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."

Understanding Immunology is a well-established introduction to this complex subject for readers with no previous exposure. It is aimed primarily at undergraduates in biological sciences, biomedical sciences and medicine. The selection and order of topic coverage is designed to instruct effectively, and a variety of boxed examples add depth and historical context for those readers wanting to go beyond the essentials.

The culmination of 30 years of research and experience in T-cell-based cancer, this book highlights and evaluates new treatments that harness the power of the T cell to attack and kill all cancer cells in our bodies. It describes how the T cell immune system can be manipulated and redirected to kill resistant cancer cells by understanding and influencing the interaction of many different immune cells in the body. Citing current experimental trials, it examines the role and pathology of T-cells and suggests additional experimental approaches to the problem.

Course covers topics in infectious diseases in children and is intended for Pediatric Infectious disease trainees, trainers, and all those who manage children with infections.

The ability to remember an antigenic encounter for several decades, even for a life time, is one of the fundamental properties of the immune system. This phenomenon known as "immunological memory," is the foundation upon which the concept if vaccination rests. Therefore, understanding the mechanisms by which immunological memory is regulated is of paramount importance. Recent advances in immunology, particularly in the field of innate immunity, suggest that the innate immune system plays fundamental roles in influencing immunological memory. Indeed, emerging evidence suggests that events that occur early, within hours if not minutes of pathogen or vaccine entry profoundly shape the quantity, quality and duration of immunological memory. The present volume assembles a collection of essays from leading experts that span the entire spectrum research from understanding the molecular mechanisms of innate immune recognition, to dendritic cell function, to the generation and maintenance of antigen-specific B and T-cell responses.

The study of immunology encompasses a vast and ever-growing body of information that in some way or other incorporates most areas of medical biological research. As the body of information in the medical sciences continues to increase its rate of expansion, one of the greatest challenges to investigators will be to integrate this information in a manner that is intellectually fruitful and productive. Considering the intended scope of this text, we could not pretend to have gone too far toward achieving such an integration--and considering the pace of change, in its very best form a measured approximation of such lofty goals might be the most we could hope for. Nevertheless, in these pages we have sought to produce a collection of information that is at once concise and up-to-date regarding areas where important developments are impacting on the way we understand the vertebrate immune system. In addition, although the information is geared toward advanced study, we have discussed some basic elements and concepts that we hope make the text a useful resource for both the immunologist and the nonspecialist. The intention is to provide the researcher, clinician, or advanced undergraduate student with a brief ov- view of specific components of the immune system, and to provide a place from which to begin further detailed study if necessary. To this end, we made every effort to supply extensive referencing--although limitations in space prevented exhaustive or complete referencing in some cases.

This second edition expands upon and updates the vital research covered in its predecessor, by presenting state-of-the-art multidisciplinary and systems-oriented approaches to complex diseases arising from and driven by the acute inflammatory response. The chapters in this volume provide an introduction to different types of computational modeling, and how these methods can be applied to specific inflammatory diseases, with a focus on providing readers a roadmap for integrating advanced mathematical and computational techniques with traditional experimental methods. In this second edition, we cover both well-established and emerging modeling methods, especially state-of-the-art machine learning approaches and the integration of data-driven and mechanistic modeling. This volume introduces the concept of Model-based Precision Medicine as an alternative approach to the current view of Precision Medicine, based on leveraging mechanistic computational modeling to decrease cost while increasing the information value of the data being obtained. By presenting the role of computational modeling as an integrated component of the research process, Complex Systems and Computational Biology Approaches to Acute Inflammation: A Framework for Model-based Precision Medicine offers a window into the recent past, the present, and the future of computationally-augmented biomedical research.

Viral Vaccines Joseph L. Melnick As with history in general, the history of vaccines needs to be reexamined and updated. My task is to look back to see what has been successful and to look forward to see what remains to be accomplished in the prevention of viral diseases by vaccines. Also, I shall refer to the pertinent material discussed at two recent conferences of the Institute of Medicine, National Academy of Sciences, on virus vaccines under development and their target populations in the United States (1985b) and in developing countries (1986). These reports, plus a third on Vaccine Supply and Innovation (1985a), should be required reading for all those in both the public and the private sector who have a responsibility or interest in vaccines for the prevention of human disease. It has been through the development and use of vaccines that many viral diseases have been brought under control. The vaccines consist either of infectious living attenu ated viruses or of noninfectious killed viruses or subviral antigens. When we look at the record, it is the live vaccines that have given the great successes in controlling diseases around the world. Examples are smallpox, yellow fever, poliomyelitis, measles, mumps, and rubella."

This thesis describes the use of biophysical and biochemical methods to prove that calcium has a positive feedback effect on amplifying and sustaining CD3 phosphorylation and should enhance T-cell sensitivity to foreign antigens. The study presented shows that calcium can regulate the signal pathway in cells not only as a secondary messenger but also through direct interactions with the phospholipid bilayer. The approach used in the thesis also represents an important advance, as it couples the use of nuclear magnetic resonance (NMR) to the analysis of signaling phenomena in living cells. Moreover, the thesis optimizes the Nanodisc assembly protocol, which can broaden its range of applications in membrane protein studies. A preliminary study on the structure of dengue virus NS2B-NS3p in complex with aprotinin, which may help to develop new drugs against the dengue virus, is also included.

Signal transduction through leukocyte receptors involves a variety of signaling molecules including kinases, phosphatases, adaptor proteins, small GTPases GTP exchange factors, membrane phospholipids as well as others. These signal transducers, regulated by inter- and intra-molecular interactions, as well as by various post-translational modifications, lead to the activation of transcription factors that mediate cellular differentiation and growth, effector cell functions, and apoptotic cell death. Several investigators from various parts of the world convened at the 3rd Lymphocyte Signal Transduction Workshop in Crete, Greece from May 27 to June 1, 2005 to discuss their most recent findings in leukocyte signaling. This volume represents a collection of topics discussed during the conference.

"Complement Systems: Methods and Protocols"is composed of32 individual chapters that describe a variety of protocols to purify and analyze the activity of the individual complement components or pathways. It includes assays that describe detection of complement SNPs, clinical methods to evaluate complement system activation and data interpretation.Written in the highly successful"Methods in Molecular Biology "series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls.

Authoritative and practical, "Complement Systems: Methods and Protocols"provides acollection of well-established classical assays and recently developed new assays to analyze the complement system activation will be useful to a wide audience of scientists."

The human immune system is a complex network of tissues and organs dispersed throughout the body. Immunology, as one of the most rapidly evolving fields in bio-medical research, has to date covered the essential cellular and molecular events neces-sary for immune responses to occur. However, it has paid relatively little attention to important developmental processes underlying the formation of the tissues themselves that carry out immune responses in humans and other mammalians. In contrast to the thymus and bone marrow that are the sole tissues for generating mature leukocytes for antigen recognition and han-dling in humans and most mammalian species, the peripheral lymphoid tissues where adaptive immune responses are focused display broad tissue distribution and possess diverse archi-tectural characteristics. These organs develop prior to the individual s exposure to external antigens, and despite their similar functions, their varied appearances indicate a substantial complexity of tissue ontogeny. This volume presents a comprehensive overview of the developmental features of the major peripheral lymphoid organs, thus examining the connection between immunological functionality and structural characteristics utilizing a developmental approach, for an audience ranging from undergraduate students to senior researchers in immunology, histology and clinical medicine."

Contents. List of Contributors. Preface. T.J. Mitchell and T.J. Williams: The role of eotaxin and related CC-chemokines in asthma and allergy. Roger J. Davis: Signal transduction by the JNK group of MAP kinases. Marie Chabot-Fletcher: TNF and IL-1 signaling to NF-kB. Anthony M. Manning: Small molecule regulators of AP-1 and NF-kB. Robert T. Abraham: Mammalian target of rapamycin: Immunosuppressive drugs offer new insights into cell growth regulation. Catherine A. Burton, John Boylan, Candy Robinson, Janet Kerr and Pamela Benfield: Constitutive expression of a tumor suppressor leads to tumor regression in a xenograft model. Steven D. Shapiro: Macrophage metalloproteinases in destructive inflammatory diseases. Nancy H. Ruddle: Lymphotoxin in inflammation and lymphoid organ development: Variations on a theme. Steven L. Kunkel, Sem H. Phan, Nicholas W. Lukacs, Cory Hogaboam and Stephen W. Chensue: Chemokine/cytokine biology during the evolution of fibrotic disease. Long Gu, Susan C. Tseng and Barrett J. Rollins: The role of MCP-1 in disease. Lisa A. Beck, Cristiana Stellato, Syed Shahabuddin, Renate Nickel and Robert P. Schleimer: The role of chemokines in allergic diseases of the airways. James Winkler and Ken Tramposch (coordicators): Ninth International Conference of the Inflammation Research Association, November 1-5, 1998: Summaries of workshops and poster discussions. William Williams and Elizabeth Arner (chair persons): Targets in rheumatoid and osteoarthritis. Lawrence Wennogle and Nancy Cusack (chair persons): Signal transduction and regulation of gene expression. James Burke and Floyd Chilton (chair persons): Mediators in inflammation and their enzymes. Denis Schrier and Fandrew Issekutz (chair persons): Cell adhesion molecules and leukocyte trafficking. Robert M. Strieter and David Underwood (chair persons): Pulmonary inflammation, fibrosis, and disease. W. Hunter and E. Turley (chair persons): Angiogenesis, wound repair and skin inflammation. Index.

Toll Receptors and the Renaissance of Innate Immunity Elizabeth H. Bassett and Tina Rich Overview n the last few pages of Immunology: The Science of Self-Nonself Discrimination Jan Klein ponders on what he would study if he were to start over in the lab. ^ Dismissing the I antibody, MHC, the T-cell and parasitology, he considers instead the phylogeny of immune reactions, particularly in ancient phyla. As for a favored cell he chooses the macrophage. Describ ing it as a ^^MddchenfUr alles," (all purpose kitchen maid) Klein believed that this immunocyte still had secrets to reveal. Toll-Like Receptor (TLR) biology would prove to be one of these secrets. Analyses of the evolution of these receptors (Tolls and TLRs) have also helped us to rethink immune system phylogeny. In the first part of this chapter the history of the discovery of Toll and TLR biology is described. The evolution of the TLR genes and theories of immune function are covered in later sections. The remainder of this book presents work from nine groups active in the field. In the first chapter, "The Function of Toll-Like Receptors", Zlatko Dembic sets the stage by introducing us to many of the components of the immune system and their relationships vis a vis Toll receptors. Zlatko finishes his chapter with a discussion about current immune system models and contributes his own 'integrity model'. Work from the laboratory of Nicholas Gay follows this in "Structures and Motifs Involved in Toll Signaling".

Influenza continues to be an ongoing problem despite the existence of vaccines and drugs. Disease outbreaks can occur relatively quickly as witnessed with the recent emergence of the influenza virus A/H1N1 pandemic. The development of new anti-influenza drugs is thus a major challenge. This volume describes all aspects of the virus structure and function relevant to infection. The focus is on drug discovery of inhibitors to the enzyme sialidase, which plays a key role in the infectious lifecycle of the virus. Following an overview of the influenza virus, the haemagglutinin, the interactions with the cell receptors and the enzymology of virus sialidase, recent results in drug design are presented. These include a full coverage of the design, synthesis and evaluation of carbohydrate as well as non-carbohydrate influenza virus sialidase inhibitors. Further reviews of the clinical experience with influenza virus sialidase inhibitors and of the development of resistance to these inhibitor drugs complement the topic.

This book grew out ofmy interest in what is often called "the immunological paradox ofpregnancy." How is it possible that the fetus-halfofwhosegenetic apparatuscomesfrom thefather and is foreign to the mother-can survive to term? This is a question that intrigues all immunologists. For me, it has been of interest ever since I heard a lecture on the subject in medical school, long before I thought ofbecoming a "professional immunologist." Indeed, the question ofthe immunological aspect of fetal survival (or demise) should be of interest to any biologist or physician. The question becomes broader ifone considers the immunologic relations between motherand fetus, because they represent a unique symbiotic union. Whatimmunologic problemsinthemothermayaffecttheoffspring, and isitpossiblethatfetal immunology willaffectthe mother? Finally, there is the question ofwhether immunology is important in recur- rent spontaneous abortion. Every authorowes the reader a general oversightofthe book in hand, indicating the terrain to be covered, and, by inference, the territory that will not be explored. 1. This is primarily a book for clinicians. I will only men- tion animal experiments and data in passing, and as they may illuminate a clinical problem or observation. 2. The interest here is the immunology ofmaterno--fetal re- lations, once a pregnancy has begun. Therefore, I will notcover immunological aspects ofsterility, nor touch on the immunological approaches to controlling fer- tility, i.e., "contraceptive vaccines." 3. This is a book mainly concerned with pathogenesis.

This volume provides in-depth reviews of model systems that exemplify the arms race in host-pathogen interactions. Somatic adaptations are responsible for the individualization of biological responses to the environment, and the continual struggle between host immune systems and invading pathogens has given rise to corresponding processes that produce molecular variation. Whether in mollusks or human beings, various host somatic mechanisms have evolved independently, providing responses to counter rapidly-changing pathogens. The pathways they utilize can include non-heritable changes involving RNA and post-translational modifications, or changes that produce somatic DNA recombination and mutation. For infectious organisms such as protozoans and flatworms, antigenic variation is central to their survival strategy. Evolving the ability to evade the host immune system not only increases their chances of survival but is also necessary for successful re-infection within the host population.

Basophils and mast cells are similar but unique secretory cells with a well-documented role in immediate-hypersensitivity reactions. The presence of these cells in various cell mediated hypersensitivity reactions, in tissues of multiple diseases, and as a component of the host reaction to injury and repair in numerous circumstances is well known. Release of stored and newly generated mediators of inflammation from basophils and mast cells contributes to the cascade of pathogenetic events in circumstances under which these release reactions occur. Despite insights acquired through studies of these pathologic events, the role of basophils and mast cells and their secretory products in health is not known. In this book, I review much of the structural information regarding basophils and mast cells of multiple species. Ultrastructural studies of rat mast cells historically precede and quantitatively exceed similar studies of basophils and mast cells of other species. Therefore, I first review these background studies as an entity. Then I discuss the contents of two prominent organelles-granules and lipid bodies-in basophils and mast cells of several species. The ultrastructural morphology of basophils and mast cells in three species is presented in detail to establish appropriate guidelines for their recognition and to provide general rules for analysis which are appropriate for the identification of these cells in other species as well."

ISPP2009, the 13th International Symposium on Phototrophic Prokaryotes, was held in Montreal, Canada, from August 9 to August 14. This was only the second time that the ISPP series was in North America. ISPP2009 was well attended with about 280 registered participants from over 30 countries. A stimulating and inf- mative program showcased the recent developments in this ever-evolving eld. This is always one of my favourite conference series to attend because not only does it inform my speci c research passions, it broadly educates me in ways that improve my teaching and increase my breadth of understanding in a variety of outside areas. Indeed, the ISPP series brings together a broad spectrum of interests, techniques, and disciplines. Both established researchers and newcomers to this eld gave oral presentations in a large number (80) of plenary and parallel symposia sessions which proved to have active audience participation and lively discussions. A large number of excellent poster presentations supplemented the oral program. I think that the high quality of the scienti c presentations, as well as the enjoyable social events, was widely appreciated. Things ran very smoothly, from the original registration to the closing ceremony, thanks to Isabel Stengler and her team at IS Event Solutions.

This Methods in Molecular Biology book offers methods for studying inflammasome function, including generation of inflammasome stimuli, monitoring of caspase-1 activity and processing, activation of IL-1 cytokines, plus lab protocols, material lists and tips.

Enzyme-linked immunospot assay (ELISPOT) has been known for some time as a unique state-of-the-art technique for studying the cytokine-secreting activity of immune system cells, and it appears to be one of the fast growing applications in biomedical research, becoming an indispensable tool in vaccine development, HIV research, transplantation studies, and cancer and allergy research. The second edition of Handbook of ELISPOT: Methods and Protocols, only the second book in the field which is entirely dedicated to ELISPOT assay, shares the detailed techniques that have been developed since the release of the popular first edition. Straight from the labs of seasoned experts, this book covers setting and performing ELISPOT assays, ELISPOT for veterinary research, advanced ELISPOT techniques, image and data analysis, as well as vaccine development and diagnostics. Written in the highly successful Methods in Molecular Biology (TM) series format, chapters include introductions to their respective chapters, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Handbook of ELISPOT: Methods and Protocols, Second Edition serves as a compilation of a technical reference and a troubleshooting guide for researchers, both experienced and novice, worldwide in order to advance the usage of this key tool.

Matters of Sport is a tribute to Eric Dunning, the leading sports sociologist in the English-speaking world. This book addresses Dunning's contributions to the sociological and historical study of sport, covering key topics such as hooliganism, celebrity and gender relations.

A broad range of leading academics from Europe and North America reflect on the ways in which Dunning's work has influenced their own research and understanding of sport.

This volume was previously published as a special issue of the journal Sport in Society.

Interleukins are a family of proteins that regulate the maturation, diff- entiation, or activation of cells involved in immunity and inflammation, and belong to a broader family termed cytokines. Collectively these proteins are the key orchestrators of host defense and the response to tissue injury. There are currently 23 different interleukins (numbered from IL-1 to IL-23), although the full extent of the interleukin family will only become clear upon analysis of the human genome sequence. Most important, interleukins are central to the pathogenesis of a wide range of diseases that involve an immune com- nent, including such conditions as rheumatoid arthritis, multiple sclerosis, ulcerative colitis, psoriasis, and asthma. Interleukins have also been imp- cated in other conditions, including cancer, migraine, myocardial infarction, and depression. In essence, when cells are activated by interleukins, a program of gene expression is initiated in the target cell that alters the cell's phenotype, leading to enhanced immune reactivity, inflammation, and/or proliferation. Interleukins are therefore at the core of the cellular basis for many diseases. They are the subject of intense investigation by biomedical researchers and the targeting or use of interleukins in the clinic is proceeding apace. Approaches such as t- geting IL-4 in asthma or IL-1 in joint disease are being pursued, and it is likely that in the next 5-10 years a number of new therapies based on either inhib- ing or administering interleukins will be available.

A synthesis of current concepts about the evaluation, treatment, and future directions in MS. On the evaluation side, the authors review the use of MRI, magnetic resonance spectroscopy, functional MRI, and three-dimensional MRI, and consider the rapidly developing body of pathologic information they have yielded. On the treatment side, the focus is on recently approved medications (Novantrone), new indications for medications (CHAMPS Trial), medications in development (Oral Interferon Tau, Oral Copaxone, and Oral Cellcept), immunosuppressive therapy for both progressive disease and symptomatic therapy; the current medications for treating relapsing-remitting MS (Avonex, Betaseron, and Copaxone) are also discussed. For future directions, the authors present the current best thinking, as well as the latest discoveries in immunology relating to MS, including groundbreaking B-cell research and its applications to specific immunotherapies, and the use of immune markers for tracking the disease.