Novartis Foundation Symposia – serie

This book features scientists from a broad spectrum of disciplines discussing recent data on aggression in laboratory animals with particular reference to possible implications for understanding human aggression.  Chapters focus on the major current experimental issues in the study of aggression in humans and animals. The extensive discussions deal with specific problems of interpretation at the molecular level, as well as general issues relating to our understanding of human and animal aggression.

Seemingly simple behaviours turn out, on reflection, to be discouragingly complex. For many years, cognitive operations such as sensation, perception, comparing percepts to stored models (short-term and long-term memory), decision-making and planning of actions were treated by most neuroscientists as separate areas of research. This was not because the neuroscience community believed these operations to act independently—it is intuitive that any common cognitive process seamlessly interweaves these operations—but because too little was known about the individual processes constituting the full behaviour, and experimental paradigms and data collection methods were not sufficiently well developed to put the processes in sequence in any controlled manner. These limitations are now being overcome in the leading cognitive neuroscience laboratories, and this book is a timely summary of the current state of the art. The theme of the book is how the brain uses sensory information to develop and decide upon the appropriate action, and how the brain determines the appropriate action to optimize the collection of new sensory information. It addresses several key questions. How are percepts built up in the cortex and how are judgments of the percept made? In what way does information flow within and between cortical regions, and what is accomplished by successive (and reverberating) stages of processing? How are decisions made about the percept subsequently acted upon, through their conversion to a response according to the learned criterion for action? How does the predicted or expected sensation interact with the actual incoming flow of sensory signals?  The chapters and discussions in the book reveal how answering these questions requires an understanding of sensory–motor loops: our perception of the world drives new actions, and the actions undertaken at any moment lead to a new ‘view’ of the world.This book is a fascinating read for all clinical and experimental psychologists  and neuroscientists, as well as anyone interested in how we perceive the world and act within it.

Heart failure is the main cause of death and disability in the industrialized world. There is a major need for novel therapeutics for prevention and reversal of cardiac pathology associated with heart failure and cardiac enlargement. Over recent years, dramatic progress has been made in unravelling the cellular circuitry involved in cardiac failure, as well as in normal cardiac growth, development and apoptosis. This work has revealed new and unexpected therapeutic targets in the heart. In addition, advances in understanding the role of stem cells in cardiac physiology have suggested strategies for cardiac repair and regeneration once thought impossible. This book describes the work of leading investigators studying the basic mechanisms of cardiac growth, function and dysfunction. There are also exciting contributions from researchers developing novel therapeutic strategies for cardiac disease. The unique feature is the discussions amongst the contributors, which always return to the same basic problem: how can new data from biological studies be used to design novel therapies for the treatment of cardiac dysfunction following myocardial infarction, hypertension and other disorders?With its strong emphasis on translational research, this book will appeal to both scientists and clinicians interested in diminishing the impact of the current epidemic of cardiac diseases.

Cl- absorption and HCO3- secretion are intimately associated processes vital to epithelial function, itself a key physiological activity. Until recently the transporters responsible remained obscure, but a breakthrough occurred with the discovery of the SLC26 transporters family. It is now clear that the SLC26 transporters have broad physiological functions since mutations in several members are linked to a variety of diseases. This book describes the properties of this family in detail, with contributions from the leading global researchers in the field. Complementary views from experts on other ion channels are offered in the discussions, which make fascinating reading. This family consists of at least 10 genes, each of which has several splice variants. Most members of the family are expressed in the luminal membrane of epithelial cells. Characterization of anion transport by three members has revealed that all function as Cl-/HCO3- exchangers, suggesting that SLC26 transporters are responsible for the luminal Cl-/HCO3- exchange activity. The SLC26 transporters are activated by the CF transmembrane conductance regulator and activate it in turn, leading to a model in which these molecules act together to mediate epithelial Cl- absorption and HCO3- secretion. The book includes chapters on the transport of other molecules by the SLC26 family, including oxalate in the kidney and sugars in cochlear hair cells amongst others. It also describes recent discoveries that most SLC26 transporters bind to scaffold proteins and that they all contain a conserved domain predicted to participate in protein-protein interactions. These suggest the SLC26 transporters exist in complexes with other Cl- and HCO3- transporters, and possibly other regulatory proteins. This book explores the functional role of these interactions, leading to better understanding of transepithelial fluid and electrolyte secretion and the diseases associated with it.

This title provides an extremely helpful analysis of genes that may be associated with autoimmunity, and answers questions such as how these genes can be identified, and how the functions of the gene products can be elucidated. Incorporating data on disease-associated chromosomal loci that has been accumulated from inbred mice, the title: descibes how some susceptibility loci may be common to many diseases, whereas others are relatively disease specificdiscusses the importance of developing criteria for establishing the significance of these different categories of disease-associated loci.

Part of the prestigious Novartis Foundation series, this volume uniquely addresses the use of innate immunity to treat or prevent infectious diseases of the lung. Innate Immunity to Pulmonary Infection: Provides a comprehensive overview of pulmonary infectious diseases, including basic pathology, current and potential therapies, and detailed consideration of the innate biological resistance mechanisms in the lungThoroughly examines the major topic of innate immunity in immunology, which is now seen as key to the pathogenesis of and vaccination strategies for infectious diseasesDescribes the genetic and environmental factors which determine the outcome of infection, such as latency of Tuberculosis, blood stream invasion from local infection, and local target tissue damageCovers the roles of cells such as neutrophils, macrophages and dendritic cells and of molecular components such as Toll-like receptorsDiscusses the clinical applications of the new knowledge regarding innate immunity and how this can be used in both treatment and prevention (vaccination) strategiesIncludes contributions from an international and interdisciplinary group of expertsInnate Immunity to Pulmonary Infection is an essential resource for researchers in both industry and academia. It is of interest for all those interested in the disciplines of immunology, virology, biology, biotechnology and genetics.

Sepsis: New Insights, New Therapies brings together contributions from an international group of experts in diverse fields to consider how the various pathways implicated in early and late sepsis interact, with a particular emphasis on novel concepts and potential new therapeutic approaches. Topics covered include adaptive immunity, inflammation, neuroendocrinology, bioenergetics and metabolism. Several chapters in the latter half of the book are particularly concerned with treatment strategies involving modulation of the neuroendocrine response. Addresses the frequent, but under-recognised condition of sepsis and discusses new ways to prevent and treat itDescribes numerous pharmacological approaches to therapy for early and late sepsisIncludes detailed discussion of the various physiological systems implicated in sepsisPresents an international perspective, featuring contributions from experts from laboratories worldwide involved in the study of sepsisSepsis: New Insights, New Therapies is an invaluable resource for all critical care physicians and researchers. It is also informative reading for immunologists, endocrinologists, neuroendocrinologists, physiologists, and pharmacologists.

The potential lipotoxic effect of accumulation of fatty acids in non-adipose tissues is thought to be a major component in the development of insulin resistance. Chronic exposure to high concentrations of free fatty acids in the blood affects pancreatic β cell function, insulin secretion and lipid synthesis in the liver, and storage in adipose tissue. Maintaining the normal levels of fatty acids requires coordinated regulation between the liver, adipose tissue and skeletal muscle. This book deals with the molecular aspects of fatty acid action in obesity and insulin resistance. The topics include lipid metabolism and adipose tissue biology, and β cell function and insulin resistance. Chapters deal with the molecular genetics and molecular physiology of energy homeostasis.

The past decade has seen mounting global concern regarding viral outbreaks such as SARS, avian influenza and West Nile virus. In 2004 and 2005, reports of bird-to-human, and possible human-to-human, transmissions of the H5N1 influenza viruses raised fears that these viruses could cause a pandemic on the scale of the Spanish flu pandemic of 1918.   Previous to this, a novel coronavirus had been identified as the aetiological agent of the severe acute respiratory syndrome (SARS), a new respiratory viral disease that emerged at the end of 2002 and caused profound disturbances in over 30 countries worldwide in 2003. It is not known whether the SARS coronavirus will re-emerge, especially since its origins and potential reservoir(s) are unresolved. However, these outbreaks have shown that these viruses can emerge in any part of the world at any time. This book critically evaluates the latest scientific evidence on novel or re-emerging viral diseases and brings together contributions from world experts on this topic, explaining best practice in their area, and discussing lessons learned and how best to collaborate to prevent and control future outbreaks. Topics covered include: the latest advances in virology, particularly in the area of epidemiologydiagnosticsanimal models for viral infectionantiviral and vaccine developmentNovel and Re-emerging Respiratory Viral Diseases offers a comprehensive and interdisciplinary account of all aspects of the topic, from basic molecular biology to public health issues, and is therefore essential reading for virologists, infectious disease specialists, public health managers, researchers and epidemiologists, as well as those working in vaccine development, pharmaceutical medicine and drug discovery

With the recent renaissance in mitochondrial biology and increasing recognition of their role in many diseases, this book provides a timely summary of the current state-of-the-art in mitochondrial research. The book opens with the regulation of mitochondrial replication and biogenesis and reviews the mechanisms and functional consequences of mitochondrial fission and fusion. Further chapters address mitochondria and oxidative stress and their roles in cell signalling and cell death. The book includes extensive, fascinating discussion of the biochemistry of mitochondrial cell signalling (especially involving calcium) and of oxidative stress. The nature of the proteins engaged in these processes, many only recently discovered, is covered in detail. Mitochondria have been strongly implicated in neurodegenerative diseases such as Parkinson’s, Huntington’s and amyotrophic lateral sclerosis. They are also affected in cancer, ageing and cardiovascular disease. The final section of the book reviews mitochondrial mutations and their consequences in ageing and other phenotypic manifestations. The authors discuss how mitochondrial proteins might constitute important therapeutic targets and describe initial attempts to develop compounds that can regulate their function.

Inflammatory bowel disease (IBD) comprises a group of idiopathic diseases of the intestine characterized by chronic inflammation of the bowel with periods of exacerbation and remission. Although the exact cause of IBD remains undetermined, the condition appears to be related to a combination of genetic and environmental factors resulting in an aberrant activation of the mucosal immune system. This book contains a series of interdisciplinary discussions between clinical and basic scientists focusing on key issues such as: <> Epithelial cell and molecular biology, including apoptosis, necrosis and cell survivalThe role of bacterial milieu and mucosal bacteria in the IBD and of prebiotic and probiotic therapyThe progress towards the identification of susceptibility genes and phenotype-determining genesThe pharmacogenetics of IBDMucosal immunology and therapeutic strategies stemming therefrom

Understanding stem cells at the molecular level is essential to understanding their behaviour in a physiological context. This volume in our acclaimed Novartis Foundation series features animated discussion from the world’s experts in this topic on the important ethical issues that are raised by research on stem cells. They review the various regulatory regimes, which apply in different countries – a key factor in determining where future stem cell research is carried out. Potential clinical applications covered in the book include the production of cardiomyocytes to replace damaged heart tissue, the production of insulin-producing cells for patients with diabetes, and the generation of neurons for the treatment of patients with Parkinson’s disease or spinal cord injury. Particular attention is paid to the factors that maintain stem cells in a pluripotent state or which drive them to create differentiated and lineage-committed cells in vitro and in vivo.  Nuclear reprogramming, the process by which a nucleus acquires developmental potential, is covered here as well. It is relevant to stem cell research generally, and also to research on the cloning of animals by nuclear transfer. This book is an essential purchase for all those engaged in stem cell research, whether in the laboratory, the clinic or the regulatory authorities.From the reviews:"...this book provides: a comprehensive overview of current issues in stem cell research, with contributions from leading figures..."—BRITISH SOCIETY OF CELL BIOLOGY

The heat shock, or cell stress, response was first identified in the polytene chromosomes of Drosophila. This was later related to the appearance of novel proteins within stressed cells, and the key signal stimulating this appearance was identified as the presence of unfolded proteins within the cell. It is now known that this is a key mechanism enabling cells to survive a multitude of physical, chemical and biological stresses. Since the promulgation of the ‘molecular chaperone’ concept as a general cellular function to control the process of correct protein folding, a large number of molecular chaperones and protein folding catalysts have been identified, and it has been recognized that not all molecular chaperones are stress proteins and vice versa. The discovery of molecular chaperones as folding proteins went hand-in-hand with their recognition as potent immunogens in microbial infection. It was subsequently shown that administration of molecular chaperones such as Hsp60, Hsp70 or Hsp90 could inhibit experimental autoimmune diseases and cancer.More recently evidence has accumulated to show that certain molecular chaperones are also present on the surface of cells or in extracellular fluids. A new paradigm is emerging: at least some molecular chaperones are secreted proteins with pro- or anti-inflammatory actions, regulating the immune response in human diseases such as coronary heart disease, diabetes and rheumatoid arthritis. In addition to having direct effects on cells, molecular chaperones can bind peptides and present them to T cells to modulate immune responses. This may be significant in the treatment of cancer.This is the first book bringing leading researchers in this field together to review and discuss: our current knowledge of cell stress response and molecular chaperonesthe changing paradigms of protein trafficking and functioncell stress proteins as immunomodulators and pro- and anti-inflammatory signalling moleculesthe role of these proteins in various chronic diseases and their potential as preventative or therapeutic agents.The Biology of Extracellular Molecular Chaperones is of particular interest to immunologists, cell and molecular biologists, microbiologists and virologists, as well as clinical researchers working in cardiology, diabetes, rheumatoid arthritis and other inflammatory diseases.

Nature employs a wide variety of sex determining mechanisms and it is only comparatively recently that the tools have become available for these to be explored at the cellular and molecular levels.  A major landmark was the discovery in 1990 of the SRY gene and the subsequent demonstration of its key role in triggering male sex determination in transgenic mice.  This book reviews and discusses our current understanding of the molecular genetic pathways of sex determination, with special emphasis on vertebrates. It features comparisons with other modes of sex determination, consideration of the biology of sexual development and discussion of the evolution of sex-determining mechanisms.By bringing together an international and interdisciplinary group of experts who study many different aspects of the problem, the book highlights much new and exciting work in this area and serves to identify and stimulate promising new research directions.

This book draws together contributions from some of the leading investigators in the field of autism to consider specific problem areas in current research. Each contributor brings expertise from a different field, providing a balanced view of the whole spectrum of study of this disorder. It covers four main areas: Twin and family studies indicate that the heritability of the underlying liability to autism exceeds 90% and point to a multifactorial causation, involving a relatively small number of susceptibility genes. The book discusses this issue in detail, along with the problem of why some additional symptoms are associated with autism while others are not.New techniques are available for examining the neurobiology of autism. The book contains results from imaging studies showing the contributions of different brain regions to autism. It includes neuropathological data and examines the neuropharmacology of autism.There is considerable discussion concerning the fundamental psychological deficit in children with autism. There is good evidence that "Theory of Mind" deficits are associated with autism and this issue is discussed in the book, as are other competing possibilities.The most important practical question facing medical and psychological practitioners is how to help children with autism. The evidence relating to possible psychological or psychiatric interventions for rehabilitation of children with autism is examined in detail. Drug treatments have generally been disappointing in this field and there is one chapter devoted specifically to this problem.The book focusses ultimately on intervention studies and so is of practical relevance to people interested in helping autistic children. In addition, it provides a very convenient summary of the principal controversies which currently exist in research on autism.

The astounding diversity of the immune system and the complexity of its regulatory pathways makes immunology a combinatorial science. Computational analysis has therefore become an essential element of immunology research and this has led to the creation of the emerging field of immunoinformatics. This book is the first to feature thorough coverage of this new field. Immunoinformatics facilitates the understanding of immune function by modelling the interactions among immunological components. Biological research provides ever deeper insights into the complexity of living organisms while computer science provides an effective means to store and analyse large volumes of complex data. Combining the two fields increases the efficiency of biological research and offers the potential for major advances in the study of biological systems.This book encompasses key developments in immunoinformatics, including immunological databases, sequence analysis, structure modelling, mathematical modelling of the immune system, simulation of laboratory experiments, statistical support for immunological experimentation and immunogenomics.The difficulties in effective application of bioinformatic tools in immunology arise at both ends of the spectrum: most immunologists have only a limited comprehension of sophisticated data analysis and applicability and limitations, while the average computer scientist lacks knowledge of the depth and complexity of biological data. The purpose of this book, therefore, is to present contributions from a multidisciplinary team of biologists and computer scientists to explore the issues related to better understanding of immune function and, in particular, to help apply new computer science methods to immunological research.Related Novartis Foundation symposia:247 In Silico Simulation of Biological ProcessesChair: Denis Noble252 Generation and effector functions of regulatory lymphocytesChair: Jean-François Bach

This book brings together contributions from key investigators in the area of Transient Receptor Potential (TRP) channel structure and function. It covers the structure, function and regulation of mammalian TRP channels and mechanisms of signal transduction. The discussions indicate research that would improve understanding of the role of TRP channels in normal cellular physiology, the involvement of TRP channels in disease states and their potential use as molecular targets for novel therapeutic agents.

Osteoarthritis is a chronic degenerative disease associated with joint pain and loss of joint function. It has an estimated incidence of 4 out of every 100 people and significantly reduces the quality of life in affected individuals. The major symptoms are chronic pain, swelling and stiffness; severe, chronic joint pain is often the central factor that causes patients to seek medical attention. Within the affected joint, there is focal degradation and remodelling of articular cartilage, new bone formation (osteophytes) and mild synovitis. Several mechanisms are thought to contribute to osteoarthritic joint pain. These include mild synovial inflammation, bone oedema, ligament stretching, osteophyte formation and cartilage-derived mediators. Changes in joint biomechanics and muscle strength also influence the severity and duration of joint pain in osteoarthritis. Within the nervous system, the relative contributions of peripheral afferent nociceptive fibres and central mechanisms remain to be defined, and there is limited information on the phenotype of sensory neurons in the OA joint. Importantly, there is no relation between clinical severity, as measured by radiographic changes, and the presence and severity of joint pain. Patients with severe joint pain may have normal joint architecture as determined by X-ray, whereas patients with considerable evidence of joint remodelling may not have significant joint pain. Treatments for osteoarthritic joint pain include non-steroidal anti-inflammatory compounds, exercise, corrective shoes and surgical intervention. There remains a critical need for improved control of joint pain in osteoarthritis.This book brings together contributions from key investigators in the area of osteoarthritic joint pain.  It covers the clinical presentation of joint pain, the pathways involved in joint pain, osteoarthritis disease processes and pain, experimental models and pain control. The discussions provide insights into the nature of osteoarthritic joint pain, identify key studies needed to advance understanding of the problem, highlight possible intervention points and indicate future pathways towards a better treatment of osteoarthritic joint pain.

This book brings together contributions from key investigators in the area of pathological pain. It covers the molecular basis of receptors and channels involved in nociception, the possible messages that cause neuropathic plasticity, spinal plasticity in neuropathy, plastic changes in opioid systems in neuropathy and opioid tolerance, and plastic changes related to pathological pain.

Although normally thought of as a sex hormone, recent research has highlighted the numerous and significant effects that oestrogen has on the CNS, extending far beyond its important reproductive role. It has been shown that oestrogen acts as a neural growth factor with important influences on the survival, plasticity, regeneration and ageing of the mammalian brain. This exciting book brings together leading clinicians and researchers to discuss oestrogen's basic mechanisms of action, the extrahypothalmic brain regions it affects, and its influence on cognitive functions in animals and humans. Finally, recent research on the role of oestrogens in ageing and dementia, including the significance of oestrogen action in Alzheimer's disease, is discussed. The 15 papers contained in this book, together with the extensive discussion sessions that follow them, reveal much new and exciting work in this area, and identify promising new research directions.

The field of neural transplantation is at a crucial stage in its development, with results of important clinical trials on transplantation in patients with Parkinson's disease expected soon and novel, alternative approaches to fetal transplantation being actively investigated. This timely book brings together leading neuroscientists, clinicians, and cell and developmenta; biologists to discuss the use of neural transplants in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and spinal cord injury. There is also extensive coverage of the potential alternatives to freshly derived fetal tissue as the source of transplants, such as xenografts, encapsulated cells and immortalized stem cells. With authoritative contributions and lively discussion sections, this book draws together much new and exciting work in this field, and identifies promising new research directions.

Brings together a cross-fertilization of ideas between human molecular genetics, develeopmental biology, tissue biology and the biochemistry of cell signalling pathways, in order to create new insights into the mechanisms of normal and abnormal skeletogenesis.

Chronic obstructive pulmonary disease (COPD) is the most common respiratory disorder of adults in the developed world and is the fourth main cause of death in the USA. It is also associated with high morbidity, and poses an enormous burden of suffering and expense. Despite this, the disease has received little attention compared with other respiratory conditions such as asthma and lung cancer. Current treatment can offer some marginal symptomatic relief but does not address the underlying disease process. Indeed, smoking cessation is the only intervention known to alter the rate of disease progression. There is clearly great need, and potential, for the development of superior therapies for symptomatic relief and disease modification. This book brings together leading researchers and physicians to discuss the most recent advances in our understanding of COPD, and draws together basic and clinical aspects relevant to the topic. Coverage includes the basic pathology, current and potential therapies, and detailed consideration of the major theories for the pathogenesis of COPD.

This book brings together scientists working at the interface between the cell cycle, cell growth and development in a variety of model systems and research paradigms. The focus is on understanding how such diverse developmental inputs can modulate cell cycle regulation and, reciprocally, how a common way of regulating cell cycle progression can participate in different developmental strategies.

This important book covers the structure and molecular biology of small round structured viruses (SSRVs) such as caliciviruses and astroviruses, and the basic pathology of infection. It provides readers with the knowledge needed to make progress in the prevention and treatment of these infections. Readers will also find an overview of gastroentitis vaccines, their structure and molecular biology, as well as the basic pathology of infection, epidemiology and surveillance. Provides an interdisciplinary approach, offering contributions from basic and clinical researchDiscusses the prevention and treatment of regimesIncludes an overview of gastroentitis vaccines

This important and exciting work brings together a high-calibre group of experts to discuss the practical application of genomic information to the development of drugs. Recent technological advances have led to a rapid acceleration in our ability to gather genetic data. The complete genetic sequences are now known for several organisms and accelerated programmes are in place for sequencing many other genomes, including human. The speed with which complete sequencing can be accomplished will continue to increase as new technologies come online. In principle, the scope for developing new diagnostic techniques and drugs is now greater than at any time in human history, but the pathway from genetic information to usable drug is a long and complex one. This major book covers such subjects as the current state of the art in squencing technology, the applications of these new technologies to sequencing the genomes of various organisms, and the challenge of proteomics. Additional contributions deal with legal and ethical implications of the new uses of genetic data, and functional genomics from the point of view of the pharmaceutical industry.

Insect-Plant Interactions and Induced Plant DefenceChair: John A. Pickett, 1999 This book examines the sophisticated mechanisms that plants use to defend themselves against attack by insects and pathogens, focusing on the networks of plant signalling pathways that underlie these defences. In response to herbivory, plants release a complex blend of as many as 100 volatile chemicals, known as semiochemicals ('sign chemicals'). These act as an airborne SOS signal, revealing the presence of the herbivore to the predators and parasitoids that are its natural enemies. Plants also have endogenous defence mechanisms that can be induced in response to pathogens, and separate chapters deal with systemic acquired resistance, phytoalexins, and the interacting pathways in pathogen and pest resistance. The book discusses underlying biochemical mechanisms by which plant stress leads to the biosynthesis of chemical signals from pools of secondary metabolite precursors, or even from the primary metabolism source. Finally, consideration is given to the possibilities for exploiting these signalling pathways by plant molecular genetics. The use of plant signals and their analogues to switch on defence pathways in crop plants is covered in depth. Bringing together contributions from entomologists, chemical ecologists, molecular biologists and plant physiologists this book is truly interdisciplinary, and will be essential reading for anyone with an interest in agricultural pest control.

This book features contributions from experts in cell biology, genetics, neurobiology, immunology and structural biology.  The unifying element is that they all study processes of cell shape change and motility.  Several key questions in this field of research are discussed: What are the organising principles behind cell shape change?Are there ‘master switches’ present in every cell type?How are extracellular signals interpreted by the cell in order to activate intracellular mechanisms?What is the influence of the extracellular matrix on cell movement and internal signalling pathways?How do pathogens subvert cellular systems in order to stimulate or block their uptake?The book addresses all of these important questions.  Data are presented on the key proteins that regulate cell shape: the GTP binding proteins of the Rho family. There are also extensive discussions of the potential applications of the data to clinical problems, particularly that of cell motility in cancer.

The book presents recent advances relating to the factors and mechanisms that regulate the growth, differentiation and function of mast cells and basophils; discussion of new technologies used to study these cells, and integration of the basic scientific findings in the context of therapeutic possibilities for the treatment of diseases such as allergic inflammation and autoimmune disease which are mediated, in part, by these granulocytes.