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  • Articles  (108,074)
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  • Articles  (108,074)
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  • 2005-2009  (28,307)
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  • 1
    Electronic Resource
    Electronic Resource
    A CELL BIOLOGICAL PERSPECTIVE ON ALZHEIMER'S DISEASE (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 25-51 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The amyloid precursor protein and the proteases cleaving this protein are important players in the pathogenesis of Alzheimer's disease via the generation of the amyloid peptide. Physiologically, the amyloid precursor protein is implied in axonal vesicular trafficking and the proteases are implicated in developmentally important signaling pathways, most significantly those involving regulated intramembrane proteolysis or RIP. We discuss the cell biology behind the amyloid and tangle hypothesis for Alzheimer's disease, drawing on the many links to the fields of cell biology and developmental biology that have been established in the recent years.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.020402.142302
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  • 2
    Electronic Resource
    Electronic Resource
    TYPE III PROTEIN SECRETION IN YERSINIA SPECIES (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 107-133 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The type III mechanism of protein secretion is a pathogenic strategy shared by a number of gram-negative pathogens of plants and animals that has evolved in order to inject virulence proteins into the cytosol of target eukaryotic cells. The pathogens of the Yersinia genus represent a model system where much progress has been made in understanding this secretion pathway. Herein, we review what has been recently learned in yersiniae about the various environmental signals that induce type III secretion, how the synthesis of secretion substrates is regulated, and how such a diverse group of proteins is recognized as a substrate for secretion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.105912
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  • 3
    Electronic Resource
    Electronic Resource
    BREAK INS AND BREAK OUTS: Viral Interactions with the Cytoskeleton of Mammalian Cells (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 135-161 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The host cytoskeleton plays important roles in the entry, replication, and egress of viruses. An assortment of viruses hijack cellular motor proteins to move on microtubules toward the cell interior during the entry process; others reverse this transport during egress to move assembling virus particles toward the plasma membrane. Polymerization of actin filaments is sometimes used to propel viruses from cell to cell, while many viruses induce the destruction of select cytoskeletal filaments apparently to effect efficient egress. Indeed, the tactics used by any given virus to achieve its infectious life cycle are certain to involve multiple cytoskeletal interactions. Understanding these interactions, and their orchestration during viral infections, is providing unexpected insights into basic virology, viral pathogenesis, and the biology of the cytoskeleton.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.105920
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  • 4
    Electronic Resource
    Electronic Resource
    CHROMOSOME-MICROTUBULE INTERACTIONS DURING MITOSIS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 193-219 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Spindle microtubules interact with mitotic chromosomes, binding to their kinetochores to generate forces that are important for accurate chromosome segregation. Motor enzymes localized both at kinetochores and spindle poles help to form the biologically significant attachments between spindle fibers and their cargo, but microtubule-associated proteins without motor activity contribute to these junctions in important ways. This review examines the molecules necessary for chromosome-microtubule interaction in a range of well-studied organisms, using biological diversity to identify the factors that are essential for organized chromosome movement. We conclude that microtubule dynamics and the proteins that control them are likely to be more important for mitosis than the current enthusiasm for motor enzymes would suggest.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.032002.132412
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  • 5
    Electronic Resource
    Electronic Resource
    THE CHLAMYDIAL INCLUSION: Escape from the Endocytic Pathway1 (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 221-245 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Chlamydiae, bacterial obligate intracellular pathogens, are the etiologic agents of several human diseases. A large part of the chlamydial intracellular survival strategy involves the formation of a unique organelle called the inclusion that provides a protected site within which they replicate. The chlamydial inclusion is effectively isolated from endocytic pathways but is fusogenic with a subset of exocytic vesicles that deliver sphingomyelin from the Golgi apparatus to the plasma membrane. A combination of host and parasite functions contribute to the biogenesis of this compartment. Establishment of the mature inclusion is accompanied by the insertion of multiple chlamydial proteins, suggesting that chlamydiae actively modify the inclusion to define its interactions with the eukaryotic host cell. Despite being sequestered within a membrane-bound vacuole, chlamydiae clearly communicate with and manipulate the host cell from within this privileged intracellular niche.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.105845
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  • 6
    Electronic Resource
    Electronic Resource
    MOLECULAR MECHANISMS OF EPITHELIAL MORPHOGENESIS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 463-493 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Epithelial morphogenesis comprises the various processes by which epithelia contribute to organ formation and body shape. These complex and diverse events play a central role in animal development and regeneration. Recently, the characterization of some of the molecular mechanisms involved in epithelial morphogenesis has provided an abundance of new information on the role and regulation of the cytoskeleton, cell-cell adhesion, and cell-matrix adhesion in these processes. In this review, we discuss our current understanding of the molecular mechanisms driving cell shape changes, cell intercalation, fusion of epithelia, ingression, egression, and cell migration. Our discussion is mostly focused on results from Drosophila and mammalian tissue culture but also draws on the insights gained from other organisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.022602.131838
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  • 7
    Electronic Resource
    Electronic Resource
    GOLGI ARCHITECTURE AND INHERITANCE (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 379-420 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Golgi inheritance proceeds via sequential biogenesis and partitioning phases. Although little is known about Golgi growth and replication (biogenesis), ultrastructural and fluorescence analyses have provided a detailed, though still controversial, perspective of Golgi partitioning during mitosis in mammalian cells. Partitioning requires the fragmentation of the juxtanuclear ribbon of interconnected Golgi stacks into a multitude of tubulovesicular clusters. This process is choreographed by a cohort of mitotic kinases and an inhibition of heterotypic and homotypic Golgi membrane-fusion events. Our model posits that accurate partitioning occurs early in mitosis by the equilibration of Golgi components on either side of the metaphase plate. Disseminated Golgi components then coalesce to regenerate Golgi stacks during telophase. Semi-intact cell and cell-free assays have accurately recreated these processes and allowed their molecular dissection. This review attempts to integrate recent findings to depict a more coherent, synthetic molecular picture of mitotic Golgi fragmentation and reassembly. Of particular importance is the emerging concept of a highly regulated and dynamic Golgi structural matrix or template that interfaces with cargo receptors, Golgi enzymes, Rab-GTPases, and SNAREs to tightly couple biosynthetic transport to Golgi architecture. This structural framework may be instructive for Golgi biogenesis and may encode sufficient information to ensure accurate Golgi inheritance, thereby helping to resolve some of the current discrepancies between different workers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.030602.133733
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  • 8
    Electronic Resource
    Electronic Resource
    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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.082503.103047
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  • 9
    Electronic Resource
    Electronic Resource
    FUNDAMENTALS OF PLANARIAN REGENERATION (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 725-757 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The principles underlying regeneration in planarians have been explored for over 100 years through surgical manipulations and cellular observations. Planarian regeneration involves the generation of new tissue at the wound site via cell proliferation (blastema formation), and the remodeling of pre-existing tissues to restore symmetry and proportion (morphallaxis). Because blastemas do not replace all tissues following most types of injuries, both blastema formation and morphallaxis are needed for complete regeneration. Here we discuss a proliferative cell population, the neoblasts, that is central to the regenerative capacities of planarians. Neoblasts may be a totipotent stem-cell population capable of generating essentially every cell type in the adult animal, including themselves. The population properties of the neoblasts and their descendants still await careful elucidation. We identify the types of structures produced by blastemas on a variety of wound surfaces, the principles guiding the reorganization of pre-existing tissues, and the manner in which scale and cell number proportions between body regions are restored during regeneration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.010403.095114
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  • 10
    Electronic Resource
    Electronic Resource
    MEMBRANE TRAFFICKING IN PLANTS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 481-504 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Plant membrane trafficking shares many features with other eukaryotic organisms, including the machinery for vesicle formation and fusion. However, the plant endomembrane system lacks an ER-Golgi intermediate compartment, has numerous Golgi stacks and several types of vacuoles, and forms a transient compartment during cell division. ER-Golgi trafficking involves bulk flow and efficient recycling of H/KDEL-bearing proteins. Sorting in the Golgi stacks separates bulk flow to the plasma membrane from receptor-mediated trafficking to the lytic vacuole. Cargo for the protein storage vacuole is delivered from the endoplasmic reticulum (ER), cis-Golgi, and trans-Golgi. Endocytosis includes recycling of plasma membrane proteins from early endosomes. Late endosomes appear identical with the multivesiculate prevacuolar compartment that lies on the Golgi-vacuole trafficking pathway. In dividing cells, homotypic fusion of Golgi-derived vesicles forms the cell plate, which expands laterally by targeted vesicle fusion at its margin, eventually fusing with the plasma membrane.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.082503.103057
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  • 11
    Electronic Resource
    Electronic Resource
    DORSAL-VENTRAL PATTERNING AND NEURAL INDUCTION IN XENOPUS EMBRYOS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 285-308 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: We review the current status of research in dorsal-ventral (D-V) patterning in vertebrates. Emphasis is placed on recent work on Xenopus, which provides a paradigm for vertebrate development based on a rich heritage of experimental embryology. D-V patterning starts much earlier than previously thought, under the influence of a dorsal nuclear -Catenin signal. At mid-blastula two signaling centers are present on the dorsal side: The prospective neuroectoderm expresses bone morphogenetic protein (BMP) antagonists, and the future dorsal endoderm secretes Nodal-related mesoderm-inducing factors. When dorsal mesoderm is formed at gastrula, a cocktail of growth factor antagonists is secreted by the Spemann organizer and further patterns the embryo. A ventral gastrula signaling center opposes the actions of the dorsal organizer, and another set of secreted antagonists is produced ventrally under the control of BMP4. The early dorsal -Catenin signal inhibits BMP expression at the transcriptional level and promotes expression of secreted BMP antagonists in the prospective central nervous system (CNS). In the absence of mesoderm, expression of Chordin and Noggin in ectoderm is required for anterior CNS formation. FGF (fibroblast growth factor) and IGF (insulin-like growth factor) signals are also potent neural inducers. Neural induction by anti-BMPs such as Chordin requires mitogen-activated protein kinase (MAPK) activation mediated by FGF and IGF. These multiple signals can be integrated at the level of Smad1. Phosphorylation by BMP receptor stimulates Smad1 transcriptional activity, whereas phosphorylation by MAPK has the opposite effect. Neural tissue is formed only at very low levels of activity of BMP-transducing Smads, which require the combination of both low BMP levels and high MAPK signals. Many of the molecular players that regulate D-V patterning via regulation of BMP signaling have been conserved between Drosophila and the vertebrates.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.011403.154124
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  • 12
    Electronic Resource
    Electronic Resource
    NUCLEAR RECEPTORS IN MACROPHAGE BIOLOGY: At the Crossroads of Lipid Metabolism and Inflammation (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 455-480 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Macrophages are essential modulators of lipid metabolism and the innate immune system. Lipid and inflammatory pathways induced in activated macrophages are central to the pathogenesis of human diseases including atherosclerosis. Recent work has shown that expression of genes involved in lipid uptake and cholesterol efflux in macrophages is controlled by peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs). Other studies have implicated these same receptors in the modulation of macrophage inflammatory gene expression. Together, these observations position PPARs and LXRs at the crossroads of lipid metabolism and inflammation and suggest that these receptors may serve to integrate these pathways in the control of macrophage gene expression. In this review, we summarize recent work that has advanced our understanding of the roles of PPARs and LXRs in macrophage biology and discuss the implication of these results for cardiovascular physiology and disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.012103.134432
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  • 13
    Electronic Resource
    Electronic Resource
    BI-DIRECTIONAL PROTEIN TRANSPORT BETWEEN THE ER AND GOLGI (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 87-123 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The endoplasmic reticulum (ER) and the Golgi comprise the first two steps in protein secretion. Vesicular carriers mediate a continuous flux of proteins and lipids between these compartments, reflecting the transport of newly synthesized proteins out of the ER and the retrieval of escaped ER residents and vesicle machinery. Anterograde and retrograde transport is mediated by distinct sets of cytosolic coat proteins, the COPII and COPI coats, respectively, which act on the membrane to capture cargo proteins into nascent vesicles. We review the mechanisms that govern coat recruitment to the membrane, cargo capture into a transport vesicle, and accurate delivery to the target organelle.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.010403.105307
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  • 14
    Electronic Resource
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    ASYMMETRIC CELL DIVISION IN C. ELEGANS: Cortical Polarity and Spindle Positioning (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 427-453 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The one-cell Caenorhabditis elegans embryo divides asymmetrically into a larger and smaller blastomere, each with a different fate. How does such asymmetry arise? The sperm-supplied centrosome establishes an axis of polarity in the embryo that is transduced into the establishment of anterior and posterior cortical domains. These cortical domains define the polarity of the embryo, acting upstream of the PAR proteins. The PAR proteins, in turn, determine the subsequent segregation of fate determinants and the plane of cell division. We address how cortical asymmetry could be established, relying on data from C. elegans and other polarized cells, as well as from applicable models. We discuss how cortical polarity influences spindle position to accomplish an asymmetric division, presenting the current models of spindle orientation and anaphase spindle displacement. We focus on asymmetric cell division as a function of the actin and microtubule cytoskeletons, emphasizing the cell biology of polarity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.19.111301.113823
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  • 15
    Electronic Resource
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    SIGNALING PATHWAYS IN INTESTINAL DEVELOPMENT AND CANCER (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 695-723 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The study of the epithelium of the adult mammalian intestine touches upon many modern aspects of biology. The epithelium is in a constant dialogue with the underlying mesenchyme to control stem cell activity, proliferation in transit-amplifying compartments, lineage commitment, terminal differentiation and, ultimately, cell death. There are spatially distinct compartments dedicated to each of these events. The Wnt, TGF-beta, BMP, Notch, and Par polarity pathways are the major players in homeostatic control of the adult epithelium. Several hereditary cancer syndromes deregulate these same signaling cascades through mutational (in)activation. Moreover, these mutations often also occur in sporadic tumors. Thus symmetry exists between the roles that these signaling pathways play in physiology and in cancer of the intestine. This is particularly evident for the Wnt/APC pathway, for which the mammalian intestine has become one of the most-studied paradigms. Here, we integrate recent knowledge of the molecular inner workings of the prototype signaling cascades with their specific roles in intestinal epithelial homeostasis and in neoplastic transformation of the epithelium.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.010403.092805
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  • 16
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    GENE CO-OPTION IN PHYSIOLOGICAL AND MORPHOLOGICAL EVOLUTION (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 53-80 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Co-option occurs when natural selection finds new uses for existing traits, including genes, organs, and other body structures. Genes can be co-opted to generate developmental and physiological novelties by changing their patterns of regulation, by changing the functions of the proteins they encode, or both. This often involves gene duplication followed by specialization of the resulting paralogous genes into particular functions. A major role for gene co-option in the evolution of development has long been assumed, and many recent comparative developmental and genomic studies have lent support to this idea. Although there is relatively less known about the molecular basis of co-option events involving developmental pathways, much can be drawn from well-studied examples of the co-option of structural proteins. Here, we summarize several case studies of both structural gene and developmental genetic circuit co-option and discuss how co-option may underlie major episodes of adaptive change in multicellular organisms. We also examine the phenomenon of intraspecific variability in gene expression patterns, which we propose to be one form of material for the co-option process. We integrate this information with recent models of gene family evolution to provide a framework for understanding the origin of co-optive evolution and the mechanisms by which natural selection promotes evolutionary novelty by inventing new uses for the genetic toolkit.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.020402.140619
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  • 17
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    THE MECHANISMS OF POLLINATION AND FERTILIZATION IN PLANTS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 81-105 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract In flowering plants, pollen grains germinate to form pollen tubes that transport male gametes (sperm cells) to the egg cell in the embryo sac during sexual reproduction. Pollen tube biology is complex, presenting parallels with axon guidance and moving cell systems in animals. Pollen tube cells elongate on an active extracellular matrix in the style, ultimately guided by stylar and embryo sac signals. A well-documented recognition system occurs between pollen grains and the stigma in sporophytic self-incompatibility, where both receptor kinases in the stigma and their peptide ligands from pollen are now known. Complex mechanisms act to precisely target the sperm cells into the embryo sac. These events initiate double fertilization in which the two sperm cells from one pollen tube fuse to produce distinctly different products: one with the egg to produce the zygote and embryo and the other with the central cell to produce the endosperm.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.083438
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  • 18
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    RECEPTOR KINASE SIGNALING IN PLANT DEVELOPMENT (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 163-192 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The Arabidopsis genome sequence has revealed that plants contain a much larger complement of receptor kinase genes than other organisms. Early analysis of these genes revealed involvement in a diverse array of developmental and defense functions that included gametophyte development, pollen-pistil interactions, shoot apical meristem equilibrium, hormone perception, and cell morphogenesis. Amino acid sequence motifs and binding studies indicate that the ectodomains are capable of binding, either directly or indirectly, various classes of molecules including proteins, carbohydrates, and steroids. Genetic and biochemical approaches have begun to identify other components of several signal transduction pathways. Some receptor-like kinases (RLKs) appear to function with coreceptors lacking kinase domains, and genome analysis suggests this might be true for many RLKs. The KAPP protein phosphatase functions as a negative regulator of at least two RLK systems, and in vitro studies suggest it could be a common component of more. Whether plant signaling systems display a modularity similar to animal systems remains to be determined. Future efforts will reveal unknown functions of other RLKs and elucidate the relationships among their signaling networks.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.083431
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  • 19
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    CELLULAR CONTROL OF ACTIN NUCLEATION (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 247-288 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Eukaryotic cells use actin polymerization to change shape, move, and internalize extracellular materials by phagocytosis and endocytosis, and to form contractile structures. In addition, several pathogens have evolved to use host cell actin assembly for attachment, internalization, and cell-to-cell spread. Although cells possess multiple mechanisms for initiating actin polymerization, attention in the past five years has focused on the regulation of actin nucleation-the formation of new actin filaments from actin monomers. The Arp2/3 complex and the multiple nucleation-promoting factors (NPFs) that regulate its activity comprise the only known cellular actin-nucleating factors and may represent a universal machine, conserved across eukaryotic phyla, that nucleates new actin filaments for various cellular structures with numerous functions. This review focuses on our current understanding of the mechanism of actin nucleation by the Arp2/3 complex and NPFs and how these factors work with other cytoskeletal proteins to generate structurally and functionally diverse actin arrays in cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.040202.112133
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  • 20
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    MEMBRANE FUSION IN EUKARYOTIC CELLS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 289-314 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Membrane fusion is a fundamental biochemical reaction and the final step in all vesicular trafficking events. It is crucial for the transfer of proteins and lipids between different compartments and for exo- and endocytic traffic of signaling molecules and receptors. It leads to the reconstruction of organelles such as the Golgi or the nuclear envelope, which decay into fragments during mitosis. Hence, controlled membrane fusion reactions are indispensible for the compartmental organization of eukaryotic cells; for their communication with the environment via hormones, neurotransmitters, growth factors, and receptors; and for the integration of cells into multicellular organisms. Intracellular pathogenic bacteria, such as Mycobacteria or Salmonellae, have developed means to control fusion reactions in their host cells. They persist in phagosomes whose fusion with lysosomes they actively suppress-a means to ensure survival inside host cells. The past decade has witnessed rapid progress in the elucidation of parts of the molecular machinery involved in these membrane fusion reactions. Whereas some elements of the fusion apparatus are remarkably similar in several compartments, there is an equally striking divergence of others. The purpose of this review is to highlight common features of different fusion reactions and the concepts that emerged from them but also to stress the differences and challenge parts of the current hypotheses. This review covers only the endoplasmic fusion reactions mentioned above, i.e., reactions initiated by contacts of membranes with their cytoplasmic faces. Ectoplasmic fusion events, which depend on an initial contact of the fusion partners via the membrane surfaces exposed to the surrounding medium are not discussed, nor are topics such as the entry of enveloped viruses, formation of syncytia, gamete fusion, or vesicle scission (a fusion reaction that leads to the fission of, e.g., transport vesicles).
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.032202.114809
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    BACTERIAL TOXINS THAT MODIFY THE ACTIN CYTOSKELETON (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 315-344 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Bacterial pathogens utilize several strategies to modulate the organization of the actin cytoskeleton. Some bacterial toxins catalyze the covalent modification of actin or the Rho GTPases, which are involved in the control of the actin cytoskeleton. Other bacteria produce toxins that act as guanine nucleotide exchange factors or GTPase-activating proteins to modulate the nucleotide state of the Rho GTPases. This latter group of toxins provides a temporal modulation of the actin cytoskeleton. A third group of bacterial toxins act as adenylate cyclases, which directly elevate intracellular cAMP to supra-physiological levels. Each class of toxins gives the bacterial pathogen a selective advantage in modulating host cell resistance to infection.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.134748
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    PROTEOLYSIS AND STEROL REGULATION (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 345-378 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The mammalian cell continuously adjusts its sterol content by regulating levels of key sterol synthetic enzymes and levels of LDL receptors that mediate uptake of cholesterol-laden particles. Control is brought about by sterol-regulated transcription of relevant genes and by regulated degradation of the committed step enzyme HMG-CoA reductase (HMGR). Current work has revealed that proteolysis is at the heart of each of these mechanistically distinct axes. Transcriptional control is effected by regulated cleavage of the membrane-bound transcription factor sterol regulatory element binding protein (SREBP), and HMGR degradation is brought about by ubiquitin-mediated degradation. In each case, ongoing cell biological processes are being harnessed to bring about regulation. The secretory pathway plays a central role in allowing sterol-mediated control of transcription. The constitutively active endoplasmic reticulum (ER) quality control apparatus is employed to bring about regulated destruction of HMGR. This review describes the methods and results of various studies to understand the mechanisms and molecules involved in these distinct but interrelated aspects of sterol regulation and the intriguing similarities that appear to exist at the levels of protein sequence and cell biology.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.032002.131219
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    PLASMODIUM SPOROZOITE MOLECULAR CELL BIOLOGY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 29-59 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Plasmodium sporozoites display complex phenotypes including gliding motility and invasion of and transmigration through cells in the mosquito vector and the vertebrate host. Sporozoite studies have been difficult to perform because of technical concerns. Nevertheless, they have already provided insights into several aspects of sporozoite biology, shared in part with other apicomplexan invasive stages. Structure/function analysis of the thrombospondin-related anonymous protein paved the way to the understanding of the molecular mechanisms of apicomplexan gliding motility and host cell invasion. Functional studies of circumsporozoite protein revealed its role in Plasmodium sporozoite morphogenesis in addition to its well-known function in host cell invasion. Transcriptional surveys, which facilitate the investigation of gene expression programs that control sporozoite phenotypes, have revealed a high degree of previously unappreciated complexity and novel proteins that mediate sporozoite host cell infection.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.011603.150935
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    THE BUDDING YEAST SPINDLE POLE BODY: Structure, Duplication, and Function (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 1-28 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Nucleation of microtubules by eukaryotic microtubule organizing centers (MTOCs) is required for a variety of functions, including chromosome segregation during mitosis and meiosis, cytokinesis, fertilization, cellular morphogenesis, cell motility, and intracellular trafficking. Analysis of MTOCs from different organisms shows that the structure of these organelles is widely varied even though they all share the function of microtubule nucleation. Despite their morphological diversity, many components and regulators of MTOCs, as well as principles in their assembly, seem to be conserved. This review focuses on one of the best-characterized MTOCs, the budding yeast spindle pole body (SPB). We review what is known about its structure, protein composition, duplication, regulation, and functions. In addition, we discuss how studies of the yeast SPB have aided investigation of other MTOCs, most notably the centrosome of animal cells.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.022003.114106
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    THE ROLE OF KNOX GENES IN PLANT DEVELOPMENT# (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 125-151 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: knox genes encode homeodomain-containing transcription factors that are required for meristem maintenance and proper patterning of organ initiation. In plants with simple leaves, knox genes are expressed exclusively in the meristem and stem, but in dissected leaves, they are also expressed in leaf primordia, suggesting that they may play a role in the diversity of leaf form. This hypothesis is supported by the intriguing phenotypes found in gain-of-function mutations where knox gene misexpression affects leaf and petal shape. Similar phenotypes are also found in recessive mutations of genes that function to negatively regulate knox genes. KNOX proteins function as heterodimers with other homeodomains in the TALE superclass. The gibberellin and lignin biosynthetic pathways are known to be negatively regulated by KNOX proteins, which results in indeterminate cell fates.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.031803.093824
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    SPECIFICATION OF TEMPORAL IDENTITY IN THE DEVELOPING NERVOUS SYSTEM (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 619-647 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The nervous system of higher organisms exhibits extraordinary cellular diversity owing to complex spatial and temporal patterning mechanisms. The role of spatial patterning in generating neuronal diversity is well known; here we discuss how neural progenitors change over time to contribute to cell diversity within the central nervous system (CNS). We focus on five model systems: the vertebrate retina, cortex, hindbrain, spinal cord, and Drosophila neuroblasts. For each, we address the following questions: Do multipotent progenitors generate different neuronal cell types in an invariant order? Do changes in progenitor-intrinsic factors or progenitor-extrinsic signals regulate temporal identity (i.e., the sequence of neuronal cell types produced)? What is the mechanism that regulates temporal identity transitions; i.e., what triggers the switch from one temporal identity to the next? By applying the same criteria to analyze each model system, we try to highlight common themes, point out unique attributes of each system, and identify directions for future research.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.19.111301.115142
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    THE ADENOMATOUS POLYPOSIS COLI PROTEIN: The Achilles Heel of the Gut Epithelium (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 337-366 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The Adenomatous Polyposis coli (APC) gene is mutated or lost in most colon cancers, and the APC protein has emerged as a multifunctional protein that is not only involved in the Wnt-regulated degradation of -catenin, but also regulates cytoskeletal proteins and thus plays a role in cell migration, cell adhesion, and mitosis. The gut epithelium is uniquely dependent on an intricate balance between a number of fundamental cellular processes including migration, differentiation, adhesion, apoptosis, and mitosis. In this review, I discuss the molecular mechanisms that govern the various functions of APC and their relationship to the role of APC in colon cancer.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.012103.094541
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    G PROTEIN CONTROL OF MICROTUBULE ASSEMBLY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 867-894 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Microtubules are dynamic polymers required for many aspects of eukaryotic cell function. The interphase microtubule network is essential for intracellular transport, organization, and cell polarization, whereas the mitotic spindle is required for chromosome segregation and cell division. Studies in different areas such as cell migration, mitosis, and asymmetric cell division have shown that Ran, Rho, and heterotrimeric G proteins regulate many aspects of microtubule functions. This review surveys how G protein-signaling coordinates microtubule polymerization and organization with specific cellular activities.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.012103.094648
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    MEMBRANE TRAFFIC EXPLOITED BY PROTEIN TOXINS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 1-24 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract A large number of protein toxins having enzymatically active A- and B-moieties that bind to cell surface receptors must be endocytosed before the A-moiety is translocated into the cytosol where it exerts its cytotoxic action. The accumulated information about the most well-studied toxins has provided a detailed picture of how they exploit the membrane trafficking systems of cells, and studies of toxin trafficking have revealed the existance of new pathways. The complexity of different endocytic mechanisms, as well as the multiple routes between endosomes and the Golgi apparatus and retrogradely to the endoplasmic reticulum (ER), are being unravelled by investigations of how toxins gain access to their targets. With increasing information about the internalization and intracellular trafficking of these opportunistic toxins, new avenues have been opened for their application in areas of medicine such as drug delivery and therapy.
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    AUTOINHIBITORY DOMAINS: Modular Effectors of Cellular Regulation (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 421-462 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Autoinhibitory domains are regions of proteins that negatively regulate the function of other domains via intramolecular interactions. Autoinhibition is a potent regulatory mechanism that provides tight "on-site" repression. The discovery of autoinhibition generates valuable clues to how a protein is regulated within a biological context. Mechanisms that counteract the autoinhibition, including proteolysis, post-translational modifications, as well as addition of proteins or small molecules in trans, often represent central regulatory pathways. In this review, we document the diversity of instances in which autoinhibition acts in cell regulation. Seven well-characterized examples (e.g., sigma70, Ets-1, ERM, SNARE and WASP proteins, SREBP, Src) are covered in detail. Over thirty additional examples are listed. We present experimental approaches to characterize autoinhibitory domains and discuss the implications of this widespread phenomenon for biological regulation in both the normal and diseased states.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.031502.133614
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    CONTROL OF DEVELOPMENTAL TIMING BY MICRORNAS AND THEIR TARGETS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 495-513 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract In Caenorhabditis elegans the timing of many developmental events is regulated by heterochronic genes. Such genes orchestrate the timing of cell divisions and fates appropriate for the developmental stage of an organism. Analyses of heterochronic mutations in the nematode C. elegans have revealed a genetic pathway that controls the timing of post-embryonic cell divisions and fates. Two of the genes in this pathway encode small regulatory RNAs. The 22 nucleotide (nt) RNAs downregulate the expression of protein-coding mRNAs of target heterochronic genes. Analogous variations in the timing of appearance of particular features have been noted among closely related species, suggesting that such explicit control of developmental timing may not be exclusive to C. elegans. In fact, some of the genes that globally pattern the temporal progression of C. elegans development, including one of the tiny RNA genes, are conserved and temporally regulated across much of animal phylogeny, suggesting that the molecular mechanisms of temporal control are ancient and universal. A very large family of tiny RNA genes called microRNAs, which are similar in structure to the heterochronic regulatory RNAs, have been detected in diverse animal species and are likely to be present in most metazoans. Functions of the newly discovered microRNAs are not yet known. Other examples of temporal programs during growth include the exquisitely choreographed temporal sequences of developmental fates in neurogenesis in Drosophila and the sequential programs of epidermal coloration in insect wing patterning. An interesting possibility is that microRNAs mediate transitions on a variety of time scales to pattern the activities of particular target protein-coding genes and in turn generate sets of cells over a period of time. Plasticity in these microRNA genes or their targets may lead to changes in relative developmental timing between related species, or heterochronic change. Instead of inventing new gene functions, even subtle changes in temporal expression of pre-existing control genes can result in speciation by altering the time at which they function.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.105832
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    REGULATORY PRINCIPLES OF DEVELOPMENTAL SIGNALING (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 515-539 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Signaling between cells is a widely used mechanism by which cell fate and tissue patterning is determined in development. We review the mechanisms by which signaling between cells is regulated so that a cell receives the right amount of signal, at the right time, to achieve its intended developmental fate and position. In nearly all cases, we find that the supply of signal factor (ligand) is the limiting step in initiating a signaling process. Ligand supply is regulated by the transcription and localization of RNA, the spread of ligand from a source, and by inhibitors that operate at several different levels. We emphasize the different regulatory strategies that operate for threshold as opposed to concentration-dependent (morphogen) signaling. Threshold signaling is extensively regulated by feedback mechanisms. Morphogen signaling is regulated quantitatively by receptor loading and transduction flow.
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    TRANSCRIPTIONAL AND TRANSLATIONAL CONTROL IN THE MAMMALIAN UNFOLDED PROTEIN RESPONSE (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 575-599 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Cells monitor the physiological load placed on their endoplasmic reticulum (ER) and respond to perturbations in ER function by a process known as the unfolded protein response (UPR). In metazoans the UPR has a transcriptional component that up-regulates expression of genes that enhance the capacity of the organelle to deal with the load of client proteins and a translational component that insures tight coupling between protein biosynthesis on the cytoplasmic side and folding in the ER lumen. Together, these two components adapt the secretory apparatus to physiological load and protect cells from the consequences of protein malfolding.
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    SIGNALING PATHWAYS IN VASCULAR DEVELOPMENT (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 541-573 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The vasculature is one of the most important and complex organs in the mammalian body. The first functional organ to form during embryonic development, the intricately branched network of endothelial and supporting periendothelial cells is essential for the transportation of oxygen and nutrients to and the removal of waste products from the tissues. Serious disruptions in the formation of the vascular network are lethal early in post-implantation development, while the maintenance of vessel integrity and the control of vessel physiology and hemodynamics have important consequences throughout embryonic and adult life. A full understanding of the signaling pathways of vascular development is important not just for understanding normal development but because of the importance of reactivation of angiogenic pathways in disease states. Clinically there is a need to develop therapies to promote new blood vessel formation in situations of severe tissue ischemia, such as coronary heart disease. In addition, there is considerable interest in developing angiogenic inhibitors to block the new vessel growth that solid tumors promote in host tissue to enhance their own growth. Already studies on the signaling pathways of normal vascular development have provided new targets for therapeutic intervention in both situations. Further understanding of the complexities of the pathways should help refine such strategies.
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    ACTIN CYTOSKELETON REGULATION IN NEURONAL MORPHOGENESIS AND STRUCTURAL PLASTICITY (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 601-635 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The actin cytoskeleton plays a major role in morphological development of neurons and in structural changes of adult neurons. This article reviews the myriad functions of actin and myosin in axon initiation, growth, guidance and branching, in morphogenesis of dendrites and dendritic spines, in synapse formation and stability, and in axon and dendrite retraction. Evidence is presented that signaling pathways involving the Rho family of small GTPases are key regulators of actin polymerization and myosin function in the context of different aspects of neuronal morphogenesis. These studies support an emerging theme: Different aspects of neuronal morphogenesis may involve regulation of common core signaling pathways, in particular the Rho GTPases.
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    STRIATED MUSCLE CYTOARCHITECTURE: An Intricate Web of Form and Function (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 637-706 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Striated muscle is an intricate, efficient, and precise machine that contains complex interconnected cytoskeletal networks critical for its contractile activity. The individual units of the sarcomere, the basic contractile unit of myofibrils, include the thin, thick, titin, and nebulin filaments. These filament systems have been investigated intensely for some time, but the details of their functions, as well as how they are connected to other cytoskeletal elements, are just beginning to be elucidated. These investigations have advanced significantly in recent years through the identification of novel sarcomeric and sarcomeric-associated proteins and their subsequent functional analyses in model systems. Mutations in these cytoskeletal components account for a large percentage of human myopathies, and thus insight into the normal functions of these proteins has provided a much needed mechanistic understanding of these disorders. In this review, we highlight the components of striated muscle cytoarchitecture with respect to their interactions, dynamics, links to signaling pathways, and functions. The exciting conclusion is that the striated muscle cytoskeleton, an exquisitely tuned, dynamic molecular machine, is capable of responding to subtle changes in cellular physiology.
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    REMEMBRANCE OF THINGS PAST: Chromatin Remodeling in Plant Development (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 707-746 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Chromatin remodeling in plants has usually been discussed in relation to aspects of genome defense such as transgene silencing and the resetting of transposon activity. The role of remodeling in controlling development has been less emphasized, although well established in animal systems. This is because cell fate in plants is often held to be entirely specified on the basis of position, apparently excluding any significant role for cell ancestry and chromatin remodeling. We argue that chromatin remodeling is used to confer mitotically heritable cell fates at late stages in pattern formation. Several examples in which chromatin remodeling factors are used to confer a memory of transient events in plant development are discussed. Because the precise biochemical functions of most remodeling factors are obscure, and little is known of plant chromatin structure, the underlying mechanisms remain poorly understood.
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    MYOGENIC REGULATORY FACTORS AND THE SPECIFICATION OF MUSCLE PROGENITORS IN VERTEBRATE EMBRYOS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 747-783 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Embryological and genetic studies of mouse, bird, zebrafish, and frog embryos are providing new insights into the regulatory functions of the myogenic regulatory factors, MyoD, Myf5, Myogenin, and MRF4, and the transcriptional and signaling mechanisms that control their expression during the specification and differentiation of muscle progenitors. Myf5 and MyoD genes have genetically redundant, but developmentally distinct regulatory functions in the specification and the differentiation of somite and head muscle progenitor lineages. Myogenin and MRF4 have later functions in muscle differentiation, and Pax and Hox genes coordinate the migration and specification of somite progenitors at sites of hypaxial and limb muscle formation in the embryo body. Transcription enhancers that control Myf5 and MyoD activation in muscle progenitors and maintain their expression during muscle differentiation have been identified by transgenic analysis. In epaxial, hypaxial, limb, and head muscle progenitors, Myf5 is controlled by lineage-specific transcription enhancers, providing evidence that multiple mechanisms control progenitor specification at different sites of myogenesis in the embryo. Developmental signaling ligands and their signal transduction effectors function both interactively and independently to control Myf5 and MyoD activation in muscle progenitor lineages, likely through direct regulation of their transcription enhancers. Future investigations of the signaling and transcriptional mechanisms that control Myf5 and MyoD in the muscle progenitor lineages of different vertebrate embryos can be expected to provide a detailed understanding of the developmental and evolutionary mechanisms for anatomical muscles formation in vertebrates. This knowledge will be a foundation for development of stem cell therapies to repair diseased and damaged muscles.
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    CELLULAR LENGTH CONTROL SYSTEMS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 677-693 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The problem of organelle size control can be addressed most simply by considering cellular structures that are linear, so that their size can be defined by a single parameter: length. We compare existing studies on several linear biological structures including prokaryotic flagella and flagellar hooks, eukaryotic flagella, sarcomere thin filaments, and microvilli. In some cases, existing evidence strongly supports the idea that length control involves a molecular ruler, in which the size of the overall structure is compared with the size of an individual molecule. In other cases, length control is likely to involve a steady-state balance of assembly and disassembly, in which one or the other rate is inherently length dependent. The lessons learned from size control in linear structures should be applicable to organelles with more complex three-dimensional structures.
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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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    THE GENETICS AND MOLECULAR BIOLOGY OF THE SYNAPTONEMAL COMPLEX (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 525-558 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The synaptonemal complex (SC) is a protein lattice that resembles railroad tracks and connects paired homologous chromosomes in most meiotic systems. The two side rails of the SC, known as lateral elements (LEs), are connected by proteins known as transverse filaments. The LEs are derived from the axial elements of the chromosomes and play important roles in chromosome condensation, pairing, transverse filament assembly, and prohibiting double-strand breaks (DSBs) from entering into recombination pathways that involve sister chromatids. The proteins that make up the transverse filaments of the SC also play a much earlier role in committing a subset of DSBs into a recombination pathway, which results in the production of reciprocal meiotic crossovers. Sites of crossover commitment can be observed as locations where the SC initiates and as immunostaining foci for a set of proteins required for the processing of DSBs to mature crossovers. In most (but not all) organisms it is the establishment of sites marking such crossover-committed DSBs that facilitates completion of synapsis (full-length extension of the SC). The function of the mature full-length SC may involve both the completion of meiotic recombination at the DNA level and the exchange of the axial elements of the two chromatids involved in the crossover. However, the demonstration that the sites of crossover formation are designated prior to SC formation, and the finding that these sites display interference, argues against a role of the mature SC in mediating the process of interference. Finally, in at least some organisms, modifications of the SC alone are sufficient to ensure meiotic chromosome segregation in the complete absence of meiotic recombination.
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    CONNEXINS AND CELL SIGNALING IN DEVELOPMENT AND DISEASE1 (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 811-838 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Gap junctions contain hydrophilic membrane channels that allow direct communication between neighboring cells through the diffusion of ions, metabolites, and small cell signaling molecules. They are made up of a hexameric array of polypeptides encoded by the connexin multi-gene family. Cell-cell communication mediated by connexins is crucial to various cellular functions, including the regulation of cell growth, differentiation, and development. Mutations in connexin genes have been linked to a variety of human diseases, including cardiovascular anomalies, peripheral neuropathy, deafness, skin disorders, and cataracts. In addition to their coupling function, recent studies suggest that connexin proteins may also mediate signaling. This could involve interactions with other protein partners that may play a role not only in connexin assembly, trafficking, gating and turnover, but also in the coordinate regulation of cell-cell communication with cell adhesion and cell motility. The integration of these cell functions is likely to be important in the role of gap junctions in development and disease.
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    ADAPTORS FOR CLATHRIN COATS: Structure and Function (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 153-191 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Clathrin-coated vesicles (CCVs) are responsible for the transport of proteins between various compartments of the secretory and endocytic systems. Clathrin forms a scaffold around these vesicles that is linked to membranes by clathrin adaptors. The adaptors simultaneously bind to clathrin and to transmembrane proteins and/or phospholipids and can also interact with each other and with other components of the CCV formation machinery. The result is a collection of proteins that can make multiple, moderate strength (M Kd) interactions and thereby establish the dynamic regulatable networks to drive vesicle genesis at the correct time and place in the cell. This review focuses on the structure of clathrin adaptors and how these structures provide functional information on the mechanism of CCV formation.
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    MECHANISMS OF POLARIZED GROWTH AND ORGANELLE SEGREGATION IN YEAST (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 559-591 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Cell polarity, as reflected by polarized growth and organelle segregation during cell division in yeast, appears to follow a simple hierarchy. On the basis of physical cues from previous cell cycles or stochastic processes, yeast cells select a site for bud emergence that also defines the axis of cell division. Once polarity is established, rho protein-based signal pathways set up a polarized cytoskeleton by activating localized formins to nucleate and assemble polarized actin cables. These serve as tracks for the transport of secretory vesicles, the segregation of the trans Golgi network, the vacuole, peroxisomes, endoplasmic reticulum, mRNAs for cell fate determination, and microtubules that orient the nucleus in preparation for mitosis, all by myosin-Vs encoded by the MYO2 and MYO4 genes. Most of the proteins participating in these processes in yeast are conserved throughout the kingdoms of life, so the emerging models are likely to be generally applicable. Indeed, several parallels to cellular organization in animals are evident.
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    THE ENGULFMENT PROCESS OF PROGRAMMED CELL DEATH IN CAENORHABDITIS ELEGANS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 193-221 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Programmed cell death involves the removal of cell corpses by other cells in a process termed engulfment. Genetic studies of the nematode Caenorhabditis elegans have led to a framework not only for the killing step of programmed cell death but also for the process of cell-corpse engulfment. This work has defined two signal transduction pathways that act redundantly to control engulfment. Signals expressed by dying cells probably regulate these C. elegans pathways. Components of the cell-corpse recognition system of one of the C. elegans pathways include the CED-7 ABC transporter, which likely presents a death ligand on the surface of the dying cell; the CED-1 transmembrane receptor, which recognizes this signal; and the CED-6 adaptor protein, which may transduce a signal from CED-1. The second C. elegans pathway acts in parallel and involves a novel Rac GTPase signaling pathway, with the components CED-2 CrkII, CED-5 DOCK180, CED-12 ELMO, and CED-10 Rac. The cell-corpse recognition system that activates this pathway remains to be characterized. In C. elegans, and possibly in mammals, the process of cell-corpse engulfment promotes the death process itself. The known mechanisms for cell-corpse engulfment leave much to be discovered concerning this fundamental aspect of metazoan biology.
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    CELL BIOLOGY OF MYCOBACTERIUM TUBERCULOSIS PHAGOSOME (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 367-394 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Phagocytosis and phagolysosome biogenesis represent fundamental biological processes essential for proper tissue homeostasis, development, elimination of invading microorganisms, and antigen processing and presentation. Phagosome formation triggers a preprogramed pathway of maturation into the phagolysosome, a process controlled by Ca2+ and the regulators of organellar trafficking centered around the small GTP-binding proteins Rabs and their downstream effectors, including lipid kinases, organellar tethering molecules, and membrane fusion apparatus. Mycobacterium tuberculosis is a potent human pathogen parasitizing macrophages. It interferes with the Rab-controlled membrane trafficking and arrests the maturing phagosome at a stage where no harm can be done to the pathogen while the delivery of nutrients and membrane to the vacuole harboring the microorganism continues. This process, referred to as the M. tuberculosis phagosome maturation arrest or inhibition of phagosome-lysosome fusion, is critical for M. tuberculosis persistence in human populations. It also provides a general model system for dissecting the phagolysosome biogenesis pathways. Here we review the fundamental trafficking processes targeted by M. tuberculosis and the mycobacterial products that interfere with phagosomal maturation.
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    CHEMOATTRACTANT SIGNALING IN DICTYOSTELIUM DISCOIDEUM (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 223-253 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Dictyostelium is an accessible organism for studies of signaling via chemoattractant receptors. Chemoattractant-mediated signaling events and components are reviewed and presented as a series of connected modules, including excitation, inhibition, G protein-independent responses, early gene expression, inositol lipids, PH domain-containing proteins, cyclic AMP signaling, polarization acquisition, actin polymerization, and cortical myosin. The network incorporates information from biochemical, genetic, and cell biological experiments carried out on living cells. The modules and connections represent current understanding, and future information is expected to modify and build upon this structure.
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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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    DYNACTIN (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 759-779 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Dynactin is a multisubunit protein complex that is required for most, if not all, types of cytoplasmic dynein activity in eukaryotes. Dynactin binds dynein directly and allows the motor to traverse the microtubule lattice over long distances. A single dynactin subunit, p150Glued, is sufficient for both activities, yet dynactin contains several other subunits that are organized into an elaborate structure. It is currently believed that the bulk of the dynactin structure participates in interactions with a wide range of cellular structures, many of which are cargoes of the dynein motor. Genetic studies verify the importance of all elements of dynactin structure to its function. Although dynein can bind some membranous cargoes independently of dynactin, establishment of a fully functional dynein-cargo link appears to depend on dynactin. In this review, I summarize what is presently known about dynactin structure, the cellular structures with which it associates, and the intermolecular interactions that underlie and regulate binding. Although the molecular details of dynactin's interactions with membranous organelles and other molecules are complex, the framework provided here is intended to distill what is presently known and to be of use to dynactin specialists and beginners alike.
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    THE WNT SIGNALING PATHWAY IN DEVELOPMENT AND DISEASE (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 781-810 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.
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    RNA TRANSLATION IN AXONS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 505-523 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The cell body has classically been considered the exclusive source of axonal proteins. However, significant evidence has accumulated recently to support the view that protein synthesis can occur in axons themselves, remote from the cell body. Indeed, local translation in axons may be integral to aspects of synaptogenesis, long-term facilitation, and memory storage in invertebrate axons, and for growth cone navigation in response to environmental stimuli in developing vertebrate axons. Here we review the evidence supporting mRNA translation in axons and discuss the potential roles that local protein synthesis may play during development and subsequent neuronal function. We advance the view that local translation provides a rapid supply of nascent proteins in restricted axonal compartments that can potentially underlie long-term responses to transient stimuli.
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    REGULATION OF MUSCLE MASS BY MYOSTATIN (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 61-86 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Myostatin is a secreted protein that acts as a negative regulator of skeletal muscle mass. During embryogenesis, myostatin is expressed by cells in the myotome and in developing skeletal muscle and acts to regulate the final number of muscle fibers that are formed. During adult life, myostatin protein is produced by skeletal muscle, circulates in the blood, and acts to limit muscle fiber growth. The existence of circulating tissue-specific growth inhibitors of this type was hypothesized over 40 years ago to explain how sizes of individual tissues are controlled. Skeletal muscle appears to be the first example of a tissue whose size is controlled by this type of regulatory mechanism, and myostatin appears to be the first example of the long-sought chalone.
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    LAMININ FUNCTIONS IN TISSUE MORPHOGENESIS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 255-284 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Significant advances have been made in the application of genetics to probe the functions of basement membrane laminins. These studies have shown that different laminin subunits profoundly affect tissue morphogenesis, starting around the time of embryonic implantation and extending through organogenesis and into the postnatal period. Collectively they have revealed common functions that include the induction and maintenance of cell polarity, the establishment of barriers between tissue compartments, the organization of cells into tissues, and the protection of adherent cells from detachment-induced cell death, anoikis. Interpreted in light of what is known about laminin structure and self-assembly and binding activities, these advances have begun to provide insights into mechanisms of action. In this review we focus on the contributions of the laminins in invertebrate and vertebrate tissue morphogenesis.
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    RETROVIRUS BUDDING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 395-425 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Human immunodeficiency virus (HIV) and other retroviruses acquire their envelopes and spread infection by budding through the limiting membranes of producer cells. To facilitate budding, retroviruses usurp a cellular pathway that is normally used to create vesicles that bud into late endosomal compartments called multivesicular bodies (MVB). Research on yeast and human MVB biogenesis has led to the identification of 25 human proteins that are required for vesicle formation and for HIV-1 budding, and has produced a working model for sequential recruitment of these proteins during MVB vesicle formation. Retroviruses can redirect this machinery to the plasma membrane and leave the cell in a single step or, alternatively, can bud directly into MVB compartments and then exit cells via the exosome pathway. Remarkably, virus release from both the plasma membrane and MVB compartments can occur directionally into specialized sites of cell-to-cell contact called virological synapses. Thus retroviruses have evolved elaborate mechanisms for escaping the cell and maximizing their chances of infecting a new host.
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    MYOSIN VI: Cellular Functions and Motor Properties (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 20 (2004), S. 649-676 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Myosin motor proteins use the energy derived from ATP hydrolysis to move cargo along actin tracks. Myosin VI, unlike almost all other myosins, moves toward the minus end of actin filaments and functions in a variety of intracellular processes such as vesicular membrane traffic, cell migration, and mitosis. These diverse roles of myosin VI are mediated by interaction with a number of different binding partners present in multi-protein complexes. Myosin VI can work in vitro as a processive dimeric motor and as a nonprocessive monomeric motor, each with a large working stroke. The possibility that both monomeric and dimeric forms of myosin VI operate in the cell may represent an important regulatory mechanism for controlling the multiple steps in transport pathways where nonprocessive and processive motors are required.
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    A TRIP THROUGH MY LIFE WITH AN IMMUNOLOGICAL THEME (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 1-28 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: In this essay, I make four points about the operation of the immune system. First, thanks to the innate immune system's regulation of the main costimulatory molecules CD80 and CD86, the immune system rarely mistakes a pathogen for a self-antigen. Second, the adaptive immune system consisting of T lymphocytes and B lymphocytes can mistake self for non-self because adaptive immunity is selected in single somatic cells. Third, the adaptive immune system of T lymphocytes and B lymphocytes is always referential to self, as it is selected on self-ligands; it persists in the periphery on self-ligands; and at least for T cells, it is dependent on self-ligands to be able to mount a response. Fourth, it is becoming clear that regulatory or suppressor T cells are our main defense against autoimmunity, as my first boss, Richard Gershon, had predicted. These cells recognize antigen as do all T cells, but they secrete the immunoregulatory cytokines IL-10 and TGFbeta.
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    NEUROENDOCRINE REGULATION OF IMMUNITY* (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 125-163 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract A reciprocal regulation exists between the central nervous and immune systems through which the CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through cytokines. The primary hormonal pathway by which the CNS regulates the immune system is the hypothalamic-pituitary-adrenal axis, through the hormones of the neuroendocrine stress response. The sympathetic nervous system regulates the function of the immune system primarily via adrenergic neurotransmitters released through neuronal routes. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. Glucocorticoids are the main effector end point of this neuroendocrine system and, through the glucocorticoid receptor, have multiple effects on immune cells and molecules. This review focuses on the regulation of the immune response via the neuroendocrine system. Particular details are presented on the effects of interruptions of this regulatory loop at multiple levels in predisposition and expression of immune diseases and on mechanisms of glucocorticoid effects on immune cells and molecules.
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    KIR: Diverse, Rapidly Evolving Receptors of Innate and Adaptive Immunity (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 217-251 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract KIR genes have evolved in primates to generate a diverse family of receptors with unique structures that enable them to recognize MHC-class I molecules with locus and allele-specificity. Their combinatorial expression creates a repertoire of NK cells that surveys the expression of almost every MHC molecule independently, thus antagonizing the spread of pathogens and tumors that subvert innate and adaptive defense by selectively downregulating certain MHC class I molecules. The genes encoding KIR that recognize classical MHC molecules have diversified rapidly in human and primates; this contrasts with conservation of immunoglobulin- and lectin-like receptors for nonclassical MHC molecules. As a result of the variable KIR-gene content in the genome and the polymorphism of the HLA system, dissimilar numbers and qualities of KIR:HLA pairs function in different humans. This diversity likely contributes variability to the function of NK cells and T-lymphocytes by modulating innate and adaptive immune responses to specific challenges.
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    SIGNAL TRANSDUCTION MEDIATED BY THE T CELL ANTIGEN RECEPTOR: The Role of Adapter Proteins* (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 371-394 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Engagement of the T cell antigen receptor (TCR) leads to a complex series of molecular changes at the plasma membrane, in the cytoplasm, and at the nucleus that lead ultimately to T cell effector function. Activation at the TCR of a set of protein tyrosine kinases (PTKs) is an early event in this process. This chapter reviews some of the critical substrates of these PTKs, the adapter proteins that, following phosphorylation on tyrosine residues, serve as binding sites for many of the critical effector enzymes and other adapter proteins required for T cell activation. The role of these adapters in binding various proteins, the interaction of adapters with plasma membrane microdomains, and the function of adapter proteins in control of the cytoskeleton are discussed.
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    T CELL MEMORY (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 551-579 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Typical immune responses lead to prominent clonal expansion of antigen-specific T and B cells followed by differentiation into effector cells. Most effector cells die at the end of the immune response but some of these cells survive and form long-lived memory cells. The factors controlling the formation and survival of memory T cells are reviewed.
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    CPG MOTIFS IN BACTERIAL DNA AND THEIR IMMUNE EFFECTS* (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 709-760 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Unmethylated CpG motifs are prevalent in bacterial but not vertebrate genomic DNAs. Oligodeoxynucleotides (ODN) containing CpG motifs activate host defense mechanisms leading to innate and acquired immune responses. The recognition of CpG motifs requires Toll-like receptor (TLR) 9, which triggers alterations in cellular redox balance and the induction of cell signaling pathways including the mitogen activated protein kinases (MAPKs) and NFkappaB. Cells that express TLR-9, which include plasmacytoid dendritic cells (PDCs) and B cells, produce Th1-like proinflammatory cytokines, interferons, and chemokines. Certain CpG motifs (CpG-A) are especially potent at activating NK cells and inducing IFN-alpha production by PDCs, while other motifs (CpG-B) are especially potent B cell activators. CpG-induced activation of innate immunity protects against lethal challenge with a wide variety of pathogens, and has therapeutic activity in murine models of cancer and allergy. CpG ODN also enhance the development of acquired immune responses for prophylactic and therapeutic vaccination.
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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.
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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 
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    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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    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 
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    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.
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    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 
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    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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    Interleukin-10 and Related Cytokines and Receptors (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 929-979 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The Class 2 alpha-helical cytokines consist of interleukin-10 (IL-10), IL-19, IL-20, IL-22, IL-24 (Mda-7), and IL-26, interferons (IFN-alpha, -beta, -e, -kappa, -omega, -delta, -tau, and -gamma) and interferon-like molecules (limitin, IL-28A, IL-28B, and IL-29). The interaction of these cytokines with their specific receptor molecules initiates a broad and varied array of signals that induce cellular antiviral states, modulate inflammatory responses, inhibit or stimulate cell growth, produce or inhibit apoptosis, and affect many immune mechanisms. The information derived from crystal structures and molecular evolution has led to progress in the analysis of the molecular mechanisms initiating their biological activities. These cytokines have significant roles in a variety of pathophysiological processes as well as in regulation of the immune system. Further investigation of these critical intercellular signaling molecules will provide important information to enable these proteins to be used more extensively in therapy for a variety of diseases.
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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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    Physiological Control of Immune Response and Inflammatory Tissue Damage by Hypoxia-Inducible Factors and Adenosine A2A Receptors* (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 657-682 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Immune cell-mediated destruction of pathogens may result in excessive collateral damage to normal tissues, and the failure to control activated immune cells may cause immunopathologies. The search for physiological mechanisms that downregulate activated immune cells has revealed a critical role for extracellular adenosine and for immunosuppressive A2A adenosine receptors in protecting tissue from inflammatory damage. Tissue damage-associated deep hypoxia, hypoxia-inducible factors, and hypoxia-induced accumulation of adenosine may represent one of the most fundamental and immediate tissue-protecting mechanisms, with adenosine A2A receptors triggering "OFF" signals in activated immune cells. In these regulatory mechanisms, oxygen deprivation and extracellular adenosine accumulation serve as "reporters," while A2A adenosine receptors serve as "sensors" of excessive tissue damage. The A2A receptor-triggered generation of intracellular cAMP then inhibits activated immune cells in a delayed negative feedback manner to prevent additional tissue damage. Targeting A2A adenosine receptors may have important clinical applications.
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    Autoimmune and Inflammatory Mechanisms in Atherosclerosis (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 22 (2004), S. 361-403 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The present review focuses on the concept that cellular and humoral immunity to the phylogenetically highly conserved antigen heat shock protein 60 (HSP60) is the initiating mechanism in the earliest stages of atherosclerosis. Subjecting arterial endothelial cells to classical atherosclerosis risk factors leads to the expression of HSP60 that then may serve as a target for pre-existent cross-reactive antimicrobial HSP60 immunity or bona fide autoimmune reactions induced by biochemically altered autologous HSP60. Endothelial cells can also bind microbial or autologous HSP60 via Toll-like receptors, providing another possibility for targetting adaptive or innate immunological effector mechanisms.
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    HUMAN AND MURINE PHENOTYPES ASSOCIATED WITH DEFECTS IN CATION-CHLORIDE COTRANSPORT (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 803-843 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract The diuretic-sensitive cotransport of cations with chloride is mediated by the cation-chloride cotransporters, a large gene family encompassing a total of seven Na-Cl, Na-K-2Cl, and K-Cl cotransporters, in addition to two related transporters of unknown function. The cation-chloride cotransporters perform a wide variety of physiological roles and differ dramatically in patterns of tissue expression and cellular localization. The renal-specific Na-Cl cotransporter (NCC) and Na-K-2Cl cotransporter (NKCC2) are involved in Gitelman and Bartter syndrome, respectively, autosomal recessive forms of metabolic alkalosis. The associated phenotypes due to loss-of-function mutations in NCC and NKCC2 are consistent, in part, with their functional roles in the distal convoluted tubule and thick ascending limb, respectively. Other cation-chloride cotransporters are positional candidates for Mendelian human disorders, and the K-Cl cotransporter KCC3, in particular, may be involved in degenerative peripheral neuropathies linked to chromosome 15q14. The characterization of mice with both spontaneous and targeted mutations of several cation-chloride cotransporters has also yielded significant insight into the physiological and pathophysiological roles of several members of the gene family. These studies implicate the Na-K-2Cl cotransporter NKCC1 in hearing, salivation, pain perception, spermatogenesis, and the control of extracellular fluid volume. Targeted deletion of the neuronal-specific K-Cl cotransporter KCC2 generates mice with a profound seizure disorder and confirms the central role of this transporter in modulating neuronal excitability. Finally, the comparison of human and murine phenotypes associated with loss-of-function mutations in cation-chloride cotransporters indicates important differences in physiology of the two species and provides an important opportunity for detailed physiological and morphological analysis of the tissues involved.
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    RENAL GENETIC DISORDERS RELATED TO K+AND Mg2+ (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 845-876 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract The recent knowledge of the renal epithelial transport systems has exploded with the identification, cloning, and characterization of a large number of membrane transport proteins. The fundamental aspects of these transporters are beginning to emerge at the molecular level and are summarized in the accompanying contributions in this volume of the Annual Review of Physiology. The aim of my review is to integrate this body of knowledge with the understanding of the clinical disorders of human mineral homeostasis that accompany gain, loss, or dysregulation of function of these transport systems. The specific focus is on the best defined human clinical syndromes in which there are derangements in K+ and Mg2+ homeostasis.
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    HYPOXIA-INDUCED ANAPYREXIA: Implications and Putative Mediators (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 263-288 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Hypoxia elicits an array of compensatory responses in animals ranging from protozoa to mammals. Central among these responses is anapyrexia, the regulated decrease of body temperature. The importance of anapyrexia lies in the fact that it reduces oxygen consumption, increases the affinity of hemoglobin for oxygen, and blunts the energetically costly responses to hypoxia. The mechanisms of anapyrexia are of intense interest to physiologists. Several substances, among them lactate, adenosine, opioids, and nitric oxide, have been suggested as putative mediators of anapyrexia, and most appear to act in the central nervous system. Moreover, there is evidence that the drop in body temperature in response to hypoxia, unlike the ventilatory response to hypoxia, does not depend on the activation of peripheral chemoreceptors. The current knowledge of the mechanisms of hypoxia-induced anapyrexia are reviewed.
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    beta-DEFENSINS IN LUNG HOST DEFENSE (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 709-748 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Host defenses at the mucosal surface of the airways evolved to present many layers of protection against inhaled microbes. Normally, the intrapulmonary airways are sterile. Airway secretions contain numerous factors with antimicrobial activity that contribute to innate defenses. Many protein and peptide components exert bacteriostatic or bacteriocidal effects against a wide variety of organisms and may act in synergistic or additive combinations. The beta-defensins are a relatively recently described family of peptide antimicrobials that are widely expressed at mucosal surfaces, including airway and submucosal gland epithelia. These small cationic peptides are products of individual genes that exhibit broad-spectrum activity against bacteria, fungi, and some enveloped viruses. Their expression in airway epithelia may be constitutive or inducible by bacterial products or pro-inflammatory cytokines. beta-defensins also act as chemokines for adaptive immune cells, including immature dendritic cells and T cells via the CCR6 receptor, and provide a link between innate and adaptive immunity. Alterations in the function of the beta-defensins may contribute to disease states. Here we review much of the biology of the beta-defensins, including gene discovery, genomic organization, molecular structure, regulation of expression, and function.
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    REGULATION OF ENDOTHELIAL NITRIC OXIDE SYNTHASE: Location, Location, Location (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 749-774 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Endothelial nitric oxide synthase (eNOS) is expressed in vascular endothelium, airway epithelium, and certain other cell types where it generates the key signaling molecule nitric oxide (NO). Diminished NO availability contributes to systemic and pulmonary hypertension, atherosclerosis, and airway dysfunction. Complex mechanisms underly the cell specificity of eNOS expression, and co- and post-translational processing leads to trafficking of the enzyme to plasma membrane caveolae. Within caveolae, eNOS is the downstream target member of a signaling complex in which it is functionally linked to both typical G protein-coupled receptors and less typical receptors such as estrogen receptor (ER) alpha and the high-density lipoprotein receptor SR-BI displaying novel actions. This compartmentalization facilitates dynamic protein-protein interactions and calcium- and phosphorylation-dependent signal transduction events that modify eNOS activity. Further understanding of these mechanisms will enable us to take preventive and therapeutic advantage of the powerful actions of NO in multiple cell types.
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    Field Physiology: Physiological Insights from Animals in Nature (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 209-238 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Whereas comparative physiology documents the range of physiological variation across a range of organisms, field physiology provides insight into the actual mechanisms an organism employs to maintain homeostasis in its everyday life. This requires an understanding of an organism's natural history and is prerequisite to developing hypotheses about physiological mechanisms. This review focuses on a few areas of field physiology that exemplify how the underlying physiology could not have been understood without appropriate field measurements. The examples we have chosen highlight the methods and inference afforded by an application of this physiological analysis to organismal function in nature, often in extreme environments. The specific areas examined are diving physiology, the thermal physiology of large endothermic fishes, reproductive physiology of air breathing vertebrates, and endocrine physiology of reproductive homeostasis. These areas form a bridge from physiological ecology to evolutionary ecology. All our examples revolve around the central issue of physiological limits as they apply to organismal homeostasis. We view this theme as the cornerstone of physiological analysis and supply a number of paradigms on homeostasis that have been tested in the context of field physiology.
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    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 
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    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.
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    Developmental Regulation of Lung Liquid Transport (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 77-101 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The developing distal lung epithelium displays an evolving liquid transport phenotype, reflecting a changing and dynamic balance between Cl- ion secretion and Na+ ion absorption, which in turn reflects changing functional requirements. Thus in the fetus, Cl--driven liquid secretion predominates throughout gestation and generates a distending pressure to stretch the lung and stimulate growth. Increasing Na+ absorptive capacity develops toward term, anticipating the switch to an absorptive phenotype at birth and beyond. There is some empirical evidence of ligand-gated regulation of Cl- transport and of regulation via changes in the driving force for Cl- secretion. Epinephrine, O2, glucocorticoid, and thyroid hormones interact to stimulate Na+ absorption by increasing Na+ pump activity and apical Na+ conductance (GNa+) to bring about the switch from net secretion to net absorption as lung liquid is cleared from the lung at birth. Postnatally, the lung lumen contains a small Cl--based liquid secretion that generates a surface liquid layer, but the lung retains a large absorptive capacity to prevent alveolar flooding and clear edema fluid. This review explores the mechanisms underlying the functional development of the lung epithelium and draws upon evidence from classic integrative physiological studies combined with molecular physiology approaches.
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    Estrogens in the Nervous System: Mechanisms and Nonreproductive Functions (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 291-313 
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    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.
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    The Role of Corepressors in Transcriptional Regulation by Nuclear Hormone Receptors (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 315-360 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Nuclear receptors (also known as nuclear hormone receptors) are hormone-regulated transcription factors that control many important physiological and developmental processes in animals and humans. Defects in receptor function result in disease. The diverse biological roles of these receptors reflect their surprisingly versatile transcriptional properties, with many receptors possessing the ability to both repress and activate target gene expression. These bipolar transcriptional properties are mediated through the interactions of the receptors with two distinct classes of auxiliary proteins: corepressors and coactivators. This review focuses on how corepressors work together with nuclear receptors to repress gene transcription in the normal organism and on the aberrations in this process that lead to neoplasia and endocrine disorders. The actions of coactivators and the contributions of the same corepressors to the functions of nonreceptor transcription factors are also touched on.
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    Myosin-1c, the Hair Cell's Adaptation Motor (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 521-545 
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    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.
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    Localization of Voltage-Gated Ion Channels IN Mammalian Brain (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 477-519 
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    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.
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    Bacteriorhodopsin (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 66 (2004), S. 665-688 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Fourier transform infrared and Raman spectroscopy, solid-state NMR, and X-ray crystallography have contributed detailed information about the structural changes in the proton transport cycle of the light-driven pump, bacteriorhodopsin. The results over the past few years add up to a step-by-step description of the configurational changes of the photoisomerized retinal, how these changes result in internal proton transfers and the release of a proton to the extracellular surface and uptake on the other side, as well as the conservation and transformation of excess free energy during the cycle.
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.082602.092845
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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 
    Details
    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.
    Type of Medium: Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032102.150251
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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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.082602.095217
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.052102.134444
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144206
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    ATTENTIONAL MODULATION OF VISUAL PROCESSING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 611-647 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Single-unit recording studies in the macaque have carefully documented the modulatory effects of attention on the response properties of visual cortical neurons. Attention produces qualitatively different effects on firing rate, depending on whether a stimulus appears alone or accompanied by distracters. Studies of contrast gain control in anesthetized mammals have found parallel patterns of results when the luminance contrast of a stimulus increases. This finding suggests that attention has co-opted the circuits that mediate contrast gain control and that it operates by increasing the effective contrast of the attended stimulus. Consistent with this idea, microstimulation of the frontal eye fields, one of several areas that control the allocation of spatial attention, induces spatially local increases in sensitivity both at the behavioral level and among neurons in area V4, where endogenously generated attention increases contrast sensitivity. Studies in the slice have begun to explain how modulatory signals might cause such increases in sensitivity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.26.041002.131039
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144220
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    HOW THE BRAIN PROCESSES SOCIAL INFORMATION: Searching for the Social Brain* (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 697-722 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Because information about gender, kin, and social status are essential for reproduction and survival, it seems likely that specialized neural mechanisms have evolved to process social information. This review describes recent studies of four aspects of social information processing: (a) perception of social signals via the vomeronasal system, (b) formation of social memory via long-term filial imprinting and short-term recognition, (c) motivation for parental behavior and pair bonding, and (d) the neural consequences of social experience. Results from these studies and some recent functional imaging studies in human subjects begin to define the circuitry of a "social brain." Such neurodevelopmental disorders as autism and schizophrenia are characterized by abnormal social cognition and corresponding deficits in social behavior; thus social neuroscience offers an important opportunity for translational research with an impact on public health.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144148
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    Signaling of Kinesthetic Information by Peripheral Sensory Receptors (1982)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 5 (1982), S. 171-188 
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    ISSN: 0147-006X
    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.ne.05.030182.001131
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    Where Does Sherrington's "Muscular Sense" Originate? Muscles, Joints, Corollary Discharges? (1982)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 5 (1982), S. 189-218 
    Details
    ISSN: 0147-006X
    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.ne.05.030182.001201
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    THE SYNAPTIC VESICLE CYCLE (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 509-547 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Neurotransmitter release is mediated by exocytosis of synaptic vesicles at the presynaptic active zone of nerve terminals. To support rapid and repeated rounds of release, synaptic vesicles undergo a trafficking cycle. The focal point of the vesicle cycle is Ca2+-triggered exocytosis that is followed by different routes of endocytosis and recycling. Recycling then leads to the docking and priming of the vesicles for another round of exo- and endocytosis. Recent studies have led to a better definition than previously available of how Ca2+ triggers exocytosis and how vesicles recycle. In particular, insight into how Munc18-1 collaborates with SNARE proteins in fusion, how the vesicular Ca2+ sensor synaptotagmin 1 triggers fast release, and how the vesicular Rab3 protein regulates release by binding to the active zone proteins RIM1alpha and RIM2alpha has advanced our understanding of neurotransmitter release. The present review attempts to relate these molecular data with physiological results in an emerging view of nerve terminals as macromolecular machines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.26.041002.131412
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    THE NEUROBIOLOGY OF THE ASCIDIAN TADPOLE LARVA: Recent Developments in an Ancient Chordate (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 453-485 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: With little more than 330 cells, two thirds within the sensory vesicle, the CNS of the tadpole larva of the ascidian Ciona intestinalis provides us with a chordate nervous system in miniature. Neurulation, neurogenesis and its genetic bases, as well as the gene expression territories of this tiny constituency of cells all follow a chordate plan, giving rise in some cases to frank structural homologies with the vertebrate brain. Recent advances are fueled by the release of the genome and EST expression databases and by the development of methods to transfect embryos by electroporation. Immediate prospects to test the function of neural genes are based on the isolation of mutants by classical genetics and insertional mutagenesis, as well as by the disruption of gene function by morpholino antisense oligo-nucleotides. Coupled with high-speed video analysis of larval swimming, optophysiological methods offer the prospect to analyze at single-cell level the function of a CNS built on a vertebrate plan.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144255
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    ELECTRICAL SYNAPSES IN THE MAMMALIAN BRAIN (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 393-418 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Many neurons in the mammalian central nervous system communicate through electrical synapses, defined here as gap junction-mediated connections. Electrical synapses are reciprocal pathways for ionic current and small organic molecules. They are often strong enough to mediate close synchronization of subthreshold and spiking activity among clusters of neurons. The most thoroughly studied electrical synapses occur between excitatory projection neurons of the inferior olivary nucleus and between inhibitory interneurons of the neocortex, hippocampus, and thalamus. All these synapses require the gap junction protein connexin36 (Cx36) for robust electrical coupling. Cx36 appears to interconnect neurons exclusively, and it is expressed widely along the mammalian neuraxis, implying that there are undiscovered electrical synapses throughout the central nervous system. Some central neurons may be electrically coupled by other connexin types or by pannexins, a newly described family of gap junction proteins. Electrical synapses are a ubiquitous yet underappreciated feature of neural circuits in the mammalian brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.26.041002.131128
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    CORTICAL NEURAL PROSTHETICS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 487-507 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Control of prostheses using cortical signals is based on three elements: chronic microelectrode arrays, extraction algorithms, and prosthetic effectors. Arrays of microelectrodes are permanently implanted in cerebral cortex. These arrays must record populations of single- and multiunit activity indefinitely. Information containing position and velocity correlates of animate movement needs to be extracted continuously in real time from the recorded activity. Prosthetic arms, the current effectors used in this work, need to have the agility and configuration of natural arms. Demonstrations using closed-loop control show that subjects change their neural activity to improve performance with these devices. Adaptive-learning algorithms that capitalize on these improvements show that this technology has the capability of restoring much of the arm movement lost with immobilizing deficits.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144233
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    CRITICAL PERIOD REGULATION (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 549-579 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Neuronal circuits are shaped by experience during critical periods of early postnatal life. The ability to control the timing, duration, and closure of these heightened levels of brain plasticity has recently become experimentally accessible, especially in the developing visual system. This review summarizes our current understanding of known critical periods across several systems and species. It delineates a number of emerging principles: functional competition between inputs, role for electrical activity, structural consolidation, regulation by experience (not simply age), special role for inhibition in the CNS, potent influence of attention and motivation, unique timing and duration, as well as use of distinct molecular mechanisms across brain regions and the potential for reactivation in adulthood. A deeper understanding of critical periods will open new avenues to "nurture the brain"-from international efforts to link brain science and education to improving recovery from injury and devising new strategies for therapy and lifelong learning.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144327
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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 
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    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144238
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    THE NOGO SIGNALING PATHWAY FOR REGENERATION BLOCK (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 27 (2004), S. 341-368 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: A hostile environment and decreased regenerative capacity may contribute to the failure of axon regeneration in the adult central nervous system. Recent studies leading to the identification of several myelin-associated inhibitors and their signaling molecules provide opportunitities to assess the contribution of these inhibitory molecules in restricting axon regeneration. These findings may ultimately allow for the development of strategies to alleviate the inhibitory effects of such molecules in an effort to encourage axon regeneration after spinal cord and brain injury.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144340
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