Книги автора: Derek J. Chadwick

The field of neural transplantation is at a crucial stage, with important clinical trials on transplantation in patients with Parkinson's disease nearing completion and novel, alternative approaches to fetal transplantation being developed. This timely book brings together leading neuroscientists, clinicians, and cell and developmental biologists to discuss the use of neural transplants in neurodegenerative disorders, such as Parkinson's disease, Huntington's chorea, 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, for example xenografts, encapsulated cells and immortalized stem cells. With authoritative contributions and lively discussion sections, this book presents much new and exciting work in this field and identifies promising new research directions.

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.

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.

ATP, the intracellular energy source, is also an extremely important cell–cell signalling molecule for a wide variety of cells across evolutionarily diverse organisms. The extracellular biochemistry of ATP and its derivatives is complex, and the multiple membrane receptors that it activates are linked to many intracellular signalling systems. Purinergic signalling affects a diverse range of cellular phenomena, including ion channel function, cytoskeletal dynamics, gene expression, secretion, cell proliferation, differentiation and cell death. Recently, this class of signalling molecules and receptors has been found to mediate communication between neurons and non-neuronal cells (glia) in the central and peripheral nervous systems. Glia are critical for normal brain function, development and response to injury. Neural impulse activity is detected by glia and purinergic signalling is emerging as a major means of integrating functional activity between neurons, glia and vascular cells in the nervous system. These interactions mediate effects of neural activity on the development of the nervous system and in association with injury, neurodegeneration, myelination and cancer. Bringing together contributions from experts in diverse fields, including glial biologists, neurobiologists and specialists in purinergic receptor structure and pharmacology, this book considers how extracellular ATP acts to integrate communication between different types of glia, and between neurons and glia. Beginning with an overview of glia and purinergic signalling, it contains detailed coverage of purine release, receptors and reagents, purinergic signalling in the neural control of glial development, glial involvement in information processing, and discussion of the interactions between neurons and microglia.

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.

ATP, the intracellular energy source, is also an extremely important cell–cell signalling molecule for a wide variety of cells across evolutionarily diverse organisms. The extracellular biochemistry of ATP and its derivatives is complex, and the multiple membrane receptors that it activates are linked to many intracellular signalling systems. Purinergic signalling affects a diverse range of cellular phenomena, including ion channel function, cytoskeletal dynamics, gene expression, secretion, cell proliferation, differentiation and cell death. Recently, this class of signalling molecules and receptors has been found to mediate communication between neurons and non-neuronal cells (glia) in the central and peripheral nervous systems. Glia are critical for normal brain function, development and response to injury. Neural impulse activity is detected by glia and purinergic signalling is emerging as a major means of integrating functional activity between neurons, glia and vascular cells in the nervous system. These interactions mediate effects of neural activity on the development of the nervous system and in association with injury, neurodegeneration, myelination and cancer. Bringing together contributions from experts in diverse fields, including glial biologists, neurobiologists and specialists in purinergic receptor structure and pharmacology, this book considers how extracellular ATP acts to integrate communication between different types of glia, and between neurons and glia. Beginning with an overview of glia and purinergic signalling, it contains detailed coverage of purine release, receptors and reagents, purinergic signalling in the neural control of glial development, glial involvement in information processing, and discussion of the interactions between neurons and microglia.

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.

Examines the establishment of the germ layers and other cell lineages in the early embryo including details of cell movements during the beginning stages of primitive streak formation. Discusses patterns of gene expression during the development of such tissues as the limb bud, skeletal, muscle and the central nervous systems placing special emphasis on commitment to particular cell types. Although it concentrates on the mouse as an example of mammalian development–chick, amphibian and Drosophila embryogenesis are employed whenever these organisms are more applicable to the study of a particular problem.

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.

How the amino acid sequence of a protein determines its three-dimensional structure is a major problem in biology and chemistry. Leading experts in the fields of NMR spectroscopy, X-ray crystallography, protein engineering and molecular modeling offer provocative insights into current views on the protein folding problem and various aspects for future progress.

Smooth muscle contraction is a vital component of the functioning of blood vessels, the uterus, airways and the bladder. Its malfunction can lead to serious pathological conditions, such as hypertension and pre-term labour. The calcium ion plays a central role in smooth muscle function, increasing in concentration for contraction and decreasing for relaxation. Calcium entry into the cell is facilitated by the sarcoplasmic reticulum (SR). This book explores the latest research on the role of the sarcoplasmic reticulum (SR) in smooth muscle function. It examines the control and modulation of the SR and how this may vary among smooth muscle types. Potential therapeutic implications are also discussed. Discusses new and exciting work in this area and identifies promising new research directions. Considers the advances in this relatively unexplored field, offering new insights into the role of the SR muscle. Brings together contributions from key workers, both in basic and clinical science, whose studies range from physiological to pathological and molecular to whole animal.

Smooth muscle contraction is a vital component of the functioning of blood vessels, the uterus, airways and the bladder. Its malfunction can lead to serious pathological conditions, such as hypertension and pre-term labour. The calcium ion plays a central role in smooth muscle function, increasing in concentration for contraction and decreasing for relaxation. Calcium entry into the cell is facilitated by the sarcoplasmic reticulum (SR). This book explores the latest research on the role of the sarcoplasmic reticulum (SR) in smooth muscle function. It examines the control and modulation of the SR and how this may vary among smooth muscle types. Potential therapeutic implications are also discussed. Discusses new and exciting work in this area and identifies promising new research directions. Considers the advances in this relatively unexplored field, offering new insights into the role of the SR muscle. Brings together contributions from key workers, both in basic and clinical science, whose studies range from physiological to pathological and molecular to whole animal.

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.

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.

A comprehensive review of current thinking on the biosynthesis, function and evolution of secondary metabolites in animals, plants and microorganisms. Examines the traditional context of secondary metabolites as natural products having no obvious part to play in the producing organism's life cycle. Covers issues related to genetic and antibiotic applications.

This book describes a diverse analysis of the five somatostatin receptors; somatostatin gene regulation; promatostatin processing; mechanisms of signal transduction; and the design and use of somatostatin analogues, including their possible clinical implications. The book will provide a comprehensive summary of the cellular and molecular biology of somatostatin and its recently isolated receptors. The book will review the design and use of specific somatostatin analogues both biochemically to characterize the specific functions of somatostatin and clinically in the treatment of various tumors.

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.

Asthma is a growing health problem throughout the developed world. This volume presents a critical review of all the possible factors for this rising trend and includes research that has not yet been published in the scientific literature. Discusses the basic biology of asthma and addresses genetic influences. Surveys the epidemiological evidence for the worldwide trends in morbidity and mortality.

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.

This book draws together contributions from basic, pharmaceutical and clinical sciences aimed at a better understanding of the structure and function of hERG and the molecular basis for compound binding. It features regulatory authority perspectives on preferred preclinical test systems and includes topics on hERG channel gating, regulation of functional expression, pharmacological properties of hERG/IKr channels, drug-induced long QT syndrome and preclinical evaluation and regulatory recommendations for assessing QT prolongation risks. Better understanding of the role of the hERG channel in drug-induced cardiac arrhythmias should ultimately lead to the development of important, new and safer medicines.