Derek J. Chadwick

Jamie A. Goode

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.

Mammalian TRP Channels as Molecular Targets

Rice is the most important food crop for half the world's population. Over the last three decades, the imporvement in human nutrition and health in Asia has largely been attributable to a relatively stable and affordable rice supply. The challenge to produce enough rice for the future, however, remains daunting, as the current rate of population growth outpaces that of increases in rice production. Science has a central role to play in raising rice productivity and this book highlights areas of plant science that are particularly relevant to solving the major constraints on rice production. Examining molecular, genetic and cellular techniques, it considers recent advances in four research approaches for increasing yields and improving the nutritional quality of rice. Plant genomics: knowing the identity and location of each gene in the rice genome is of immense value in all aspects of rice science and cultivar improvement. Molecular biological approaches to increase yield: to produce more biomass by increasing photosynthetic rate and duration, and by improving grain filling. Enhancing tolerance to biotic and abiotic stresses: with new DNA array technologies, it is now possible to assess global genomic response to stresses. Understanding the relationships among stress pathways may create new opportunities for gene manipulation to enhance tolerance to multiple biotic and abiotic stresses. Improving nutritional quality in the grain: knowledge of the biosynthesis of micronutrients in plants permits genetic engineering of metabolic pathways to enhance the availability of micronutrients.

Improving Yield, Stress Tolerance and Grain Quality

Rice Biotechnology

Gail Cardew

The use of oligonucleotides as therapeutic agents rests upon their ability to interfere, in a sequence-specific manner, with the fundamental machinery of protein synthesis either by binding to the mRNAs transcribed from a gene or by binding directly to a target gene. This approach can be used not only for inhibition of the synthesis of host proteins but also of those required by invading pathogens. Potential therapeutic applications are enormous, ranging over hypertension, cardiovascular disease, autoimmune disease, vital and other parasitic infections (especially HIV), and cancer. This book discusses the chemistry and pharmacokinetics of oligonucleotides and their analogues, and surveys the results of structure-activity studies and current clinical trials. It also critically reviews the problems with antisense therapy, such as the enzymatic destruction of oligonucleotides, the doses required for a therapeutic response, the difficulty in directing oligonucleotides to particular target tissues and cells, the need for parenteral administration, and doubts concerning the mechanism of action (especially problems associated with non-specific binding to proteins) and long-term effects.

Oligonucleotides as Therapeutic Agents

Gregory R. Bock

Julie Whelan

As part of a continuing effort to tackle issues of major social concern, this 280th conference of internationally recognized experts from the fields of molecular biology, medicine, philosophy, theology, and the law looks into the scientific, legal, ethical, social, and economic issues confronting man and his ability to map and sequence the human genome. A wide variety of subjects are covered, including prenatal diagnosis, advances in the genetics of psychiatric disorders, the problems associated with polygenic disease, and the limits to genetic intervention in humans. The symposium also discusses genetic manipulation, commercial exploitation, and legal implications.

Science, Law and Ethics

Human Genetic Information

Kate Ackrill

Prestigious contributors summarize current knowledge regarding the biosynthesis of tetrapyrrole pigments--chlorophyll, haem, vitamin B12. Describes the structure and regulation of key enzymes along with various pathways, molecular genetic studies and structural characterization of the natural biosynthetic intermediates.

The Biosynthesis of the Tetrapyrrole Pigments

Kate Widdows

Classical studies of steroid hormones are concerned with their regulation of protein synthesis via the modulation of genomic transcription. But many of the actions of these hormones occur too rapidly to be explained in this manner, particularly their effects on the central nervous system. This text deals with recent discoveries showing that steroids can modulate the activity of some neurotransmitters. It explores the role of GABA as an important regulator of neuronal activity in the central nervous system and its inhibitory action as mediated via the GABA receptor and potentiated by steroids. In addition, the binding of steroids to cell membranes, the components involved and the outcome of such interactions are described. Also discusses possible uses of steroids as anesthetics and anticonvulsants.

Steroids and Neuronal Activity

Antibiotic Resistance: Origins, Evolution, Selection and Spread Chairman: Stuart B. Levy, 1997 Over the last 50 years, the rapid increase in the use of antibiotics, not only in people, but also in animal husbandry and agriculture, has delivered a selection unprecedented in the history of evolution. Consequently, society is facing one of its gravest public health problems-the emergence of infectious bacteria with resistance to many, and in some cases all, available antibiotics. This book brings together a multidisciplinary group of experts to discuss this problem. It begins by examining the origins of resistance and goes on to look at how the use of antibiotics in human medicine and farming/agriculture has selected for resistant bacteria. Separate chapters describe the evolution of resistance determinants and how these are spread both within and between bacterial species. Finally, the book contains discussions on strategies for countering the threat of antibiotic resistance. A major re-thinking of our approach to the treatment of infectious diseases is proposed-that antibiotic resistance should be seen as a problem created by the disruption of normal microbial ecology. To restore efficacy to earlier antibiotics, and to maintain the success of new antibiotics that are introduced, we need to use these drugs in a way that ensures an ecological balance that favours the predominance of susceptible bacteria.

Origins, Evolution, Selection and Spread

Antibiotic Resistance

David Evered

Reviews recent basic research into IgE, mast cells, and the allergic response and the relevance of this work to human pathophysiology, and discusses new methods of treatment. This symposium is unique in the IgE field for its breadth of coverage and interdisciplinary nature, and it shows the benefits from the current rapid expansion of knowledge in cell biology, immunology, and molecular genetics, as well as the potential clinical significance of this research to clinical immunologists and allergologists.

IgE, Mast Cells and the Allergic Response

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.

Development, Activation and Roles in Allergic / Autoimmune Disease

Mast Cells and Basophils

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.

Osteoarthritic Joint Pain

Joan Marsh

Recent application of the techniques of molecular biology and patch-clamp physiology has led to rapid advances in understanding the molecular events in chemosensory transduction. In this book, the latest results are presented and discussed by leading scientists. The extensive coverage encompasses many important topics, including mucous domains; microchemical heterogeneity in the mucociliary complex of the olfactory epithelium; membrane currents and mechanisms of olfactory transduction, and genetic and pathological taste variation.

The Molecular Basis of Smell and Taste Transduction

Many different pathological conditions are currently under investigation as therapeutic targets of purines including cancer, cardiovascular conditions, behavioural disorders, inflammation, immunoregulation, and neuroendocrine function. This book draws together research on all aspects of P2 purinoceptors and discusses their use in different therapeutic areas.

Localization, Function and Transduction Mechanisms

P2 Purinoceptors

Prestigious contributors describe the genetic, molecular, anatomical and neurochemical mechanisms and pathways that operate to regulate and control circadian rhythmicity and functioning in organisms ranging from unicellular algae to human beings. Also considers the implications of the basic and clinical research for humans.

Circadian Clocks and Their Adjustment

The ability at the molecular level to keep track of time is a property shared by organisms ranging from the simplest unicells to humans. The primary feature of these biological clocks is their ability to entrain to environmental stimuli. The dominant stimulus comes from environmental light cues, which requires the existence of photopigments sensitive to light. The exact identity of the molecules involved in circadian photoreception has remained elusive. The classical view of the circadian system is of diverse physiological rhythms regulated by a centralized clock structure. This book presents evidence that challenges this view. Experiments in both vertebrate and invertebrate systems demonstrate that the circadian timing system is dispersed throughout the animal and suggest that possibly every cell contains an autonomous clock mechanism. A variety of tissues and cells contain have been shown to maintain an oscillation when placed in vitro and removed from any external cues or signals that originate from the classical clock structures and/or the environment. This book draws together contributions from an international and interdisciplinary group of experts whose work is focused on all aspects of the topic. Coverage includes the mechanisms of light signalling to the vertebrate clock, the connections between central and peripheral clocks, circadian gene expression patterns and output pathways of clock mechanisms.

Molecular Clocks and Light Signalling

Drawing together contributions from a diverse group of international experts in the field, this collection of papers examines the biology and pathology of elastin at the molecular level. Topics include the structure, ultrastructure and function of elastin; elastin regulation; elastin's role in aging, lung development and disease and atherosclerosis; as well as related aspects of pharmacology and nutrition.

The Molecular Biology and Pathology of Elastic Tissues

The pacemaking and conduction system (PCS) is vital for generating and synchronizing the heart beat. Dysfunction of this system can be a direct cause of cardiac conduction disturbance, arrhythmias and sudden cardiac death. A wealth of information has been collected over many years on the unique histological, morphological and phenotypic characteristics of specialized cardiac tissues. The cellular and molecular mechanisms that govern development of the PCS are now starting to be understood. This book draws together contributions from an international and interdisciplinary group of experts working on both basic and clinical aspects of cardiac development. It features reviews of the structure and function of the developing PCS, discussion of the molecular and cellular mechanisms regulating embryological development of this system and studies on the fundamental basis of PCS pathology. The book also considers how novel therapeutic interventions based on understanding of the developmental biology of cardiac pacemaking and conduction tissues might ultimately impact on clinical medicine.

Development of the Cardiac Conduction System

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 chaperones the changing paradigms of protein trafficking and function cell stress proteins as immunomodulators and pro- and anti-inflammatory signalling molecules the 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.

The Biology of Extracellular Molecular Chaperones

Oxygen sensing is a key physiological function of many tissues, but the identity of the sensor, the signalling pathways linking the sensor to the effector, and the endpoint effector mechanisms are all subjects of controversy. This book evaluates the various mediators that have been proposed, including the mitochondria, NAD(P)H oxidases, cytochrome p450 enzymes, and direct effects on enzymes and ion channels. There has been a resurgence of interest in the role of mitochondria, based partly on the ability of mitochondrial inhibitors to mimic hypoxia, but there is little consensus concerning mechanisms. Some favour the view that the primary signalling event is a reduction in cell redox state and reactive oxygen species (ROS) due to general inhibition of the electron transport chain (ETC); others support a key role for complex III of the ETC and an increase in ROS generation, while others doubt either of these components is the key intermediary. All these hypotheses are discussed in the book, together with conceptual problems concerning the ability of mitochondria to respond to physiological hypoxia. The other area of controversy covered in the book is the identity of the endpoint effector(s). Some authors favour K+ channel inhibition, followed by depolarization and Ca2+ entry via L-type channels, while others propose that release of Ca2+ from intracellular stores, or capacitative Ca2+ entry and other voltage-independent pathways may be more important. The book also describes evidence for an endothelium-dependent Ca2+-sensitizing pathway involving Rho and possibly other kinases. While some of these differences can be attributed to variation between tissues, many must be related to differences in interpretation or methodology. In this book, experts in the field of acute oxygen sensing working in different tissues address these controversies and their possible origins, and discuss possible approaches whereby these controversies might be resolved. The book will be of great interest to all those working in fields where oxygen sensing is important, particularly cancer and wound healing, as well as researchers in drug discovery and biotechnology.

Signalling Pathways in Acute Oxygen Sensing

A compilation of articles by prominent experts in their respective fields on compensation for and collaboration with indigenous people in regard to their knowledge and provision of rare plants which are used for some of the most potent drugs in Western medicine.

Ethnobotany and the Search for New Drugs

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 lung Thoroughly examines the major topic of innate immunity in immunology, which is now seen as key to the pathogenesis of and vaccination strategies for infectious diseases Describes 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 damage Covers the roles of cells such as neutrophils, macrophages and dendritic cells and of molecular components such as Toll-like receptors Discusses the clinical applications of the new knowledge regarding innate immunity and how this can be used in both treatment and prevention (vaccination) strategies Includes contributions from an international and interdisciplinary group of experts Innate 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.

Derek J. Chadwick

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