ALBERT

Notes: Abstract Ventricular fibrillation (VF) is the major immediate cause of sudden cardiac death. Traditionally, VF has been defined as turbulent cardiac electrical activity, which implies a large amount of irregularity in the electrical waves that underlie ventricular excitation. During VF, the heart rate is too high (〉 550 excitations/minute) to allow adequate pumping of blood. In the electrocardiogram (ECG), ventricular complexes that are ever-changing in frequency, contour, and amplitude characterize VF. This article reviews prevailing theories for the initiation and maintenance of VF, as well as its spatio-temporal organization. Particular attention is given to recent experiments and computer simulations suggesting that VF may be explained in terms of highly periodic three-dimensional rotors that activate the ventricles at exceedingly high frequency. Such rotors may show at least two different behaviors: (a) At one extreme, they may drift throughout the heart at high speeds producing beat-to-beat changes in the activation sequence. (b) At the other extreme, rotors may be relatively stationary, activating the ventricles at such high frequencies that the wave fronts emanating from them breakup at varying distances, resulting in complex spatio-temporal patterns of fibrillatory conduction. In either case, the recorded ECG patterns are indistinguishable from VF. The data discussed have paved the way for a better understanding of the mechanisms of VF in the normal, as well as the diseased, human heart. When the heart is diseased, its work is imperfectly performed: the vessels proceeding from the heart become inactive, so that you cannot feel them ... If the heart trembles, has little power and sinks, the disease is advancing and death is near. Ebers Papyrus ~3500 BC

Notes: Abstract We use a comparative approach to examine some of the physiological traits that make flight possible. Comparisons of related fliers and runners suggest that fliers generally have higher aerobic metabolic capacities than runners but that the difference is highly dependent on the taxa studied. The high metabolic rates of fliers relative to runners, especially in insects, are correlated with high locomotory muscle cycle frequencies and low efficiences of conversion of metabolic power to mechanical power. We examine some factors that produce variation in flight respiration and energetics. Air temperature strongly affects the flight metabolic rate of some insects and birds. Flight speed interacts with flier mass, so that small fliers tend to exhibit a Jshaped power curve and larger fliers a U-shaped power curve. As body size increases, mass-specific aerobic flight metabolism decreases in most studies, but mass-specific power output is constant or increases, leading to an increase in efficiency with size. Intraspecific studies have revealed specific genetically based effects on flight metabolism and power output and multiple ecological correlates of flight capabilities.

Notes: Abstract Thyroid hormone is essential for normal development, differentiation, and metabolic balance. Thyroid hormone action is mediated by multiple thyroid hormone receptor isoforms derived from two distinct genes. The thyroid hormone receptors belong to a nuclear receptor superfamily that also includes receptors for other small lipophilic hormones. Thyroid hormone receptors function by binding to specific thyroid hormone-responsive sequences in promoters of target genes and by regulating transcription. Thyroid hormone receptors often form heterodimers with retinoid X receptors. Heterodimerization is regulated through distinct mechanisms that together determine the specificity and flexibility of the sequence recognition. Amino-terminal regions appear to modulate thyroid hormone receptor function in an isoform-dependent manner. Unliganded thyroid hormone receptor represses transcription through recruitment of a corepressor complex, which also includes Sin3A and histone deacetylase. Ligand binding alters the conformation of the thyroid hormone receptor in such a way as to release the corepressor complex and recruit a coactivator complex that includes multiple histone acetyltransferases, including a steroid receptor family coactivator, p300/CREB-binding protein-associated factor (PCAF), and CREB binding protein (CBP). The existence of histone-modifying activities in the transcriptional regulatory complexes indicates an important role of chromatin structure. Stoichiometric, structural, and sequence-specific rules for coregulator interaction are beginning to be understood, as are aspects of the tissue specificity of hormone action. Moreover, knockout studies suggest that the products of two thyroid hormone receptor genes mediate distinct functions in vivo. The increased understanding of the structure and function of thyroid hormone receptors and their interacting proteins has markedly clarified the molecular mechanisms of thyroid hormone action.

Notes: Abstract Chloride secretion is the major determinant of mucosal hydration thoughout the gastrointestinal tract, and chloride transport is also pivotal in the regulation of fluid secretion by organs that drain into the intestine. Moreover, there are pathological consequences if chloride secretion is either reduced or increased such as in cystic fibrosis and secretory diarrhea, respectively. With the molecular cloning of many of the proteins and regulatory factors that make up the chloride secretory mechanism, there have been significant advances in our understanding of this process at the cellular level. Similarly, emerging data have clarified the intercellular relationships that govern the extent of chloride secretion. The goal of our article is to review this area of investigation, with an emphasis on recent developments and their implications for the physiology and pathophysiology of chloride transport.

Notes: Abstract Epithelial tissues such as kidney, lung, and breast arise through branching morphogenesis of a pre-existing epithelial structure. They share common morphological stages and a need for regulation of a similar set of developmental decisions-where to start; when, where, and in which direction to branch; and how many times to branch-decisions requiring regulation of cell proliferation, apoptosis, invasiveness, and cell motility. It is likely that similar molecular mechanisms exist for the epithelial branching program. Here we focus on the development of the collecting system of the kidney, where, from recent data using embryonic organ culture, cell culture models of branching morphogenesis, and targeted gene deletion experiments, the outlines of a working model for branching morphogenesis begin to emerge. Key branching morphogenetic molecules in this model include growth factors, transcription factors, distal effector molecules (such as extracellular matrix proteins, integrins, proteinases and their inhibitors), and genes regulating apoptosis and cell proliferation.

Notes: Abstract Motor systems can adapt rapidly to changes in external conditions and to switching of internal goals. They can also adapt slowly in response to training, alterations in the mechanics of the system, and any changes in the system resulting from injury. This article reviews the mechanisms underlying short- and long-term adaptation in rhythmic motor systems. The neuronal networks underlying the generation of rhythmic motor patterns (central pattern generators; CPGs) are extremely flexible. Neuromodulators, central commands, and afferent signals all influence the pattern produced by a CPG by altering the cellular and synaptic properties of individual neurons and the coupling between different populations of neurons. This flexibility allows the generation of a variety of motor patterns appropriate for the mechanical requirements of different forms of a behavior. The matching of motor output to mechanical requirements depends on the capacity of pattern-generating networks to adapt to slow changes in body mechanics and persistent errors in performance. Afferent feedback from body and limb proprioceptors likely plays an important role in driving these long-term adaptive processes.

Notes: Abstract In recent years, it has become apparent that ligand-gated ion channels (ionotropic receptors) in the neuronal plasma membrane interact via their cytoplasmic domains with a multitude of intracellular proteins. Different classes of ligand-gated channels associate with distinct sets of intracellular proteins, often through specialized scaffold proteins containing PDZ domains. These specific interactions link the receptor channel to the cortical cytoskeleton and to appropriate signal transduction pathways in the cell. Thus ionotropic receptors are components of extensive protein complexes that are likely involved in the subcellular targeting, cytoskeletal anchoring, and localized clustering of the receptors at specific sites on the neuronal surface. In addition to structural functions, receptor-associated proteins can play important roles as activity modulators or downstream effectors of ligand-gated channels.

Notes: Abstract Mortality of infants of 〈1-kg birth weight has decreased because of surfactant treatments, antenatal glucocorticoid treatments, and new ventilation strategies. However, many of these infants develop a chronic lung disease characterized by an arrest of lung development and interference with alveolarization. Antenatal glucocorticoids can induce early lung maturation clinically, but new information from transgenic and other experimental models indicates that traditional explanations for glucocorticoid effects on the developing lung are inadequate. These very preterm infants have lungs with small lung gas volumes and delicate lung tissue that are susceptible to injury with the initiation of ventilation and subsequent ventilation. Antenatal proinflammatory exposures are frequent in very preterm infants, and postnatal injury is associated with elevations of proinflammatory cytokines in the lungs. One hypothesis is that proinflammatory cytokines can promote or interfere with lung development as well as promote lung injury. Mechanisms of lung injury being characterized in the adult lung may have unique characteristics in the developing lung.

Notes: Abstract This review inverts the idiom "family values" to show the value of the family. It grounds this value in family economic activity but advocates an interactive approach in which cultural commitments to the family influence economic and political outcomes. Historical and ethnographic research on the family is mustered to illustrate the interaction and then combined with theories of capitalism and nationalism to account for the resonance of the family values discourse. A final section reviews the potential dangers of family-focused research. That tradesman who does not delight in his family will never long delight in his business. D. Defoe

Notes: Abstract Significant changes occurred in human evolution between 2.5 and 1.8 million years ago. Stone tools first appeared, brains expanded, bodies enlarged, sexual dimorphism in body size decreased, limb proportions changed, cheek teeth reduced in size, and crania began to share more unique features with later Homo. Although the two earliest species of Homo, H. habilis and H. rudolfensis, retained many primitive features in common with australopithecine species, they both shared key unique features with later species of Homo. Two of the most conspicuous shared derived characters were the sizes of the brain and masticatory apparatus relative to body weight. Despite the shared derived characters of H. habilis and H. rudolfensis, one unexpected complication in the transition from australopithecine to Homo was that the postcranial anatomy of H. habilis retained many australopithecine characteristics. H. rudolfensis, however, seems to have had a more human-like body plan, similar to later species of Homo. H. rudolfensis may therefore represent a link between Australopithecus and Homo.

Notes: Abstract This paper provides a survey of critical discourse analysis (CDA), a recent school of discourse analysis that concerns itself with relations of power and inequality in language. CDA explicitly intends to incorporate social-theoretical insights into discourse analysis and advocates social commitment and interventionism in research. The main programmatic features and domains of enquiry of CDA are discussed, with emphasis on attempts toward theory formation by one of CDA's most prominent scholars, Norman Fairclough. Another section reviews the genesis and disciplinary growth of CDA, mentions some of the recent critical reactions to it, and situates it within the wider picture of a new critical paradigm developing in a number of language-oriented (sub) disciplines. In this critical paradigm, topics such as ideology, inequality, and power figure prominently, and many scholars productively attempt to incorporate social-theoretical insights into the study of language.

Notes: Abstract Some scholars have championed the view that small-scale societies are conservers or even creators of biodiversity. Others have argued that human populations have always modified their environments, often in ways that enhance short-term gains at the expense of environmental stability and biodiversity conservation. Recent ethnographic studies as well as theory from several disciplines allow a less polarized assessment. We review this body of data and theory and assess various predictions regarding sustainable environmental utilization. The meaning of the term conservation is itself controversial. We propose that to qualify as conservation, any action or practice must not only prevent or mitigate resource overharvesting or environmental damage, it must also be designed to do so. The conditions under which conservation will be adaptive are stringent, involving temporal discounting, economic demand, information feedback, and collective action. Theory thus predicts, and evidence suggests, that voluntary conservation is rare. However, sustainable use and management of resources and habitats by small-scale societies is widespread and may often indirectly result in biodiversity preservation or even enhancement via creation of habitat mosaics.

Notes: Abstract The synoptic coverage offered by satellites provides unparalleled opportunities for monitoring active volcanoes, and opens new avenues of scientific inquiry. Thermal infrared radiation can be used to monitor levels of activity, which is useful for automated eruption detection and for studying the emplacement of lava flows. Satellite radars can observe volcanoes through clouds or at night, and provide high-resolution topographic data. In favorable conditions, radar inteferometery can be used to measure ground deformation associated with eruptive activity on a centimetric scale. Clouds from explosive eruptions present a pressing hazard to aviation; therefore, techniques are being developed to assess eruption cloud height and to discriminate between ash and meterological clouds. The multitude of sensors to be launched on future generations of space platforms promises to greatly enhance volcanological studies, but a satellite dedicated to volcanology is needed to meet requirements of aviation safety and volcano monitoring.

Notes: Abstract A review of the geologic history of the Himalayan-Tibetan orogen suggests that at least 1400 km of north-south shortening has been absorbed by the orogen since the onset of the Indo-Asian collision at about 70 Ma. Significant crustal shortening, which leads to eventual construction of the Cenozoic Tibetan plateau, began more or less synchronously in the Eocene (50-40 Ma) in the Tethyan Himalaya in the south, and in the Kunlun Shan and the Qilian Shan some 1000-1400 km in the north. The Paleozoic and Mesozoic tectonic histories in the Himalayan-Tibetan orogen exerted a strong control over the Cenozoic strain history and strain distribution. The presence of widespread Triassic flysch complex in the Songpan-Ganzi-Hoh Xil and the Qiangtang terranes can be spatially correlated with Cenozoic volcanism and thrusting in central Tibet. The marked difference in seismic properties of the crust and the upper mantle between southern and central Tibet is a manifestation of both Mesozoic and Cenozoic tectonics. The former, however, has played a decisive role in localizing Tertiary contractional deformation, which in turn leads to the release of free water into the upper mantle and the lower crust of central Tibet, causing partial melting in the mantle lithosphere and the crust.

Notes: Abstract Pollen grains preserved in lake and bog sediment provide a record of past vegetation that has been an important source of information about climate and land cover during the Quaternary Period. Yet from the beginning, questions have been raised about the source area of pollen in sediment. Interpretation has been hampered by the lack of well-developed theory treating the relationship between the spatial distribution of trees on the landscape and the percentages of pollen in sediment. Within the past decade, however, new theory, models, and empirical data show how heterogeneous vegetation is represented by pollen. The distinction between "local" and "regional" pollen is explained by the Prentice-Sugita dispersal/deposition models, which predict how the ratio of regional to local pollen changes with lake size. Sugita's model simulating a landscape with heterogeneous vegetation predicts the size of the relevant source area-the area of vegetation reflected in between-lake variations in pollen loading-while demonstrating that regional pollen from beyond this distance is homogeneous at all lakes of similar size. By predicting the way landscape patterns will be reflected in pollen records, simulation models can improve research design and lead to more detailed and spatially precise records of past vegetation, enhancing continental-scale climate reconstructions.

Notes: Abstract Volcanic systems are swarms of tectonic fractures and basalt volcanoes formed as a result of plate-pull (as the plates are pulled apart) associated with the mid-ocean ridges and the magma dynamics of the Iceland Mantle Plume. Most systems are 40-150 km long, 5-20 km wide, and develop a central volcano. They supply magma to all eruptions in Iceland. Data obtained in the last few years have greatly improved our knowledge of their volcanotectonic environment; as a result, the geometry of the plume is better constrained, and the crust, previously considered thin (~10 km), is now modeled as thick (~20-40 km). Depending on the location of the volcanic systems, their activity either decreases or increases faulting in the two main seismic zones. From this, we can infer that emplacement of the feeder-dike to the largest historical eruption in Iceland (that of Laki in 1783) increased shear stress in the South Iceland Seismic Zone and almost certainly triggered the largest (M~7.1 in 1784) historical earthquake in Iceland.

Notes: Abstract Strong heterogeneity at a variety of scale lengths has been imaged in the lowermost mantle using different forward and inverse methods. Coherent patterns in differential travel times of waves that sample the base of the mantle-such as diffracted shear waves (Sdiff) and compressional waves (Pdiff)-are readily apparent, and are compared with results from tomographic studies. Travel time and waveform modeling studies have demonstrated the presence of intense lateral variations in a variety of mapped features, such as a regionally detected high velocity D" layer, ultra-low velocity zones, D" anisotropy, strong scattering and heterogeneity. Such short-wavelength variations currently preclude confident mapping of D" structure at smaller scales. Issues of seismic resolution and uncertainties are emphasized here, as well as the limitations of one-dimensional modeling/averaging in highly heterogeneous environments.

Notes: Abstract A neurochemically distinct population of koniocellular (K) neurons makes up a third functional channel in primate lateral geniculate nucleus. As part of a general pattern, K neurons form robust layers through the full representation of the visual hemifield. Similar in physiology and connectivity to W cells in cat lateral geniculate nucleus, K cells form three pairs of layers in macaques. The middle pair relays input from short-wavelength cones to the cytochrome-oxidase blobs of primay visual cortex (V1), the dorsal-most pair relays low-acuity visual information to layer I of V1, and the ventral-most pair appears closely tied to the function of the superior colliculus. Throughout each K layer are neurons that innervate extrastriate cortex and that are likely to sustain some visual behaviors in the absence of V1. These data show that several pathways exist from retina to V1 that are likely to process different aspects of the visual scene along lines that may remain parallel well into V1.

Notes: Abstract The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area. Much of the progress has come from studies of fear, and especially fear conditioning. This work has pinpointed the amygdala as an important component of the system involved in the acquisition, storage, and expression of fear memory and has elucidated in detail how stimuli enter, travel through, and exit the amygdala. Some progress has also been made in understanding the cellular and molecular mechanisms that underlie fear conditioning, and recent studies have also shown that the findings from experimental animals apply to the human brain. It is important to remember why this work on emotion succeeded where past efforts failed. It focused on a psychologically well-defined aspect of emotion, avoided vague and poorly defined concepts such as "affect," "hedonic tone," or "emotional feelings," and used a simple and straightforward experimental approach. With so much research being done in this area today, it is important that the mistakes of the past not be made again. It is also time to expand from this foundation into broader aspects of mind and behavior

Notes: Abstract A typical scene contains many different objects that, because of the limited processing capacity of the visual system, compete for neural representation. The competition among multiple objects in visual cortex can be biased by both bottom-up sensory-driven mechanisms and top-down influences, such as selective attention. Functional brain imaging studies reveal that, both in the absence and in the presence of visual stimulation, biasing signals due to selective attention can modulate neural activity in visual cortex in several ways. Although the competition among stimuli for representation is ultimately resolved within visual cortex, the source of top-down biasing signals derives from a network of areas in frontal and parietal cortex.

Notes: Abstract One of the most significant developments in biology in the past half century was the emergence, in the late 1950s and early 1960s, of neuroscience as a distinct discipline. We review here factors that led to the convergence into a common discipline of the traditional fields of neurophysiology, neuroanatomy, neurochemistry, and behavior, and we emphasize the seminal roles played by David McKenzie Rioch, Francis O Schmitt, and especially Stephen W Kuffler in creating neuroscience as we now know it. The application of the techniques of molecular and cellular biology to the study of the nervous system has greatly accelerated our understanding of the mechanisms involved in neuronal signaling, neural development, and the function of the major sensory and motor systems of the brain. The elucidation of the underlying causes of most neurological and psychiatric disorders has proved to be more difficult; but striking progress is now being made in determining the genetic basis of such disorders as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and a number of ion channel and mitochondrial disorders, and a significant start has been made in identifying genetic factors in the etiology of such disorders as manic depressive illness and schizophrenia. These developments presage the emergence in the coming decades of a new nosology, certainly in neurology and perhaps also in psychiatry, based not on symptomatology but on the dysfunction of specific genes, molecules, neuronal organelles and particular neural systems.

Notes: Abstract Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency.

Notes: Abstract The immune system is composed of single cells, and its function is entirely dependent on the capacity of these cells to traffic, localize within tissues, and interact with each other in a precisely coordinated fashion. There is growing evidence that the large families of chemokines and chemokine receptors provide a flexible code for regulating cell traffic and positioning in both homeostatic and inflammatory conditions. The regulation of chemokine receptor expression during development and following cell activation explains the complex migratory pathways taken by dendritic cells, T and B lymphocytes, providing new insights into the mechanisms that control priming, effector function, and memory responses.

Notes: Abstract The success of combination antiretroviral therapy for HIV-1 infection has generated interest in mechanisms by which the virus can persist in the body despite the presence of drugs that effectively inhibit key steps in the virus life cycle. It is becoming clear that viral reservoirs established early in the infection not only prevent sterilizing immunity but also represent a major obstacle to curing the infection with the potent antiretroviral drugs currently in use. Mechanisms of viral persistence are best considered in the context of the dynamics of viral replication in vivo. Virus production in infected individuals is largely the result of a dynamic process involving continuous rounds of de novo infection of and replication in activated CD4+ T cells with rapid turnover of both free virus and virus-producing cells. This process is largely, but not completely, interrupted by effective antiretroviral therapy. After a few months of therapy, plasma virus levels become undetectable in many patients. Analysis of viral decay rates initially suggested that eradication of the infection might be possible. However, there are several potential cellular and anatomical reservoirs for HIV-1 that may contribute to long-term persistence of HIV-1. These include infected cell in the central nervous system and the male urogenital tract. However, the most worrisome reservoir consists of latently infected resting memory CD4+ T cells carrying integrated HIV-1 DNA. Definitive demonstration of the presence of this form of latency required development of methods for isolating extremely pure populations of resting CD4+ T cells and for demonstrating that a small fraction of these cells contain integrated HIV-1 DNA that is competent for replication if the cells undergo antigen-driven activation. Most of the latent virus in resting CD4+ T cells is found in cells of the memory phenotype. The half-life of this latent reservoir is extremely long (44 months). At this rate, eradication of this reservoir would require over 60 years of treatment. Thus, latently infected resting CD4+ T cells provide a mechanism for life-long persistence of replication-competent forms of HIV-1, rendering unrealistic hopes of virus eradication with current antiretroviral regimens. The extraordinary stability of the reservoir may reflect gradual reseeding by a very low level of ongoing viral replication and/or mechanisms that contribute to the intrinsic stability of the memory T cell compartment. Given the substantial long-term toxicities of current combination therapy regimens, novel approaches to eradicating this latent reservoir are urgently needed.

Notes: Abstract 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.

Notes: Abstract Clonal deletion of autoreactive T cells in the thymus is not the sole mechanism for the induction of tolerance to self-antigens since partial depletion of peripheral CD4+ T cells from neonatal and adult animals results in the development of organ-specific autoimmunity. Reconstitution of these immunodeficient animals with populations of regulatory CD4+T cells prevents the development of autoimmunity. The lineage of regulatory CD4+ T cells is generated in the thymus and can be distinguished from effector cells by the expression of unique membrane antigens. The target antigens for these suppressor populations and their mechanisms of action remain poorly defined. Depletion of regulatory T cells may be useful in the induction of immunity to weak antigens, such as tumor-specific antigens. Conversely, enhancement of regulatory T cell function may be a useful adjunct to the therapy of autoimmune diseases and for prevention of allograft rejection.

Notes: Abstract The cellular dynamics of the immune system are complex and difficult to measure. Access to this problematic area has been greatly enhanced by the recent development of tetrameric complexes of MHC class I glycoprotein + peptide (tetramers) for the direct staining of freshly isolated, antigen-specific CD8+ T cells. Analysis to date with both naturally acquired and experimentally induced infections has established that the numbers of virus-specific CD8+ T cells present during both the acute and memory phases of the host response are more than tenfold in excess of previously suspected values. The levels are such that the virus-specific CD8+ set is readily detected in the human peripheral blood lymphocyte compartment, particularly during persistent infections. Experimentally, it is now possible to measure the extent of cycling for tetramer +CD8+ T cells during the acute and memory phases of the host response to viruses. Dissection of the phenotypic, functional, and molecular diversity of CD8+ T cell populations has been greatly facilitated. It is hoped it will also soon be possible to analyze CD4+ T cell populations in this way. Though these are early days and there is an enormous amount to be done, our perceptions of the shape of virus-specific cell-mediated immunity are changing rapidly.

Notes: Abstract Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Notes: Abstract The development and widespread use of vaccines against infectious agents have been a great triumph of medical science. One reason for the success of currently available vaccines is that they are capable of inducing long-lived antibody responses, which are the principal agents of immune protection against most viruses and bacteria. Despite these successes, vaccination against intracellular organisms that require cell-mediated immunity, such as the agents of tuberculosis, malaria, leishmaniasis, and human immunodeficiency virus infection, are either not available or not uniformly effective. Owing to the substantial morbidity and mortality associated with these diseases worldwide, an understanding of the mechanisms involved in generating long-lived cellular immune responses has tremendous practical importance. For these reasons, a new form of vaccination, using DNA that contains the gene for the antigen of interest, is under intensive investigation, because it can engender both humoral and cellular immune responses. This review focuses on the mechanisms by which DNA vaccines elicit immune responses. In addition, a list of potential applications in a variety of preclinical models is provided.

Notes: Abstract The membrane protein complex CD19/CD21 couples the innate immune recognition of microbial antigens by the complement system to the activation of B cells. CD21 binds the C3d fragment of activated C3 that becomes covalently attached to targets of complement activation, and CD19 co-stimulates signaling through the antigen receptor, membrane immunoglobulin. CD21 is also expressed by follicular dendritic cells and mediates the long-term retention of antigen that is required for the maintenance of memory B cells. Understanding of the biology of this receptor complex has been enriched by analyses of genetically modified mice; these analyses have uncovered roles not only in positive responses to foreign antigens, but also in the development of tolerance to self-antigens. Studies of signal transduction have begun to determine the basis for the coreceptor activities of CD19. The integration of innate and adaptive immune recognition at this molecular site on the B cell guides the appropriate selection of antigen by adaptive immunity and emphasizes the importance of this coreceptor complex.

Notes: Abstract The human thymus is a complex chimeric organ comprised of central (thymic epithelial space) and peripheral (perivascular space) components that functions well into adult life to produce naive T lymphocytes. Recent advances in identifying thymic emigrants and development of safe methods to study thymic function in vivo in adults have provided new opportunities to understand the role that the human thymus plays in immune reconstitution in aging, in bone marrow transplantation, and in HIV-1 infection. The emerging concept is that there are age-dependent contributions of thymic emigrants and proliferation of postthymic T cells to maintain the peripheral T cell pool and to contribute to T cell regeneration, with the thymus contributing more at younger ages and peripheral T cell expansion contributing more in older subjects. New studies have revealed a dynamic interplay between postnatal thymus output and peripheral T cell pool proliferation, which play important roles in determining the nature of immune reconstitution in congenital immunodeficiency diseases, in bone marrow transplantation, and in HIV-1 infection. In this paper, we review recent data on human postnatal thymus function that, taken together, support the notion that the human thymus is functional well into the sixth decade and plays a role throughout life to optimize human immune system function.

Notes: Abstract Multiple functions have recently been identified for the neonatal Fc receptor FcRn. In addition, a human homolog of the rodent forms of FcRn has been identified and characterized. This major histocompatibility complex class I-related receptor plays a role in the passive delivery of immunoglobulin (Ig)Gs from mother to young and the regulation of serum IgG levels. In addition, FcRn expression in tissues such as liver, mammary gland, and adult intestine suggests that it may modulate IgG transport at these sites. These diverse functions are apparently brought about by the ability of FcRn to bind IgGs and transport them within and across cells. However, the molecular details as to how FcRn traffics within cells have yet to be fully understood, although in vitro systems have been developed for this purpose. The molecular nature of the FcRn-IgG interaction has been studied extensively and encompasses residues located at the CH2-CH3 domain interface of the Fc region of IgG. These Fc amino acids are highly conserved in rodents and man and interact with residues primarily located on the alpha2 domain of FcRn. Thus, it is now possible to engineer IgGs with altered affinities for FcRn, and this has relevance to the modulation of IgG serum half-life and maternofetal IgG transport for therapeutic applications.

Notes: Abstract Genomic-scale experimentation aims to view biological processes as a whole, yet with molecular precision. Using massively parallel DNA microarray technology, the mRNA expression of tens of thousands of genes can be measured simultaneously. Mathematical distillation of this flood of gene expression data reveals a deep molecular and biological logic underlying gene expression programs during cellular differentiation and activation. Genes that encode components of the same multi-subunit protein complex are often coordinately regulated. Coordinate regulation is also observed among genes whose products function in a common differentiation program or in the same physiological response pathway. Recent application of gene expression profiling to the immune system has shown that lymphocyte differentiation and activation are accompanied by changes of hundreds of genes in parallel. The databases of gene expression emerging from these studies of normal immune responses will be used to interpret the pathological changes in gene expression that accompany autoimmunity, immune deficiencies, and cancers of immune cells.

Notes: Abstract The chloroplast adenosine triphosphate (ATP) synthase is located in the thylakoid membrane and synthesizes ATP from adenosine diphosphate and inorganic phosphate at the expense of the electrochemical proton gradient formed by light-dependent electron flow. The structure, activities, and mechanism of the chloroplast ATP synthase are discussed. Emphasis is given to the inherent structural asymmetry of the ATP synthase and to the implication of this asymmetry to the mechanism of ATP synthesis and hydrolysis. A critical evaluation of the evidence in support of and against the notion that one part of the enzyme rotates with respect to other parts during catalytic turnover is presented. It is concluded that although rotation can occur, whether it is required for activity of the ATP synthase has not been established unequivocally.

Notes: Abstract Growth and development of all plant cells and organs relies on a fully functional cytoskeleton comprised principally of microtubules and microfilaments. These two polymeric macromolecules, because of their location within the cell, confer structure upon, and convey information to, the peripheral regions of the cytoplasm where much of cellular growth is controlled and the formation of cellular identity takes place. Other ancillary molecules, such as motor proteins, are also important in assisting the cytoskeleton to participate in this front-line work of cellular development. Roots provide not only a ready source of cells for fundamental analyses of the cytoskeleton, but the formative zone at their apices also provides a locale whereby experimental studies can be made of how the cytoskeleton permits cells to communicate between themselves and to cooperate with growth-regulating information supplied from the apoplasm.

Notes: Abstract With the advent of high-throughput DNA sequencing and whole-genome analysis, it has become clear that the coding portions of the genome are organized hierarchically in gene families and superfamilies. Because the hierarchy of genes, like that of living organisms, reflects an ancient and continuing process of gene duplication and divergence, many of the conceptual and analytical tools used in phylogenetic systematics can and should be used in comparative genomics. Phylogenetic principles and techniques for assessing homology, inferring relationships among genes, and reconstructing evolutionary events provide a powerful way to interpret the ever increasing body of sequence data. In this review, we outline the application of phylogenetic approaches to comparative genomics, beginning with the inference of phylogeny and the assessment of gene orthology and paralogy. We also show how the phylogenetic approach makes possible novel kinds of comparative analysis, including detection of domain shuffling and lateral gene transfer, reconstruction of the evolutionary diversification of gene families, tracing of evolutionary change in protein function at the amino acid level, and prediction of structure-function relationships. A marriage of the principles of phylogenetic systematics with the copious data generated by genomics promises unprecedented insights into the nature of biological organization and the historical processes that created it.

Notes: Abstract Iron is an essential cofactor in a variety of cellular processes. Except for a few unusual bacterial species, iron is indispensable for living organisms. However, free iron is toxic because of its propensity to induce the formation of dangerous free radicals. Consequently, iron balance is tightly regulated. Disorders of iron homeostasis are among the most common afflictions of humans. This review discusses inherited iron deficiency and iron overload disorders and recent insights into their pathophysiology.

Notes: Abstract The entire 3.6-MbpDNA sequence of a human major histocompatibility complex derived from a composite of DNA clones from different haplotypes, was completed in 1999, primarily through the work of four main groups. At that time, it was the longest contiguous human DNA sequence to have been determined. The sequence is of extremely high quality and accuracy. In this review, we discuss how the DNA sequence has facilitated our understanding of the biology and genetics of the major histocompatibility complex. We suggest some ways in which the sequence may be exploited in the future to explore the relationship between the extraordinary polymorphism of the region and its association with both autoimmune and infectious diseases.

Notes: Abstract The advent of whole-genome data resources-not only sequence but also other genome-scale data collections such as gene expression, protein interaction, and genetic variation-is having two marked, complementary effects on the relatively new discipline of bioinformatics. First, the veritable flood of data is creating a need and demand for new tools for dealing adequately with the deluge, and, second, the unprecedented extent, diversity, and impending completeness of the data sets are creating opportunities for new approaches to discovery based on computational methods.

Notes: Abstract This review discusses the prospects for understanding the genetic basis of complex traits in humans. We take the view that work done on Drosophila melanogaster can serve as a model for understanding complex traits in humans, and the literature on this model system, as well as on humans, is reviewed. The prospects for success in understanding the genetic basis of complex traits depend, in part, on the nature of the forces acting on genetic variation. We suggest that different experimental approaches should be undertaken for traits caused by common genetic variants versus those arising from rare genetic variants.

Notes: Abstract Throughout the twentieth century and continuing into the present, the general public has been fascinated by advances in genetic knowledge. At times, individuals and groups have either inadvertently or deliberately misused genetic knowledge in the service of political goals. At other times, advances in genetics have challenged deeply held societal or religious beliefs. During the 1990s, there were many advances that focused an unprecedented level of public attention and concern on genetics. In particular, the public has expressed deep concern about gene mapping, cloning, and genetically modified foods. In each case, the origin of the concern and the nature of the public response have been different. I consider these topics and argue that the scientific community must increase its commitment to public discourse.

Notes: Abstract The determination of the order of genes along cereal chromosomes indicates that the cereals can be described as a single genetic system. Such a framework provides an opportunity to combine data generated from the studies on different cereals, enables chromosome evolution to be traced, and sheds light on key structures involved in cereal chromosome pairing. Centromeric and telomeric regions have been highlighted as important in these processes.

Notes: Abstract Plant development involves specification and elaboration of axes of asymmetry. The apical-basal and inside-outside axes arise in embryogenesis, and are probably oriented maternally. They are maintained during growth post-germination and interact to establish novel axes of asymmetry in flowers and lateral organs (such as leaves). Whereas the genetic control of axis elaboration is now partially understood in embryos, floral meristems, and organs, the underlying mechanisms of axis specification remain largely obscure. Less functionally significant aspects of plant asymmetry (e.g. the handedness of spiral phyllotaxy) may originate in random events and therefore have no genetic control.

Notes: Abstract The spatial and temporal regulation of calcium concentration in plant cells depends on the coordinate activities of channels and active transporters located on different organelles and membranes. Several Ca2+ pumps have been identified and characterized by functional expression of plant genes in a yeast mutant (K616). This expression system has opened the way to a genetic and biochemical characterization of the regulatory and catalytic features of diverse Ca2+ pumps. Plant Ca2+-ATPases fall into two major types: AtECA1 represents one of four or more members of the type IIA (ER-type) Ca2+-ATPases in Arabidopsis, and AtACA2 is one of seven or more members of the type IIB (PM-type) Ca2+-ATPases that are regulated by a novel amino terminal domain. Type IIB pumps are widely distributed on membranes, including the PM (plasma membrane), vacuole, and ER (endoplasmic reticulum). The regulatory domain serves multiple functions, including autoinhibition, calmodulin binding, and sites for modification by phosphorylation. This domain, however, is considerably diverse among several type IIB ATPases, suggesting that the pumps are differentially regulated. Understanding of Ca2+ transporters at the molecular level is providing insights into their roles in signaling networks and in regulating fundamental processes of cell biology.

Notes: Abstract During the past decade, much progress has been made in understanding how the adult fly is built. Some old concepts such as those of compartments and selector genes have been revitalized. In addition, recent work suggests the existence of genes involved in the regionalization of the adult that do not have all the features of selector genes. Nevertheless, they generate morphological distinctions within the body plan. Here we re-examine some of the defining criteria of selector genes and suggest that these newly characterized genes fulfill many, but not all, of these criteria. Further, we propose that these genes can be classified according to the domains in which they function. Finally, we discuss experiments that address the molecular mechanisms by which selector and selector-like gene products function in the fly.

Notes: Abstract Stomatal guard cells are unique as a plant cell model and, because of the depth of present knowledge on ion transport and its regulation, offer a first look at signal integration in higher plants. A large body of data indicates that Ca2+ and H+ act independently, integrating with protein kinases and phosphatases, to control the gating of the K+ and Cl- channels that mediate solute flux for stomatal movements. Oscillations in the cytosolic-free concentration of Ca2+ contribute to a signaling cassette, integrated within these events through an unusual coupling with membrane voltage for solute homeostasis. Similar cassettes are anticipated to include control pathways linked to cytosolic pH. Additional developments during the last two years point to events in membrane traffic that play equally important roles in stomatal control. Research in these areas is now adding entirely new dimensions to our understanding of guard cell signaling.

Notes: Abstract Many bisexual flowering plants possess a reproductive strategy called self-incompatibility (SI) that enables the female tissue (the pistil) to reject self but accept non-self pollen for fertilization. Three different SI mechanisms are discussed, each controlled by two separate, highly polymorphic genes at the S-locus. For the Solanaceae and Papaveraceae types, the genes controlling female function in SI, the S-RNase gene and the S-gene, respectively, have been identified. For the Brassicaceae type, the gene controlling male function, SCR/SP11, and the gene controlling female function, SRK, have been identified. The S-RNase based mechanism involves degradation of RNA of self-pollen tubes; the S-protein based mechanism involves a signal transduction cascade in pollen, including a transient rise in [Ca2+]i and subsequent protein phosphorylation/dephosphorylation; and the SRK (a receptor kinase) based mechanism involves interaction of a pollen ligand, SCR/SP11, with SRK, followed by a signal transduction cascade in the stigmatic surface cell.

Notes: Abstract Ethylene regulates a multitude of plant processes, ranging from seed germination to organ senescence. Of particular economic importance is the role of ethylene as an inducer of fruit ripening. Ethylene is synthesized from S-adenosyl-L-methionine via 1-aminocyclopropane-1-carboxylic acid (ACC). The enzymes catalyzing the two reactions in this pathway are ACC synthase and ACC oxidase. Environmental and endogenous signals regulate ethylene biosynthesis primarily through differential expression of ACC synthase genes. Components of the ethylene signal transduction pathway have been identified by characterization of ethylene-response mutants in Arabidopsis thaliana. One class of mutations, exemplified by etr1, led to the identification of the ethylene receptors, which turned out to be related to bacterial two-component signaling systems. Mutations that eliminate ethylene binding to the receptor yield a dominant, ethylene-insensitive phenotype. CTR1 encodes a Raf-like Ser/Thr protein kinase that acts downstream from the ethylene receptor and may be part of a MAP kinase cascade. Mutants in CTR1 exhibit a constitutive ethylene-response phenotype. Both the ethylene receptors and CTR1 are negative regulators of ethylene responses. EIN2 and EIN3 are epistatic to CTR1, and mutations in either gene lead to ethylene insensitivity. Whereas the function of EIN2 in ethylene transduction is not known, EIN3 is a putative transcription factor involved in regulating expression of ethylene-responsive genes. Biotechnological modifications of ethylene synthesis and of sensitivity to ethylene are promising methods to prevent spoilage of agricultural products such as fruits, whose ripening is induced by ethylene.

Notes: Abstract The ezrin-radixin-moesin (ERM) family of proteins have emerged as key regulatory molecules in linking F-actin to specific membrane proteins, especially in cell surface structures. Merlin, the product of the NF2 tumor suppressor gene, has sequence similarity to ERM proteins and binds to some of the same membrane proteins, but lacks a C-terminal F-actin binding site. In this review we discuss how ERM proteins and merlin are negatively regulated by an intramolecular association between their N- and C-terminal domains. Activation of at least ERM proteins can be accomplished by C-terminal phosphorylation in the presence of PIP2. We also discuss membrane proteins to which ERM and merlin bind, including those making an indirect linkage through the PDZ-containing adaptor molecules EBP50 and E3KARP. Finally, the function of these proteins in cortical structure, endocytic traffic, signal transduction, and growth control is discussed.

Notes: Abstract Circadian rhythms are oscillations in the biochemical, physiological, and behavioral functions of organisms that occur with a periodicity of approximately 24 h. They are generated by a molecular clock that is synchronized with the solar day by environmental photic input. The cryptochromes are the mammalian circadian photoreceptors. They absorb light and transmit the electromagnetic signal to the molecular clock using a pterin and flavin adenine dinucleotide (FAD) as chromophore/cofactors, and are evolutionarily conserved and structurally related to the DNA repair enzyme photolyase. Humans and mice have two cryptochrome genes, CRY1 and CRY2, that are differentially expressed in the retina relative to the opsin-based visual photoreceptors. CRY1 is highly expressed with circadian periodicity in the mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN). Mutant mice lacking either Cry1 or Cry2 have impaired light induction of the clock gene mPer1 and have abnormally short or long intrinsic periods, respectively. The double mutant has normal vision but is defective in mPer1 induction by light and lacks molecular and behavioral rhythmicity in constant darkness. Thus, cryptochromes are photoreceptors and central components of the molecular clock. Genetic evidence also shows that cryptochromes are circadian photoreceptors in Drosophila and Arabidopsis, raising the possibility that they may be universal circadian photoreceptors. Research on cryptochromes may provide new understanding of human diseases such as seasonal affective disorder and delayed sleep phase syndrome.

Notes: Abstract The faithful segregation of genetic information requires highly orchestrated changes of chromosome structure during the mitotic cell cycle. The linkage between duplicated sister DNAs is established during S phase and maintained throughout G2 phase (cohesion). In early mitosis, dramatic structural changes occur to produce metaphase chromosomes, each consisting of a pair of compacted sister chromatids (condensation). At anaphase onset, a signal is produced to disrupt the linkage between sister chromatids (separation), allowing them to be pulled apart to opposite poles of the cell. This review discusses our current understanding of the three stages of large-scale structural changes of chromosomes in eukaryotic cells. Recent genetic and biochemical studies have identified key components involved in these processes and started to uncover hitherto unexpected functional links between mitotic chromosome dynamics and other important chromosome functions.

Notes: Abstract Homotypic (self) fusion of yeast vacuoles, which is essential for the low copy number of this organelle, uses catalytic elements similar to those used in heterotypic vesicular trafficking reactions between different organelles throughout nature. The study of vacuole inheritance has benefited from the ease of vacuole isolation, the availability of the yeast genome sequence and numerous mutants, and from a rapid, quantitative in vitro assay of fusion. The soluble proteins and small molecules that support fusion are being defined, conserved membrane proteins that catalyze the reaction have been identified, and the vacuole membrane has been solubilized and reconstituted into fusion-competent proteoliposomes, allowing the eventual purification of all needed factors. Studies of homotypic vacuole fusion have suggested a modified paradigm of membrane fusion in which integral membrane proteins termed "SNAREs" can form stable complexes in cis (when on the same membrane) as well as in trans (when anchored to opposing membranes). Chaperones (NSF/Sec18p, LMA1, and alpha-SNAP/Sec17p) disassemble cis-SNARE complexes to prepare for the docking of organelles rather than to drive fusion. The specificity of organelle docking resides in a cascade of trans-interactions (involving Rab-like GTPases), "tethering factors," and trans-SNARE pairing. Fusion itself, the mixing of the membrane bilayers and the organelle contents, is triggered by calcium signaling.

Notes: Abstract Microtubules are polymers that are essential for, among other functions, cell transport and cell division in all eukaryotes. The regulation of the microtubule system includes transcription of different tubulin isotypes, folding of alpha/beta-tubulin heterodimers, post-translation modification of tubulin, and nucleotide-based microtubule dynamics, as well as interaction with numerous microtubule-associated proteins that are themselves regulated. The result is the precise temporal and spatial pattern of microtubules that is observed throughout the cell cycle. The recent high-resolution analysis of the structure of tubulin and the microtubule has brought new insight to the study of microtubule function and regulation, as well as the mode of action of antimitotic drugs that disrupt normal microtubule behavior. The combination of structural, genetic, biochemical, and biophysical data should soon give us a fuller understanding of the exquisite details in the regulation of the microtubule cytoskeleton.

Notes: Abstract This review summarizes the progress made in our understanding of peroxisome biogenesis in the last few years, during which the functional roles of many of the 23 peroxins (proteins involved in peroxisomal protein import and peroxisome biogenesis) have become clearer. Previous reviews in the field have focussed on the metabolic functions of peroxisomes (1, 2), aspects of import/biogenesis (3, 4, 5, 6, 7), the role of peroxins in human disease (2, 8), and involvement of the endoplasmic reticulum in peroxisome membrane biogenesis (9, 10, 11) as well as the degradation of this organelle (5, 12). This review refers to some of the earlier work for the sake of introduction and continuity but deals primarily with the more recent progress. The principal areas of progress are the identification of new peroxins, definition of protein-protein interactions among peroxins leading to the recognition of complexes involved in peroxisomal protein import, insight into the biogenesis of peroxisomal membrane proteins, and, of most importance, the elucidation of the role of many conserved peroxins in human disease. Given the rapid progress in the field, this review also highlights some of the unanswered questions that remain to be tackled.

Notes: Abstract The past few years have seen exciting advances in understanding the structure and function of catalytic RNA. Crystal structures of several ribozymes have provided detailed insight into the folds of RNA molecules. Models of other biologically important RNAs have been constructed based on structural, phylogenetic, and biochemical data. However, many questions regarding the catalytic mechanisms of ribozymes remain. This review compares the structures and possible catalytic mechanisms of four small self-cleaving RNAs: the hammerhead, hairpin, hepatitis delta virus, and in vitro-selected lead-dependent ribozymes. The organization of these small catalysts is contrasted to that of larger ribozymes, such as the group I intron.

Notes: Abstract Antibody molecules elicited with rationally designed transition-state analogs catalyze numerous reactions, including many that cannot be achieved by standard chemical methods. Although relatively primitive when compared with natural enzymes, these catalysts are valuable tools for probing the origins and evolution of biological catalysis. Mechanistic and structural analyses of representative antibody catalysts, generated with a variety of strategies for several different reaction types, suggest that their modest efficiency is a consequence of imperfect hapten design and indirect selection. Development of improved transition-state analogs, refinements in immunization and screening protocols, and elaboration of general strategies for augmenting the efficiency of first-generation catalytic antibodies are identified as evident, but difficult, challenges for this field. Rising to these challenges and more successfully integrating programmable design with the selective forces of biology will enhance our understanding of enzymatic catalysis. Further, it should yield useful protein catalysts for an enhanced range of practical applications in chemistry and biology.

Notes: Abstract In just a few short years, the chemical ligation of unprotected peptide segments in aqueous solution has established itself as the most practical method for the total synthesis of native proteins. A wide range of proteins has been prepared. These synthetic molecules have led to the elucidation of gene function, to the discovery of novel biology, and to the determination of new three-dimensional protein structures by both NMR and X-ray crystallography. The facile access to novel analogs provided by chemical protein synthesis has led to original insights into the molecular basis of protein function in a number of systems. Chemical protein synthesis has also enabled the systematic development of proteins with enhanced potency and specificity as candidate therapeutic agents.

Notes: Abstract Platelet-activating factor (PAF) is a phospholipid with potent, diverse physiological actions, particularly as a mediator of inflammation. The synthesis, transport, and degradation of PAF are tightly regulated, and the biochemical basis for many of these processes has been elucidated in recent years. Many of the actions of PAF can be mimicked by structurally related phospholipids that are derived from nonenzymatic oxidation, because such compounds can bind to the PAF receptor. This process circumvents much of the biochemical control and presumably is regulated primarily by the rate of degradation, which is catalyzed by PAF acetylhydrolase. The isolation of cDNA clones encoding most of the key proteins involved in regulating PAF has allowed substantial recent progress and will facilitate studies to determine the structural basis for substrate specificity and the precise role of PAF in physiological events.

Notes: Abstract The process of mRNA turnover is a critical component of the regulation of gene expression. In the past few years a discrete set of pathways for the degradation of polyadenylated mRNAs in eukaryotic cells have been described. A major pathway of mRNA degradation in yeast occurs by deadenylation of the mRNA, which leads to a decapping reaction, thereby exposing the mRNA to rapid 5' to 3' exonucleolytic degradation. A critical step in this pathway is decapping, since it effectively terminates the existence of the mRNA and is the site of numerous control inputs. In this review, we discuss the properties of the decapping enzyme and how its activity is regulated to give rise to differential mRNA turnover. A key point is that decapping appears to be controlled by access of the enzyme to the cap structure in a competition with the translation initiation complex. Strikingly, several proteins required for mRNA decapping show interactions with the translation machinery and suggest possible mechanisms for the triggering of mRNA decapping.

Notes: Abstract Helicases are motor proteins that couple the hydrolysis of nucleoside triphosphate (NTPase) to nucleic acid unwinding. The hexameric helicases have a characteristic ring-shaped structure, and all, except the eukaryotic minichromosomal maintenance (MCM) helicase, are homohexamers. Most of the 12 known hexameric helicases play a role in DNA replication, recombination, and transcription. A human genetic disorder, Bloom's syndrome, is associated with a defect in one member of the class of hexameric helicases. Significant progress has been made in understanding the biochemical properties, structures, and interactions of these helicases with DNA and nucleotides. Cooperativity in nucleotide binding was observed in many, and sequential NTPase catalysis has been observed in two proteins, gp4 of bacteriophage T7 and rho of Escherichia coli. The crystal structures of the oligomeric T7 gp4 helicase and the hexamer of RepA helicase show structural features that substantiate the observed cooperativity, and both are consistent with nucleotide binding at the subunit interface. Models are presented that show how sequential NTP hydrolysis can lead to unidirectional and processive translocation. Possible unwinding mechanisms based on the DNA exclusion model are proposed here, termed the wedge, torsional, and helix-destabilizing models.

Notes: Abstract GTPase-activating proteins (GAPs) regulate heterotrimeric G proteins by increasing the rates at which their alpha subunits hydrolyze bound GTP and thus return to the inactive state. G protein GAPs act allosterically on Galpha subunits, in contrast to GAPs for the Ras-like monomeric GTP-binding proteins. Although they do not contribute directly to the chemistry of GTP hydrolysis, G protein GAPs can accelerate hydrolysis 〉2000-fold. G protein GAPs include both effector proteins (phospholipase C-beta, p115RhoGEF) and a growing family of regulators of G protein signaling (RGS proteins) that are found throughout the animal and fungal kingdoms. GAP activity can sharpen the termination of a signal upon removal of stimulus, attenuate a signal either as a feedback inhibitor or in response to a second input, promote regulatory association of other proteins, or redirect signaling within a G protein signaling network. GAPs are regulated by various controls of their cellular concentrations, by complex interactions with Gbetagamma or with Gbeta5 through an endogenous Ggamma-like domain, and by interaction with multiple other proteins.

Notes: Abstract Multistep chemical reactions are increasingly seen as important in a growing number of complex biotransformations. Covalently attached prosthetic groups or swinging arms, and their associated protein domains, are essential to the mechanisms of active-site coupling and substrate channeling in a number of the multifunctional enzyme systems responsible. The protein domains, for which the posttranslational machinery in the cell is highly specific, are crucially important, contributing to the processes of molecular recognition that define and protect the substrates and the catalytic intermediates. The domains have novel folds and move by virtue of conformationally flexible linker regions that tether them to other components of their respective multienzyme complexes. Structural and mechanistic imperatives are becoming apparent as the assembly pathways and the coupling of multistep reactions catalyzed by these dauntingly complex molecular machines are unraveled.

Notes: Abstract Atrial fibrillation (AF) was recognized and studied extensively in the early twentieth century, but many fundamental aspects of the arrhythmia were poorly understood until quite recently. It is now recognized that AF can be initiated by a variety of mechanisms that share the ability to cause extremely rapid, irregular atrial electrical activity. Once initiated, AF causes alterations in atrial electrical properties (electrical remodeling), including both rapid functional changes and slower alterations in ion channel gene expression, which promote the maintenance of AF and facilitate reinitiation of the arrhythmia should it terminate. Electrical remodeling decreases the atrial refractory period in a heterogeneous way, thus decreasing the size and stability of potential functional atrial reentry waves and promoting multiple-circuit reentry. Whatever the initial cause of AF, electrical remodeling is likely to be a final common pathway that ultimately supervenes. Recent advances in understanding ion channel function, regulation, and remodeling at the molecular level have allowed for a much more detailed appreciation of the basic determinants of AF. Improvements in the clinical management of AF will inevitably follow the recent advances in our understanding of its detailed pathophysiology.

Notes: Abstract In order to fly, insects require flight muscles that constitute at least 12 to 16% of their total mass, and flight performance increases as this percentage increases. However, flight muscles are energetically and materially expensive to build and maintain, and investment in flight muscles constrains other aspects of function, particularly female fecundity. This review examines ways in which insects vary the size of their flight muscles, and how variation in the relative size and composition of flight muscles affects flight performance. Sources of variability in flight muscle size and composition include genetic differences within and between species, individual phenotypic responses to environmental stimuli, and maturational changes that occur before and during the adult stage. Insects have evolved a wide variety of ways to adjust flight muscle size and contractile performance in order to meet demands imposed by variation in life history and ecology.

Notes: Abstract An underpinning of basic physiology and clinical medicine is that specific protein complements underlie cell and organ function. In the heart, contractile protein changes correlating with functional alterations occur during both normal development and the development of numerous pathologies. What has been lacking for the majority of these observations is an extension of correlation to causative proof. More specifically, different congenital heart diseases are characterized by shifts in the motor proteins, and the genetic etiologies of a number of different dilated and hypertrophic cardiomyopathies have been established as residing at loci encoding the contractile proteins. To establish cause, or to understand development of the pathophysiology over an animal's life span, it is necessary to direct the heart to synthesize, in the absence of other pleiotropic changes, the candidate protein. Subsequently one can determine whether or how the protein's presence causes the effects either directly or indirectly. By affecting the heart's protein complement in a defined manner, the potential to establish the function of different proteins and protein isoforms exists. Transgenesis provides a means of stably modifying the mammalian genome. By directing expression of engineered proteins to the heart, cardiac contractile protein profiles can be effectively remodeled and the resultant animal used to study the consequences of a single, genetic manipulation at the molecular, biochemical, cytological, and physiological levels.

Notes: Abstract The multiple endocrine neoplasia syndromes form a distinct group of genetic tumor syndromes. They include multiple endocrine neoplasia types 1 and 2, von Hippel Lindau syndrome, neurofibromatosis, and Carney complex. Research over the past decade has identified a molecular basis for each of these syndromes. This knowledge has revolutionized not only the clinical management but also has illuminated the field of human cancer research by the identification of new and important genes critical for regulation of cell growth, differentiation, and death. This review focuses on the structure, physiologic function, and molecular abnormalities of the genes involved in these syndromes.

Notes: Abstract In contrast to the airways, the defects in colonic function in cystic fibrosis (CF) patients are closely related to the defect in CFTR. The gastrointestinal phenotype of CF transgenic mice closely resembles the phenotype in CF patients, which clearly indicates the crucial role of CFTR in colonic Cl- secretion and the absence of an effective compensation. In the colon, stimulation of CFTR Cl- channels involves cAMP- or cGMPdependent phosphorylation. Exocytosis is not involved. Activation of CFTR leads to coactivation of basolateral KVLQT1-type K+ channels and inhibition of luminal Na+ channels (ENaC). In contrast to cultured cells, Ca2+ does not activate luminal Cl- channels in intact enterocytes. It activates basolateral SK4-type K+ channels and luminal K+ channels, which provide additional driving force for Cl- exit. The magnitude of Cl- secretion, however, completely depends on the presence of at least a residual CFTR function in the luminal membrane. These findings have been clearly demonstrated by Ussing chamber experiments in colon epithelium biopsies of CF and normal individuals: Colonic Cl- secretion in CF patients is variable and reflects the genotype; a complete defect of CFTR is paralleled by the absence of Cl- secretion and unmasks Ca2+-regulated K+ channels in the luminal membrane; overabsorption of Na+ in CF reflects the absence of ENaC inhibition by CFTR; and the functional status of CF colon can be mimicked by the complete suppression of cAMP stimulation in enterocytes of healthy individuals.

Notes: Abstract Molecular and functional evidence indicates that a variety of Ca2+dependent chloride (Cl(Ca)) channels are involved in fluid secretion from secretory epithelial cells in different tissues and species. Most Cl(Ca) channels so far characterized have an I- permeability greater than Cl-, and most are sensitive to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). Whole-cell Cl(Ca) currents show outward rectification. Single-channel current voltage relationships are linear with conductances ranging from 2 to 30 pS. Some Cl(Ca) channels are blocked by Ca2+-calmodulin-dependent protein kinase (CAMKII) inhibitors. Others, such as the Cl(Ca) channels of parotid and submandibular acinar cells, appear to be directly regulated by Ca2+. In native cells, the Cl(Ca) channels are located on the apical plasma membrane and activated by localized mechanisms of Ca2+ release. This positioning allows the Cl(Ca) channel to respond specifically to localized Ca2+ signals that do not invade other regions of the cell. The Cl(Ca) follows the rising phase of the Ca2+ signal, but in the falling phase hysteresis occurs where the Cl(Ca) current decays more rapidly than the underlying Ca2+. The future elucidation of the identity and mechanisms of regulation of Cl(Ca) channels will be critical to our understanding of stimulus-secretion coupling.

Notes: Abstract Plasma membrane Na+-Ca2+ exchange is an essential component of Ca2+ signaling pathways in several tissues. Activity is especially high in the heart where the exchanger is an important regulator of contractility. An expanding exchanger superfamily includes three mammalian Na+-Ca2+ exchanger genes and a number of alternative splicing products. New information indicates that the exchanger protein has nine transmembrane segments. The exchanger, which transports Na+ and Ca2+, is also regulated by these substrates. Some molecular information is available on regulation by Na+ and Ca2+ and by PIP2 and phosphorylation. Altered expression of the exchanger in pathophysiological states may contribute to various cardiac phenotypes. Use of transgenic approaches is beginning to improve our knowledge of exchanger function.

Notes: Abstract From the ability to successfully manipulate the mouse genome has come important transgenic and gene-targeted knockout models that impact many areas of biomedical research. Genetically engineered mouse models geared toward the study of cardiovascular regulation have recently been described and provide powerful tools to study normal and compromised cardiac physiology. The genetic manipulation of the adrenergic receptor (AR) signaling system in the heart, including its regulation by desensitizing kinases, has shed light on the role of this signaling pathway in the regulation of cardiac contractility. One major finding, supported by several mouse models, is that in vivo contractility can be enhanced via alteration of myocardial AR signaling. Thus genetic manipulation of this critical receptor system in the heart represents a novel therapeutic approach for improving function of the failing heart.

Notes: Abstract Regulation of intracellular Ca2+ provides a means by which the strength and duration of cardiac muscle contraction is altered on a beat-to-beat basis. Ca2+ homeostasis is maintained by proteins of the outer cell membrane or sarcolemma and the sarcoplasmic reticulum, which is the major intracellular Ca2+ storage organelle. Recently, genetic engineering techniques designed to induce specific mutations, manipulate expression levels, or change a particular isoform of various membrane Ca2+-handling proteins have provided novel approaches in elucidating the physiological role of these gene products in the mammalian heart. This review summarizes findings in murine genetic models with alterations in the expression levels of the sarcolemmal Ca2+-ATPase and Na+/Ca2+ exchanger, which move Ca2+ across the cell membrane, and the sarcoplasmic reticulum proteins, which are involved in Ca2+ sequestration (Ca2+-ATPase and its regulator, phospholamban), Ca2+ storage (calsequestrin), and Ca2+ release (ryanodine receptor, FK506-binding protein and junctin) during excitation-contraction coupling. Advances in genetic technology, coupled with the development of miniaturized technology to assess cardiac function at multiple levels in the mouse, have added a wealth of new information to our understanding of the functional role of each of these membrane Ca2+-handling proteins in cardiac physiology and pathophysiology. Furthermore, these genetic models have provided valuable insights into the compensatory cross-talk mechanisms between the major membrane Ca2+-handling proteins in the mammalian heart.

Notes: Abstract Regulated assembly of a highly specialized interconnecting network of vascular endothelial and supportive cells is fundamental to embryonic development and organogenesis, as well as to postnatal tissue repair in metazoans. This review advances an "endotheliocentric" model that defines tasks required of endothelial cells and describes molecular controls that regulate steps in activation, assembly, and maturation of new vessels. In addition to the classical assembly mechanisms-angiogenesis and vasculogenesis-endothelial cells are also recruited into vascular structures from the circulatory system in adult animals and from resident mesenchymally derived progenitors during organogenesis of kidney and other organs. Paracrine signaling cascades regulated by hypoxia initiate a sequentially coordinated series of endothelial responses, including matrix degradation, migration, proliferation, and morphogenetic remodeling. Surface receptors on committed endothelial lineage progenitors transduce cues from extracellular-matrix-associated proteins and cell-cell contact to direct migration, matrix attachment, proliferation, targeting and cell-cell assembly, and vessel maturation. Through their capacity to spatially segregate and temporally integrate a diverse range of extracellular signals, endothelial cells determine their migratory paths, cellular partners, and life-or-death responses to local cues.

Notes: Figure 1 Figure 1 This essay summarizes the four careers of George and Louise Spindler over a 50-year period-psychological anthropology, anthropology and education, teaching, and editing. Our relations with Indian tribes with which we worked are described. Special attention is given to illusions affecting the construction of education in American schools, to the use of projective techniques in studies among Native American communitites, and to studies in urbanizing German villages. The concept of cultural therapy is introduced. Publications from each of our four careers are sampled.

Notes: Abstract As we enter the twenty-first century, the terrain on which social policy is made is changing rapidly. This has resulted in anthropologists, in combination with other social scientists, giving serious attention to the impact of this new phase of globalization on changes in social and environmental policies. This review focuses on the ways in which anthropology as a field has contributed, and continues to contribute, to social policy research, practice, and advocacy in the current international context. Given the limited space allotted, we have selected the following six arenas of public policy for analysis and description: (a) links between globalization processes and policy on the national and local levels; (b) social welfare policy, including employment and family welfare survival strategies; (c) the impact of structural adjustment and economic restructuring on migration and labor force incorporation; (d) policies in the north and south related to global agriculture, social inequality, and the manipulations of some multinational corporations; (e) policies affecting sustainable agriculture; and (f) the role of anthropologists in examining the impact of political and economic hegemony on the environment.

Notes: Abstract This review discusses anthropological research that analyzes the practices through which individuals and groups produce music, video, film, visual arts, and theater, and the ideological and institutional frameworks within which these processes occur. Viewing these media and popular culture forms as arenas in which social actors struggle over social meanings and as visible evidence of social processes and social relations, this research addresses the social, political, and aesthetic dimensions of these productions. The review considers the ways these studies treat the material and discursive practices of cultural producers as complex, often contradictory, sites of social reproduction and as potential sites of social transformation. It also considers the ways this research responds to the challenges associated with conducting fieldwork and producing ethnography in and about a global economy and "media-saturated" world.

Notes: Abstract Twenty years after the Viking Mission, Mars is again being scrutinized in the light of a flood of information from spacecraft missions to Mars, the Hubble Space Telescope, and the SNC meteorites. This review provides an overview of the current understanding of Mars, especially in light of the data being returned from the Mars Global Surveyor Mission. Mars does not now have a global magnetic field, but the presence of crustal anomalies indicates that a global field existed early in Martian history. The topography, geodetic figure, and gravitational field are known to high precision. The northern hemisphere is lower and has a thinner and stronger crust than the southern hemisphere. The global weather and the thermal structure of the atmosphere have been monitored for more than a year. Surface-atmosphere interaction has been investigated by observations of surface features, polar caps, atmospheric dust, and condensate clouds. The surface has been imaged at very high resolution and spectral measures have been obtained to quantify surface characteristics and geologic processes. Many questions remain unanswered, especially about the earliest period of Mars' history.

Notes: Abstract Non-avian dinosaur reproductive and parenting behaviors were mostly similar to those of extant archosaurs. Non-avian dinosaurs were probably sexually dimorphic and some may have engaged in hierarchical rituals. Non-avian coelurosaurs (e.g. Troodontidae, Oviraptorosauria) had two active oviducts, each of which produced single eggs on a daily or greater time scale. The eggs of non-coelurosaurian dinosaurs (e.g. Ornithischia, Sauropoda) were incubated in soils, whereas the eggs of non-avian coelurosaurs (e.g. Troodon, Oviraptor) were incubated with a combination of soil and direct parental contact. Parental attention to the young was variable, ranging from protection from predators to possible parental feeding of nest-bound hatchlings. Semi-altricial hadrosaur hatchlings exited their respective nests near the time of their first linear doubling. Some reproductive behaviors, once thought exclusive to Aves, arose first in non-avian dinosaurs. The success of the Dinosauria may be related to reproductive strategies.

Notes: Abstract The Lachlan Fold Belt (Lachlan Orogen) of eastern Australia was part of a Paleozoic convergent plate margin that stretched around the supercontinent of Gondwana from South America to Australia. Lower Paleozoic (545-365 Ma) deep-water, quartz-rich turbidites, calcalkaline volcanic rocks, and voluminous granitic plutons dominate the Lachlan Orogen. These rocks overlie a mafic lower crust of oceanic affinity. Shortening and accretion of the Lachlan occurred through stepwise deformation and metamorphism from Late Ordovician (~450 Ma) through early Carboniferous times, with dominant events at about 440-430 Ma and 400-380 Ma. The development and accretion of the Lachlan Orogen and other related belts within the Tasmanides added about 2.5 Mkm2 to the surface area of Gondwana. The sedimentary, magmatic, and deformational processes converted an oceanic turbidite fan system into continental crust of normal thickness. The addition of this recycled continental detritus and juvenile material to Australia represents an under-recognized continental crustal growth mechanism that has been important thoughout earth history.

Notes: Abstract Temperature changes at the Earth's surface propagate downward into the subsurface and impart a thermal signature to the rocks. This signature can be measured in boreholes and then analyzed to reconstruct the surface temperature history over the past several centuries. The ability to resolve surface temperature history from subsurface temperatures diminishes with time. Microclimatic effects associated with the topography and vegetation patterns at the site of a borehole, along with local anthropogenic perturbations associated with land use change, can obscure the regional climate change signal. Regional and global ensembles of boreholes reveal the broader patterns of temperature changes at the Earth's surface. The average surface temperature of the continents has increased by about 1.0 K over the past 5 centuries; half of this increase has occurred in the twentieth century alone.

Notes: Abstract The mantle plume hypothesis was proposed thirty years ago by Jason Morgan to explain hotspot volcanoes such as Hawaii. A thermal diapir (or plume) rises from the thermal boundary layer at the base of the mantle and produces a chain of volcanoes as a plate moves on top of it. The idea is very attractive, but direct evidence for actual plumes is weak, and many questions remain unanswered. With the great improvement of seismic imagery in the past ten years, new prospects have arisen. Mantle plumes are expected to be rather narrow, and their detection by seismic techniques requires specific developments as well as dedicated field experiments. Regional travel-time tomography has provided good evidence for plumes in the upper mantle beneath a few hotspots (Yellowstone, Massif Central, Iceland). Beneath Hawaii and Iceland, the plume can be detected in the transition zone because it deflects the seismic discontinuities at 410 and 660 km depths. In the lower mantle, plumes are very difficult to detect, so specific methods have been worked out for this purpose. There are hints of a plume beneath the weak Bowie hotspot, as well as intriguing observations for Hawaii. Beneath Iceland, high-resolution tomography has just revealed a wide and meandering plume-like structure extending from the core-mantle boundary up to the surface. Among the many phenomena that seem to take place in the lowermost mantle (or D"), there are also signs there of the presence of plumes. In this article I review the main results obtained so far from these studies and discuss their implications for plume dynamics. Seismic imaging of mantle plumes is still in its infancy but should soon become a turbulent teenager.

Notes: Abstract Two fundamental aspects of frequency analysis shape the functional organization of primary auditory cortex. For one, the decomposition of complex sounds into different frequency components is reflected in the tonotopic organization of auditory cortical fields. Second, recent findings suggest that this decomposition is carried out in parallel for a wide range of frequency resolutions by neurons with frequency receptive fields of different sizes (bandwidths). A systematic representation of the range of frequency resolution and, equivalently, spectral integration shapes the functional organization of the iso-frequency domain. Distinct subregions, or "modules," along the iso-frequency domain can be demonstrated with various measures of spectral integration, including pure-tone tuning curves, noise masking, and electrical cochlear stimulation. This modularity in the representation of spectral integration is expressed by intrinsic cortical connections. This organization has implications for our understanding of psychophysical spectral integration measures such as the critical band and general cortical coding strategies.

Notes: Abstract 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.

Notes: Abstract Recent gene discovery approaches have led to a new era in our understanding of the molecular basis of circadian oscillators in animals. A conserved set of genes in Drosophila and mammals (Clock, Bmal1, Period, and Timeless) provide a molecular framework for the circadian mechanism. These genes define a transcription-translation-based negative autoregulatory feedback loop that comprises the core elements generating circadian rhythmicity. This circadian core provides a focal point for understanding how circadian rhythms arise, how environmental inputs entrain the oscillatory system, and how the circadian system regulates its outputs. The addition of molecular genetic approaches to the existing physiological understanding of the mammalian circadian system provides new opportunities for understanding this basic life process.

Notes: Abstract Cell death via apoptosis is a prominent feature in mammalian neural development. Recent studies into the basic mechanism of apoptosis have revealed biochemical pathways that control and execute apoptosis in mammalian cells. Protein factors in these pathways play important roles during development in regulating the balance between neuronal life and death. Additionally, mounting evidence indicates such pathways may also be activated during several neurodegenerative diseases, resulting in improper loss of neurons.

Notes: Abstract A growing number of neurodegenerative diseases have been found to result from the expansion of an unstable trinucleotide repeat. Over the past 6 years, researchers have focused on identifying the mechanism by which the expanded polyglutamine tract renders a protein toxic to a subset of vulnerable neurons. In this review, we summarize the clinicopathologic features of these disorders (spinobulbar muscular atrophy, Huntington disease, and the spinocerebellar ataxias, including dentatorubropallidoluysian atrophy), describe the genes involved and what is known about their products, and discuss the model systems that have lent insight into pathogenesis. The review concludes with a model for pathogenesis that illuminates the unifying features of these polyglutamine disorders. This model may prove relevant to other neurodegenerative disorders as well.

Notes: Abstract Many ion channels and receptors display striking phenotypes for gainof-function mutations but milder phenotypes for null mutations. Gain of molecular function can have several mechanistic bases: selectivity changes, gating changes including constitutive activation and slowed inactivation, elimination of a subunit that enhances inactivation, decreased drug sensitivity, changes in regulation or trafficking of the channel, or induction of apoptosis. Decreased firing frequency can occur via increased function of K+ or Cl- channels. Channel mutants also cause gain-of-function syndromes at the cellular and circuit level; of these syndromes, the cardiac long-QT syndromes are explained in a more straightforward way than are the epilepsies. G protein- coupled receptors are also affected by activating mutations.

Notes: Abstract Until recently, most neuroscientists did not regard consciousness as a suitable topic for scientific investigation. This reluctance was based on certain philosophical mistakes, primarily the mistake of supposing that the subjectivity of consciousness made it beyond the reach of an objective science. Once we see that consciousness is a biological phenomenon like any other, then it can be investigated neurobiologically. Consciousness is entirely caused by neurobiological processes and is realized in brain structures. The essential trait of consciousness that we need to explain is unified qualitative subjectivity. Consciousness thus differs from other biological phenomena in that it has a subjective or first-person ontology, but this subjective ontology does not prevent us from having an epistemically objective science of consciousness. We need to overcome the philosophical tradition that treats the mental and the physical as two distinct metaphysical realms. Two common approaches to consciousness are those that adopt the building block model, according to which any conscious field is made of its various parts, and the unified field model, according to which we should try to explain the unified character of subjective states of consciousness. These two approaches are discussed and reasons are given for preferring the unified field theory to the building block model. Some relevant research on consciousness involves the subjects of blindsight, the split-brain experiments, binocular rivalry, and gestalt switching.

Notes: Abstract Like many other complex biological phenomena, pain is starting to be studied at the level of the gene. Advances in molecular biological technology have allowed the cloning, mapping, and sequencing of genes, and also the ablility to disrupt their function entirely (i.e. via transgenic knoockouts). With these new tools at hand, pain researchers have begun in earnest the task of defining (a) which of the 70,000- 150,000 mammalian genes are involved in the mediation of pain, and (b) which of the pain-relevant genes are polymorphic, contributing to both natural variation in responses and pathology. Although there are only a few known examples in which single gene mutations in humans are associated with pain conditions (e.g. an inherited form of migraine and congenital insensitivity to pain), it is likely that others will be identified. Concurrently, a variety of genes have been implicated in both the transmission and control of "pain" messages in animals. The present review summarizes current progress to these ends, focusing on both transgenic (genebehavior) and classical genetic (behaviorgene) approaches in both humans and laboratory mice.

Notes: Abstract The process of clonal selection is a central feature of the immune system, but immune specificity is also regulated by receptor selection, in which the fate of a lymphocyte's antigen receptor is uncoupled from that of the cell itself. Whereas clonal selection controls cell death or survival in response to antigen receptor signaling, receptor selection regulates the process of V(D)J recombination, which can alter or fix antigen receptor specificity. Receptor selection is carried out in both T and B cells and can occur at different stages of lymphocyte differentiation, in which it plays a key role in allelic exclusion, positive selection, receptor editing, and the diversification of the antigen receptor repertoire. Thus, the immune system takes advantage of its control of V(D)J recombination to modify antigen receptors in such a way that self/non-self discrimination is enhanced. New information about receptor editing in T cells and B-1 B cells is also discussed.

Notes: Abstract Major histocompatibility complex (MHC) class II molecules are cell surface proteins that present peptides to CD4+ T cells. In addition to these wellcharacterized molecules, two other class II-like proteins are produced from the class II region of the MHC, HLA-DM (DM) and HLA-DO (DO) (called H2-M, or H2-DM and H2-O in the mouse). The function of DM is well established; it promotes peptide loading of class II molecules in the endosomal/lysosomal system by catalyzing the release of CLIP peptides (derived from the class II-associated invariant chain) in exchange for more stably binding peptides. While DM is present in all class II- expressing antigen presenting cells, DO is expressed mainly in B cells. In this cell type the majority of DM molecules are not present as free heterodimers but are instead associated with DO in tight heterotetrameric complexes. The association with DM is essential for the intracellular transport of DO, and the two molecules remain associated in the endosomal system. DO can clearly modify the peptide exchange activity of DM both in vitro and in vivo, but the physiological relevance of this interaction is still only partly understood.

Notes: Abstract During the last five years, the development of bioinformatics and EST databases has been primarily responsible for the identification of many new chemokines and chemokine receptors. The chemokine field has also received considerable attention since chemokine receptors were found to act as co-receptors for HIV infection (1). In addition, chemokines, along with adhesion molecules, are crucial during inflammatory responses for a timely recruitment of specific leukocyte subpopulations to sites of tissue damage. However, chemokines and their receptors are also important in dendritic cell maturation (2), B (3), and T (4) cell development, Th1 and Th2 responses, infections, angiogenesis, and tumor growth as well as metastasis (5). Furthermore, an increase in the number of chemokine/receptor transgenic and knock-out mice has helped to define the functions of chemokines in vivo. In this review we discuss some of the chemokines' biological effects in vivo and in vitro, described in the last few years, and the implications of these findings when considering chemokine receptors as therapeutic targets.

Notes: Abstract Allergic diseases affect approximately one third of the general population. This class of disease, characterized by elevated serum IgE levels and hypersensitivity to normally innocuous antigen, can manifest in practically any mucosal tissue or as a systemic response. A few examples of serious allergic diseases include asthma, dermatitis, bee sting allergy, food allergy, conjunctivitis, and severe systemic anaphylaxis. Taken together, allergic diseases constitute one of the major problems of modern day medicine. A considerable portion of the healthcare budget is expended in the treatment of allergic disease, and morbidity rates of inner city asthmatics are rising steadily. Due to the enormity of the problem, there has been a worldwide effort to identify factors that contribute to the etiology of allergic diseases. Epidemiologic studies of multigeneration families and large numbers of twins clearly indicate a strong genetic component to atopic diseases. At least two independently segregating diseasesusceptibility genes are thought to come together with environmental factors to result in allergic inflammation in a particular tissue. On the basis of the strong genetic studies, multiple groups have attempted to identify disease-susceptibility genes via either a candidate gene approach or by genome-wide scans. Both of these approaches have implicated multiple regions in the human and mouse genomes, which are currently being evaluated as harboring putative atopy genes.

Notes: Abstract The recognition of polarized T cell subsets defined by cytokine production was followed by a search to define the factors controlling this phenomenon. Suitable in vitro systems allowed the development of cytokine "recipes" that induced rapid polarization of naive T cells into Th1 or Th2 populations. The next phase of work over the past several years has begun to define the intracellular processes set into motion during Th1/Th2 development, particularly by the strongly polarizing cytokines IL-12 and IL-4. Although somewhat incomplete, what has emerged is a richly detailed tapestry of signaling and transcription, controlling an important T cell developmental switch. In addition several new mediators of control have emerged, including IL-18, the intriguing Th2-selective T1/ST2 product, and heterogeneity in dendritic cells capable of directing cytokine-independent Th development.

Notes: Abstract Mammalian reproduction poses an immunological paradox because fetal alloantigens encoded by genes inherited from the father should provoke responses by maternal T cells leading to fetal loss. Current understanding of T cell immunobiology and the critical role of inflammatory processes during pregnancy is reviewed and discussed. Lessons derived from studies on the regulation of T cell responsiveness during mammalian gestation are considered in the wider context of T cell tolerance toward some microbial infections and tumors, avoidance of autoimmunity, and tissue allograft rejection.

Notes: Abstract 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.

Notes: Abstract NF-kappaB (nuclear factor-kappaB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-kappaB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression. NF-kappaB is normally sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-kappaB is controlled by a family of inhibitory proteins, IkappaBs, which bind NF-kappaB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus where it regulates gene transcription. NF-kappaB activation represents a paradigm for controlling the function of a regulatory protein via ubiquitination-dependent proteolysis, as an integral part of a phosphorylationbased signaling cascade. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. The multisubunit IkappaB kinase (IKK) responsible for inducible IkappaB phosphorylation is the point of convergence for most NF-kappaB-activating stimuli. IKK contains two catalytic subunits, IKKalpha and IKKbeta, both of which are able to correctly phosphorylate IkappaB. Gene knockout studies have shed light on the very different physiological functions of IKKalpha and IKKbeta. After phosphorylation, the IKK phosphoacceptor sites on IkappaB serve as an essential part of a specific recognition site for E3RSIkappaB/beta-TrCP, an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IkappaB ubiquitination and degradation. A variety of other signaling events, including phosphorylation of NF-kappaB, hyperphosphorylation of IKK, induction of IkappaB synthesis, and the processing of NF-kappaB precursors, provide additional mechanisms that modulate the level and duration of NF-kappaB activity.