in rheumatic fever and the role of Klebsiella in the development of ankylosing spondylitis.

Biomedical scientists widely acknowledge that individuals' immune respon siveness is important in resistance to infections by microorganisms, including fungi. Because of the devastating acquired immunodeficiency syndrome (AIDS) epidemic, caused by the human immunodeficiency retrovirus, it is now accepted that suppressed immune responses, especially cellular immu nity, are important contributors to increased individual susceptibility to opportunistic infections-including infections caused by fungi which were at one time thought to be very lowly or nonpathogenic. Within the last few years, there has been an almost explosive increase in interest and studies concerning the nature and mechanisms of the immune response to fungal infections. Many immunologists who are not well versed in mycology have begun to study the nature and mechanisms of antifungal immunity using a wide variety of newer as well as more conventional immunologic technologies, both in vivo and in vitro. Up to the 1980s, however, there was little interest among basic immunologists concerning fungal immunity. This situation has changed dramatically in the past half decade, mainly because of AIDS.

With all the enormous resources that are invested in medicine, it is sometimes a mystery why there is so much sickness still in evidence. Our life span, though higher than at any time in history, has now leveled off and has not significantly increased in the last two generations. There is a one-third increase in long-term illness in the last 20 years and a 44% increase in cancer incidence, which are not related to demographic issues. In some modern countries, the level of morbidity (defined as days off work because of sickness) has increased by two thirds in this time. Despite $1 trillion spent on cancer research in 20 years, the "War On Cancer" has recently been pronounced a complete failure by the u. s. President's Cancer Panel. Evidently we still have a long way to go. The goal of "Health for All by the Year 2000" as the World Health Organization has put it, is another forgotten dream. As ever, the answer will be found in breaking out of the old philosophical patterns and discovering the new, as yet unacceptable concepts. The problems of medicine today require a Kuhnian breakthrough into new paradigms, and new ways of thinking. And these new ways will not be mere variations of the old, but radical departures. This book, and the conference upon which it was based, is part of a search for these new pathways.

The interplay between tumors and their immunologic microenvironment is complex, difficult to decipher, but its understanding is of seminal importance for the development of novel prognostic markers and therapeutic strategies. The present review discusses tumor-immune interactions in several human cancers that illustrate various aspects of this complexity and proposes an integrated scheme of the impact of local immune reactions on clinical outcome. Current active immunotherapy trials have shown durable tumor regressions in a fraction of patients. However, clinical efficacy of current vaccines is limited, possibly because tumors skew the immune system by means of myeloid-derived suppressor cells, inflammatory type 2 T cells and regulatory T cells (Tregs), all of which prevent the generation of effector cells. To improve the clinical efficacy of cancer vaccines in patients with metastatic disease, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome Tregs and allow the breakdown of the immunosuppressive tumor microenvironment.

This book covers all aspects of oxygen delivery to tissue, including blood flow and its regulation as well as oxygen metabolism. Special attention will be paid to methods of oxygen measurement in living tissue and application of these technologies to understanding physiological and biochemical basis for pathology related to tissue oxygenation. This book is multidisciplinary and designed to bring together experts and students from a range of research fields including biochemical engineering, physiology, microcirculation, and hematology.

This series of books, devoted to aspects of blood cell biochemistry, development, immu nology, and ultrastructure, has evolved and separated from the long-established Plenum series Subcellular Biochemistry. It is the intention of these volumes to draw together related areas of investigation and to provide, in the fullness of time, complete coverage of this rapidly advancing important biomedical discipline. Both fundamental and medically applied topics, dealing with normal and pathological cells, will be included. This, the first volume of the series, contains a diverse collection of chapters, all of which relate to erythroid cells. The range of material included is extremely broad and the authors have used contrasting technical approaches, both within their personal experimen tal studies and within their manuscripts. This has led to the production of a very interest ing compilation, which does, nevertheless, possess a strong overall thematic unity. As with all edited volumes, some topics of importance and interest are not included. This may be because of oversight on my part, as editor, or because the authors originally selected failed to submit their manuscript by the agreed-upon submission date. For these omissions I take full responsibility and trust that at least some of the topics omitted, for instance membrane cation transport systems, will be covered within a future volume of the series. This book commences with two chapters of a developmental nature."

Since programmed cell death was first described in insects in 1964 and apoptosis was described in 1972, rapid progress has been made in understanding the basic mechanisms and genes regulating programmed cell death and apoptosis. In addition, defects in various genes regulating programmed cell death have been delineated in several experimental models of human diseases. This volume surveys various aspects of these rapidly developing areas of research in programmed cell death/apoptosis. This volume should be of interest to basic immunologists and molecular biologists. The volume begins with a historical perspective of cell death. The remainder of the volume is divided into four different parts. Part I deals with the signaling pathways in apoptosis, including cell cycle control of apoptosis, role of ceramide in apoptosis, role of antibody signaling, and biochemical regulation of apoptosis. The mechanisms for recognition of apoptotic lymphocytes by macrophages are also reviewed. Part II examines the role of various genes that regulate apoptosis, including the role ofFas, FasL, and other TNF family members in apoptosis and homeostatic regulation of immune response. Recently described splice variants and their influence on apoptosis are also reviewed, and the role of the members of the Bcl-2 family in apoptosis is discussed in detail. Part III reviews various aspects of apoptosis in B lymphocytes, including mechanisms that regulate apoptosis/survival of B lymphocytes and the regulation of Fas-mediated apoptosis in B lymphocytes.

Blood Cell Biochemistry was initially conceived as part of the Plenum series Subcellular Biochemistry, from which it has developed into a separate series. The present volume is devoted primarily to contributions on megakaryocytes and platelets and, to a lesser extent, to macrophages and eosinophils. The book does not attempt a rigorous or total coverage of the particular topics; it represents the areas of current scientific activity and interest that were selected by the editor at the commencement of this project. In general, the approach has been similar to that adopted for Volume 1 of the series (Erythroid Cells); the same approach will be followed subsequently in Volume 3 (Lymphocytes and Granulocytes). This book opens with a developmentally oriented chapter by Janine Breton-Gorius on megakaryocyte maturation and platelet release in normal conditions, which serves to set the scene ultrastructurally for much of the data that follow. The biosynthesis and process ing of platelet glycoproteins in megakaryocytes is dealt with by Alain Duperray and his colleagues, and thereby provides an in-depth biochemical survey of the megakaryocyte. The applications and strengths of crossed immunoelectrophoresis for the study of platelet membrane proteins is then covered by Simon Karpatkin, and a detailed account of the heredity disorders of platelet function is provided by Francine Rendu and Evelyne Dupuy."

Adaptive immune responses serve as a key defense mechanism for the control of infections in vertebrates. Immune responses must be of sufficient strength to contain invading pathogens, antigen specific responses require regulatory mechanisms to ensure termination or downmodulation to avoid excessive damage to the host tissue. For both branches of the adaptive immune system, regulatory molecules i.e. coreceptors and ligands have been identified that control the signaling cascades initiated by engagement of the T cell and B cell antigen receptors. This book describes biological functions as well as molecular mechanisms of these molecules.

Discrimination of self from nonself is the major function of the immune system and understanding the mechanism(s) involved a main employer of immunologists. Hence, the age-old puzzle of why a fetus that contains a panel of major histocompatibility (MHC) antigens derived from its mother and its father is not rejected (spontaneously aborted) by lymphocytes from its mother who should theoretically recognize foreign MHC molecules from the father has remained of great interest. This dilemma has enticed immunologists and developmental biologists for many years. This volume was created to present the information currently on hand in this subject to the scientific public. The guest editor, Professor Lars Olding, has a long and distinguished history of contributions in this field, having been one of the main propo nents of the argument that lymphocytes from the fetus play an active role in this process by suppressing lymphocytes from the mother from proliferating and thereby acting as killer cells. His work has defined the phenomenon and identified suppressor molecules (factors) involved in the process. In a different but related chapter, Margareta Unander extends such observations to the clinical study of women with repeated "habitual" mIS carriages."

These proceedings contain selected contributions from the participants to the Fourth International Symposium on Dendritic cells that was held in Venice (Lido) Italy, from Oc tober 5 to 10, 1996. The symposium was attended by more than 500 scientists coming from 24 different countries. Studies on dendritic cells (DC) have been greatly hampered by the difficulties in preparing sufficient cell numbers and in a reasonable pure form. At this meeting it has been shown that large quantities of DC can be generated from precursors in both mice and humans, and this possibility has enormously encouraged studies aimed to characterize DC physiology and DC-specific genes, and to employ DC therapeutically as adjuvants for im munization. The possibility of generating large numbers of autologous DC that can be used in the manipulation of the immune response against cancer and infectious diseases has tremendously boosted dendritic cell research and the role of DC in a number of medi cal areas has been heatedly discussed."

Since the turn of the century, certain parasitic diseases of livestock have frus trated efforts to bring them under control by vaccination techniques; East Coast fever and trypanosomiasis are two such diseases. East Coast fever (ECF) kills a half million cattle annually; and 3 million are killed each year by trypanosomia sis, which is widely spread over tropical Mrica. Together, these diseases have closed some 7 million square kilometers of land to livestock grazing-land that might otherwise support an additional 120 million head of cattle. In 1970 W.A. Malmquist of the U.S. Department of Agriculture, in collabora tion with K.N. Brown, M.P. Cunningham, and other associates at the East African Veterinary Research Organization in Kenya, succeeded in cultivating in vitro the protozoal organisms responsible for East Coast fever. This success, obtained utilizing tissue cultures, encouraged a number of organizations to support research on these parasites in an accelerated effort to develop field vaccines."

This volume is based on the proceedings of the International Symposium on Bacterial Endotoxins held in Japan. May 11-14. 1988 and sponsored by the International Endotoxin Society and the International Society for Immuno pharmacology. Speakers and participants of this symposium provided new information concerning fundamental and clinical aspects of endotoxin research conducted over the last half decade or so. Advances have been made in understanding the structure and nature of endotoxin molecules and their effects on a wide variety of both cellular and subcellular aspects, of immunity. metabolism and physiology. both in vivo and in vitro. Endotoxins are constituents of gram negative bacteria. Since their original discovery in the nineteenth century. many laboratories studied their chemical composition. their physico- and immunochemica1 properties. as well as their pharmacological and physiological effects on the host. Much is now known about the chemical structure of the endotoxins. There is also a grow ing body of information concerning the multiple effects of endotoxins on the host including immune mechanisms. Some effects have been found to be benefi cial to the host and endotoxins are being used more frequently to induce important mediators of immunity as well as increasing resistance against infections by many microorganisms as well as inhibiting growth of tumors in experimental animal models and in man."

Chlamydia pneumoniae is a bacteria that is most commonly known for causing colds and pneumonia. However, researchers have recently found a link between C. pneumoniae and atherosclerosis, a clogging of the arteries that causes heart attack and stroke. In addition, ongoing research is showing that certain strains may play a role in asthma, multiple sclerosis, Alzheimer's disease, and arthritis. This volume, part of the Infectious Agents and Pathogenesis series, is a complete portrait of C. pneumoniae and what is currently known about it.

New information is developing so rapidly in the entire field of immunology that one is unable to remain abreast of all advancing fronts. In many cases, consider able information has accumulated as the result of the efforts of many investigators, but the conclusions from the various laboratories have not been summarized recently in a comprehensible manner. One such situation has to do with work on IgD. An up-to-date report on this immunoglobulin was included in Volume 10f this series, but since that time there has been considerable progress in the deter mination of its structure and function. In the present volume Leslie and Martin have reviewed the accomplishments of recent years and the problems remaining to be solved. New information regarding the concentration of IgD in body fluids in normal and disease states is presented. Studies of the ontogeny of surface IgD in animals are described, and the fmdings imply that it may be important in the primary immune response. The role of IgD on lymphocyte surfaces is thoroughly discussed especially in terms of stimulating or suppressive combinations of signals delivered to the lymphocyte by agents which bind or alter the surface rt: ceptors. The authors conclude by proposing a model for plasma-cell differentiation which accounts fo the existence of triple Ig-bearing cells, many IgM-IgD-bearing cells, and the low percentage of cells bearing a single isotype. Sometimes the serum of an individual contains abnormally large amounts of two distinct, homogeneous populations of immunoglobulins."

Immunocytochemistry and in situ hybridization are widely used biomedical sciences. They are essential in medical diagnosis and in cell biology research. Affinity labeling is the central goal of the experimental strategy involving a series of techniques in a logical order; from the effects of specimen fixation, through specimen preparation to expose the antigen, to optimizing immunolabeling, to assessing the result and finally to safety considerations. Numerous examples of these techniques in biomedical sciences are included, as well as experimental assays and practical tips. This survey of methods will serve as an invaluable reference source in any laboratory setting (academic, industrial or clinical) involved in research in almost every branch of biology or medicine, as well as in pharmaceutical, biotechnological and clinical applications.

Because of several valid (and some invalid) reasons, the research field of tumor immunology has been declining in popularity. The Simplistic dogmas, articles of faith, and theories of the late 1960s and early 1970s on the immuno logical mechanisms of the host-tumor interrelationships have frequently been refuted by some of the new developments in cancer biology, cancer biochem istry, and immunology. Furthermore, some of the conventional assays used to monitor "tumor-host immune relations" did not always reflect the host's true clinical situation or his prognosis. Several approaches to immunological interven tion were less successful than expected. In addition, the concept of "immune surveillance," which was basic to many researchers in the field of cancer im munology, seemed to fall apart. Much of the criticism was based on results from solid, well-performed, and well-controlled experiments, but there was also un just criticism based on ill-conceived and badly performed studies, and on misin terpretations of experimental data. There are many misconceptions about the tumor-host relationship. It is very often assumed that tumor immunity, as expressed systemically, is truly reflected at the tumor site. Several studies reported in this volume and elsewhere indicate that such is not always the case. Certain immune effectors may be selectively prevented from reaching the tumor site or the close vicinity of the tumor cells because of mechanical or chemical barriers, whereas others may be selectively attracted to the site by chemotaxis or other mechanisms."