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  • Annual Reviews
  • 2000-2004  (5,338)
  • 1
    Electronic Resource
    Electronic Resource
    Metabolic Rate and Body Temperature Reduction During Hibernation and Daily Torpor (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 239-274 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Although it is well established that during periods of torpor heterothermic mammals and birds can reduce metabolic rates (MR) substantially, the mechanisms causing the reduction of MR remain a controversial subject. The comparative analysis provided here suggests that MR reduction depends on patterns of torpor used, the state of torpor, and body mass. Daily heterotherms, which are species that enter daily torpor exclusively, appear to rely mostly on the fall of body temperature (Tb) for MR reduction, perhaps with the exception of very small species and at high torpor Tb, where some metabolic inhibition may be used. In contrast, hibernators (species capable of prolonged torpor bouts) rely extensively on metabolic inhibition, in addition to Tb effects, to reduce MR to a fraction of that observed in daily heterotherms. In small hibernators, metabolic inhibition and the large fall of Tb are employed to maximize energy conservation, whereas in large hibernators, metabolic inhibition appears to be employed to facilitate MR and Tb reduction at torpor onset. Over the ambient temperature (Ta) range where torpid heterotherms are thermo-conforming, the Tb-Ta differential is more or less constant despite a decline of MR with Ta; however, in thermo-regulating torpid individuals, the Tb-Ta differential is maintained by a proportional increase of MR as during normothermia, albeit at a lower Tb. Thermal conductance in most torpid thermo-regulating individuals is similar to that in normothermic individuals despite the substantially lower MR in the former. However, conductance is low when deeply torpid animals are thermo-conforming probably because of peripheral vasoconstriction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.115105
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  • 2
    Electronic Resource
    Electronic Resource
    Learning Mechanisms in Addiction: Synaptic Plasticity in the Ventral Tegmental Area as a Result of Exposure to Drugs of Abuse (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 447-475 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: One of the central questions in neurobiology is how experience modifies neural function, and how changes in the nervous system permit an animal to adapt its behavior to a changing environment. Learning and adaptation to a host of different environmental stimuli exemplify processes we know must alter the nervous system because the behavioral output changes after experience. Alterations in behavior after exposure to addictive drugs are a striking example of chemical alterations of nervous system function producing long-lasting changes in behavior. The alterations produced in the central nervous system (CNS) by addictive drugs are of interest because of their relationship to human substance abuse but also because these CNS alterations produce dramatic, easily observed alterations in behavior in response to discrete stimuli. Considerable study has been given to behavioral and biochemical correlates of addiction over the past 50 or more years; however, our understanding of the cellular physiological responses of affected CNS neurons is in its infancy. This review focuses on alterations in cellular and synaptic physiology in the ventral tegmental area (VTA) in response to addictive drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.112534
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  • 3
    Electronic Resource
    Electronic Resource
    Localization of Voltage-Gated Ion Channels IN Mammalian Brain (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 477-519 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The intrinsic electrical properties of neurons are shaped in large part by the action of voltage-gated ion channels. Molecular cloning studies have revealed a large family of ion channel genes, many of which are expressed in mammalian brain. Much recent effort has focused on determining the contribution of the protein products of these genes to neuronal function. This requires knowledge of the abundance and distribution of the constituent subunits of the channels in specific mammalian central neurons. Here we review progress made in recent studies aimed at localizing specific ion channel subunits using in situ hybridization and immunohistochemistry. We then discuss the implications of these results in terms of neuronal physiology and neuronal mechanisms underlying the observed patterns of expression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.113328
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  • 4
    Electronic Resource
    Electronic Resource
    Myosin-1c, the Hair Cell's Adaptation Motor (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 521-545 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Given their prominent actin-rich subcellular specializations, it is no surprise that mechanosensitive hair cells of the inner ear exploit myosin molecules-the only known actin-dependent molecular motors-to carry out exotic but essential tasks. Recent experiments have confirmed that an unconventional myosin isozyme, myosin-1c, is a component of the hair cell's adaptation-motor complex. This complex carries out slow adaptation, provides tension to sensitize transduction channels, and may participate in assembly of the transduction apparatus. This review focuses on the detailed operation of the adaptation motor and the functional consequences of the incorporation of this specific myosin isozyme into the motor complex.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.112842
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  • 5
    Electronic Resource
    Electronic Resource
    Epithelial-Mesenchymal Interactions in the Developing Lung (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 625-645 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Classical experiments in embryology have shown that normal growth, morphogenetic patterning, and cellular differentiation in the developing lung depend on interactive signaling between the endodermal epithelium and mesenchyme derived from splanchnic mesoderm. These interactions are mediated by a myriad of diffusible factors that are precisely regulated in their temporal and spatial expression. In this review we first describe factors regulating formation of the embryonic foregut. We then discuss the experiments demonstrating the importance of tissue interactions in lung patterning and differentiation. Finally, we detail the roles that a few key signaling systems-fibroblast growth factors and their receptors, sonic hedgehog and Gli genes, Wnt genes and beta-catenin, and BMP4-play as mediators of epithelial-mesenchymal interactions in the developing lung.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.135749
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  • 6
    Electronic Resource
    Electronic Resource
    Control of the Size of the Human Muscle Mass (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 799-828 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: This review is divided into two parts, the first dealing with the cell and molecular biology of muscle in terms of growth and wasting and the second being an account of current knowledge of physiological mechanisms involved in the alteration of size of the human muscle mass. Wherever possible, attempts have been made to interrelate the information in each part and to provide the most likely explanation for phenomena that are currently only partially understood. The review should be of interest to cell and molecular biologists who know little of human muscle physiology and to physicians, physiotherapists, and kinesiologists who may be familiar with the gross behavior of human muscle but wish to understand more about the underlying mechanisms of change.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.052102.134444
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  • 7
    Electronic Resource
    Electronic Resource
    Some Early History of Membrane Molecular Biology (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 1-27 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: This article is mostly about the beginnings of the molecular biology of membranes, covering the decade 1964-1974. It is difficult to read (or write) this article because of a sense of deja vu. Most of the material in it is considered commonplace today, having been established experimentally since then. But at the time this work was begun, practically nothing was known about the molecular structure and the mechanisms of the functions of membranes. This situation existed because no membrane proteins of the kind I called integral had as yet been isolated in a pure state, and therefore none had had their amino acid sequence determined. The first integral membrane protein to be so characterized was human erythrocyte glycophorin, in 1978. It was the use of the thermodynamic reasoning that had been developed for the study of water-soluble proteins, together with the information from several key experiments carried out in a number of laboratories during the early decade, that led us to the fluid mosaic model of membrane structure in 1972. Without direct evidence to confirm the model in 1971-1972, my colleagues and I nevertheless had the confidence in it to pursue some of the consequences of the model for a new understanding of many membrane functions, which I present here in some detail. Finally, I discuss two recent high-resolution X-ray crystallographic studies of integral proteins to ask how well the structural and functional proposals that we derived from the fluid mosaic model fit these remarkably detailed X-ray results.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032902.131835
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  • 8
    Electronic Resource
    Electronic Resource
    Myocardial Aging and Senescence: Where Have the Stem Cells Gone? (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 29-48 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Heart failure remains a leading cause of hospital admissions and mortality in the elderly, and current interventional approaches often fail to treat the underlying cause of pathogenesis. Preservation of structure and function in the aging myocardium is most likely to be successful via ongoing cellular repair and replacement, as well as survival of existing cardiomyocytes that generate contractile force. Research has led to a paradigm shift driven by application of stem cells to generate cardiovascular cell lineages. Early controversial findings of pluripotent precursors adopting cardiac phenotypes are now widely accepted, and current debate centers upon the efficiency of progenitor cell incorporation into the myocardium. Much work remains to be done in determining the relevant progenitor cell population and optimizing conditions for efficient differentiation and integration. Significant implications exist for treatment of pathologically damaged or aging myocardium since future interventional approaches will capitalize upon the use of cardiac stem cells as therapeutic reagents.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.140723
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  • 9
    Electronic Resource
    Electronic Resource
    Metabolic Regulation of Potassium Channels (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 131-159 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Potassium (K+) channels exist in all three domains of organisms: eubacteria, archaebacteria, and eukaryotes. In higher animals, these membrane proteins participate in a multitude of critical physiological processes, including food and fluid intake, locomotion, stress response, and cognitive functions. Metabolic regulatory factors such as O2, CO2/pH, redox equivalents, glucose/ATP/ADP, hormones, eicosanoids, cell volume, and electrolytes regulate a diverse group of K+ channels to maintain homeostasis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.041002.142720
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  • 10
    Electronic Resource
    Electronic Resource
    Biochemical Indicators of Stress and Metabolism: Applications for Marine Ecological Studies (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 183-207 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Studies investigating the effects of temperature, food availability, or other physical factors on the physiology of marine animals have led to the development of biochemical indicators of growth rate, metabolic condition, and physiological stress. Measurements of metabolic enzyme activity and RNA/DNA have been especially valuable as indicators of condition in studies of marine invertebrates and fishes, groups for which accurate determination of field metabolic rates is difficult. Properly calibrated and applied, biochemical indicators have been successfully used in studies of rocky intertidal ecology, where two decades of experimentation have generated rigorous, testable models for determining the relative influences of biotic and abiotic factors on species distribution, abundance, and interaction. Biochemical indicators of condition and metabolic activity (metabolic enzymes, RNA/DNA) have been used to test nutrient-productivity models by demonstrating tight linkages between nearshore oceanographic processes (such as upwelling) and benthic rocky intertidal ecosystems. Indices of condition and heat stress (heat shock proteins, or Hsps) have begun to be used to test environmental stress models by comparing condition, activity, and Hsp expression of key rocky intertidal predator and prey species. Using biochemical indicators of condition and stress in natural systems holds great promise for understanding mechanisms by which organisms respond to rapid environmental change.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.114509
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  • 11
    Electronic Resource
    Electronic Resource
    Estrogens in the Nervous System: Mechanisms and Nonreproductive Functions (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 291-313 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The past decade has witnessed a growing interest in estrogens and their activity in the central nervous system, which was originally believed to be restricted to the control of reproduction. It is now well accepted that estrogens modulate the activity of all types of neural cells through a multiplicity of mechanisms. Estrogens, by binding to two cognate receptors ERalpha and ERbeta, may interact with selected promoters to initiate the synthesis of target proteins. Alternatively, the hormone receptor complex may interfere with intracellular signaling at both cytoplasmic and nuclear levels. The generation of cellular and animal models, combined with clinical and epidemiological studies, has allowed us to appreciate the neurotrophic and neuroprotective effects of estrogens. These findings are of major interest because estradiol might become an important therapeutic agent to maintain neural functions during aging and in selected neural diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032802.154945
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  • 12
    Electronic Resource
    Electronic Resource
    THE PEOPLING OF THE NEW WORLD: Perspectives from Molecular Anthropology (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Anthropology 33 (2004), S. 551-583 
    Details
    ISSN: 0084-6570
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Ethnic Sciences , Biology
    Notes: A number of important insights into the peopling of the New World have been gained through molecular genetic studies of Siberian and Native American populations. These data indicate that the initial migration of ancestral Amerindian originated in south-central Siberia and entered the New World between 20,000-14,000 calendar years before present (cal yr BP). These early immigrants probably followed a coastal route into the New World, where they expanded into all continental regions. A second migration that may have come from the same Siberian region entered the Americas somewhat later, possibly using an interior route, and genetically contributed to indigenous populations from North and Central America. In addition, Beringian populations moved into northern North America after the last glacial maximum (LGM) and gave rise to Aleuts, Eskimos, and Na-Dene Indians.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.anthro.33.070203.143932
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  • 13
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    NEW TECHNOLOGIES AND LANGUAGE CHANGE: Toward an Anthropology of Linguistic Frontiers (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Anthropology 33 (2004), S. 103-115 
    Details
    ISSN: 0084-6570
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Ethnic Sciences , Biology
    Notes: Research to date on the relationship between new communications technologies and language emphasizes linguistic and social differences between online and off-line interactions and the impact of global English on the non-English-speaking world. These studies conclude, for the most part, that computer-mediated communication reproduces the social, political, and economic relations that exist in the real world. Related areas of research, including ethnographies of global hip hop and studies of urban hybrid language varieties, offer important models for using anthropological approaches to advance our understanding of the interconnections and situated-ness, of language, new technologies, global media, and social change.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.anthro.33.070203.143921
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  • 14
    Electronic Resource
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    LANGUAGE REVITALIZATION AND NEW TECHNOLOGIES: Cultures of Electronic Mediation and the Refiguring of Communities (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Anthropology 33 (2004), S. 21-45 
    Details
    ISSN: 0084-6570
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Ethnic Sciences , Biology
    Notes: Recently, language activists and linguists have begun using new technologies in projects aimed at revitalizing the practice of lesser-used languages. This review explores related work, emphasizing how practices of electronic mediation enabled by such technologies both shape and are informed by linguistic ideologies, which in turn crucially influence the possible revived use or abandonment of linguistic varieties. New technologies are treated as part of cultures of electronic mediation, connecting sociocultural valuations to mediated discourse. Their use often has important political implications, given that projects of language revitalization are often linked to claims of ethnolinguistic recognition. Finally, because documentation of lesser-used languages using digital technologies also results in the production of new cultural objects to be stored, displayed, and circulated, attention is also focused on the forms of sociality sustained by the creation and exchange of such electronic artifacts.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.anthro.33.070203.143900
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  • 15
    Electronic Resource
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    HANG ON TO YOUR SELF: Of Bodies, Embodiment, and Selves (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Anthropology 33 (2004), S. 251-269 
    Details
    ISSN: 0084-6570
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Ethnic Sciences , Biology
    Notes: During the past twenty years the human body evolved from a rather marginal social fact into a notion of central concern to current social and cultural anthropology. But recent studies question the idea of the body as a given physical entity. They focus on the experience or threat of finiteness, limitation, and vulnerability and also raise doubts regarding the individuality of the self: Instead they emphasize its fragmentary character and focus on the embodied uncertainties (such as hybridity or irony) of human existence. In three main sections (respectively, on the social body, embodiment, and subjectivity) this review eclectically explores an anthropological debate that also betrays a more generalized and rising concern in Western society with bodiliness and bodily appearance. From the discussion, the body emerges as a changing relationship that, at the same time, unfolds as an ethical horizonand challengefor the (un)making of self, identity, and belonging.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.anthro.33.070203.143749
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  • 16
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    INSCRIBING THE BODY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Anthropology 33 (2004), S. 319-344 
    Details
    ISSN: 0084-6570
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Ethnic Sciences , Biology
    Notes: Inscriptions on the body, especially tattoo, scarification, and body paint, have been part of ethnographic literature since before the birth of anthropology as a discipline. Anthropology's origins as the study of the exotic Other can be seen in the early descriptions of the body art of non-Western peoples. Anthropologists have generally focused on how the inscribed body serves as a marker of identity in terms of gender, age, and political status. More recently, scholars interested in this subject have looked also at issues of modernity, authenticity, and representation. The recent focus on the inscribed body responds to postmodern theory, the importance of body art in contemporary Western culture, reflections on the meaning of representations of the exotic, and an interest in the visible surface of the body as the interface between the individual and society. This article reviews recent literature in anthropology and related disciplines pertaining to the cultural construction of the inscribed body.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.anthro.33.070203.143947
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  • 17
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    GEOMORPHOLOGY: A Sliver Off the Corpus of Science (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Earth and Planetary Sciences 32 (2004), S. 1-12 
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    ISSN: 0084-6597
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Geosciences , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.earth.32.032803.153614
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  • 18
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    THE MIRROR-NEURON SYSTEM (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 169-192 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: A category of stimuli of great importance for primates, humans in particular, is that formed by actions done by other individuals. If we want to survive, we must understand the actions of others. Furthermore, without action understanding, social organization is impossible. In the case of humans, there is another faculty that depends on the observation of others' actions: imitation learning. Unlike most species, we are able to learn by imitation, and this faculty is at the basis of human culture. In this review we present data on a neurophysiological mechanism-the mirror-neuron mechanism-that appears to play a fundamental role in both action understanding and imitation. We describe first the functional properties of mirror neurons in monkeys. We review next the characteristics of the mirror-neuron system in humans. We stress, in particular, those properties specific to the human mirror-neuron system that might explain the human capacity to learn by imitation. We conclude by discussing the relationship between the mirror-neuron system and language.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144230
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  • 19
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    THE NEURAL BASIS OF TEMPORAL PROCESSING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 307-340 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: A complete understanding of sensory and motor processing requires characterization of how the nervous system processes time in the range of tens to hundreds of milliseconds (ms). Temporal processing on this scale is required for simple sensory problems, such as interval, duration, and motion discrimination, as well as complex forms of sensory processing, such as speech recognition. Timing is also required for a wide range of motor tasks from eyelid conditioning to playing the piano. Here we review the behavioral, electrophysiological, and theoretical literature on the neural basis of temporal processing. These data suggest that temporal processing is likely to be distributed among different structures, rather than relying on a centralized timing area, as has been suggested in internal clock models. We also discuss whether temporal processing relies on specialized neural mechanisms, which perform temporal computations independent of spatial ones. We suggest that, given the intricate link between temporal and spatial information in most sensory and motor tasks, timing and spatial processing are intrinsic properties of neural function, and specialized timing mechanisms such as delay lines, oscillators, or a spectrum of different time constants are not required. Rather temporal processing may rely on state-dependent changes in network dynamics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144247
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  • 20
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    SENSORY SIGNALS IN NEURAL POPULATIONS UNDERLYING TACTILE PERCEPTIONAND MANIPULATION (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 53-77 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: For humans to manipulate an object successfully, the motor control system must have accurate information about parameters such as the shape of the stimulus, its position of contact on the skin, and the magnitude and direction of contact force. The same information is required for perception during haptic exploration of an object. Much of these data are relayed by the mechanoreceptive afferents innervating the glabrous skin of the digits. Single afferent responses are modulated by all the relevant stimulus parameters. Thus, only in complete population reconstructions is it clear how each of the parameters can be signaled to the brain independently when many are changing simultaneously, as occurs in most normal movements or haptic exploration. Modeling population responses reveals how resolution is affected by neural noise and intrinsic properties of the population such as the pattern and density of innervation and the covariance of response variability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.26.041002.131032
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  • 21
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    VISUAL MOTOR COMPUTATIONS IN INSECTS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 679-696 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: With their relatively simple nervous systems and purpose-designed behaviors and reflexes, insects are an excellent organism in which to investigate how visual information is acquired and processed to guide locomotion and navigation. Flies maintain a straight course and monitor their motion through the environment by sensing the patterns of optic flow induced in the eyes. Bees negotiate narrow gaps by balancing the speeds of the images in their two eyes, and they control flight speed by holding constant the average image velocity as seen with their two eyes. Bees achieve a smooth landing on a horizontal surface by holding the image velocity of the surface constant during approach, thus ensuring that flight speed is automatically close to zero at touchdown. Foraging bees estimate the distance that they have traveled to reach a food source by integrating the optic flow experienced en route; this integration gives them a visually driven "odometer." Insects have also evolved sophisticated visuomotor mechanisms for pursuing prey or mates and possibly for concealing their own motion while shadowing objects of interest.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144343
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  • 22
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    CEREBELLUM-DEPENDENT LEARNING: The Role of Multiple Plasticity Mechanisms (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 581-609 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The cerebellum is an evolutionarily conserved structure critical for motor learning in vertebrates. The model that has influenced much of the work in the field for the past 30 years suggests that motor learning is mediated by a single plasticity mechanism in the cerebellum: long-term depression (LTD) of parallel fiber synapses onto Purkinje cells. However, recent studies of simple behaviors such as the vestibulo-ocular reflex (VOR) indicate that multiple plasticity mechanisms contribute to cerebellum-dependent learning. Multiple plasticity mechanisms may provide the flexibility required to store memories over different timescales, regulate the dynamics of movement, and allow bidirectional changes in movement amplitude. These plasticity mechanisms must act in combination with appropriate information-coding strategies to equip motor-learning systems with the ability to express learning in correct contexts. Studies of the patterns of generalization of motor learning in the VOR provide insight about the coding of information in neurons at sites of plasticity. These principles emerging from studies of the VOR are consistent with results concerning more complex behaviors and thus may reflect general principles of cerebellar function.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144238
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    CELLULAR MECHANISMS OF NEURONAL POPULATION OSCILLATIONS IN THE HIPPOCAMPUS IN VITRO (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 247-278 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: A variety of population oscillations, at frequencies ~5 Hz up to 200 Hz and above, can be induced in hippocampal slices either by (a) manipulation of the ionic environment, or (b) by stimulation of metabotropic receptors; brief oscillations can even occur spontaneously. In this review, we consider in vitro theta (4-12 Hz), gamma/beta (15-70 Hz), and very fast oscillations (VFO) (〉70 Hz). Many in vitro oscillations are gated by synaptic inhibition but are influenced by electrical coupling as well; one type depends solely on electrical coupling. For some oscillations dependent upon inhibition, the detailed firing patterns of interneurons can influence long-range synchronization. Two sorts of electrical coupling are important in modulating or generating various in vitro oscillations: (a) between interneurons, primarily between dendrites; and (b) between axons of pyramidal neurons. VFO can exist in isolation or can act as generators of gamma frequency oscillations. Oscillations at gamma frequencies and below probably create conditions under which synaptic plasticity can occur, between selected neurons-even those separated by significant axonal conduction delays.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144303
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    PLASTICITY OF THE SPINAL NEURAL CIRCUITRY AFTER INJURY* (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 145-167 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Motor function is severely disrupted following spinal cord injury (SCI). The spinal circuitry, however, exhibits a great degree of automaticity and plasticity after an injury. Automaticity implies that the spinal circuits have some capacity to perform complex motor tasks following the disruption of supraspinal input, and evidence for plasticity suggests that biochemical changes at the cellular level in the spinal cord can be induced in an activity-dependent manner that correlates with sensorimotor recovery. These characteristics should be strongly considered as advantageous in developing therapeutic strategies to assist in the recovery of locomotor function following SCI. Rehabilitative efforts combining locomotor training pharmacological means and/or spinal cord electrical stimulation paradigms will most likely result in more effective methods of recovery than using only one intervention.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144308
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    DESENSITIZATION OF G PROTEIN-COUPLED RECEPTORS AND NEURONAL FUNCTIONS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 107-144 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: G protein-coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modern pharmacology. Over 90% of nonsensory GPCRs are expressed in the brain, where they play important roles in numerous neuronal functions. GPCRs can be desensitized following activation by agonists by becoming phosphorylated by members of the family of G protein-coupled receptor kinases (GRKs). Phosphorylated receptors are then bound by arrestins, which prevent further stimulation of G proteins and downstream signaling pathways. Discussed in this review are recent progress in understanding basics of GPCR desensitization, novel functional roles, patterns of brain expression, and receptor specificity of GRKs and betaarrestins in major brain functions. In particular, screening of genetically modified mice lacking individual GRKs or betaarrestins for alterations in behavioral and biochemical responses to cocaine and morphine has revealed a functional specificity in dopamine and mu-opioid receptor regulation of locomotion and analgesia. An important and specific role of GRKs and betaarrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules in certain brain disorders, such as addiction, Parkinson's disease, mood disorders, and schizophrenia. Furthermore, the utility of a pharmacological strategy aimed at targeting this GPCR desensitization machinery to regulate brain functions can be envisaged.
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    Immunological Memory to Viral Infections1 (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 711-743 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The purpose of immunological memory is to protect the host from reinfection, to control persistent infections, and, through maternal antibody, to protect the host's immunologically immature offspring from primary infections. Immunological memory is an exclusive property of the acquired immune system, where in the presence of CD4 T cell help, T cells and B cells clonally expand and differentiate to provide effector systems that protect the host from pathogens. Here we describe how T and B cell memory is generated in response to virus infections and how these cells respond when the host is infected again by similar or different viruses.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104527
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    T Lymphocyte-Endothelial Cell Interactions (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 683-709 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Human vascular endothelial cells (EC) basally display class I and II MHC-peptide complexes on their surface and come in regular contact with circulating T cells. We propose that EC present microbial antigens to memory T cells as a mechanism of immune surveillance. Activated T cells, in turn, provide both soluble and contact-dependant signals to modulate normal EC functions, including formation and remodeling of blood vessels, regulation of blood flow, regulation of blood fluidity, maintenance of permselectivity, recruitment of inflammatory leukocytes, and antigen presentation leading to activation of T cells. T cell interactions with vascular EC are thus bidirectional and link the immune and circulatory systems.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104639
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    Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 745-763 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The memory T cell pool functions as a dynamic repository of antigen-experienced T lymphocytes that accumulate over the lifetime of the individual. Recent studies indicate that memory T lymphocytes contain distinct populations of central memory (TCM) and effector memory (TEM) cells characterized by distinct homing capacity and effector function. This review addresses the heterogeneity of TCM and TEM, their differentiation stages, and the current models for their generation and maintenance in humans and mice.
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    The Role of Complement in the Development of Systemic Lupus Erythematosus (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 431-456 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Complement has both beneficial and deleterious roles in the pathogenesis of systemic lupus erythematosus (SLE). On the one hand, patients with SLE present with decreased complement levels and with complement deposition in inflammed tissues, suggestive of a harmful role of complement in the effector phase of disease. On the other hand, homozygous deficiency of any of the classical pathway proteins is strongly associated with the development of SLE. There are two main hypotheses to explain these observations. The first invokes an important role for complement in the physiological waste-disposal mechanisms of dying cells and immune complexes. The second hypothesis is based around the role of complement in determining the activation thresholds of B and T lymphocytes, with the proposal that complement deficiency causes incomplete maintenance of peripheral tolerance. These two hypotheses are not mutually exclusive. In addition, there is evidence for a contribution from other genetic factors in determining the phenotype of disease in the absence of complement.
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    Self- and Nonself-Recognition by C-Type Lectins on Dendritic Cells (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 33-54 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to naive T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class I and II molecules. DCs are well equipped to distinguish between self- and nonself-antigens by the variable expression of cell-surface receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically quiescent but use their antigen-handling capacities to maintain peripheral tolerance. DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.
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    Immunity to Tuberculosis (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 599-623 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Only 5 to 10% of immunocompetent humans are susceptible to tuberculosis, and over 85% of them develop the disease exclusively in the lungs. Human immunodeficiency virus (HIV)-infected humans, in contrast, can develop systemic disease that is more quickly lethal. This is in keeping with other evidence showing that susceptible humans generate some level of Th1 immunity to Mycobacterium tuberculosis (Mtb) infection. Tuberculosis in mice is also exclusively a lung disease that is progressive and lethal, in spite of the generation of Th1-mediated immunity. Thus mouse tuberculosis is a model of tuberculosis in susceptible humans, as is tuberculosis in guinea pigs and rabbits. Inability to resolve infection and prevent disease may not be a consequence of the generation of an inadequate number of Th1 cells but of an intrinsic deficiency in macrophage function that prevents these cells from expressing immunity. If this proves to be true, vaccinating susceptible humans against tuberculosis will be a difficult task.
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    Chemokines in Innate and Adaptive Host Defense: Basic Chemokinese Grammar for Immune Cells (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 891-928 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Chemokines compose a sophisticated communication system used by all our cell types, including immune cells. Chemokine messages are decoded by specific receptors that initiate signal transduction events leading to a multitude of cellular responses, leukocyte chemotaxis and adhesion in particular. Critical determinants of the in vivo activities of chemokines in the immune system include their presentation by endothelial cells and extracellular matrix molecules, as well as their cellular uptake via "silent" chemokine receptors (interceptors) leading either to their transcytosis or to degradation. These regulatory mechanisms of chemokine histotopography, as well as the promiscuous and overlapping receptor specificities of inflammation-induced chemokines, shape innate responses to infections and tissue damage. Conversely, the specific patterns of homeostatic chemokines, where each chemokine is perceived by a single receptor, are charting lymphocyte navigation routes for immune surveillance. This review presents our current understanding of the mechanisms that regulate the cellular perception and pathophysiologic meaning of chemokines.
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    Molecular Defects in Human Severe Combined Immunodeficiency and Approaches to Immune Reconstitution (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 625-655 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Mutations in nine different genes have been found to cause the human severe combined immunodeficiency syndrome. The products of three of the genes-IL-2RG, Jak3, and IL-7Ralpha-are components of cytokine receptors, and the products of three more-RAG1, RAG2, and Artemis-are essential for effecting antigen receptor gene rearrangement. Additionally, a deficiency of CD3delta, a component of the T-cell antigen receptor, results in a near absence of circulating mature CD3+ T cells and a complete lack of gamma/delta T cells. Adenosine deaminase deficiency results in toxic accumulations of metabolites that cause T cell apoptosis. Finally, a deficiency of CD45, a critical regulator of signaling thresholds in immune cells, also causes SCID. Approaches to immune reconstitution have included bone marrow transplantation and gene therapy. Bone marrow transplantation, both HLA identical unfractionated and T cell-depleted HLA haploidentical, has been very successful in effecting immune reconstitution if done in the first 3.5 months of life and without pretransplant chemotherapy. Gene therapy was highly successful in nine infants with X-linked SCID, but the trials have been placed on hold due to the development of a leukemic process in two of the children because of insertional oncogenesis.
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    Drosophila: The Genetics of Innate Immune Recognition and Response (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 457-483 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Because of the evolutionary conservation of innate mechanisms of host defense, Drosophila has emerged as an ideal animal in which to study the genetic control of immune recognition and responses. The discovery that the Toll pathway is required for defense against fungal infection in Drosophila was pivotal in studies of both mammalian and Drosophila immunity. Subsequent genetic screens in Drosophila to isolate additional mutants unable to induce humoral responses to infection have identified and ordered the function of components of two signaling cascades, the Toll and Imd pathways, that activate responses to infection. Drosophila blood cells also contribute to host defense through phagocytosis and signaling, and may carry out a form of self-nonself recognition that is independent of microbial pattern recognition. Recent work suggests that Drosophila will be a useful model for dissecting virulence mechanisms of several medically important pathogens.
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    Phosphoinositide 3-Kinase: Diverse Roles in Immune Cell Activation (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 563-598 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Cells of the immune system carry out diverse functions that are controlled by surface receptors for antigen, costimulatory molecules, cytokines, chemokines, and other ligands. A shared feature of signal transduction downstream of most receptors on immune cells, as in nonhematopoietic cell types, is the activation of phosphoinositide 3-kinase (PI3K). The mechanism by which this common signaling event is elicited by distinct receptors and contributes to unique functional outcomes is an intriguing puzzle. Understanding how specificity is achieved in PI3K signaling is of particular significance because altered regulation of this pathway is observed in many disease states, including leukemia and lymphoma. Here we review recent advances in the understanding of PI3K signaling mechanisms in different immune cells and receptor systems. We emphasize the concept that PI3K and its products are components of complex networks of interacting proteins and second messengers, rather than simple links in linear signaling cascades.
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    Naturally Arising CD4+ Regulatory T Cells for Immunologic Self-Tolerance and Negative Control of Immune Responses (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 531-562 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Naturally occurring CD4+ regulatory T cells, the majority of which express CD25, are engaged in dominant control of self-reactive T cells, contributing to the maintenance of immunologic self-tolerance. Their depletion or functional alteration leads to the development of autoimmune disease in otherwise normal animals. The majority, if not all, of such CD25+CD4+ regulatory T cells are produced by the normal thymus as a functionally distinct and mature subpopulation of T cells. Their repertoire of antigen specificities is as broad as that of naive T cells, and they are capable of recognizing both self and nonself antigens, thus enabling them to control various immune responses. In addition to antigen recognition, signals through various accessory molecules and via cytokines control their activation, expansion, and survival, and tune their suppressive activity. Furthermore, the generation of CD25+CD4+ regulatory T cells in the immune system is at least in part developmentally and genetically controlled. Genetic defects that primarily affect their development or function can indeed be a primary cause of autoimmune and other inflammatory disorders in humans. Based on recent advances in our understanding of the cellular and molecular basis of this T cell-mediated immune regulation, this review discusses how naturally arising CD25+CD4+ regulatory T cells contribute to the maintenance of immunologic self-tolerance and negative control of various immune responses, and how they can be exploited to prevent and treat autoimmune disease, allergy, cancer, and chronic infection, or establish donor-specific transplantation tolerance.
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    GENETIC TESTING IN PRIMARY CARE (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Genomics and Human Genetics 5 (2004), S. 1-14 
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    ISSN: 1527-8204
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Rapid advances in genetic research are leading to an expanding array of genetic tests. Primary care providers will increasingly be challenged to identify patients whose symptoms, physical findings, or family history indicate the need for genetic testing, and to determine how to use genetic information most effectively to improve disease prevention. In addressing these challenges, practitioners will need to consider the range of different uses of genetic testing, including diagnosis in symptomatic and asymptomatic people, risk assessment, reproductive decision-making, and population screening. They will need a set of core skills and knowledge to evaluate family history and to recognize clinical findings that indicate genetic risk. At the same time, the primary care perspective will contribute to the evaluation of appropriate uses of genetic testing. A partnership between medical genetics and primary care will help to ensure the development of effective policies, educational tools, and practice guidelines for the coming era of genomic health care.
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    GENETIC SCREENING: Carriers and Affected Individuals (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Genomics and Human Genetics 5 (2004), S. 57-69 
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    ISSN: 1527-8204
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Genetic screening utilizes analytical approaches adapted for high throughput to identify carrier and affected individuals in a targeted population. Currently, genetic screening focuses on carrier screening, prenatal screening, and newborn screening. Newborn screening should serve as a model for all genetic screening, with more than forty years of experience and numerous lessons learned. As with all genetic screening, there are policy concerns in newborn screening regarding which disorders and technologies should be selected, and how centralized or decentralized the process to set policy should be. The need to share experiences and develop databases transcends all other policy considerations in genetic screening. The future will see population-based screening for adult-onset disorders. However, there needs to be extensive research to define predictive risk for various ethnocultural groups and to determine effective interventions. Ethical concerns regarding the timing of population screening, as well as the scope of use of information, will need to be resolved if genomic medicine will achieve its promise of a predictive, preventive, and personalized medicine.
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    FINDING PROSTATE CANCER SUSCEPTIBILITY GENES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Genomics and Human Genetics 5 (2004), S. 151-175 
    Details
    ISSN: 1527-8204
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Prostate cancer is a heterogeneous disease with multiple loci contributing to susceptibility. Traditionally, genome-wide scans using high-risk families have utilized stratification by number of affected individuals, family history of other cancers, or family age at diagnosis to improve genetic homogeneity. In addition to locus heterogeneity, for later onset diseases such as prostate cancer, a major limitation to mapping efforts is that key parental DNA samples are rarely available. The lack of available samples from upper generations reduces inheritance information, and as a result, the standard 10-cM genome scan does not provide full power to detect linkage. To increase the ability to find disease-associated loci, much denser genome-wide scans must be undertaken in multiple ethnic groups. In addition, new ways of defining homogenous subsets of families need to be developed.
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    NEW DEVELOPMENTS IN MITOCHONDRIAL ASSEMBLY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 309-335 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The mitochondrion has developed an elaborate translocation system for the import of nuclear-coded proteins and the export of proteins coded on the mitochondrial genome. Precursor proteins contain targeting and sorting information to reach the mitochondrion, whereas the translocons recognize the information and direct the precursor to the correct compartment. The outer membrane contains the TOM (translocase of the outer membrane) complex for translocation and the SAM (sorting and assembly machinery) complex for assembly of outer membrane proteins with complex topologies. At the inner membrane, the TIM23 (translocase of the inner membrane) mediates the import of mitochondrial proteins with a typical N-terminal targeting sequence, and the TIM22 complex mediates the import of polytopic inner membrane proteins. Based on its prokaryotic origin, the inner membrane also contains several components that mediate the export and assembly of proteins from within the matrix. Together the translocation and assembly complexes coordinate assembly of the mitochondrion.
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    CORTICAL NEURONAL MIGRATION MUTANTS SUGGEST SEPARATE BUT INTERSECTING PATHWAYS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 593-618 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: During brain development, neurons migrate great distances from proliferative zones to generate the cortical gray matter. A series of studies has identified genes that are critical for migration and targeting of neurons to specific brain regions. These genes encode three basic groups of proteins and produce three distinct phenotypes. The first group encodes cytoskeletal molecules and produces graded and dosage-dependent effects, with a significant amount of functional redundancy. This group also appears to play important roles during the initiation and ongoing progression of neuronal movement. The second group encodes signaling molecules for which homozygous mutations lead to an inverted cortex. In addition, this group is responsible for movement of neurons through anatomic boundaries to specific cortical layers. The third group encodes enzymatic regulators of glycosylation and appears to delineate where neuronal migration will arrest. There is significant cross-talk among these different groups of molecules, suggesting possible points of pathway convergence.
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    MEMBRANE DOMAINS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 839-866 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Considerable evidence shows that lateral inhomogeneities in lipid composition and physical properties exist in biological membranes. These membrane lipid domains are proposed to play important roles in processes such as signal transduction and membrane traffic. However, there is not at present an adequate description of the nature of these lipid domains in terms of their size, abundance, composition, or dynamics. We discuss the current analyses of the properties and function of membrane domains in cells and compare their properties with chemically simpler model membrane systems that can be understood in greater detail.
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    MOLECULAR MECHANISMS OF MAMMALIAN DNA REPAIR AND THE DNA DAMAGE CHECKPOINTS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 39-85 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: DNA damage is a relatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismic death. Damage to DNA induces several cellular responses that enable the cell either to eliminate or cope with the damage or to activate a programmed cell death process, presumably to eliminate cells with potentially catastrophic mutations. These DNA damage response reactions include: (a) removal of DNA damage and restoration of the continuity of the DNA duplex; (b) activation of a DNA damage checkpoint, which arrests cell cycle progression so as to allow for repair and prevention of the transmission of damaged or incompletely replicated chromosomes; (c) transcriptional response, which causes changes in the transcription profile that may be beneficial to the cell; and (d) apoptosis, which eliminates heavily damaged or seriously deregulated cells. DNA repair mechanisms include direct repair, base excision repair, nucleotide excision repair, double-strand break repair, and cross-link repair. The DNA damage checkpoints employ damage sensor proteins, such as ATM, ATR, the Rad17-RFC complex, and the 9-1-1 complex, to detect DNA damage and to initiate signal transduction cascades that employ Chk1 and Chk2 Ser/Thr kinases and Cdc25 phosphatases. The signal transducers activate p53 and inactivate cyclin-dependent kinases to inhibit cell cycle progression from G1 to S (the G1/S checkpoint), DNA replication (the intra-S checkpoint), or G2 to mitosis (the G2/M checkpoint). In this review the molecular mechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed.
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    PALMITOYLATION OF INTRACELLULAR SIGNALING PROTEINS: Regulation and Function (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 559-587 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Protein S-palmitoylation is the thioester linkage of long-chain fatty acids to cysteine residues in proteins. Addition of palmitate to proteins facilitates their membrane interactions and trafficking, and it modulates protein-protein interactions and enzyme activity. The reversibility of palmitoylation makes it an attractive mechanism for regulating protein activity, and this feature has generated intensive investigation of this modification. The regulation of palmitoylation occurs through the actions of protein acyltransferases and protein acylthioesterases. Identification of the protein acyltransferases Erf2/Erf4 and Akr1 in yeast has provided new insight into the palmitoylation reaction. These molecules work in concert with thioesterases, such as acyl-protein thioesterase 1, to regulate the palmitoylation status of numerous signaling molecules, ultimately influencing their function. This review discusses the function and regulation of protein palmitoylation, focusing on intracellular proteins that participate in cell signaling or protein trafficking.
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    OPIOID RECEPTORS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 953-990 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Opioid receptors belong to the large superfamily of seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental physiological importance mediating the actions of the majority of known neurotransmitters and hormones. Opioid receptors are particularly intriguing members of this receptor family. They are activated both by endogenously produced opioid peptides and by exogenously administered opiate compounds, some of which are not only among the most effective analgesics known but also highly addictive drugs of abuse. A fundamental question in addiction biology is why exogenous opioid drugs, such as morphine and heroin, have a high liability for inducing tolerance, dependence, and addiction. This review focuses on many aspects of opioid receptors with the aim of gaining a greater insight into mechanisms of opioid tolerance and dependence.
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    EUKARYOTIC mRNA DECAPPING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 861-890 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Eukaryotic mRNAs are primarily degraded by removal of the 3' poly(A) tail, followed either by cleavage of the 5' cap structure (decapping) and 5'-〉3' exonucleolytic digestion, or by 3' to 5' degradation. mRNA decapping represents a critical step in turnover because this permits the degradation of the mRNA and is a site of numerous control inputs. Recent analyses suggest decapping of an mRNA consists of four central and related events. These include removal, or inactivation, of the poly(A) tail as an inhibitor of decapping, exit from active translation, assembly of a decapping complex on the mRNA, and sequestration of the mRNA into discrete cytoplasmic foci where decapping can occur. Each of these steps is a demonstrated, or potential, site for the regulation of mRNA decay. We discuss the decapping process in the light of these central properties, which also suggest fundamental aspects of cytoplasmic mRNA physiology that connect decapping, translation, and storage of mRNA.
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    REGULATION OF TELOMERASE BY TELOMERIC PROTEINS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 177-208 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Telomeres are essential for genome stability in all eukaryotes. Changes in telomere functions and the associated chromosomal abnormalities have been implicated in human aging and cancer. Telomeres are composed of repetitive sequences that can be maintained by telomerase, a complex containing a reverse transcriptase (hTERT in humans and Est2 in budding yeast), a template RNA (hTERC in humans and Tlc1 in yeast), and accessory factors (the Est1 proteins and dyskerin in humans and Est1, Est3, and Sm proteins in budding yeast). Telomerase is regulated in cis by proteins that bind to telomeric DNA. This regulation can take place at the telomere terminus, involving single-stranded DNA-binding proteins (POT1 in humans and Cdc13 in budding yeast), which have been proposed to contribute to the recruitment of telomerase and may also regulate the extent or frequency of elongation. In addition, proteins that bind along the length of the telomere (TRF1/TIN2/tankyrase in humans and Rap1/Rif1/Rif2 in budding yeast) are part of a negative feedback loop that regulates telomere length. Here we discuss the details of telomerase and its regulation by the telomere.
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    LYSOPHOSPHOLIPID RECEPTORS: Signaling and Biology (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 321-354 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Lysophospholipids (LPs), such as lysophosphatidic acid and sphingosine 1-phosphate, are membrane-derived bioactive lipid mediators. LPs can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes that include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis. In recent years, identification of multiple cognate G protein-coupled receptors has provided a mechanistic framework for understanding how LPs play such diverse roles. Generation of LP receptor-null animals has allowed rigorous examination of receptor-mediated physiological functions in vivo and has identified new functions for LP receptor signaling. Efforts to develop LP receptor subtype-specific agonists/antagonists are in progress and raise expectations for a growing collection of chemical tools and potential therapeutic compounds. The rapidly expanding literature on the LP receptors is herein reviewed.
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    DIRECTED EVOLUTION OF NUCLEIC ACID ENZYMES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 791-836 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Just as Darwinian evolution in nature has led to the development of many sophisticated enzymes, Darwinian evolution in vitro has proven to be a powerful approach for obtaining similar results in the laboratory. This review focuses on the development of nucleic acid enzymes starting from a population of random-sequence RNA or DNA molecules. In order to illustrate the principles and practice of in vitro evolution, two especially well-studied categories of catalytic nucleic acid are considered: RNA enzymes that catalyze the template-directed ligation of RNA and DNA enzymes that catalyze the cleavage of RNA. The former reaction, which involves attack of a 2'- or 3'-hydroxyl on the alpha-phosphate of a 5'-triphosphate, is more difficult. It requires a comparatively larger catalytic motif, containing more nucleotides than can be sampled exhaustively within a starting population of random-sequence RNAs. The latter reaction involves deprotonation of the 2'-hydroxyl adjacent to the cleavage site, resulting in cleaved products that bear a 2',3'-cyclic phosphate and 5'-hydroxyl. The difficulty of this reaction, and therefore the complexity of the corresponding DNA enzyme, depends on whether a catalytic cofactor, such as a divalent metal cation or small molecule, is present in the reaction mixture.
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    CYTOCHROME C-MEDIATED APOPTOSIS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 87-106 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Apoptosis, or programmed cell death, is involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. Apoptosis is executed by a subfamily of cysteine proteases known as caspases. In mammalian cells, a major caspase activation pathway is the cytochrome c-initiated pathway. In this pathway, a variety of apoptotic stimuli cause cytochrome c release from mitochondria, which in turn induces a series of biochemical reactions that result in caspase activation and subsequent cell death. In this review, we focus on the recent progress in understanding the biochemical mechanisms and regulation of the pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values.
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    REGULATION OF TELOMERASE BY TELOMERIC PROTEINS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 177-208 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Telomeres are essential for genome stability in all eukaryotes. Changes in telomere functions and the associated chromosomal abnormalities have been implicated in human aging and cancer. Telomeres are composed of repetitive sequences that can be maintained by telomerase, a complex containing a reverse transcriptase (hTERT in humans and Est2 in budding yeast), a template RNA (hTERC in humans and Tlc1 in yeast), and accessory factors (the Est1 proteins and dyskerin in humans and Est1, Est3, and Sm proteins in budding yeast). Telomerase is regulated in cis by proteins that bind to telomeric DNA. This regulation can take place at the telomere terminus, involving single-stranded DNA-binding proteins (POT1 in humans and Cdc13 in budding yeast), which have been proposed to contribute to the recruitment of telomerase and may also regulate the extent or frequency of elongation. In addition, proteins that bind along the length of the telomere (TRF1/TIN2/tankyrase in humans and Rap1/Rif1/Rif2 in budding yeast) are part of a negative feedback loop that regulates telomere length. Here we discuss the details of telomerase and its regulation by the telomere.
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    DNA POLYMERASE gamma, THE MITOCHONDRIAL REPLICASE 1 (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 293-320 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: DNA polymerase (pol) gamma is the sole DNA polymerase in animal mitochondria. Biochemical and genetic evidence document a key role for pol gamma in mitochondrial DNA replication, and whereas DNA repair and recombination were thought to be limited or absent in animal mitochondria, both have been demonstrated in recent years. Thus, the mitochondrial replicase is also apparently responsible for the relevant DNA synthetic reactions in these processes. Pol gamma comprises a catalytic core in a heterodimeric complex with an accessory subunit. The two-subunit holoenzyme is an efficient and processive polymerase, which exhibits high fidelity in nucleotide selection and incorporation while proofreading errors with its intrinsic 3' 5' exonuclease. Incorporation of nucleotide analogs followed by proofreading failure leads to mitochondrial toxicity in antiviral therapy, and misincorporation during DNA replication leads to mitochondrial mutagenesis and dysfunction. This review describes our current understanding of pol gamma biochemistry and biology, and it introduces other key proteins that function at the mitochondrial DNA replication fork.
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    ANALYZING CELLULAR BIOCHEMISTRY IN TERMS OF MOLECULAR NETWORKS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 1051-1087 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: One way to understand cells and circumscribe the function of proteins is through molecular networks. These networks take a variety of forms including webs of protein-protein interactions, regulatory circuits linking transcription factors and targets, and complex pathways of metabolic reactions. We first survey experimental techniques for mapping networks (e.g., the yeast two-hybrid screens). We then turn our attention to computational approaches for predicting networks from individual protein features, such as correlating gene expression levels or analyzing sequence coevolution. All the experimental techniques and individual predictions suffer from noise and systematic biases. These problems can be overcome to some degree through statistical integration of different experimental datasets and predictive features (e.g., within a Bayesian formalism). Next, we discuss approaches for characterizing the topology of networks, such as finding hubs and analyzing subnetworks in terms of common motifs. Finally, we close with perspectives on how network analysis represents a preliminary step toward a systems approach for modeling cells.
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    STRUCTURE AND FUNCTION OF TOLC: The Bacterial Exit Duct for Proteins and Drugs (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 467-489 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The bacterial TolC protein plays a common role in the expulsion of diverse molecules, which include protein toxins and antibacterial drugs, from the cell. TolC is a trimeric 12-stranded alpha/beta barrel, comprising an alpha-helical trans-periplasmic tunnel embedded in the outer membrane by a contiguous beta-barrel channel. This structure establishes a 140 A long single pore fundamentally different to other membrane proteins and presents an exit duct to substrates, large and small, engaged at specific inner membrane translocases. TolC is open to the outside medium but is closed at its periplasmic entrance. When TolC is recruited by a substrate-laden translocase, the entrance is opened to allow substrate passage through a contiguous machinery spanning the entire cell envelope, from the cytosol to the external environment. Transition to the transient open state is achieved by an iris-like mechanism in which entrance alpha-helices undergo an untwisting realignment, thought to be stabilized by interaction with periplasmic helices of the translocase. TolC family proteins are ubiquitous among gram-negative bacteria, and the conserved entrance aperture presents a possible cheomotherapeutic target in multidrug-resistant pathogens.
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    EMERGING PRINCIPLES OF CONFORMATION-BASED PRION INHERITANCE (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 617-656 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The prion hypothesis proposes that proteins can act as infectious agents. Originally formulated to explain transmissible spongiform encephalopathies (TSEs), the prion hypothesis has been extended with the finding that several non-Mendelian traits in fungi are due to heritable changes in protein conformation, which may in some cases be beneficial. Although much remains to be learned about the specific role of cellular cofactors, mechanistic parallels between the mammalian and yeast prion phenomena point to universal features of conformation-based infection and inheritance involving propagation of ordered beta-sheet-rich protein aggregates commonly referred to as amyloid. Here we focus on two such features and discuss recent efforts to explain them in terms of the physical properties of amyloid-like aggregates. The first is prion strains, wherein chemically identical infectious particles cause distinct phenotypes. The second is barriers that often prohibit prion transmission between different species. There is increasing evidence suggesting that both of these can be manifestations of the same phenomenon: the ability of a protein to misfold into multiple self-propagating conformations. Even single mutations can change the spectrum of favored misfolded conformations. In turn, changes in amyloid conformation can shift the specificity of propagation and alter strain phenotypes. This model helps explain many common and otherwise puzzling features of prion inheritance as well as aspects of noninfectious diseases involving toxic misfolded proteins.
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    USING PROTEIN FOLDING RATES TO TEST PROTEIN FOLDING THEORIES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 837-859 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The fastest simple, kinetically two-state protein folds a million times more rapidly than the slowest. Here we review many recent theories of protein folding kinetics in terms of their ability to qualitatively rationalize, if not quantitatively predict, this fundamental experimental observation.
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    INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS AS SIGNAL INTEGRATORS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 437-465 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The inositol 1,4,5 trisphosphate (IP3) receptor (IP3R) is a Ca2+ release channel that responds to the second messenger IP3. Exquisite modulation of intracellular Ca2+ release via IP3Rs is achieved by the ability of IP3R to integrate signals from numerous small molecules and proteins including nucleotides, kinases, and phosphatases, as well as nonenzyme proteins. Because the ion conduction pore composes only ~5% of the IP3R, the great bulk of this large protein contains recognition sites for these substances. Through these regulatory mechanisms, IP3R modulates diverse cellular functions, which include, but are not limited to, contraction/excitation, secretion, gene expression, and cellular growth. We review the unique properties of the IP3R that facilitate cell-type and stimulus-dependent control of function, with special emphasis on protein-binding partners.
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    THE SIR2 FAMILY OF PROTEIN DEACETYLASES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 417-435 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The yeast SIR protein complex has been implicated in transcription silencing and suppression of recombination. The Sir complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4, the SIR2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD+-dependent deacetylase, which is broadly conserved from bacteria to higher eukaryotes. In this review, we discuss the role of NAD+, the unusual products of the deacetylation reaction, the Sir2 structure, and the Sir2 chemical inhibitors and activators that were recently identified. We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging.
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    RETURN OF THE GDI: The GoLoco Motif in Cell Division (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 925-951 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The GoLoco motif is a 19-amino-acid sequence with guanine nucleotide dissociation inhibitor activity against G-alpha subunits of the adenylyl-cyclase-inhibitory subclass. The GoLoco motif is present as an independent element within multidomain signaling regulators, such as Loco, RGS12, RGS14, and Rap1GAP, as well as in tandem arrays in proteins, such as AGS3, G18, LGN, Pcp-2/L7, and Partner of Inscuteable (Pins/Rapsynoid). Here we discuss the biochemical mechanisms of GoLoco motif action on G-alpha subunits in light of the recent crystal structure of G-alpha-i1 bound to the RGS14 GoLoco motif. Currently, there is sparse evidence for GoLoco motif regulation of canonical G-protein-coupled receptor signaling. Rather, studies of asymmetric cell division in Drosophila and Caenorhabditis elegans, as well as mammalian mitosis, implicate GoLoco proteins, such as Pins, GPR-1/GPR-2, LGN, and RGS14, in mitotic spindle organization and force generation. We discuss potential mechanisms by which GoLoco/Galpha complexes might modulate spindle dynamics.
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    INTERMEDIATE FILAMENTS: Molecular Structure, Assembly Mechanism, and Integration Into Functionally Distinct Intracellular Scaffolds (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 749-789 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The superfamily of intermediate filament (IF) proteins contains at least 65 distinct proteins in man, which all assemble into ~10 nm wide filaments and are principal structural elements both in the nucleus and the cytoplasm with essential scaffolding functions in metazoan cells. At present, we have only circumstantial evidence of how the highly divergent primary sequences of IF proteins lead to the formation of seemingly similar polymers and how this correlates with their function in individual cells and tissues. Point mutations in IF proteins, particularly in lamins, have been demonstrated to lead to severe, inheritable multi-systemic diseases, thus underlining their importance at several functional levels. Recent structural work has now begun to shed some light onto the complex fine tuning of structure and function in these fibrous, coiled coil forming multidomain proteins and their contribution to cellular physiology and gene regulation.
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    THE EXCITEMENT OF DISCOVERY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 1-37 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: I had the good luck to start research at the dawn of molecular biology when it was possible to ask fundamental questions about the nature of the nucleic acids and how information is transferred in living systems. The search for answers led me into many different areas, often with the question of how molecular structure leads to biological function. Early work in this period provided some of the roots supporting the current explosive developments in life sciences. Here I give a brief account of my development, describe some contributions, and provide a hint of the exhilaration in discovering new things. Most of all, I had the good fortune to have inspiring teachers, stimulating colleagues, and excellent students.
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    NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY OF HIGH-MOLECULAR-WEIGHT PROTEINS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 107-146 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Recent developments in NMR spectroscopy, which include new experiments that increase the lifetimes of NMR signals or that precisely define the orientation of internuclear bond vectors with respect to a common molecular frame, have significantly increased the size of proteins for which quantitative structural and dynamic information can be obtained. These experiments have, in turn, benefited from new labeling strategies that continue to drive the field. The utility of the new methodology is illustrated by considering applications to malate synthase G, a 723 residue enzyme, which is the largest single polypeptide chain for which chemical shift assignments have been obtained to date. New experiments developed specifically to address the complexity and low sensitivity of spectra recorded on this protein are presented. A discussion of the chemical information that is readily available from studies of systems in the 100 kDa mol wt range is included. Prospects for membrane protein structure determination are discussed briefly in the context of an application to an Escherichia coli enzyme, PagP, localized to the outer membrane of gram-negative bacteria.
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    STRUCTURAL BASIS OF ION PUMPING BY CA2+-ATPASE OF THE SARCOPLASMIC RETICULUM (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 269-292 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The structures of the Ca2+-ATPase (SERCA1a) have been determined for five different states by X-ray crystallography. Detailed comparison of the structures in the Ca2+ bound form and unbound (but thapsigargin bound) form reveals that very large rearrangements of the transmembrane helices take place accompanying Ca2+ dissociation and binding and that they are mechanically linked with equally large movements of the cytoplasmic domains. The meanings of the rearrangements of the transmembrane helices and those of the cytoplasmic domains as well as the mechanistic roles of phosphorylation are now becoming clear. Furthermore, the roles of critical amino acid residues identified by extensive mutagenesis studies are becoming evident in terms of atomic structure.
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    PYRIDOXAL PHOSPHATE ENZYMES: Mechanistic, Structural, and Evolutionary Considerations (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 383-415 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Pyridoxal phosphate (PLP)-dependent enzymes are unrivaled in the diversity of reactions that they catalyze. New structural data have paved the way for targeted mutagenesis and mechanistic studies and have provided a framework for interpretation of those results. Together, these complementary approaches yield new insight into function, particularly in understanding the origins of substrate and reaction type specificity. The combination of new sequences and structures enables better reconstruction of their evolutionary heritage and illuminates unrecognized similarities within this diverse group of enzymes. The important metabolic roles of many PLP-dependent enzymes drive efforts to design specific inhibitors, which are now guided by the availability of comprehensive structural and functional databases. Better understanding of the function of this important group of enzymes is crucial not only for inhibitor design, but also for the design of improved protein-based catalysts.
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    STRUCTURE AND FUNCTION OF TOLC: The Bacterial Exit Duct for Proteins and Drugs (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 467-489 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The bacterial TolC protein plays a common role in the expulsion of diverse molecules, which include protein toxins and antibacterial drugs, from the cell. TolC is a trimeric 12-stranded alpha/beta barrel, comprising an alpha-helical trans-periplasmic tunnel embedded in the outer membrane by a contiguous beta-barrel channel. This structure establishes a 140 A long single pore fundamentally different to other membrane proteins and presents an exit duct to substrates, large and small, engaged at specific inner membrane translocases. TolC is open to the outside medium but is closed at its periplasmic entrance. When TolC is recruited by a substrate-laden translocase, the entrance is opened to allow substrate passage through a contiguous machinery spanning the entire cell envelope, from the cytosol to the external environment. Transition to the transient open state is achieved by an iris-like mechanism in which entrance alpha-helices undergo an untwisting realignment, thought to be stabilized by interaction with periplasmic helices of the translocase. TolC family proteins are ubiquitous among gram-negative bacteria, and the conserved entrance aperture presents a possible cheomotherapeutic target in multidrug-resistant pathogens.
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    EMERGING PRINCIPLES OF CONFORMATION-BASED PRION INHERITANCE (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 617-656 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The prion hypothesis proposes that proteins can act as infectious agents. Originally formulated to explain transmissible spongiform encephalopathies (TSEs), the prion hypothesis has been extended with the finding that several non-Mendelian traits in fungi are due to heritable changes in protein conformation, which may in some cases be beneficial. Although much remains to be learned about the specific role of cellular cofactors, mechanistic parallels between the mammalian and yeast prion phenomena point to universal features of conformation-based infection and inheritance involving propagation of ordered beta-sheet-rich protein aggregates commonly referred to as amyloid. Here we focus on two such features and discuss recent efforts to explain them in terms of the physical properties of amyloid-like aggregates. The first is prion strains, wherein chemically identical infectious particles cause distinct phenotypes. The second is barriers that often prohibit prion transmission between different species. There is increasing evidence suggesting that both of these can be manifestations of the same phenomenon: the ability of a protein to misfold into multiple self-propagating conformations. Even single mutations can change the spectrum of favored misfolded conformations. In turn, changes in amyloid conformation can shift the specificity of propagation and alter strain phenotypes. This model helps explain many common and otherwise puzzling features of prion inheritance as well as aspects of noninfectious diseases involving toxic misfolded proteins.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.72.121801.161837
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    DIRECTED EVOLUTION OF NUCLEIC ACID ENZYMES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 791-836 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Just as Darwinian evolution in nature has led to the development of many sophisticated enzymes, Darwinian evolution in vitro has proven to be a powerful approach for obtaining similar results in the laboratory. This review focuses on the development of nucleic acid enzymes starting from a population of random-sequence RNA or DNA molecules. In order to illustrate the principles and practice of in vitro evolution, two especially well-studied categories of catalytic nucleic acid are considered: RNA enzymes that catalyze the template-directed ligation of RNA and DNA enzymes that catalyze the cleavage of RNA. The former reaction, which involves attack of a 2'- or 3'-hydroxyl on the alpha-phosphate of a 5'-triphosphate, is more difficult. It requires a comparatively larger catalytic motif, containing more nucleotides than can be sampled exhaustively within a starting population of random-sequence RNAs. The latter reaction involves deprotonation of the 2'-hydroxyl adjacent to the cleavage site, resulting in cleaved products that bear a 2',3'-cyclic phosphate and 5'-hydroxyl. The difficulty of this reaction, and therefore the complexity of the corresponding DNA enzyme, depends on whether a catalytic cofactor, such as a divalent metal cation or small molecule, is present in the reaction mixture.
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    RETURN OF THE GDI: The GoLoco Motif in Cell Division (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 925-951 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The GoLoco motif is a 19-amino-acid sequence with guanine nucleotide dissociation inhibitor activity against G-alpha subunits of the adenylyl-cyclase-inhibitory subclass. The GoLoco motif is present as an independent element within multidomain signaling regulators, such as Loco, RGS12, RGS14, and Rap1GAP, as well as in tandem arrays in proteins, such as AGS3, G18, LGN, Pcp-2/L7, and Partner of Inscuteable (Pins/Rapsynoid). Here we discuss the biochemical mechanisms of GoLoco motif action on G-alpha subunits in light of the recent crystal structure of G-alpha-i1 bound to the RGS14 GoLoco motif. Currently, there is sparse evidence for GoLoco motif regulation of canonical G-protein-coupled receptor signaling. Rather, studies of asymmetric cell division in Drosophila and Caenorhabditis elegans, as well as mammalian mitosis, implicate GoLoco proteins, such as Pins, GPR-1/GPR-2, LGN, and RGS14, in mitotic spindle organization and force generation. We discuss potential mechanisms by which GoLoco/Galpha complexes might modulate spindle dynamics.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073756
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    THE BIOLOGY OF XYLEM FLUID-FEEDING INSECT VECTORS OF XYLELLA FASTIDIOSA AND THEIR RELATION TO DISEASE EPIDEMIOLOGY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Entomology 49 (2004), S. 243-270 
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    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Xylophagous leafhopppers are common and abundant insects of tropical and subtropical environments and play important ecological roles in these ecosystems. The feeding biology of these insects is unique in terms of their high feeding rates and a digestive physiology that allows them to assimilate amino acids, organic acids, and sugars at approximately 99% efficiency. For those species well studied, fluctuations in plant xylem chemistry and tension appear to determine the diurnal and seasonal use of their host plants. Relatively few species of xylem fluid-feeding leafhoppers are considered important pests in commercial agriculture, as they transmit the bacterial plant pathogen Xylella fastidiosa. X. fastidiosa induces diseases of grapevines, citrus, coffee, almond, alfalfa, stone fruits, landscape ornamentals, and native hardwoods for which there is no cure. Two Xylella diseases, citrus variegated chlorosis (CVC) and Pierce's disease (PD) of grapevines, have emerged as important issues within the past decade. In Brazil, CVC became important in the early 1990s and has now expanded throughout many citrus-growing areas of South America and threatens to spread to North America. The recent establishment of the exotic glassy-winged sharpshooter (Homalodisca coagulata) in California now threatens much of the United States' wine grape, table grape, and almond production. The spread of H. coagulata throughout southern California and the spread of CVC northward from Argentina through Brazil exemplifies the biological risks from exotic species. The occurrence and epidemiology of leafhopper-vectored Xylella diseases are discussed.
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    URL: http://dx.doi.org/10.1146/annurev.ento.49.061802.123403
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    PLANT-INSECT INTERACTIONS IN FRAGMENTED LANDSCAPES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Entomology 49 (2004), S. 405-430 
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    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Population and community ecology need a large-scale perspective because local patterns (of biodiversity) and processes (trophic interactions) are influenced by the regional setting. The ratio of the foraging range and/or dispersal ability to the distance between landscape elements influences local population dynamics. The spatial scale experienced by a species may be linked to its trophic level and also to traits such as body size, resource specialization, rarity, and population size variability. Hence, communities are assemblages of species with different spatial strategies. Effects of habitat loss and habitat fragmentation on plant-herbivore, herbivore-enemy, as well as plant-pollinator interactions are contingent on species and landscape. Metapopulation theory provides a unifying frame to approach plant-insect systems across fragmented landscape, although the landscape context is often ignored. In some cases theory is far ahead of empirical research. We call for more population data on large spatial and temporal scales to better understand plant-insect populations across fragmented landscapes.
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    INSECT WALKING AND ROBOTICS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Entomology 49 (2004), S. 51-70 
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    ISSN: 0066-4170
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: With the advent of significant collaborations between researchers who study insect walking and robotics engineers interested in constructing adaptive legged robots, insect walking is once again poised to make a more significant scientific contribution than the numbers of participants in the field might suggest. This review outlines current knowledge of the physiological basis of insect walking with an emphasis on recent new developments in biomechanics and genetic dissection of behavior, and the impact this knowledge is having on robotics. Engineers have begun to team with neurobiologists to build walking robots whose physical design and functional control are based on insect biology. Such an approach may have benefits for engineering, by leading to the construction of better-performing robots, and for biology, by allowing real-time and real-world tests of critical hypotheses about how locomotor control is effected. It is argued that in order for the new field of biorobotics to have significant influence it must adopt criteria for performance and an experimental approach to the development of walking robots.
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    URL: http://dx.doi.org/10.1146/annurev.ento.49.061802.123257
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    Molecular and Integrative Physiology of Intestinal Peptide Transport (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 361-384 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Intestinal protein digestion generates a huge variety and quantity of short chain peptides that are absorbed into intestinal epithelial cells by the PEPT1 transporter in the apical membrane of enterocytes. PEPT1 operates as an electrogenic proton/peptide symporter with the ability to transport essentially every possible di- and tripeptide. Transport is enantio-selective and involves a variable proton-to-substrate stoichiometry for uptake of neutral and mono- or polyvalently charged peptides. Neither free amino acids nor peptides containing four or more amino acids are accepted as substrates. The structural similarity of a variety of drugs with the basic structure of di- or tripeptides explains the transport of aminocephalosporins and aminopenicillins, selected angiotensin-converting inhibitors, and amino acid-conjugated nucleoside-based antiviral agents by PEPT1. The high transport capacity of PEPT1 allows fast and efficient intestinal uptake of the drugs but also of amino acid nitrogen even in states of impaired mucosal functions. Transcriptional and post-transcriptional regulation of PEPT1 occurs in response to alterations in the nutritional status and in disease states, suggesting a prime role of this transporter in amino acid absorption.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.144149
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    Oral Rehydration Therapy: New Explanations for an Old Remedy (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 385-417 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Diarrheal diseases are among the most devastating illnesses globally, but the introduction of oral rehydration therapy has reduced mortality due to diarrhea from 〉5 million children, under the age of 5, in 1978 to 1.3 million in 2002. Variations of this simple therapy of salts and sugars are prevalent in traditional remedies in cultures world-wide, but only in the past four decades have the scientific bases for these remedies begun to be elucidated. This review aims to provide a broad understanding of the cellular basis of oral rehydration therapy. The features integral to the success of oral rehydration therapy are active glucose transport in the small intestine, commensal bacteria, and short-chain fatty acid transport in the colon. The review examines these processes and their regulation and considers new approaches that might supplement oral rehydration therapy in controlling diarrheal diseases.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032902.134726
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    The Extracellular Cyclic AMP-Adenosine Pathway in Renal Physiology (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 571-599 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Many cell types in the kidney express adenosine receptors, and adenosine has multiple effects on renal function. Although adenosine is produced within the kidney by several biochemical reactions, recent studies support a novel mechanism for renal adenosine production, the extracellular cAMP-adenosine pathway. This extracellular cAMP-adenosine pathway is initiated by efflux of cAMP from cells following activation of adenylyl cyclase. Extracellular cAMP is then converted to adenosine by the serial actions of ecto-phosphodiesterase and ecto-5'-nucleotidase. When extracellular cAMP is converted to adenosine near the biophase of cAMP production and efflux, this local extracellular cAMP-adenosine pathway permits tight coupling of the site of adenosine production to the site of adenosine receptors. cAMP in renal compartments may also be formed by tissues/organs remote from the kidney. For example, stimulation of hepatic adenylyl cyclase by the pancreatic hormone glucagon increases circulating cAMP, which is filtered at the glomerulus and concentrated in the tubular lumen as water is extracted from the ultrafiltrate. Conversion of hepatic-derived cAMP to adenosine in the kidney completes a pancreatohepatorenal cAMP-adenosine pathway that may serve as an endocrine link between the pancreas, liver, and kidney.
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    Genetically Engineered Mouse Models for Lung Cancer (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 647-663 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The lung is a complex organ consisting of numerous cell types that function to ensure sufficient gas exchange to oxygenate the blood. In order to accomplish this function, the lung must be exposed to the external environment and at the same time maintain a homeostatic balance between its function in gas exchange and the maintenance of inflammatory balance. During the past two decades, as molecular methodologies have evolved with the sequencing of entire genomes, the use of in vivo models to elucidate the molecular mechanisms involved in pulmonary physiology and disease have increased. The mouse has emerged as a potent model to investigate pulmonary physiology due to the explosion in molecular methods that now allow for the developmental and tissue-specific regulation of gene transcription. Initial efforts to manipulate gene expression in the mouse genome resulted in the generation of transgenic mice characterized by the constitutive expression of a specific gene and knockout mice characterized by the ablation of a specific gene. The utility of these original mouse models was limited, in many cases, by phenotypes resulting in embryonic or neonatal lethality that prevented analysis of the impact of the genetic manipulation on pulmonary biology. Second-generation transgenic mouse models employ multiple strategies that can either activate or silence gene expression thereby providing extensive temporal and spatial control of the experimental parameters of gene expression. These highly regulated mouse models are intended to serve as a foundation for further investigation of the molecular basis of human disease such as tumorigenesis. This review describes the principles, progress, and application of systems that are currently employed in the conditional regulation of gene expression in the investigation of lung cancer.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.134301
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    The Cytochrome bc1 Complex: Function in the Context of Structure (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 689-733 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The bc1 complexes are intrinsic membrane proteins that catalyze the oxidation of ubihydroquinone and the reduction of cytochrome c in mitochondrial respiratory chains and bacterial photosynthetic and respiratory chains. The bc1 complex operates through a Q-cycle mechanism that couples electron transfer to generation of the proton gradient that drives ATP synthesis. Genetic defects leading to mutations in proteins of the respiratory chain, including the subunits of the bc1 complex, result in mitochondrial myopathies, many of which are a direct result of dysfunction at catalytic sites. Some myopathies, especially those in the cytochrome b subunit, exacerbate free-radical damage by enhancing superoxide production at the ubihydroquinone oxidation site. This bypass reaction appears to be an unavoidable feature of the reaction mechanism. Cellular aging is largely attributable to damage to DNA and proteins from the reactive oxygen species arising from superoxide and is a major contributing factor in many diseases of old age. An understanding of the mechanism of the bc1 complex is therefore central to our understanding of the aging process. In addition, a wide range of inhibitors that mimic the quinone substrates are finding important applications in clinical therapy and agronomy. Recent structural studies have shown how many of these inhibitors bind, and have provided important clues to the mechanism of action and the basis of resistance through mutation. This paper reviews recent advances in our understanding of the mechanism of the bc1 complex and their relation to these physiologically important issues in the context of the structural information available.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.150251
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    Viral-Based Myocardial Gene Therapy Approaches to Alter Cardiac Function (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 49-75 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: In recent years there has been a rapid expansion in our understanding of the molecular biology that underpins human physiology. In the heart, elegant molecular pathways have been elucidated, and derangements in these pathways have been identified as factors in cardiac disease. However, as our understanding has grown, we have recognized that there exist only relatively crude tools to effect changes in molecular pathophysiology. The ultimate promise of gene therapy is to correct the molecular derangements that cause illness. To bring this promise to fruition in the clinical arena, many problems need to be solved, and chief among these remains reliable and robust delivery of genes to the target organ. To this end, viral vectors have been utilized with success more frequently than any other method of gene delivery. The use of these vectors in the heart has already offered promising novel benefit for human ischemic heart disease, and studies in animal models have given glimpses of hope that gene therapy may provide future therapeutic benefit in heart failure by improving cardiac function.
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    Structure and Function of Glutamate Receptor Ion Channels1 (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 161-181 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: A vast number of proteins are involved in synaptic function. Many have been cloned and their functional role defined with varying degrees of success, but their number and complexity currently defy any molecular understanding of the physiology of synapses. A beacon of success in this medieval era of synaptic biology is an emerging understanding of the mechanisms underlying the activity of the neurotransmitter receptors for glutamate. Largely as a result of structural studies performed in the past three years we now have a mechanistic explanation for the activation of channel gating by agonists and partial agonists; the process of desensitization, and its block by allosteric modulators, is also mostly explained; and the basis of receptor subtype selectivity is emerging with clarity as more and more structures are solved. In the space of months we have gone from cartoons of postulated mechanisms to hard fact. It is anticipated that this level of understanding will emerge for other synaptic proteins in the coming decade.
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    Sleep and Circadian Rhythms in Mammalian Torpor (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 275-289 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Sleep and circadian rhythms are the primary determinants of arousal state, and torpor is the most extreme state change that occurs in mammals. The view that torpor is an evolutionary extension of sleep is supported by electrophysiological studies. However, comparisons of factors that influence the expression of sleep and torpor uncover significant differences. Deep sleep immediately following torpor suggests that torpor is functionally a period of sleep deprivation. Recent studies that employ post-torpor sleep deprivation, however, show that the post-torpor intense sleep is not homeostatically regulated, but might be a reflection of synaptic loss and replacement. The circadian system regulates sleep expression in euthermic mammals in such a way that would appear to preclude multiday bouts of torpor. Indeed, the circadian system is robust in animals that show shallow torpor, but its activity in hibernators is at least damped if not absent. There is good evidence from some species, however, that the circadian system plays important roles in the timing of bouts of torpor.
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    Alterations in SP-B and SP-C Expression in Neonatal Lung Disease (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 601-623 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The hydrophobic surfactant proteins, SP-B and SP-C, have important roles in surfactant function. The importance of these proteins in normal lung function is highlighted by the lung diseases associated with abnormalities in their expression. Mutations in the gene encoding SP-B result in severe, fatal neonatal lung disease, and mutations in the gene encoding SP-C are associated with chronic interstitial lung diseases in newborns, older children, and adults. This work reviews the current state of knowledge concerning the lung diseases associated with mutations in the SP-B and SP-C genes, and the potential roles of abnormal SP-B and SP-C expression and genetic variation in these genes in other lung diseases.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.134711
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    Interpreting the BOLD Signal (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 735-769 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The development of functional magnetic resonance imaging (fMRI) has brought together a broad community of scientists interested in measuring the neural basis of the human mind. Because fMRI signals are an indirect measure of neural activity, interpreting these signals to make deductions about the nervous system requires some understanding of the signaling mechanisms. We describe our current understanding of the causal relationships between neural activity and the blood-oxygen-level-dependent (BOLD) signal, and we review how these analyses have challenged some basic assumptions that have guided neuroscience. We conclude with a discussion of how to use the BOLD signal to make inferences about the neural signal.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.66.082602.092845
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    Control of the Size of the Human Muscle Mass (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 799-828 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: This review is divided into two parts, the first dealing with the cell and molecular biology of muscle in terms of growth and wasting and the second being an account of current knowledge of physiological mechanisms involved in the alteration of size of the human muscle mass. Wherever possible, attempts have been made to interrelate the information in each part and to provide the most likely explanation for phenomena that are currently only partially understood. The review should be of interest to cell and molecular biologists who know little of human muscle physiology and to physicians, physiotherapists, and kinesiologists who may be familiar with the gross behavior of human muscle but wish to understand more about the underlying mechanisms of change.
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    Live Optical Imaging of Nervous System Development (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 771-798 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Although development of the nervous system is inherently a process of dynamic change, until recently it has generally been investigated by inference from static images. However, advances in live optical imaging are now allowing direct observation of growth, synapse formation, and even incipient function in the developing nervous system, at length scales from molecules to cortical regions, and over timescales from milliseconds to months. In this review, we provide technical background and present examples of how these new methods, including confocal and two-photon microscopy, GFP-based markers, and functional indicators, are being applied to provide fresh insight into long-standing questions of neural development.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.66.082602.095217
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    THE EVOLUTION OF HUMAN SKIN AND SKIN COLOR (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Anthropology 33 (2004), S. 585-623 
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    ISSN: 0084-6570
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Ethnic Sciences , Biology
    Notes: Humans skin is the most visible aspect of the human phenotype. It is distinguished mainly by its naked appearance, greatly enhanced abilities to dissipate body heat through sweating, and the great range of genetically determined skin colors present within a single species. Many aspects of the evolution of human skin and skin color can be reconstructed using comparative anatomy, physiology, and genomics. Enhancement of thermal sweating was a key innovation in human evolution that allowed maintenance of homeostasis (including constant brain temperature) during sustained physical activity in hot environments. Dark skin evolved pari passu with the loss of body hair and was the original state for the genus Homo. Melanin pigmentation is adaptive and has been maintained by natural selection. Because of its evolutionary lability, skin color phenotype is useless as a unique marker of genetic identity. In recent prehistory, humans became adept at protecting themselves from the environment through clothing and shelter, thus reducing the scope for the action of natural selection on human skin.
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    URL: http://dx.doi.org/10.1146/annurev.anthro.33.070203.143955
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    LANGUAGE BIRTH AND DEATH (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Anthropology 33 (2004), S. 201-222 
    Details
    ISSN: 0084-6570
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Ethnic Sciences , Biology
    Notes: Since the late 1980s, language endangerment and death have been discussed as if the phenomena had no connection at all with language birth. More recently the phenomena have been associated almost exclusively with the intense and pervasive economic globalization of same period, a process that some authors have reduced too easily to the McDonaldization phenomenon. Moreover, the relation of globalization to different forms of colonization has been poorly articulated. As a matter of fact, little of the longer history of population movements and contacts since the dawn of agriculture has been invoked in the literature on language endangerment to give some broader perspective on the mechanisms of language birth and death and on the ecological factors that bear on how they proceed. This review aims to remedy these shortcomings in our scholarship.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.anthro.33.070203.143852
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    THE BODY BEAUTIFUL: Symbolism and Agency in the Social World (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Anthropology 33 (2004), S. 297-317 
    Details
    ISSN: 0084-6570
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Ethnic Sciences , Biology
    Notes: The prominence of the body in popular culture has prompted intense academic interest in recent decades. Seeking to overturn a naturalistic approach to the body as a biological given, this broad literature redefines the body as a sociocultural and historical phenomenon. Within anthropology, two primary theoretical orientations toward the body have emerged: the body as "symbol" and the body as "agent." This review article provides an overview of these dominant theoretical approaches in the context of recent scholarship on body ideals and, in particular, the body beautiful. The review explores also the body beautiful as a primary site for the construction and performance of gender, and specifically of femininity, with examples drawn from the abundant literature on women's bodies.
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    URL: http://dx.doi.org/10.1146/annurev.anthro.33.070203.143754
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    THE WORLD IN DRESS: Anthropological Perspectives on Clothing, Fashion, and Culture (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Anthropology 33 (2004), S. 369-392 
    Details
    ISSN: 0084-6570
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Ethnic Sciences , Biology
    Notes: Clothing research has attracted renewed interest in anthropology over the past two decades, experiencing a florescence that had been kept within bounds by reigning theoretical paradigms. The works have been influenced by general explanatory shifts in anthropology, which inform disparate bodies of clothing research that otherwise have little unity. The most noticeable trend is a preoccupation with agency, practice, and performance that considers the dressed body as both subject in, and object of, dress practice. The turn to consumption as a site and process of meaning making is evident also in clothing research. Dress has been analyzed, by and large, as representing something else rather than something in its own right, although new efforts to reengage materiality suggest that this approach is changing. Little work has been done on clothing production issues, though some scholars examine the significance of dress in the context of the entire economic circuit and the unequal relationships between its actors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.anthro.33.070203.143805
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    CULTURE, GLOBALIZATION, MEDIATION (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Anthropology 33 (2004), S. 345-367 
    Details
    ISSN: 0084-6570
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Ethnic Sciences , Biology
    Notes: This chapter reviews the literature on media and globalization. It develops the argument that this literature foregrounds a problem that, ironically, it also largely disavows: namely, the question of mediation as a general foundation of social life. I explore the origins of this contradiction in the emergence of globalization studies out of earlier traditions in media and cultural studies. I suggest that the failure to move beyond this impasse has perpetuated a surprising and debilitating reliance on substantialist and essentialist models of culture, models that are both at odds with the critical thrust of globalization studies and fully complicit with the agendas of public and commercial bureaucracies. The review tracks the recurrence of such thinking in several key strands of globalization studies and proceeds to outline an alternative ethnographic and theoretical strategy on the basis of a general theory of media and mediation.
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    URL: http://dx.doi.org/10.1146/annurev.anthro.33.070203.143809
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    THE AMYGDALA MODULATES THE CONSOLIDATION OF MEMORIES OF EMOTIONALLY AROUSING EXPERIENCES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 1-28 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Converging findings of animal and human studies provide compelling evidence that the amygdala is critically involved in enabling us to acquire and retain lasting memories of emotional experiences. This review focuses primarily on the findings of research investigating the role of the amygdala in modulating the consolidation of long-term memories. Considerable evidence from animal studies investigating the effects of posttraining systemic or intra-amygdala infusions of hormones and drugs, as well as selective lesions of specific amygdala nuclei, indicates that (a) the amygdala mediates the memory-modulating effects of adrenal stress hormones and several classes of neurotransmitters; (b) the effects are selectively mediated by the basolateral complex of the amygdala (BLA); (c) the influences involve interactions of several neuromodulatory systems within the BLA that converge in influencing noradrenergic and muscarinic cholinergic activation; (d) the BLA modulates memory consolidation via efferents to other brain regions, including the caudate nucleus, nucleus accumbens, and cortex; and (e) the BLA modulates the consolidation of memory of many different kinds of information. The findings of human brain imaging studies are consistent with those of animal studies in suggesting that activation of the amygdala influences the consolidation of long-term memory; the degree of activation of the amygdala by emotional arousal during encoding of emotionally arousing material (either pleasant or unpleasant) correlates highly with subsequent recall. The activation of neuromodulatory systems affecting the BLA and its projections to other brain regions involved in processing different kinds of information plays a key role in enabling emotionally significant experiences to be well remembered.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144157
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    THE HUMAN VISUAL CORTEX (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 649-677 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The discovery and analysis of cortical visual areas is a major accomplishment of visual neuroscience. In the past decade the use of noninvasive functional imaging, particularly functional magnetic resonance imaging (fMRI), has dramatically increased our detailed knowledge of the functional organization of the human visual cortex and its relation to visual perception. The fMRI method offers a major advantage over other techniques applied in neuroscience by providing a large-scale neuroanatomical perspective that stems from its ability to image the entire brain essentially at once. This bird's eye view has the potential to reveal large-scale principles within the very complex plethora of visual areas. Thus, it could arrange the entire constellation of human visual areas in a unified functional organizational framework. Here we review recent findings and methods employed to uncover the functional properties of the human visual cortex focusing on two themes: functional specialization and hierarchical processing.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144220
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    Multiple Roles of Antimicrobial Defensins, Cathelicidins, and Eosinophil-Derived Neurotoxin in Host Defense* (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 181-215 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Mammals generate a diverse array of antimicrobial proteins, largely represented by defensins or cathelicidins. The direct in vitro microbicidal activity of antimicrobial proteins has long been considered an important innate immune defense, although the in vivo relevance has only very recently been established for certain defensins and cathelicidins. Mammalian defensins and cathelicidins have also been shown to have multiple receptor-mediated effects on immune cells. Beta-defensins interact with CCR6; murine beta-defensin-2 in addition activates TLR4. Cathelicidins act on FPRL1-expressing cells. Furthermore, several defensins have considerable immunoenhancing activity. Thus, it appears that mammalian antimicrobial proteins contribute to both innate and adaptive antimicrobial immunity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104603
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    Ubiquitin Ligases and the Immune Response (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 81-127 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Ubiquitin (Ub)-protein conjugation represents a novel means of posttranscriptional modification in a proteolysis-dependent or -independent manner. E3 Ub ligases play a key role in governing the cascade of Ub transfer reactions by recognizing and catalyzing Ub conjugation to specific protein substrates. The E3s, which can be generally classified into HECT-type and RING-type families, are involved in the regulation of many aspects of the immune system, including the development, activation, and differentiation of lymphocytes, T cell-tolerance induction, antigen presentation, immune evasion, and virus budding. E3-promoted ubiquitination affects a wide array of biological processes, such as receptor downmodulation, signal transduction, protein processing or translocation, protein-protein interaction, and gene transcription, in addition to proteasome-mediated degradation. Deficiency or mutation of some of the E3s like Cbl, Cbl-b, or Itch, causes abnormal immune responses such as autoimmunity, malignancy, and inflammation. This review discusses our current understanding of E3 Ub ligases in both innate and adaptive immunity. Such knowledge may facilitate the development of novel therapeutic approaches for immunological diseases.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104813
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    The Role of Suppressors of Cytokine Signaling (SOCS) Proteins in Regulation of the Immune Response (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 503-529 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Cytokines are an integral component of the adaptive and innate immune responses. The signaling pathways triggered by the engagement of cytokines with their specific cell surface receptors have been extensively studied and have provided a profound understanding of the intracellular machinery that translates exposure of cells to cytokine to a coordinated biological response. It has also become clear that cells have evolved sophisticated mechanisms to prevent excessive responses to cytokines. In this review we focus on the suppressors of cytokine signaling (SOCS) family of cytoplasmic proteins that completes a negative feedback loop to attenuate signal transduction from cytokines that act through the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. SOCS proteins inhibit components of the cytokine signaling cascade via direct binding or by preventing access to the signaling complex. The SOCS proteins also appear to target signal transducers for proteasomal destruction. Analyses of genetically modified mice in which SOCS proteins are overexpressed or deleted have established that this family of negative regulators has indispensable roles in regulating cytokine responses in cells of the immune system as well as other tissues. Emerging evidence also suggests that disruption of SOCS expression or activity is associated with several immune and inflammatory diseases, raising the prospect that manipulation of SOCS activity may provide a novel future therapeutic strategy in the management of immunological disorders.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.22.091003.090312
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    Starting at the Beginning: New Perspectives on the Biology of Mucosal T Cells (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 217-246 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The gastrointestinal tract is the central organ for uptake of fluids and nutrients, and at the same time it forms the main protective barrier between the sterile environment of the body and the outside world. In mammals, the intestine has further evolved to harbor a vast load of commensal bacteria that have important functions for the host. Discrimination by the host defense system of nonself from self can prevent invasion of pathogens, but equivalent responses to dietary or colonizing bacteria can lead to devastating consequences for the organism. This dilemma imposed by the gut environment has probably contributed significantly to the evolutionary drive that has led to sophisticated mechanisms and diversification of the immune system to allow for protection while maintaining the integrity of the mucosal barrier. The immense expansion and specialization of the immune system is particularly mirrored in the phylogeny, ontogeny, organization, and regulation of the adaptive intraepithelial lymphocytes, or IEL, which are key players in the unique intestinal defense mechanisms that have evolved in mammals.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104522
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    Genetics, FACS, Immunology, and Redox: A Tale of Two Lives Intertwined (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 1-31 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104727
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    The BCR-ABL Story: Bench to Bedside and Back (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 247-306 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The twenty-first century is beginning with a sharp turn in the field of cancer therapy. Molecular targeted therapies against specific oncogenic events are now possible. The BCR-ABL story represents a notable example of how research from the fields of cytogenetics, retroviral oncology, protein phosphorylation, and small molecule chemical inhibitors can lead to the development of a successful molecular targeted therapy. Imatinib mesylate (Gleevec, STI571, or CP57148B) is a direct inhibitor of ABL (ABL1), ARG (ABL2), KIT, and PDGFR tyrosine kinases. This drug has had a major impact on the treatment of chronic myelogenous leukemia (CML) as well as other blood neoplasias and solid tumors with etiologies based on activation of these tyrosine kinases. Analysis of CML patients resistant to BCR-ABL suppression by Imatinib mesylate coupled with the crystallographic structure of ABL complexed to this inhibitor have shown how structural mutations in ABL can circumvent an otherwise potent anticancer drug. The successes and limitations of Imatinib mesylate hold general lessons for the development of alternative molecular targeted therapies in oncology.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104753
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    CD1: Antigen Presentation and T Cell Function (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 817-890 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: This review summarizes the major features of CD1 genes and proteins, the patterns of intracellular trafficking of CD1 molecules, and how they sample different intracellular compartments for self- and foreign lipids. We describe how lipid antigens bind to CD1 molecules with their alkyl chains buried in hydrophobic pockets and expose their polar lipid headgroup whose fine structure is recognized by the TCR of CD1-restricted T cells. CD1-restricted T cells carry out effector, helper, and adjuvant-like functions and interact with other cell types including macrophages, dendritic cells, NK cells, T cells, and B cells, thereby contributing to both innate and adaptive immune responses. Insights gained from mice and humans now delineate the extensive range of diseases in which CD1-restricted T cells play important roles and reveal differences in the role of CD1a, CD1b, and CD1c in contrast to CD1d. Invariant TCRalpha chains, self-lipid reactivity, and rapid effector responses empower a subset of CD1d-restricted T cells (NKT cells) to have unique effector functions without counterpart among MHC-restricted T cells. This review describes the function of CD1-restricted T cells in antimicrobial responses, antitumor immunity, and in regulating the balance between tolerance and autoimmunity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104608
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    The Three Es of Cancer Immunoediting (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 329-360 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models-together with compelling data from human patients-indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed "cancer immunoediting." In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting-elimination, equilibrium, and escape.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104803
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    CD40/CD154 Interactions at the Interface of Tolerance and Immunity (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 307-328 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that alphaCD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of alphaCD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104533
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    Ligands for L-Selectin: Homing, Inflammation, and Beyond (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 129-156 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Understanding the molecular basis of lymphocyte homing to lymphoid organs was originally a problem of concern only to immunologists. With the discovery of l-selectin and its ligands, interested scientists have expanded to include glycobiologists, immunopathologists, cancer biologists, and developmental biologists. Going beyond its first discovered role in homing to lymph nodes, the l-selectin system is implicated in such diverse processes as inflammatory leukocyte trafficking in both acute and chronic settings, hematogenous metastasis of carcinoma cells, effector mechanisms for inflammatory demyelination of axons, and implantation of the early mammalian embryo. This review focuses on the ligands for l-selectin that are found on vascular endothelium, leukocytes, carcinoma cells, and at various extravascular sites. The discovery of selectins and their ligands has validated the long-predicted hypothesis that carbohydrate-directed cell adhesion is relevant in eukaryotic systems. Emphasis will be given to the carbohydrate and sulfation modifications of the ligands, which enable recognition by l-selectin. The rapid "homing" of labeled cells into the lymph nodes presumably had its basis in the special affinity of small lymphocytes for the endothelium of the postcapillary venules. Gowans & Knight (1)
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    URL: http://dx.doi.org/10.1146/annurev.immunol.21.090501.080131
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