bluuebunny/crossref_metadata_2025 huggingface dataset:
Gesture
Authors: Kendon Adam
Published: July 2002

The integration of gesture with speech production is described, and the various ways in which—in conversational settings—gesture functions in relation to spoken discourse are discussed. Cultural differences in gesture use are outlined, and the possible relationship between these differences and language differences, on the one hand, and the microecology of social life, on the other, are considered. Conventionalization in speech-associated gestures and in gestures that can be used without speech is discussed. Various kinds of “gesture systems” and sign languages used in speaking communities (alternate sign languages) are described along with their relationships to spoken language. Fully autonomous sign languages, as developed among the deaf, are briefly considered in regard to how signs and signing may be related to gestures and gesturing.
WITTGENSTEIN AND ANTHROPOLOGY
Authors: Das Veena
Published: July 2002

▪ Abstract  This essay explores the theme of Wittgenstein as a philosopher of culture. The primary text on which the essay is based is Philosophical Investigations; it treats Stanley Cavell's work as a major guide for the understanding and reception of Wittgenstein into anthropology. Some Wittgensteinian themes explored in the essay are the idea of culture as capability, horizontal and vertical limits to forms of life, concepts of everyday life in the face of skepticism, and the complexity of the inner in relation to questions of belief and pain. While an attempt has been made to relate these ideas to ethnographic descriptions, the emphasis in this essay is on the question of how anthropology may receive Wittgenstein.
Evolutionary Perspective on Human Growth
Authors: Bogin Barry
Published: July 2002

▪ Abstract  To better understand both the shared and special features of human growth, this article explores the evolution of growth patterns of mammals in general and primates in particular. Special attention is paid to several competing hypotheses concerning the adaptive value of the juvenile stage to the life history of the social mammals. One hypothesis claims that all social mammals have a juvenile stage of life, but although most primate species are social, not all primates show a juvenile stage of life history. There is also controversy over whether the adolescent growth spurt is a uniquely human feature. On the basis of empirical observations and evolutionary considerations, I conclude that the human adolescent growth spurt in stature and skeletal maturation is species specific, not found in any other primate species. Finally, data and theory are used to advance a philosophy of human growth. An acceptable philosophy must acknowledge the mammalian and primate foundations for the human pattern of growth. But a robust philosophy of human growth must also account for the ecology to which the human species, indeed any species, is adapted. Accordingly, a philosophy of human growth must allow for the evolution of variations on common themes and of new stages of growth that may be unique to the human species.
Colonial Linguistics
Authors: Errington Joseph
Published: July 2002

▪ Abstract  Academic knowledge of human linguistic diversity owes much to descriptions written, over four centuries ago, under the aegis of European colonial regimes around the world. This comparative review considers a small part of that body of linguistic descriptive work relative to its conditions of production: authorial interests that animated such writings, ideological and institutional milieux that enabled and shaped them, and the authoritative character they took on as natural symbols of colonial difference. European technologies of literacy enabled missionary and nonmissionary linguistic work that resulted in representations of languages as powerful icons of spiritual, territorial, and historical hierarchies that emerged in colonial societies. As descriptions of languages traveled from exotic colonial peripheries to European metropoles, they came under the purview of comparative philology. This disciplinary precursor to modern linguistics helped to legitimize colonial linguistic projects and legislate colonial difference on a global scale.
Adaptations to Altitude: A Current Assessment
Authors: Beall Cynthia M.
Published: July 2002

▪ Abstract  The high-altitude Andean and Tibetan Plateaus offer natural experimental settings for investigating the outcome of the past action of evolution and adaptation as well as those ongoing processes. Both Andean and Tibetan high-altitude natives are descended from sea-level ancestors; thus both initially encountered chronic, lifelong high-altitude hypoxia with the same homeostatic “toolbox” that evolved at sea level for responding to brief and transient hypoxia. Yet now they differ phenotypically in many traits thought to be important for offsetting chronic high-altitude hypoxia. Compared on the basis of mean values of five traits, the characteristics of Tibetan high-altitude natives differ more than those of Andean high-altitude natives from the ancestral or unselected response to chronic hypoxia exhibited by acclimatized lowlanders. This suggests that different evolutionary processes have occurred in the two geographically separate areas, although it is not clear why or how those processes differed. Answers to those questions require better knowledge of the prehistory of human populations on the plateaus, as well as information on new phenotypes and the relationship between phenotype and genotype.
CHARGED DUST DYNAMICS IN THE SOLAR SYSTEM
Authors: Horányi Mihály
Published: July 2002

▪ Abstract  In most space environments, dust particles are exposed to plasmas and UV radiation and, consequently, carry electrostatic charges. Their motion is influenced by electric and magnetic fields in addition to gravity, drag, and radiation pressure. On the surface of the Moon, in planetary rings, or at comets, for example, electromagnetic forces can shape the spatial and size distribution of micron-sized charged dust particles. The dynamics of small charged dust particles can be surprisingly complex, leading to levitation, rapid transport, energization and ejection, capture, and the formation of new planetary rings.

This review briefly discusses the most important processes that determine the charge state of dust particles immersed in plasmas and the resulting dynamics on exposed dusty surfaces and in planetary magnetospheres.
LOW SURFACE BRIGHTNESS GALAXIES
Authors: Impey Chris , Bothun Greg
Published: July 2002

▪ Abstract  The properties of galaxies that are lower in surface brightness than the dark night sky are reviewed. There are substantial selection effects against the discovery of galaxies that are unevolved or diffuse; these systems are missing from most wide field catalogs. Low surface brightness galaxies make up a significant amount of the luminosity density of the local universe. They contribute substantial but poorly determined amounts to the census of baryons and dark matter. Low surface brightness galaxies are also relevant to the interpretation of quasar absorption lines and to the understanding of rapidly evolving galaxy populations in the more distant universe. Theories of galaxy formation and evolution must accomodate the properties of these diffuse stellar systems.
PATHOLOGIC CONFORMATIONS OF PRION PROTEINS
Authors: Cohen Fred E. , Prusiner Stanley B.
Published: July 2002

While many aspects of prion disease biology are unorthodox, perhaps the most fundamental paradox is posed by the coexistence of inherited, sporadic, and infectious forms of these diseases. Sensible molecular mechanisms for prion propagation must explain all three forms of prion diseases in a manner that is compatible with the formidable array of experimental data derived from histopathological, biochemical, biophysical, human genetic, and transgenetic studies. In this review, we explore prion disease pathogenesis initially from the perspective of an autosomal dominant inherited disease. Subsequently, we examine how an intrinsically inherited disease could present in sporadic and infectious forms. Finally, we explore the phenomenologic constraints on models of prion replication with a specific emphasis on biophysical studies of prion protein structures.
Transport of Molecules, Particles, and Cells in Solid Tumors
Authors: Jain Rakesh K.
Published: July 2002

▪ Abstract  Extraordinary advances in molecular biology and biotechnology have led to the development of a vast number of therapeutic anti-cancer agents. To reach cancer cells in a tumor, a blood-borne therapeutic molecule, particle, or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium, which it then must migrate through. Unfortunately, tumors often develop in ways that hinder these steps. The goal of research in this area is to analyze each of these steps experimentally and theoretically and integrate the resulting information into a unified theoretical framework. This paradigm of analysis and synthesis has fostered a better understanding of physiological barriers in solid tumors and aided in the development of novel strategies to exploit and/or overcome these barriers for improved cancer detection and treatment.
Ultrasound Processing and Computing: Review and Future Directions
Authors: York George , Kim Yongmin
Published: July 2002

▪ Abstract  Since the introduction of medical ultrasound in the 1950s, modern diagnostic ultrasound has progressed to see many major diagnostic tools come into widespread clinical use, such as B-mode imaging, color-flow imaging, and spectral Doppler. New applications, such as panoramic imaging, three-dimensional imaging, and quantitative imaging, are now beginning to be offered on some commercial ultrasound machines and are expected to grow in popularity. In this review, we focus on the various algorithms, their processing requirements, and the challenges of these ultrasound modes. Whereas the older, mature B and color-flow modes could be systolically implemented using hardwired components and boards, new applications, such as three-dimensional imaging and image feature extraction, are being implemented more by using programmable processors. This trend toward programmable ultrasound machines will continue, because the programmable approach offers the advantages of quick implementation of new applications without any additional hardware and the flexibility to adapt to the changing requirements of these dynamic new applications.
Biomolecular Simulations: Recent Developments in Force Fields, Simulations of Enzyme Catalysis, Protein-Ligand, Protein-Protein, and Protein-Nucleic Acid Noncovalent Interactions
Authors: Wang Wei , Donini Oreola , Reyes Carolina M. , Kollman Peter A.
Published: July 2002

▪ Abstract  Computer modeling has been developed and widely applied in studying molecules of biological interest. The force field is the cornerstone of computer simulations, and many force fields have been developed and successfully applied in these simulations. Two interesting areas are (a) studying enzyme catalytic mechanisms using a combination of quantum mechanics and molecular mechanics, and (b) studying macromolecular dynamics and interactions using molecular dynamics (MD) and free energy (FE) calculation methods. Enzyme catalysis involves forming and breaking of covalent bonds and requires the use of quantum mechanics. Noncovalent interactions appear ubiquitously in biology, but here we confine ourselves to review only noncovalent interactions between protein and protein, protein and ligand, and protein and nucleic acids.
HISTORICAL BIOGEOGRAPHY OF WEST INDIAN VERTEBRATES
Authors: Hedges S. Blair
Published: July 2002

▪ Abstract  The vertebrate fauna of the West Indies (1262 species) exhibits high levels of endemism and has a taxonomic composition characteristic of more isolated oceanic islands. Many groups that are widespread on the mainland are absent in the islands, and some of those present are characterized by large adaptive radiations. The growing fossil record of West Indian vertebrates, including mid-Tertiary amber fossils (considered here to be 20–30 million years old), indicates that this pattern of reduced higher-taxon diversity has persisted for a long period of time. Phylogenetic relationships of nonvolant groups display a strong South American influence, whereas volant groups (birds and bats) and freshwater fish show closer ties with Central and North America. Molecular estimates of divergence times between island taxa and their mainland counterparts indicate a Cenozoic origin (within the last 65 million years) for nearly all groups examined. Together, data from different sources point to an origin by overwater dispersal for a large majority of the vertebrate fauna. The prevailing current direction, from southeast to northwest, and the wide scattering of estimated times of origin suggest that much of the nonvolant fauna arrived by flotsam carried from the mouths of major rivers in northeastern South America. Spatial relationships, especially considering low sea levels during the Pleistocene, appear to better explain the routes of colonization taken by the volant fauna and freshwater fish. Caribbean geologic history does not preclude an origin by late Mesozoic vicariance for several possibly ancient groups, although an early Cenozoic arrival by dispersal also cannot be discounted. An integrative approach to historical biogeography is shown to be more insightful than the current trend in the field, cladistic biogeography, which places prime emphasis only on phylogenetic relationships.
ENVIRONMENTALISSUESALONG THEUNITEDSTATES-MEXICOBORDER: Drivers of Change and Responses of Citizens and Institutions
Authors: Liverman Diana M. , Varady Robert G. , Chávez Octavio , Sánchez Roberto
Published: July 2002

▪ Abstract  The US-Mexico border region illustrates the challenges of binational environmental management in the context of a harsh physical environment, rapid growth, and economic integration. Transboundary and shared resources and conflicts include limited surface water supplies, depletion of groundwater, air and water pollution, hazardous waste, and conservation of important natural ecosystems. Public policy responses to environmental problems on the border include binational institutions such as the IBWC, BECC and CEC, the latter two established in response to environmental concerns about the North American Free Trade Agreement (NAFTA). Environmental social movements and nongovernmental organizations have also become important agents in the region. These new institutions and social movements are especially interesting on the Mexican side of the border where political and economic conditions have often limited environmental enforcement and conservation, and where recent policy changes also include changes in land and water law, political democratization, and government decentralization.
GEOENGINEERING THE CLIMATE: History and Prospect
Authors: Keith David W.
Published: July 2002

▪ Abstract  Geoengineering is the intentional large-scale manipulation of the environment, particularly manipulation that is intended to reduce undesired anthropogenic climate change. The post-war rise of climate and weather modification and the history of U.S. assessments of the CO2-climate problem is reviewed. Proposals to engineer the climate are shown to be an integral element of this history. Climate engineering is reviewed with an emphasis on recent developments, including low-mass space-based scattering systems for altering the planetary albedo, simulation of the climate's response to albedo modification, and new findings on iron fertilization in oceanic ecosystems. There is a continuum of human responses to the climate problem that vary in resemblance to hard geoengineering schemes such as space-based mirrors. The distinction between geoengineering and mitigation is therefore fuzzy. A definition is advanced that clarifies the distinction between geoengineering and industrial carbon management. Assessment of geoengineering is reviewed under various framings including economics, risk, politics, and environmental ethics. Finally, arguments are presented for the importance of explicit debate about the implications of countervailing measures such as geoengineering.
THE ECOLOGY AND BEHAVIOR OF BURYING BEETLES
Authors: Scott Michelle Pellissier
Published: July 2002

▪ Abstract  Burying beetles conceal small vertebrate carcasses underground and prepare them for consumption by their young. This review places their complex social behavior in an ecological context that focuses on the evolution of biparental care and communal breeding. Both males and females provide extensive parental care, and the major benefit of male assistance is to help defend the brood and carcass from competitors. As intensity and type of competition vary, so do the effectiveness and duration of male care. In many species, a single brood may be reared on large carcasses by more than one male and/or female. Limited reproductive opportunities, the greater effectiveness of groups in preventing the probability of brood failure (especially that caused by competing flies), and the superabundance of food on large carcasses have contributed to the evolution of this cooperative behavior.
MODELS OFDIVISION OFLABOR INSOCIALINSECTS
Authors: Beshers Samuel N. , Fewell Jennifer H.
Published: July 2002

▪ Abstract  Division of labor is one of the most basic and widely studied aspects of colony behavior in social insects. Studies of division of labor are concerned with the integration of individual worker behavior into colony level task organization and with the question of how regulation of division of labor may contribute to colony efficiency.

Here we describe and critique the current models concerned with the proximate causes of division of labor in social insects. The models have identified various proximate mechanisms to explain division of labor, based on both internal and external factors. On the basis of these factors, we suggest a classification of the models. We first describe the different types of models and then review the empirical evidence supporting them.

The models to date may be considered preliminary and exploratory; they have advanced our understanding by suggesting possible mechanisms for division of labor and by revealing how individual and colony-level behavior may be related. They suggest specific hypotheses that can be tested by experiment and so may lead to the development of more powerful and integrative explanatory models.
Biology and Management of Economically Important Lepidopteran Cereal Stem Borers in Africa
Authors: Kfir Rami , Overholt W. A. , Khan Z. R. , Polaszek A.
Published: July 2002

▪ Abstract  Cereals (maize, sorghum, millet, rice) are extremely important crops grown in Africa for human consumption. Of the various insect pests attacking cereal crops in Africa, lepidopteran stem borers are by far the most injurious. All 21 economically important stem borers of cultivated grasses in Africa are indigenous except Chilo partellus, which invaded the continent from India, and C. sacchariphagus, which has recently been found in sugarcane in Mozambique. C. partellus is competitively displacing indigenous stem borers in East and southern Africa. A parasitoid, Cotesia flavipes, was introduced from Pakistan for biological control of C. partellus and caused a 32–55% decrease in stem borer densities. This article is an attempt to summarize the status of knowledge about economically important cereal stem borers in Africa with emphasis on their distribution, pest status and yield losses, diapause, natural enemies, cultural control, host plant resistance, and biological control. Special attention is given to Busseola fusca and C. partellus, the most important pests of maize and grain sorghum.
ELECTROHYDRODYNAMICS: The Taylor-Melcher Leaky Dielectric Model
Authors: Saville D. A.
Published: July 2002

▪ Abstract  Electrohydrodynamics deals with fluid motion induced by electric fields. In the mid 1960s GI Taylor introduced the leaky dielectric model to explain the behavior of droplets deformed by a steady field, and JR Melcher used it extensively to develop electrohydrodynamics. This review deals with the foundations of the leaky dielectric model and experimental tests designed to probe its usefulness. Although the early experimental studies supported the qualitative features of the model, quantitative agreement was poor. Recent studies are in better agreement with the theory. Even though the model was originally intended to deal with sharp interfaces, contemporary studies with suspensions also agree with the theory. Clearly the leaky dielectric model is more general than originally envisioned.
GENETIC COUNSELING: Clinical and Ethical Challenges
Authors: Mahowald M. B. , Verp M. S. , Anderson R. R.
Published: July 2002

▪ Abstract  After explaining the origin, nature, and goals of genetic counseling, we consider the impact of the Human Genome Project on its practice. In light of the availability of presymptomatic tests for late-onset disorders and the possibility of preventive behavior or treatment, we examine the apparent conflict between nondirectiveness and directiveness in genetic counseling. We discuss views of genetic counselors, medical geneticists, and counselees on specific issues, and document gender differences in attitudes toward genetic ties to offspring. Because genetic discrimination and unequal access to genetic services are likely to increase with advances in genetics, we conclude that efforts of genetic counselors to adhere to the principle of justice or equity in their practice cannot be successful without governmental and public support, as well as support from researchers and colleagues in health care.
THE GENETICS OF BREAST CANCER SUSCEPTIBILITY
Authors: Rahman Nazneen , Stratton Michael R.
Published: July 2002

▪ Abstract  Following the genomic localization and subsequent identification of the breast cancer susceptibility genes, BRCA1 and BRCA2, the basic patterns of cancer risk associated with mutations in these genes have been defined. In addition, preliminary insights into the prevalence of mutations and their contributions to cancer incidence have been acquired. Features of breast and other cancers that develop in these genetic syndromes have now been investigated and shown to differ from sporadic versions of the same neoplasms. However, several areas are complex and require further clarification. There remain discrepancies between published cancer risk estimates. Furthermore, there may be variation in cancer risk between different mutations in the same gene and there is preliminary evidence that genetic and nongenetic influences may modify risks. Finally, it is probable that the genes underlying a substantial component of susceptibility to breast cancer remain to be identified.
CD28/B7 SYSTEM OF T CELL COSTIMULATION
Authors: Lenschow Deborah J. , Walunas Theresa L. , Bluestone Jeffrey A.
Published: July 2002

▪ Abstract  T cells play a central role in the initiation and regulation of the immune response to antigen. Both the engagement of the TCR with MHC/Ag and a second signal are needed for the complete activation of the T cell. The CD28/B7 receptor/ligand system is one of the dominant costimulatory pathways. Interruption of this signaling pathway with CD28 antagonists not only results in the suppression of the immune response, but in some cases induces antigen-specific tolerance. However, the CD28/B7 system is increasingly complex due to the identification of multiple receptors and ligands with positive and negative signaling activities. This review summarizes the state of CD28/B7 immunobiology both in vitro and in vivo; summarizes the many experiments that have led to our current understanding of the participants in this complex receptor/ligand system; and illustrates the current models for CD28/B7-mediated T cell and B cell regulation. It is our hope and expectation that this review will provoke additional research that will unravel this important, yet complex, signaling pathway.
DIVERGENT ROLES FOR FcRECEPTORS AND COMPLEMENT IN VIVO
Authors: Ravetch Jeffrey V. , Clynes Raphael A.
Published: July 2002

▪ Abstract  Recent results obtained in mice deficient in either FcRs or complement have revealed distinct functions for these two classes of molecules. While each is capable of interacting with antibodies or immune complexes, the two systems mediate distinct biological effector responses. Complement-deficient mice are unable to mediate innate immune responses to several bacterial pathogens and bacterial toxins, yet respond normally to the presence of cytotoxic antibodies and pathogenic immune complexes. In contrast, FcR-deficient mice display no defects in innate immunity or susceptibility to a variety of pathogens, yet they are unable to mediate inflammatory responses to cytotoxic IgG antibodies or IgG immune complexes, despite the presence of a normal complement system. These results lead to the surprising conclusion that these two systems have evolved distinct functions in host immunity, with complement and its receptors mediating the interaction of natural antibodies (IgM) with pathogens to effect protection, while FcRs couple the interaction of IgG antibodies to effector cells to trigger inflammatory sequelae. These results necessitate a fundamental revision of the role of these antibody-binding systems in the immune response.
THE ROLE OF COMPLEMENT AND COMPLEMENT RECEPTORS IN INDUCTION AND REGULATION OF IMMUNITY
Authors: Carroll Michael C.
Published: July 2002

▪ Abstract  Covalent attachment of activated complement C3 (C3d) to antigen links innate and adaptive immunity by targeting antigen to follicular dendritic cells (FDC) and B cells via specific receptors CD21 and CD35. Recent characterization of knockout mice deficient in complement components C3, C4, or the receptors CD21 and CD35 as well as biochemical studies of the CD21/CD19/Tapa-1 coreceptor on B cells have helped to elucidate the mechanism of complement regulation of both B-1 and B-2 lymphocytes. Interestingly, natural antibody of the adaptive immune system provides a major recognition role in activation of the complement system, which in turn enhances activation of antigen-specific B cells. Enhancement of the primary and secondary immune response to T-dependent antigens is mediated by coligation of the coreceptor and the B cell antigen receptor, which dramatically increases follicular retention and B cell survival within the germinal center. Most recent evidence suggests that complement also regulates elimination of self-reactive B cells, as breeding of mice that are deficient in C4 or CD21/CD35 with the lupus-prone strain of lpr mice demonstrates an exacerbation of disease due to an increase in autoantibodies.
NATURAL KILLER CELLS IN ANTIVIRAL DEFENSE: Function and Regulation by Innate Cytokines
Authors: Biron Christine A. , Nguyen Khuong B. , Pien Gary C. , Cousens Leslie P. , Salazar-Mather Thais P.
Published: July 2002

▪ Abstract  Natural killer (NK) cells are populations of lymphocytes that can be activated to mediate significant levels of cytotoxic activity and produce high levels of certain cytokines and chemokines. NK cells respond to and are important in defense against a number of different infectious agents. The first indications for this function came from the observations that virus-induced interferons α/β (IFN-α and -β) are potent inducers of NK cell-mediated cytotoxicity, and that NK cells are important contributors to innate defense against viral infections. In addition to IFN-α/β, a wide range of other innate cytokines can mediate biological functions regulating the NK cell responses of cytotoxicity, proliferation, and gamma interferon (IFN-γ) production. Certain, but not all, viral infections induce interleukin 12 (IL-12) to elicit NK cell IFN-γ production and antiviral mechanisms. However, high levels of IFN-α/β appear to be unique and/or uniquely dominant in the context of viral infections and act to regulate other innate responses, including induction of NK cell proliferation in vivo and overall negative regulation of IL-12 production. A detailed picture is developing of particular innate cytokines activating NK cell responses and their consorted effects in providing unique endogenous milieus promoting downstream adaptive responses, most beneficial in defense against viral infections.
POPULATION BIOLOGY OF HIV-1 INFECTION: Viral and CD4+T Cell Demographics and Dynamics in Lymphatic Tissues
Authors: Haase A. T.
Published: July 2002

▪ Abstract  Human immunodeficiency virus-1 (HIV-1) is usually transmitted through sexual contact and in the very early stages of infection establishes a persistent infection in lymphatic tissues (LT). Virus is produced and stored at this site in a dynamic process that slowly depletes the immune system of CD4+T cells, setting the stage for AIDS. In this review, I describe the changes in viral and CD4+T cell populations in LT over the course of infection and after treatment. I present recent evidence that productively infected CD4+T cells play an important role in establishing persistent infection from the onset, and that the LT are the major reservoir where virus is produced and stored on follicular dendritic cells (FDCs). I discuss the methods used to define the size of viral and CD4+T cell populations in LT and the nature of virus-host cell interactions in vivo. These experimental approaches have identified populations of latently and chronically infected cells in which virus can elude host defenses, perpetuate infection, and escape eradication by highly active antiretroviral treatment (HAART). I discuss the dramatic impact of HAART on suppressing virus production, reducing the pool of stored virus, and restoring CD4+T cell populations. I discuss the contributions of thymopoiesis and other renewal mechanisms, lymphatic homeostasis and trafficking to these changes in CD4+T cell populations in LT, and conclude with a model of immune depletion and repopulation based on the limited regenerative capacity of the adult and the uncompensated losses of productively infected cells that treatment stems. The prediction of this model is that immune regeneration will be slow, variable, and partial. It is nonetheless encouraging to know that even in late stages of infection, control of active replication of HIV-1 provides an opportunity for the immune system to recover from the injuries inflicted by infection.
Glucocorticoids in T Cell Development and Function
Authors: Ashwell Jonathan D. , Lu Frank W. M. , Vacchio Melanie S.
Published: July 2002

Glucocorticoids are small lipophilic compounds that mediate their many biological effects by binding an intracellular receptor (GR) that, in turn, translocates to the nucleus and directly or indirectly regulates gene transcription. Perhaps the most recognized biologic effect of glucocorticoids on peripheral T cells is immunosuppression, which is due to inhibition of expression of a wide variety of activationinduced gene products. Glucocorticoids have also been implicated in Th lineage development (favoring the generation of Th2 cells) and, by virtue of their downregulation of fasL expression, the inhibition of activation-induced T cell apoptosis. Glucocorticoids are also potent inducers of apoptosis, and even glucocorticoid concentrations achieved during a stress response can cause the death of CD4+CD8+thymocytes. Perhaps surprisingly, thymic epithelial cells produce glucocorticoids, and based upon in vitro and in vivo studies of T cell development it has been proposed that these locally produced glucocorticoids participate in antigen-specific thymocyte development by inhibiting activation-induced gene transcription and thus increasing the TCR signaling thresholds required to promote positive and negative selection. It is anticipated that studies in animals with tissue-specific GR-deficiency will further elucide how glucocorticoids affect T cell development and function.
The RAG Proteins and V(D)J Recombination: Complexes, Ends, and Transposition
Authors: Fugmann Sebastian D. , Lee Alfred Ian , Shockett Penny E. , Villey Isabelle J. , Schatz David G.
Published: July 2002

V(D)J recombination proceeds through a series of protein:DNA complexes mediated in part by the RAG1 and RAG2 proteins. These proteins are responsible for sequence-specific DNA recognition and DNA cleavage, and they appear to perform multiple postcleavage roles in the reaction as well. Here we review the interaction of the RAG proteins with DNA, the chemistry of the cleavage reaction, and the higher order complexes in which these events take place. We also discuss postcleavage functions of the RAG proteins, including recent evidence indicating that they initiate the process of coding end processing by nicking hairpin DNA termini. Finally, we discuss the evolutionary and functional implications of the finding that RAG1 and RAG2 constitute a transposase, and we consider RAG protein biochemistry in the context of several bacterial transposition systems. This suggests a model of the RAG protein active site in which two divalent metal ions serve alternating and opposite roles as activators of attacking hydroxyl groups and stabilizers of oxyanion leaving groups.
Chromatin Structure and Gene Regulation in the Immune System
Authors: Smale Stephen T. , Fisher Amanda G.
Published: July 2002

The development of the immune system and the host response to microbial infection rely on the activation and silencing of numerous, differentially expressed genes. Since the mid-1980s, a primary goal has been to identify transcription factors that regulate specific genes and specific immunological processes. More recently, there has been a growing appreciation of the role of chromatin structure in gene regulation. Before most activators of a gene access their binding sites, a transition from a condensed to a decondensed chromatin structure appears to take place. The activation of transcription is then accompanied by the remodeling of specific nucleosomes. Conversely, the acquisition of a more condensed chromatin structure is often associated with gene silencing. Chromatin structure is a particularly significant contributor to gene regulation because it is likely to be a major determinant of cell identity and cell memory. That is, the propagation of decondensed chromatin at specific loci through DNA replication and cell division helps a cell remember which genes are expressed constitutively in that cell type or are poised for expression upon exposure to a stimulus. Here we review recent progress toward understanding the role of chromatin in the immune system. The interleukin-4 gene serves as a primary model for exploring the events involved in the acquisition and heritable maintenance of a decondensed chromatin structure. Studies of the interleukin-12 p40 and interferon-β genes are then reviewed for insight into the mechanisms by which the remodeling of specific nucleosomes in the vicinity of a promoter can contribute to rapid activation following cell stimulation. Finally, basic principles of gene silencing are discussed.
Structure and Function of Natural Killer Cell Receptors: Multiple Molecular Solutions to Self, Nonself Discrimination
Authors: Natarajan Kannan , Dimasi Nazzareno , Wang Jian , Mariuzza Roy A. , Margulies David H.
Published: July 2002

In contrast to T cell receptors, signal transducing cell surface membrane molecules involved in the regulation of responses by cells of the innate immune system employ structures that are encoded in the genome rather than generated by somatic recombination and that recognize either classical MHC-I molecules or their structural relatives (such as MICA, RAE-1, or H-60). Considerable progress has recently been made in our understanding of molecular recognition by such molecules based on the determination of their three-dimensional structure, either in isolation or in complex with their MHC-I ligands. Those best studied are the receptors that are expressed on natural killer (NK) cells, but others are found on populations of T cells and other hematopoietic cells. These molecules fall into two major structural classes, those of the immunoglobulin superfamily (KIRs and LIRs) and of the C-type lectin-like family (Ly49, NKG2D, and CD94/NKG2). Here we summarize, in a functional context, the structures of the murine and human molecules that have recently been determined, with emphasis on how they bind different regions of their MHC-I ligands, and how this allows the discrimination of tumor or virus-infected cells from normal cells of the host.
GONADOTROPIN-RELEASING HORMONE AND ITS ANALOGS
Authors: Conn, Ph.D P. Michael , Crowley William F.
Published: July 2002

▪ Abstract  GnRH and its analogues have led to exciting new avenues of therapy in virtually every subspecialty of internal medicine as well as in gynecology, pediatrics, and urology. Since their discovery in 1971, it has been demonstrated that GnRH and its analogues enable medical professionals to influence the hypothalamic-pituitary-gonadal axis in two distinct classes of therapeutic applications. The first provides natural sequence GnRH in a pulsatile fashion via portable infusion pumps to mimic the normal physiology of hypothalamic GnRH secretion and restores reproductive potential to infertile men and women with disorders of endogenous GnRH secretion. The second mode uses long-acting GnRH agonists administered in a depot delivery to produce a paradoxical desensitization of pituitary gonadotropin secretion which, in turn, results in a complete ablation of the reproductive axis. This biochemical castration induced by GnRH agonist administration is a safe, effective, complete, and reversible method of removing the overlay of gonadal steroids from a variety of diseases which they are known to exacerbate. These diseases include endometriosis and uterine fibroids in women, prostate cancer in men, and precocious puberty in both sexes.

This review examines the physiologic and pharmacologic principles underlying the advances produced by these agents, the mechanism of action of GnRH and its analogues at the cellular level, and the individual therapeutic applications to which these analogues have been applied. Because virtually every subspecialty of medicine will be touched by the GnRH analogues, this review provides an overview and background of their use.
NICOTINE ADDICTION AND TREATMENT
Authors: Rose, Ph.D Jed E.
Published: July 2002

▪ Abstract  The persistence of cigarette smoking despite widespread awareness of adverse health effects results from an underlying addiction to nicotine. Unaided attempts to quit smoking are generally unsuccessful. This article discusses nicotine addiction and therapeutic techniques that have been or are being developed to relieve smoking withdrawal symptoms and promote abstinence from smoking. These techniques include nicotine chewing gum, skin patches, nasal sprays, and inhalers, as well as pharmacotherapies such as mecamylamine and clonidine, serotonergic treatments such as buspirone, and antidepressants such as buproprion. A nondrug approach using cigarette substitutes that mimic the airway sensations produced by cigarette smoke is also discussed.
NITRIC OXIDE SYNTHASE: Role in the Genesis of Vascular Disease
Authors: Cooke, MD John P. , Dzau, MD Victor J.
Published: July 2002

▪ Abstract  The product of nitric oxide (NO) synthase is the most potent endogenous vasodilator known. NO not only is a potent vasodilator, it also inhibits platelet adherence and aggregation, reduces adherence of leukocytes to the endothelium, and suppresses proliferation of vascular smooth muscle cells. A number of disorders are associated with reduced synthesis and/or increased degradation of vascular NO. These include hypercholesterolemia, diabetes mellitus, hypertension, and tobacco use. The endothelial dysfunction caused by these disorders contributes to the alterations in vascular function and structure observed in these conditions. A reduction in the activity of vascular NO likely plays a significant role in the development of atherosclerosis. Insights into the mechanisms by which NO production or activity is altered in these states will lead to new therapeutic strategies in the treatment of a number of vascular disorders, including hypertension, atherosclerosis, restenosis, and thrombosis.
Dendritic Cell Vaccines for Cancer Immunotherapy
Authors: Timmerman, MD John M. , Levy, MD Ronald
Published: July 2002

Human tumors express a number of protein antigens that can be recognized by T cells, thus providing potential targets for cancer immunotherapy. Dendritic cells (DCs) are rare leukocytes that are uniquely potent in their ability to present antigens to T cells, and this property has prompted their recent application to therapeutic cancer vaccines. Isolated DCs loaded with tumor antigen ex vivo and administered as a cellular vaccine have been found to induce protective and therapeutic anti-tumor immunity in experimental animals. In pilot clinical trials of DC vaccination for patients with non-Hodgkin's lymphoma and melanoma, induction of anti-tumor immune responses and tumor regressions have been observed. Additional trials of DC vaccination for a variety of human cancers are under way, and methods for targeting tumor antigens to DCs in vivo are also being explored. Exploitation of the antigen-presenting properties of DCs thus offers promise for the development of effective cancer immunotherapies.
Tissue Engineering: Current State and Prospects
Authors: Stock Ulrich A. , Vacanti Joseph P.
Published: July 2002

▪ Abstract  Organ shortage and suboptimal prosthetic or biological materials for repair or replacement of diseased or destroyed human organs and tissues are the main motivation for increasing research in the emerging field of tissue engineering. No organ or tissue is excluded from this multidisciplinary research field, which aims to provide vital tissues with the abilities to function, grow, repair, and remodel. There are several approaches to tissue engineering, including the use of cells, scaffolds, and the combination of the two. The most common approach is biodegradable or resorbable scaffolds configured to the shape of the new tissue (e.g. a heart valve). This scaffold is seeded with cells, potentially derived from either biopsies or stem cells. The seeded cells proliferate, organize, and produce cellular and extracellular matrix. During this matrix formation, the starter matrix is degraded, resorbed, or metabolized. First clinical trials using skin or cartilage substitutes are currently under way. Both the current state of the field and future prospects are discussed.
Hematopoietic Stem and Progenitor Cells: Clinical and Preclinical Regeneration of the Hematolymphoid System
Authors: Shizuru Judith A. , Negrin Robert S. , Weissman Irving L.
Published: July 2002

A vast literature exists on the biology of blood formation and regeneration under experimental and clinical conditions. The field of hematopoiesis was recently advanced by the capacity to purify to homogeneity primitive hematopoietic stem and progenitor cells. Isolation of cells at defined maturational stages has enhanced the understanding of the fundamental nature of stem cells, including how cell fate decisions are made, and this understanding is relevant to the development of other normal as well as malignant tissues. This review updates the basic biology of hematopoietic stem cells (HSC) and progenitors, the evolving use of purified HSC as grafts for clinical hematopoietic cell transplantation (HCT) including immune tolerance induction, and the application of HSC biology to other stem cell fields.
Aerotaxis and Other Energy-Sensing Behavior in Bacteria
Authors: Taylor Barry L. , Zhulin Igor B. , Johnson Mark S.
Published: July 2002

▪ Abstract  Energy taxis is widespread in motile bacteria and in some species is the only known behavioral response. The bacteria monitor their cellular energy levels and respond to a decrease in energy by swimming to a microenvironment that reenergizes the cells. This is in contrast to classical Escherichia coli chemotaxis in which sensing of stimuli is independent of cellular metabolism. Energy taxis encompasses aerotaxis (taxis to oxygen), phototaxis, redox taxis, taxis to alternative electron acceptors, and chemotaxis to a carbon source. All of these responses share a common signal transduction pathway. An environmental stimulus, such as oxygen concentration or light intensity, modulates the flow of reducing equivalents through the electron transport system. A transducer senses the change in electron transport, or possibly a related parameter such as proton motive force, and initiates a signal that alters the direction of swimming. The Aer and Tsr proteins in E. coli are newly recognized transducers for energy taxis. Aer is homologous to E. coli chemoreceptors but unique in having a PAS domain and a flavin-adenine dinucleotide cofactor that is postulated to interact with a component of the electron transport system. PAS domains are energy-sensing modules that are found in proteins from archaea to humans. Tsr, the serine chemoreceptor, is an independent transducer for energy taxis, but its sensory mechanism is unknown. Energy taxis has a significant ecological role in vertical stratification of microorganisms in microbial mats and water columns. It plays a central role in the behavior of magnetotactic bacteria and also appears to be important in plant-microbe interactions.
DEVELOPMENT OF THE VERTEBRATE NEUROMUSCULAR JUNCTION
Authors: Sanes Joshua R. , Lichtman Jeff W.
Published: July 2002

▪ Abstract  We describe the formation, maturation, elimination, maintenance, and regeneration of vertebrate neuromuscular junctions (NMJs), the best studied of all synapses. The NMJ forms in a series of steps that involve the exchange of signals among its three cellular components—nerve terminal, muscle fiber, and Schwann cell. Although essentially any motor axon can form NMJs with any muscle fiber, an additional set of cues biases synapse formation in favor of appropriate partners. The NMJ is functional at birth but undergoes numerous alterations postnatally. One step in maturation is the elimination of excess inputs, a competitive process in which the muscle is an intermediary. Once elimination is complete, the NMJ is maintained stably in a dynamic equilibrium that can be perturbed to initiate remodeling. NMJs regenerate following damage to nerve or muscle, but this process differs in fundamental ways from embryonic synaptogenesis. Finally, we consider the extent to which the NMJ is a suitable model for development of neuron-neuron synapses.
The Relationship between Neuronal Survival and Regeneration
Authors: Goldberg Jeffrey L. , Barres Ben A.
Published: July 2002

The ability of peripheral nervous system (PNS) but not central nervous system (CNS) neurons to regenerate their axons is a striking peculiarity of higher vertebrates. Much research has focused on the inhibitory signals produced by CNS glia that thwart regenerating axons. Less attention has been paid to the injury-induced loss of trophic stimuli needed to promote the survival and regeneration of axotomized neurons. Could differences in the mechanisms that control CNS and PNS neuronal survival and growth also contribute to the disparity in regenerative capacity? Here we review recent studies concerning the nature of the signals necessary to promote neuronal survival and growth, with an emphasis on their significance to regeneration after CNS injury.