It has been shown that the amino terminus and second extracellular loop (EC2) of CXCR2 are crucial for ligand binding and receptor activation. The lack of an ionic lock motif in the third intracellular loop of CXCR2 focuses an investigation of the mechanism by which these two extracellular regions contribute to receptor recognition and activation. The first objective of this investigation was to predict the structure of CXCR2 based on known structures of crystallized GPCRs. Rhodopsin, [beta]2- adrenergic receptor, CXCR4 were used for homology modeling of CXCR2 structure. Highly conserved motifs found in sequence alignments of the template GPCRs were helpful to generate CXCR2 models. We also studied solvent accessibility of residues in the EC2 of CXCR2 in the inactive state. Most of the residues in the EC2 were found to be solvent accessible in the inactive state, suggesting the residues might be involved in ligand recognition. Second, we studied the role of charged residues in the EC2 of CXCR2 in ligand binding and receptor activation using constitutively active mutants (CAM) of CXCR2, D9K and D9R. Combinatorial mutations consisting of the CAM in the amino terminus and single mutations of charged residues in the EC2 were generated to study two concepts including "attraction" and "repulsion" models. The mutant receptors were used to test their effects on cell surface expression, ligand binding, receptor activation through PLC-[beta]3, and cellular transformation. All the mutations in the repulsion model result in CXCR2 receptors that are unable to bind ligand, suggesting that each of the Arg residues in the EC2 are important for ligand recognition. Interestingly, mutations in the attraction model partially inhibited receptor activation by the CAM D9K, suggesting that Glu198 and Asp199 residues in the EC2 are associated with receptor activation. Furthermore, a novel CAM, E198A/D199A, was identified in this study. These negatively charged residues are very close to a conserved disulfide bond linking the EC2 and the third transmembrane. In this sense, these current discoveries concerning the structural basis of CXCR2 and interdisciplinary approaches would provide new insights to investigate unknown mechanisms of interaction with its cognate ligands and receptor activation.

The Cytokines of the Immune System catalogs cytokines and links them to physiology and pathology, providing a welcome and hugely timely tool for scientists in all related fields. In cataloguing cytokines, it lists their potential for therapeutic use, links them to disease treatments needing further research and development, and shows their utility for learning about the immune system. This book offers a new approach in the study of cytokines by combining detailed guidebook-style cytokine description, disease linking, and presentation of immunologic roles. - Supplies new ideas for basic and clinical research - Provides cytokine descriptions in a guidebook-style, cataloging the origins, structures, functions, receptors, disease-linkage, and therapeutic potentials - Offers a textbook-style view on the immune system with the immunologic role of each cytokine

The past several years have seen a rapid advancement in our understanding of how CXCR4 transmits the extracellular CXCL12 signal into intracellular signaling, which ultimately causes cell migration along with other signaling outcomes critical in both immune cell function and various cancers. We began this project uncertain as to the stoichiometry of CXCL12:CXCR4 binding, and through various functional and structural studies were able to settle on an early complex model with 1:1 stoichiometry (chapters 2&3). An improvement in our ability to model the CXCL12:CXCR4 complex was enabled by the solution of the vMIP-II:CXCR4 crystal structure by our laboratory soon after, and other landmarks in chemokine receptor structural determination (chapter 4) have allowed for a global understanding of chemokine:receptor structure to emerge. At this point the structural link between CXCL12 N-terminus binding and the more conserved intracellular aspects of CXCR4 activation is finally coming into view. In our latest soon to be submitted study, we provide functional evidence decisively supporting the orientation proposed in our current model, as well as revealing previously unrecognized complexity in the nature of CXCR4 activation (chapter 5). In chapter 6, we comprehensively discuss tentative but exciting possible explanations for evidence in our latest findings of greater complexity in chemokine:chemokine receptor signaling than has been appreciated. We have progressed from a rough understanding of how CXCL12 activates CXCR4 to an experimentally validated full-length CXCL12:CXCR4 signaling complex model. Ultimately, we have made significant contributions to understanding the structure of CXCR4 bound to CXCL12, the precise mechanism whereby CXCL12 stabilizes CXCR4's active state(s), and the complexity of the downstream functional consequences of receptor activation.

GPCR Signaling in Cancer, Volume 145, the latest release in the Advances in Cancer Research series, highlights recent developments in the area of GPCRs and cancer biology. Chapters included in this volume cover several GPCRs and their downstream effectors as case examples to highlight their fundamental understanding and therapeutic potential. Specific chapters address the Role of GRKs and beta-arrestins in cancer, Atypical GPCRs in cancer, the Role of a chemokine receptor (CCR) 5 in cancer, Targeting G protein-coupled receptors for therapeutics in cancer, Emerging GPCR signaling pathways in cancer, and more. G protein-coupled receptors (GPCRs) constitute a large family of cell surface receptors which are involved in nearly every cellular and physiological event. These receptors can recognize a broad array of ligands and they are targeted by nearly one third of the currently prescribed drugs including anti-cancer therapeutics. Covers the latest concepts in GPCR signaling and their relevancy to cancer biology Presents new indications for anti-cancer therapeutic programs Includes sections on cross-talk and signaling networks of GPCRs and effectors in molecular oncology and therapeutics

A guide to the practice of stem cell transplantation, its status in the treatment of various disorders and the problems that arise after transplantation, aimed at the whole transplant team. - An up to date guide to best practice in the use of stem cell transplantation, covering current status in the treatment of malignant and non-malignant conditions, practical aspects and problems such as infection and graft versus host disease. - Has a practical, accessible approach with free use of algorithms, list tables. - Aimed at the whole transplant team - this is an interdisciplinary field. - International contributor team with editors in the UK and USA. - Illustrated in colour throughout.

This volume, new to The Receptors series, focuses on several areas, including the birth, maturation, and structure of Chemokines; Neutrophil, Dendritic, and Lymphocyte trafficking; and Chemokine Receptors in diseases such as AIDs and lung cancer. In particular the book contains cutting-edge information ranging from basic molecular and cellular mechanisms to physiological and pathological roles of chemokines.

Biological processes are driven by complex systems of functionally interacting signaling molecules. Thus, understanding signaling molecules is essential to explain normal or pathological biological phenomena. A large body of clinical and experimental data has been accumulated over these years, albeit in fragmented state. Hence, systems biological approaches concomitant with the understanding of each molecule are ideal to delineate signaling networks/pathways involved in the biologically important processes. The control of these signaling pathways will enrich our healthier life. Currently, there are more than 30,000 genes in human genome. However, not all the proteins encoded by these genes work equally in order to maintain homeostasis. Understanding the important signaling molecules as completely as possible will significantly improve our research-based teaching and scientific capabilities. This encyclopedia presents 350 biologically important signaling molecules and the content is built on the core concepts of their functions along with early findings written by some of the world’s foremost experts. The molecules are described by recognized leaders in each molecule. The interactions of these single molecules in signal transduction networks will also be explored. This encyclopedia marks a new era in overview of current cellular signaling molecules for the specialist and the interested non-specialist alike During past years, there were multiple databases to gather this information briefly and very partially. Amidst the excitement of these findings, one of the great scientific tasks of the coming century is to bring all the useful information into a place. Such an approach is arduous but at the end will infuse the lacunas and considerably be a streamline in the understanding of vibrant signaling networks. Based on this easy-approach, we can build up more complicated biological systems.

This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.

The fourth edition of The Cytokine Handbook provides an encyclopedic coverage of the molecules that induce and regulate immune responses. Expanded to two volumes, the scope of the book has been broadened to include a major emphasis on the clinical applications of cytokines. The early chapters discuss individual cytokines, chemokines and receptors. Additional chapters discuss the clinical implications and applications of cytokines, including cytokine gene transfer, antisense therapy and assay systems.

Foods and Dietary Supplements in the Prevention and Treatment of Disease in Older Adults focuses on the ways in which food and dietary supplements affect the major health problems of aging adults. Researchers in nutrition, diet, epidemiology, and aging studies, as well as healthcare providers who work with elderly patients will use this comprehensive resource as a tool in their long-term goal of preventing and treating chronic disease within the elderly. This book brings together a broad range of experts working on the different aspects of foods and dietary supplements (vitamins, herbs, plant extracts, etc.) in health promotion and disease prevention. They have contributed chapters which define a range of ways in which foods, nutriceuticals, and dietary supplements prevent disease and promote health in older adults. They begin by reviewing the medicinal role of foods, herbal, and dietary supplements in health promotion in older adults, as well as some of the most commonly used supplements in elder "self-medication." They review the most recent studies of how foods, herbal, and dietary supplements are effective in the prevention and treatment of cancer, cardiovascular disease, diabetes, and other obesity associated diseases in older adults. Then they consider alcohol, other drugs, and plant based drugs of abuse which can adversely affect the health of older adults. Lastly, they consider foods and dietary supplements in gene regulation in older adults. - Investigates the important nutritional requirements of the aging population in health and in relation to various acute and chronic diseases - Explores the nutritional effects of botanical extracts and components that can have important health promotion benefits, and risks, to ensure safe consumption - Reviews studies of common diseases within the aging population including cancer, cardiovascular, metabolic, and infectious diseases that can alter the intake of foods, supplements, and/or requirements for various nutrients - Investigates the mechanisms of action of components of foods and dietary supplements, in particular gene activation and epigenetics