2. The Translational Machinery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Translation Initiation in Prokaryotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Translation Initiation in Eukaryotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 14 Translation Elongation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Translation Termination in Prokaryotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Translation Termination in Eukaryotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Error Correction in Translation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 A Structural Basis of Error Correction in Translation . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Ribosome Editing: A Failsafe Error Correction Mechanism . . . . . . . . . . . . . . . . 22 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 3. Errors During Elongation Can Cause Translational 29 Frameshifting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spontaneous Frameshifting Versus Programmed Frameshifting . . . . . . . . . . 30 Spontaneous Frameshifts Can Be Induced at Specific Codons . . . . . . . . . . . . 31 4. Programmed +1 Frameshifting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 The pifE Gene of E. coli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Using the pifE System to Study General Frameshifting in E. coli . . . . . . . . 46 Ty Retrotransposons in Yeast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Frameshifting in Retrotransposon Ty1 Occurs by tRNA Slippage . . . . . . . 48 Frameshifting in Retrotransposon Ty3 Occurs by Out-of-Frame Binding of tRNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 The Rat Ornithine Decarboxylase Antizyme Gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 5. Programmed -1 Frameshifting in Eukaryotes . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Programmed -1 Frameshifting in Eukaryotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 -1 Frameshifting Occurs on a "Slippery Heptamer" . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 The Simultaneous-Slippage Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 of -1 Frameshifting by a Downstream Pseudoknot . . . . . . . . . . 77 Stimulation Does the Pseudoknot Only Block Passage of the Ribosome? . . . . . . . . . .

Molecular biology has rapidly advanced since the discovery of the basic flow of information in life, from DNA to RNA to proteins. While there are several important and interesting exceptions to this general flow of information, the importance of these biological macromolecules in dictating the phenotypic nature of living creatures in health and disease is paramount. In the last one and a half decades, and particularly after the completion of the Human Genome Project, there has been an explosion of technologies that allow the broad characterization of these macromolecules in physiology, and the perturbations to these macromolecules that occur in diseases such as cancer. In this volume, we will explore the modern approaches used to characterize these macromolecules in an unbiased, systematic way. Such technologies are rapidly advancing our knowledge of the coordinated and complicated changes that occur during carcinogenesis, and are providing vital information that, when correctly interpreted by biostatistical/bioinformatics analyses, can be exploited for the prevention, diagnosis, and treatment of human cancers. The purpose of this volume is to provide an overview of modern molecular biological approaches to unbiased discovery in cancer research. Advances in molecular biology allowing unbiased analysis of changes in cancer initiation and progression will be overviewed. These include the strategies employed in modern genomics, gene expression analysis, and proteomics.

Lifestyle, in any part of the world, is associated with the occurrence of major chronic diseases, including coronary heart disease, hypertension, and stroke; many distinct types of cancer; and adult onset diabetes (11,22,70,75). One important element of lifestyle is tobacco use, which appreciably increases the risk of a number of chronic diseases (21). Other lifestyle factors relate to nutritional traditions, alcohol use, and exercise (11,30,58,60,70,71). The underlying evidence is, in part, based on the evidence of specific diseases in relation to dietary habits in a given geographic region, as well as changes in such disease occurrences in migrant populations from a low risk to a high risk area, and vice versa (25,42). Populations that customarily consume fruits and vegetables and also whole grain cereal products generally have a lower risk of cardiovascular diseases and specific types of cancer than populations with a lower intake of such foods, everything else being equal (63). In the last few years, research has provided mechanistic explanations as to the reasons for the protective effects of specific foods. This paper will emphasize the mechanisms whereby cancer risks are reduced by dietary modification.

THIS BOOK collects together papers given at a NATO Advanced Research Workshop held at Il Ciocco (Lucca), Italy, from the 9th to the 15th April, 1989. It sets out to present the current state of understanding of the principles governing the way fluxes and concentrations are maintained and controlled in metabolic systems. Although this is a topic that has held the interest of biochemists for many years, it is only quite recently that the methods of analysing the kinetics of multi-enzyme pathways developed over the past two decades have come to be widely discussed or applied experimentally. Many biochemists remain sceptical that the new methods offer a real advance (except in complexity) over the landmark discoveries of the 1950s and 1960s relating to inhibition of enzymes at branch-points by the end products of metabolic pathways, and the interpretation of allosteric effects and cooperativity. Even those who have become convinced that the classical ideas provide only the starting point for understanding metabolic control have been by no means unanimous in their assess ment of the direction in which one should advance. In this book we have tried to include all of the current points of view, including the view that the classical theories tell us all that we need to know. We have not seen it as our role as editors to paper over the cracks that exist and to pretend that we can speak to the world with one voice."

JIMD Reports publishes case and short research reports in the area of inherited metabolic disorders. Case reports highlight some unusual or previously unrecorded feature relevant to the disorder, or serve as an important reminder of clinical or biochemical features of a Mendelian disorder.

Reed B. Wic1mer Section on Genetics of Simple Eukaryotes Laboratory of Biochemical Pharmacology National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases Bethesda, Maryland 20892 While most genes are chromosomal, the nonchromosomal genes have played a disproportionate role in molecular biology, in part because of their easy accessibility and in part because they represent the most mobile portion of a cell's genome. This is particularly evident in prokaryotes, where plas- mids and phages have been the central objects of study. The lower eukaryotes, including fungi and yeasts, protozoa, slime molds, algae, and other single-celled nucleated species, have long had an important role in genetic research. They have recently gained dramatic popularity with the development of transformation methods for Saccharomy- ~, Neurospora, Schizosaccharomyces, Dictyostelium, and others of this group. The realization that Saccharomyces has oncogenes, RNA tumor virus- es, estrogens, a polypeptide sex hormone with close homology to human lactate dehydrogenase, intervening sequences, and all the mitotic, mito- chondrial, and other structures typical of so-called "higher" eukaryotic organisms has confirmed the use of such organisms as model systems. Their use in biotechnology also shows great promise.

This book emerged from a series of lectures on crop evolution at the Faculty of Agriculture of The Hebrew University of Jerusalem. While many textbooks are available on general evolution, only a few deal with evolution under domestication. This book is a modest attempt to bridge this gap. It was written for advanced undergraduate and graduate students in the fields of crop evolution, ethnobotany, plant breeding and related subjects. Evolution under domestication is unique in the general field of plant evolution for three main reasons: (a) it is recent, having started not much more than 10 000 years ago with the emergence of agri culture; (b) the original plant material, i. e. the wild progenitors of many important crop plants, still grow in their natural habitats; (c) man played in this process. These factors enable a more reliable a major role assessment of the impact of different evolutionary forces such as hybridization, migration, selection and drift under new circumstances. Interestingly, a great part of evolution under domestication has been unconscious and a result of agricultural practices which have created a new selection criteria, mostly against characters favored by natural selec tion. Introducing crop plants to new territories exposed them to different ecological conditions enhancing selection for new characters. Diversity in characters associated with crop plants evolution is virtually absent in theit wild progenitors and most of it has evolved under domestication."

Following pioneering work by Harrison on amphibian limbs in the 1920s and by Saunders (1948) on the apical ridge in chick limbs, limb development became a classical model system for investigating such fundamental developmental issues as tissue interactions and induction, and the control of pattern formation. Earlier international conferences, at Grenoble 1972, Glasgow 1976,and Storrs, Connecticut 1982, reflected the interests and technology of their time. Grenoble was concerned with ectoderm-mesenchyme interaction, but by the time of the Glasgow meeting, the zone of polarizing activity (ZPA) and its role in control of patterning was the dominant theme. Storrs produced the first intimations that the ZPA could be mimicked by retinoic acid (RA), but the diversity of extracellular masrix ~olecules,particularly in skeletogenesis,was the main focus of attention. By 1990, the paradigms had again shifted. Originally, the planners of the ARW saw retinoic acid (as a possible morphogen controlling skeletal patterning), the variety of extracellular matrix components and their roles, and the developmental basis of limb evolution as the leading contemporary topics. However, as planning proceeded, it was clear that the new results emerging from the use of homeobox gene probes (first developed to investigate the genetic control of patterning of Drosophila embryos) to analyse the localised expression of "patterning genes" in limb buds would also be an important theme.

Serpins (serine protease inhibitors) are a superfamily of proteins whose physiologi- cal action is primarily targeted to inhibiting serine proteases. There are instances where serpins are not inhibitors (and can carry steroid hormones for instance), yet key structural and functional elements found in all serpins are maintained in these 'non-inhibitor' ser- pins. Many serpins have well-described biological properties which influence pathophysi- ological events, including: antithrombin (historically called antithrombin III), ai-protease inhibitor (historically called ai-antitrypsin), and plasminogen activator inhibitor-I, just to mention a few. A deficiency or defect in antithrombin leads to venous thromboembolic disease, while a deficiency or defect in ai-protease inhibitor is associated with chronic obstructive pulmonary emphysema. In contrast, it has been suggested that increased levels of plasminogen activator inhibitor-l may be a predisposition to myocardial infarction. The list goes on for each of our own "favorite" serpin. The biological roles found for serpins are key participants in almost every physiological event. In other words, serine proteases are needed for many events in biology and the role of serpins to down regulate these pro- teases is essential. Thus, just using these three examples above for serpins and their patho- physiological roles reminds us that the medical costs to control such events is significant worldwide.

Microarray technology is a major experimental tool for functional genomic explorations, and will continue to be a major tool throughout this decade and beyond. The recent explosion of this technology threatens to overwhelm the scientific community with massive quantities of data. Because microarray data analysis is an emerging field, very few analytical models currently exist. Methods of Microarray Data Analysis is one of the first books dedicated to this exciting new field. In a single reference, readers can learn about the most up-to-date methods ranging from data normalization, feature selection and discriminative analysis to machine learning techniques. Currently, there are no standard procedures for the design and analysis of microarray experiments. Methods of Microarray Data Analysis focuses on two well-known data sets, using a different method of analysis in each chapter. Real examples expose the strengths and weaknesses of each method for a given situation, aimed at helping readers choose appropriate protocols and utilize them for their own data set. In addition, web links are provided to the programs and tools discussed in several chapters. This book is an excellent reference not only for academic and industrial researchers, but also for core bioinformatics/genomics courses in undergraduate and graduate programs.

Genomic instability is a major threat to living organisms. To counteract the damaging effects posed by endogenous and environmental agents, such as chemicals or radiation, micro-organisms devote several percent of their genome to encode proteins that function in the repair and recombination of DNA. For many years, a relatively small group of scientists have carefully delineated the molecular mechanisms of these repair processes, using the simplest model systems available, namely Escherichia coli and Saccharomyces cerevisiae. These studies, which until recently had only moderate impact outside of the field, now provide the cornerstone for exciting new research into analogous processes in human cells. The reason for this is the revelation that the biochemical pathways for the accurate replication, repair and recombination of DNA have been conserved through evolution. New research shows that human cells use DNA repair mechanisms that are analogous to those found in bacteria to overcome the damaging effects of environmental mutagens and carcinogens. Of particular significance is the observation that certain cancers are caused by defects in DNA repair enzymes. For example, the human inherited non-polyposis colon cancer is now known to be caused by defects in the enzymes that repair DNA mismatches. Because much detailed information has been accumulated in studies of analogous mismatch repair proteins from bacteria, rapid progress can now be made.

Biochemistry And Genetics of RecQ-Helicases provides a background into the role of helicases in general and RecQ helicases specifically in DNA repair. Helicases- enzymes which break down hydrogen bonds between nucleic acid strands in a nucleoside triphosphate-dependent manner-are ubiquitous in biology, participating in processes as diverse as replication, repair, recombination, transcription, and translation. The RecQ-family helicases are a group of helicases which have important roles in the maintenance of genomic stability in many organisms. In humans, mutations in three RecQ-family helicases lead to disease. This book thoroughly examines these helicases. Mutations in the BLM gene lead to Bloom syndrome, a disorder characterized by a susceptibility to many types of cancer. Mutations in the WRN gene cause Werner syndrome, a disease which in some respects resembles premature aging. Finally, mutations in a newly characterized RecQ-family member, RECQ4, may lead to the very rare recessive disorder Rothmund-Thomson syndrome, a condition characterized by developmental abnormalities and some aging-like manifestations. This book is intended for any researchers invested in these particular disorders, or with a general interest in DNA.

The current volume includes chapters on peroxisomal disorders, genetic aspects of cancer, Gaucher disease, and other topics.

It is nearly a decade since the first Male Mediated Developmental Toxicity conference was held in Pittsburgh. The continuing public/scientific interest, growing amounts of animal data, introduction of innovative technologies, and increasing quantity of human epidemiological studies all suggest that male-mediated developmental toxicity is of major concern. A number of researchers concluded that a Second International Confer- ence on Male Mediated Developmental Toxicity was necessary. The ensuing volume is particularly timely because it impacts on areas of special emphasis in many countries, with respect to children's and reproductive health, as well as to basic molecular mecha- nisms of environmental insult, and genetic susceptibility and predisposition. The Programme and Local Organizing Committee, composed of Barbara Hales (Chair, McGill University), BernardRobaire (McGill University), Daniel G. Cyr (INRS/ Armand Frappier), Jacquetta M. Trasler (McGill University), Andrew F. Olshan (Uni- versity of North Carolina), Sally Perreault Damey (US EPA), Donald R. Mattison (March of Dimes), and Jan M. Friedman (University of British Columbia), spent over two years identifying individuals who had made key contributions in this field over the past decade and planning various aspects of the meeting. The meeting was held in Montreal in June 2001. A total of 132 persons, coming from five continents and representing some 18countries, took an active role in the proceedings. The conference was considered by all attendees to be a rousing success. Important discussions were held in the four break-out sessions, with a preliminary set of recommendations for action being presented by each panel.

''A valuable resource for those concerned with experimental teratology and risk assessment and those requiring general information about the causes of birth defects. The treatment of these issues is sophisticated, succinct, and logical.'' --- American Scientist, from a review of a previous volume The current volume covers intergenerational factors in pregnancy outcome, the thresholds for developmental toxicants, and four other subjects.

The Human Genome Project, an endeavor to map and sequence the entire human genome, has been in existence for almost seven years. One result of this effort has been the development of increasingly detailed genetic and physical maps spanning large regions of virtually every chromosome. Paralleling this has been the increasingly high resolution mapping of many &wnetic diseases. Together, these developments have facilitated the isolation of specific disease genes and are now motivating the construction of comprehensive transcriptional maps. This latter endeavor represents a new facet of the genome project, and as such requires the recognition and solution of a new set of problems, with the attendant development and application of a new set of techniques. The First International Workshop on the Identification of Transcribed Sequences in the Human Genome was held in 1991 and was attended by 23 investigators. Discussions at this meeting were largely devoted to defining the magnitude of the problem and describing the available techniques. A small number of laboratories reported the development of new techniques (at that time, for example, exon trapping, cDNA hybrid selection, direct cDNA screening, use of splice junction conserved sequences, etc.), but data were too limited to permit comparisons of their relative efficiencies.

2 The role of Ca+ as an internal messenger in visual transduction of vertebrate and invertebrate organisms has been explored intensely in the recent past. Since the 2 early 1970s, calcium ions and cyclic GMP (whose levels are controlled by Ca+ in vertebrates) have been recognized as important second messengers. Particularly in 2 the last decade, however, the role of Ca+ in visual transduction has been re-evalu- ated and a proliferation of research has documented a multiplicity of roles. 2 It is now evident that Ca+ modulates phototransduction by acting at several 2 sites through a host of small Ca+ -binding proteins. For example, in phototransduction 2 of vertebrates, Ca+-free forms of guanylate cyclase activating proteins (GCAPs) activate guanylate cyclase, modulating levels of cOMP, a key event in the return of photoreceptors to pre-bleach conditions. Defects in genes encoding guanylate cy- clase or guanylate cyclase activating proteins lead to severe diseases of the retina (e. g. , Leber congenital amaurosis, rod/cone dystrophy, or cone dystrophy), thus em- phasizing the important role of these proteins in phototransduction. Similarly, mu- 2 tant genes encoding cation or Ca+ channels (cyclic nucleotide-gated cation chan- 2 nels located in the cell membrane and L-type voltage-gated Ca+ channels located at the synapse of photo receptors) lead to retinitis pigmentosa or congenital stationary night blindness. In phototransduction of invertebrate organisms (e. g. , Drosophila 2 and Limulus), the role of Ca+ is similarly central, but distinct, from that of vertebrates.

During the last few years, an explosion of infonnation has come from human genetics and molecular and cell biological studies as to the genetic basis for a number of fonns of inherited retinal degenerations. These disorders have plagued mankind for millennia because they take from otherwise healthy individuals the precious gift of sight. The fundamental advances in recent years have identified a number of genes involved in the groups of diseases which hopefully will lead to discoveries that may, in the not too distant future, allow the prevention and possible cure of some of these blinding eye disorders. To foster a forum for discussions of studies on degenerative retinal disorders, we convened a symposium on retinal degenerations in 1984, at the VIth International Congress of Eye Research Meeting, held in Alicante, Spain. Because of the success of this meeting and the subsequent publication, we have since organized a series of biennial satellite meetings on retinal degenerations for the ISER congresses held in Nagoya, Japan (1986), San Francisco (1988) and Helsinki (1990). Each of these satellite symposium on retinal degenerations was accompanied by a published proceedings volume. This volume is the fifth in this series and contains the proceedings of the Sardinia Symposium on Retinal Degeneration held September 15-20, 1992, as a satellite meeting of the 10th International Congress of Eye Research.

nd During June 13 -June 23 1996, the 2 EL. B. A. Foundation course on Genome, a NATO Advanced Study Institute, was held at Marcian Marina, Isle of Elba, Italy, - sponsored by the North Atlantic Treaty Organization and the EL. B. A. Fundation. The subject of the course was "Genome Structure and Function" with participants selected worldwire from 15 afferent countries. The purpose of the course and of the resulting book is the study of DNA structure (from the primary to the quintemary) and gene expression in the control of cell function and cell cycle progression; the topics were presented by top experts, covering both structural (cbwn to the atomic resolution) and functional (cbwn to gene level) aspects. The topics were presented by top experts and scientists active in the field, with the goal to give an insight into modm problems of genome study and recent ochievements in related fielm of molecular and cell biology, genetic engineering, biochemistry and biophysics, oncology and biotechnology. This resulting book is intenred to give a broad perspecti ve of the current stand of these fields. The major emphasis is towarm a reep unrerstanang of DNA structure and function in intetphase and metaphase chromosomes, originating by the parallel biophysical (namely NMR X-Ray and neutron scattering, spectropolarimetry, image analysis, calorimetry) and biochemical study conwcted on a wire range of cell systems placing the emphasis on either the higher orrer DNA structure or gene structure and function.

The Ontogeny of Human Bonding Systems takes an interdisciplinary look at the phenomena of human bonding. The authors draw upon behavioral genetics, molecular genetics of behavior, cognitive and affective neuroscience, evolutionary psychology, human ethology, behavioral ecology, and the study of attachment processes within developmental psychology. The topics will emphasize human reproduction, and fertility-related behavior in particular, and the evolutionary origins and neural underpinnings of such behavior. This book is for anyone interested in the evolutionary origins, neural underpinnings, and psychological structure involved in human relationships.

~he major theme of this book is the development of the vertebrate central nervous system. ~is volume contains summaries of most of the invited participants at the NA~ advanced study institute entitled "Development of central nervous system in vertebrates" held in Maratea, Italy, from June 23-July 5, 1991. In order to address this topic, we have drawn upon a selection of current studies dealing with molecular, cellular and system analysis which specifically pertain to the general principles of the development. ~he major aim of this institute was to bring together a select group of investigators who would present their views on the current issues in their respective fields and to foster extensive discussions amongst participants in smaller groups. Such interactions brought together the exchanges of ideas amongst participants and helped clarify the intricate details and formulate new vistas and collaborations. Since the study of nervous system development has focused mostly on the origin of neuron and glia cells, the area of current research was represented by talks on early cellular events including effects of growth factors, BOX and other gene expressions and cell lineage of specific cell type(s). Formation of specific cell types and the specific neuronal connections have been a major theme in the study of the nervous system development. Recent technical advances has resulted in new information at both cellular and molecular levels which have provided new details. Current research was represented by "selective" topics discussed at the meeting.

This book, which results from the dramatic increase in interest in the control mechanism employed in gene expression and the importance of the regulated proteins, presents new information not covered in Translational Regulation of Gene Expression, which was published in 1987. It is not a revision of the earlier book but, rather, an extension of that volume witl, special emphasis on mecha nIsm. As the reader will discover, there is enormous diversity in the systems employing genes for translational regulation in order to regulate the appearance of the final product-the protein. Thus, we find that important proteins such as protooncogenes, growth factors, stress proteins, cytokines, lymphokines, iron storage and iron-uptake proteins, and a panorama of prokaryotic proteins, as well as eukaryotic viral proteins, are translationally regulated. Since for some gene products the degree of control is greater by a few orders of magnitude than their transcription, we can state that for these genes, at least, the expression is translationall y controlled. Translational regulation of gene expression in eukaryotes has emerged in the last few years as a major research field. The present book describes mechanisms of translational regulation in bacteria, yeast, and eukaryotic viruses, as well as in eukaryotic genes. In this book we try to provide in-depth coverage by including important examples from each group rather than systematically including all additional systems not described in the previous volume.

This volume reports the proceedings of a NATO Advanced Workshop held in Castelvecchio Pas coli, Italy, from August 28 - September 1, 1989. An important inspiration for this Workshop came from our studies in Helsinki and Denmark, which have found that exposure to an influenza epidemic during the second trimester of fetal development increases the risk of adult schizophrenia. This finding has stimulated an important new hypothesis in the study of the etiology of schizophrenia. It has suggested the possiblity that disturbances of brain development during gestation may contribute to the risk of adult schizophrenia. We determined that it would be of value to bring together schizophrenia researchers and those doing basic studies of the development of the brain. Both groups of researchers were encouraged to communicate at a level that would help other scientists to integrate their knowledge and techniques into their own discipline. For this reason, perhaps, the papers of this volume are remarkably clear and not difficult to understand. The first four chapters describe the neurochemical and structural aspects of brain development. The chapter by Dziegielewska and Saunders discusses transport mechanisms and the properties of endogenous and exogenous substances that control the internal environment of the developing brain. In the second chapter, Nowakowski reports on his studies of the develop ment of the hippocampus in mice genetically inbred to exhibit disruptions of neural migration.

Since 1984, we have organized satellite symposia on retinal degenerations that are held in conjunction with the biennial International Congress of Eye Research. The timing and location of our Retinal Degeneration Symposia have allowed scientists and clinicians from around the world to convene and present their exciting new findings. The symposia have been arranged to allow ample time for discussions and one-on-one interactions in a relaxed atmosphere, where international friendships and collaborations could be established. The IXth International Symposium on Retinal Degeneration was held on October 9-14, 2000 in Durango, Colorado and was attended by over 100 scientists from six continents. This book contains many of their presentations. Several events of note occurred at this meeting. First, thanks to the generous support of the Foundation Fighting Blindness, we were able to sponsor the travel of 11 young scientists from six countries. Most of them have contributed chapters to this volume. The response to the travel program was so overwhelming that we will make it regular feature of our meeting. This will allow other bright, young investigators to be introduced to the world experts who study retinal degenerations. Second, about 40% of the scientists who attended this meeting were there for the first time. We believe that this indicates a growing interest in retinal degeneration research and ensures that new talent will be attracted to this important area of investigation. The symposium received support from several organizations.

An early view of eukaryotic chromosomes was that of static structures, which stored DNA not in use within a given cell type. It was thought that packaging of DNA into higher levels of chromatin structure would suffice to repress gene expression and that the challenge to the cell would be to rescue specific sequences from these structures. The exten sive packaging of inactive DNA was considered the primary difference between eukaryotic and prokaryotic genomes and except for that point both would be similarly regulated by cis-acting sequences and trans acting factors. Our view of eukaryotic chromosomes has evolved dra matically over the last decade. The picture of chromosomes that is emerging is that of dynamic breathing organelles actively regulating the flow of genetic information from the genome. Indeed chromatin is so fluid that even maintaining gene quiescence is an active process and is tightly regulated. Chromatin dynamics is a consequence of protein complexes that modify histones, remove histone modifications, mobi lize nucleosomes or stabilize nucleosomes. Awide variety of such com plexes have now been described. Some are abundant and may play glo bal roles in chromosome fluidity and function. Others are more rare and specialized for specific functions at discreet loci. Moreover, several complexes share biochemical activities and genetic studies suggest overlapping functions in vivo. Many components of these complexes were first revealed in genetic screens, while others were discovered by novel cell biological or biochemical approaches.