Blood Cell Biochemistry was initially conceived as part of the Plenum series Subcellular Biochemistry, from which it has developed into a separate series. The present volume is devoted primarily to contributions on megakaryocytes and platelets and, to a lesser extent, to macrophages and eosinophils. The book does not attempt a rigorous or total coverage of the particular topics; it represents the areas of current scientific activity and interest that were selected by the editor at the commencement of this project. In general, the approach has been similar to that adopted for Volume 1 of the series (Erythroid Cells); the same approach will be followed subsequently in Volume 3 (Lymphocytes and Granulocytes). This book opens with a developmentally oriented chapter by Janine Breton-Gorius on megakaryocyte maturation and platelet release in normal conditions, which serves to set the scene ultrastructurally for much of the data that follow. The biosynthesis and process ing of platelet glycoproteins in megakaryocytes is dealt with by Alain Duperray and his colleagues, and thereby provides an in-depth biochemical survey of the megakaryocyte. The applications and strengths of crossed immunoelectrophoresis for the study of platelet membrane proteins is then covered by Simon Karpatkin, and a detailed account of the heredity disorders of platelet function is provided by Francine Rendu and Evelyne Dupuy."

To produce a comprehensive overview of macrophages and related cell types in a short review volume is an impossible task. When I selected the topics to be included, some equally important areas were omitted by necessity, and for this I apologize. My choices have been somewhat eclectic, touching subjects of personal interest (such as osteoclast biology and macrophage electrophysiology) or of current fashion (apopto sis, antigen processing, cell adhesion molecules). The book has also had to encompass areas of a more general flavor to provide balance for the general reader (such as reviews of macrophage development, heterogeneity, and function, and of the surface molecules expressed by macrophages). I thank all the authors for their prompt sub missions; all have been of high quality, and my editorial tasks, thankfully, have been minimal. Michael A. Horton London, United Kingdom ix Contents Chapter J An Overview of Receptors of MPS Cells lain Fraser and Siam on Gordon 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2. The Mononuclear Phagocyte System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3. Diversity of Macrophage Plasma Membrane Receptors. . . . . . . . . . . . . . . . 6 3. 1 A Structural Approach to Classification . . . . . . . . . . . . . . . . . . . . . . . . . . 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3. 2 Multisubunit Receptors 3. 3 Soluble Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3. 4 Lectins and Lectin-Like Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 4. Functions and Selected Examples. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4. 1 Growth, Differentiation, and Modulation . . . . . . . . . . . . . . . . . . . . . . . . 14 4. 2 Cell-Cell and Cell-Matrix Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4. 3 Endocytosis and Scavenger Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4. 4 Secretory Responses and Biosynthesis of Effector Molecules . . . . . . 17 5. Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 . . . . . . . . . . . . . . . . . . . .

The last few years have witnessed an explosion of both interest and knowledge about apoptosis, the process by which a cell actively commits suicide. The number of publications on the topic has increased from nothing in the early 1980s to more than 10,000 papers annually today. It is now well recognized that apoptosis is essential in many aspects of normal development and is required for maintaining tissue homeostasis. The idea that life requires death seems somewhat paradoxical, but cell suicide is essential for an animal to survive. For example, without selective destruction of "non-self" T cells, an animal would lack immunity. Similarly, meaningful neural connections in the brain are whittled from a mass of cells. Further, developmental cell remodeling during tissue maturation involves programmed cell death as the major mechanism for functional and structural safe transition of undifferentiated cells to more specialized counterparts. Apoptosis research, with roots in biochemistry, developmental and cell biology, genetics, and immunology, embraces this long-ignored natural law. Failure to properly regulate apoptosis can have catastrophic consequences. Cancer and many diseases (AIDS, Alzheimer's disease, Parkinson's disease, heart attack, stroke, etc. ) are thought to arise from deregulation of apoptosis. As apoptosis emerges as a key biological regulatory mechanism, it has become harder and harder to keep up with new developments in this field.

This volume brings together the disciplines of plant and animal genome research, and serves as an opportunity for scientists from both fields to compare results, problems and prospects.

Antibodies have long been used in the biomedical sciences as in vitro tools for the identification, purification and functional manipulation of target antigens. They are also being exploited in vivo for diagnostic and therapeutic applications and play an important role in cancer and AIDS research. This book summarizes preclinical studies from laboratories worldwide that have used intrabodies - intracellular antibodies - for gene therapy and research applications.

Over the past decade, our laboratory and others have been concerned with molecular archaeological studies aimed at revealing the origins and evolutionary histories of permeases (1). These studies have revealed that several different families, defined on the basis of sequence similarities, arose independently of each other, at different times in evolutionary history, following different routes. When complete microbial genomes first became available for analysis, we adapted p- existing software and designed new programs that allowed us quickly to identify probable transmembrane proteins, estimate their topologies and determine the likelihood that they function in transport (2). This work allowed us to expand previously-recognized families and to identify dozens of new families. All of this work then led us to attempt to design a rational but comprehensive classification system that would be applicable to the complete complement of transport systems found in all living organisms (3). The classification system that we have devised is based primarily on mode of transport and energy coupling mechanism, secondarily on molecular phylogeny, and lastly on the substrate specificities of the individual permeases (4).

Analytical Molecular Biology illustrates the importance of simple analytical methods applied to some basic molecular biology problems, with an emphasis on the importance of biological problems, rather than the complexity of mathematics. First, the book examines crucial experimental data for a specific problem. Mathematical models will then be constructed with explicit inclusion of biological facts. From such models, predictions can be deduced and then suggest further experimental studies. A few important molecular biology problems will be discussed in the order of the complexity of the mathematical models. Based on such illustrations, the readers can then develop their own analytical methods to study their own problems. This book is for anyone who knows they need to learn how to apply mathematical models to biology, but doesn't necessarily want to, from practicing researchers looking to acquire more analytical tools to advanced students seeking a clear, explanatory text.

With the coming of the new millennium we are witnessing a revolution in our understanding of cancer genetics. These are very exciting times. Today we have at our disposal the technology to diagnose abnormalities in our cancer genes and the means to correct the deficit and very soon we will have the complete sequence of the human genome. With the use of gene chip technology the way doctors will be able to assess patients will change completely. Today we can diagnose abnormalities in ten thousand genes and within a short period of time we will be able to screen through our genome and discover potential abnormalities in our proto-oncogenes, tumour suppressor genes, differentiating genes, apoptotic genes and pro-inflammatory genes. In this book various authors have highlighted specific genes that could be expressed, overexpressed, neutralised or h- nessed to achieve cancer control. The problem of transferring the therapeutic gene into the cancer cell has been partly addressed with major developments in the field of naked plasmid DNA, adenovirus, retrovirus and adeno-associated viruses. However, further improvements are yet to be made to achieve significant gene transfer. Gene expression, in particular specificity of gene transfer, is obviously an important issue and one which is highlighted in this book by the use of specific promoter.

Through the use of dramatic narratives, The Drama of DNA brings to life the complexities raised by the application of genomic technologies to health care and diagnosis. This creative, pedagogical approach shines a unique light on the ethical, psychosocial, and policy challenges that emerge as comprehensive sequencing of the human genome transitions from research to clinical medicine. Narrative genomics aims to enhance understanding of how we evaluate, process, and share genomic information, and to cultivate a deeper appreciation for difficult decisions encountered by health care professionals, bioethicists, families, and society as this technology reaches the bedside.
This innovative book includes both original genomic plays and theatrical excerpts that illuminate the implications of genomic information and emerging technologies for physicians, scientists, counselors, patients, blood relatives, and society. In addition to the plays, the authors provide an analytical foundation to frame the many challenges that often arise.

This book will describe the nuclear encoded genes and their expressed proteins of mitochondrial oxidative phosphorylation. Most of these genes occur in eukaryotic cells, but not in bacteria or archaea. The main function of mitochondria, the synthesis of ATP, is performed at subunits of proton pumps (complexes I, III, IV and V), which are encoded on mitochondrial DNA. The nuclear encoded subunits have mostly a regulatory function. However, the specific physiological functions of the nuclear encoded subunits of complexes I, III, IV, and V are mostly unknown. New data indicates that they are essential for life of higher organisms, which is characterized by an adult life without cell division (postmeiotic stage) in most tissues, after the juvenile growth. For complex IV (cytochrome c oxidase) some of these subunits occur in tissue-specific (subunits IV, VIa, VIb, VIIa, VIII), developmental-specific (subunits IV, VIa, and VIIa) as well as species-specific isoforms. Defective genes of some subunits were shown to induce mitochondrial diseases. Mitochondrial genes and human diseases will also be covered.

Systems Metabolic Engineering is changing the way microbial cell factories are designed and optimized for industrial production. Integrating systems biology and biotechnology with new concepts from synthetic biology enables the global analysis and engineering of microorganisms and bioprocesses at super efficiency and versatility otherwise not accessible. Without doubt, systems metabolic engineering is a major driver towards bio-based production of chemicals, materials and fuels from renewables and thus one of the core technologies of global green growth. In this book, Christoph Wittmann and Sang-Yup Lee have assembled the world leaders on systems metabolic engineering and cover the full story - from genomes and networks via discovery and design to industrial implementation practises. This book is a comprehensive resource for students and researchers from academia and industry interested in systems metabolic engineering. It provides us with the fundaments to targeted engineering of microbial cells for sustainable bio-production and stimulates those who are interested to enter this exiting research field.

Trypanosomes are unicellular protozoa of ancient evolutionary origin that are responsible for several tropical diseases, such as African sleeping sickness. Over the last few decades, research in trypanosome biology has revealed many unique and fascinating features, many of which have helped to establish new paradigms in other biological systems. This applies in particular to studies in gene expression and regulation, which benefit enormously from the trypanosome genome projects and from the new genome-wide approaches recently introduced in trypanosome research. This volume covers the most important aspects of biosynthesis, processing, and functions of RNA in trypanosomes, ranging from transcription to RNA editing, mRNA splicing/translation/turnover, processing of transfer and ribosomal RNA, RNA interference, and current transcriptome-wide analyses. Recent progress in RNA-focused research in trypanosomatids promises to yield novel insights into trypanosome-specific features, as well as to reveal in the process new potential therapeutic strategies for combating these parasitic diseases.

The rapidly developing field of systems biology is influencing many aspects of biological research and is expected to transform biomedicine. Some emerging offshoots and specialized branches in systems biology are receiving particular attention and are becoming highly active areas of research. This collection of invited reviews describes some of the latest cutting-edge experimental and computational advances in these emerging sub-fields of systems biology. In particular, this collection focuses on the study of mammalian embryonic stem cells; new technologies involving mass-spectrometry proteomics; single cell measurements; methods for modeling complex stochastic systems; network-based classification algorithms; and the revolutionary emerging field of systems pharmacology.

Long non-coding RNAs (lncRNAs), tentatively defined as ncRNAs of more than two hundred nucleotides in length, are characterized by the complexity and diversity of their sequences and mechanisms of action. Based on genome-wide studies, more than 3,300 of them exist, but to date only the limited number of functional lncRNAs have been identified and characterized. Nonetheless, lncRNAs have emerged as key molecules involved in the control of transcriptional and posttranscriptional gene regulatory pathways. They take part in the recruitment of chromatin modifying complexes and regulate splicing, localization, stability and translation of the target mRNAs. This book provides an overview of the rapidly advancing field of long ncRNAs, describing the epigenetic and non-epigenetic mechanisms by which they regulate various biological functions in model systems, from yeast to mammals. The role of ncRNAs in sex chromosome dosage compensation in flies and mammals is described, as well as their role in centromere and telomere biology. Long non-coding RNAs involved in environmental stress response and development are presented and their mechanisms of action discussed.

This book represents a selected group of manuscripts from lecturers participating in the NATO/Gulbenkian Foundation sponsored course on Somatic Cell Genetics held May 31 to June 12, 1981 in the Hotel Montechoro in the Algarve of Portugal. The text will provide those students who could not attend the meeting with a current survey of important advances in the field of Somatic Cell Genet- ics. It is not possible to recapture here all the lectures, semi- nar discussions, student and faculty interactions, the ambience of the Algarve and the time devoted exclusively to scientific discus- sion. In summary, I feel that this book is good, but the scien- tists, the students, and the entire course were better. Somatic Cell Genetics is a broad subject area and one which has contributed significantly to Our understanding of the mammalian cell. Drs. Caskey, Buttin, Siminovitch, and Lechner elected in designing the course to focus on the results obtained with cultured animal cells.

In this volume of Recent Advances in Phytochmistry you will find a record of the pioneering attempts of plant biochemists and molecular biologists to modify the patterns of secondary metabolism in plants, as presented at the 33rd annual meeting of the Phytochemical Society of North America, in Asilomar, California, on June 27 -July I, 1993. The studies described here represent a marriage of the newest of technologies with one of the oldest human activities, exploitation of plant chemistry. They also represent the beginning of a new era of phytochemical research, an era that will undoubtedly begin to provide answers to some of the long-standing questions that have absorbed plant biochemists for the past century. There is, for instance, a common deflating experience to which every worker in the area of plant secondary metabolism can probably relate. After hearing about the latest research findings regarding some aspect of remarkable compound "X", someone in the audience finally directs the inevitable question at the hapless speaker. "Tell me, is anything known as to the biological role of compound "X" in the plant?" The answer, in most cases, must be "essentially nothing"! This is a frustrating scenario for both the speaker and the audience, since the very fact that a complex biosynthetic pathway remains encoded in a plant genome points to an associated selective advantage. The problem is that establishing the nature and scale of that advantage is a very complex task.

The study of the insulin-like growth factor (IGF) family has become an exciting area of investigation. Initially, this family consisted of ligands (insulin, IGF-I and IGF-m and receptors (the insulin receptor, the type I or IGF-I receptor and the type II or IGF-IYM-6-P receptor). Subsequently, it was discovered that six specific binding proteips (lGFBPs 1-6) playa major role in the actions of this growth factor family. In addition, there are now more potential receptors when one considers the possible roles of the insulin-receptor related receptor (IRR) and hybrid receptor dimers composed of insulin and IGF-I receptor (half-receptors). Another important aspect of this area of research is the realization that the IGFs are not only essential for normal growth and development but, in addition play an important role in the normal specialized function(s) of all tissues of the body, including the nervous system, skeleton, reproductive system, kidney, and the immune system, to name but a few. The development of recombi tant human IGF-I for clinical testing has been a major breakthrough for investigators. Potential uses include wound healing, reversal of catabolic states, diabetes, bone remodeling, recovery from acute renal failure and many others. will determine both its use and its potential hazards.

In Gene Regulatory Sequences and Human Disease, the Editor will introduce the different technological advances that led to this breakthrough. In addition, several examples will be provided of nucleotide variants in noncoding sequences that have been shown to be associated with various human diseases.

The conference entitled "The Translational Apparatus" was held in Berlin from October 31 to November 5, 1992, in honorem et memoriam of H. G. Wittmann. The presentations of the rewarding, enjoyable and scientifically exciting week in Berlin were a fitting appreciation of this great man, and all participants and speakers contributed to the success of the meeting. The second reason for holding the Berlin meeting was to convene a group of scientists for a state-of-the-art presentation on ribosomes and related subjects; the outcome is this book. We have broadened the spectrum of topics to cover activities preceding and following pure ribosomal functions, such as "Synthetases" and "Protein Sorting", respectively, and we took the liberty of ordering the contributions in a way which does not always reflect the order of speakers. We are grateful to the authors who patiently tolerated our organization and our regulations for manuscripts. K.H. Nierhaus F. Franceschi A.R. Subramanian v CONTENTS I. tRNA and Aminoaeyl-tRNA Synthetases 1. The Crystal Structure of SeryI-tRNA Synthetase and its Complexes with A TP and tRNASer...1 S. Cusack, C. Berthet-Colominas, V. Biou, F. Borel, M. Fujinaga, M. Hartlein, I.

The purpose of this and future volumes of the Handbook of Genetics is to bring together a collection of relatively short, authoritative essays or annotated compilations of data on topics of~ignificance to geneticists. Many of the essays will deal with various aspects of the biology of certain species selected because they are favorite subjects for genetic investigation in nature or the laboratory. Often there will be an encyclopedic amount o( information available on such a species, with new papers appearing daily. Most of these will be written for specialists in a jargon that is bewildering to a novice and sometimes even to a veteran geneticist working with evolu tionarily distant organisms. For such readers what is needed is a written introduction to the morphology, life cycle, reproductive behavior, and cul ture methods for the species in question. What are its particular ad vantages (and disadvantages) for genetic study, and what have we learned from it? Where are the classic papers, the key bibliographies, and how or mutant strains? A list giving the sym does one get stocks of wild type bolism for unknown mutations is helpful, but it need include only those mutants that have been retained and are thus available for future studies. Other data, such as up-to-date genetic and cytological maps, listings of break points for chromosomal aberrations, mitotic karyotypes, and hap loid DNA values, will be included when available.

These are exciting days in biology; chromosome such functional attributes of chromosomes as research is no exception. Twenty years ago when replication, dosage compensation and cellular Caspersson and coworkers showed that meta response to DNA lesions. It is only recently that a phase chromosomes are structurally not homo molecular view of the meiotic cell division is geneous through their length, a new world was beginning to emerge: chapter ten refers to human in the offing. Application of various molecular meiosis and the next to molecular events in techniques in chromosome research has subse meiotic prophase in the baker's yeast. Another quently narrowed down the gap between the chapter is on aneuploidy in man and the Djungarian levels of microscopic and molecular understand hamster. The role of chromosome rearrange ing of chromosome organization. While complex ments and oncogenes in malignancy and the ities of older questions of chromosome/ parallelism between the neoplastic and phy chromatin organization are being understood, logenetic chromosomal alterations are discussed newer dimensions and perspectives have been in the next two chapters. Recent introduction of gained with respect to their structure and func potentially useful methods of chromosome isola tions. Even more, novel chromosome techniques tion by flow cytometry, and mapping of structural have become an integral component of clinical ly and functionally distinct domains on metaphase and molecular genetic methodologies."

One outstanding question in biology is the problem of devel opment: how the genetic instructions encoded in the DNA become expressed in the morphological, physiological, and behavioral features of multicellular organisms, through an ordered sequence of events that extend from the first cell division of the zygote to the adult stage and eventual death. The problem is how a one dimensional array of instructions is transformed into a four dimensional entity, the organism that exists in space and time. Understanding this transformation is, nevertheless, necessary for mastering the process of evolution. One hundred and twenty-five years after The Origin of Species, we have gained some understanding of evolution at the genetic level. Genetic information is stored in the linear sequence of nucleotides in the DNA. Gene mutations, chromosomal reorganiza tions, and a host of related processes introduce variation in the sequence and the amount of DNA. The fate of these variations is determined by interactions within the genome and with the outside environment that are largely understood. We have recently gained a glimpse of how the genome of eukaryotes is organized and will learn much more about it in the future, now that we have the research tools for it."

The newest installment in this superb series presents descriptions of the latest DNA recombinants molecule technology. The text combines reports on basic research in genetics with discussions of specific new industrial applications (as well as refinements of older ones) that are likely to prove highly profitable in the years to come.