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  • Articles  (4,973)
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  • 1950  (47)
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  • Articles  (4,973)
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  • 2020-2022  (4,018)
  • 2000-2004  (908)
  • 1950-1954  (47)
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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
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    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
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    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
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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 
    Details
    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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  • 9
    Electronic Resource
    Electronic Resource
    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 
    Details
    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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  • 10
    Electronic Resource
    Electronic Resource
    RECEPTOR KINASE SIGNALING IN PLANT DEVELOPMENT (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 163-192 
    Details
    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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  • 11
    Electronic Resource
    Electronic Resource
    CELLULAR CONTROL OF ACTIN NUCLEATION (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 18 (2002), S. 247-288 
    Details
    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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  • 12
    Electronic Resource
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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).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.032202.114809
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  • 13
    Electronic Resource
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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 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.134748
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  • 14
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.032002.131219
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  • 15
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.011502.142107
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  • 16
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.031502.133614
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  • 17
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.105832
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  • 18
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.083458
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  • 19
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.011402.160624
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  • 20
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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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    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.105825
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  • 21
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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 
    Details
    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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    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.031802.150501
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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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    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.012502.105840
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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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    URL: http://dx.doi.org/10.1146/annurev.cellbio.18.040202.114836
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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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    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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    URL: http://dx.doi.org/10.1146/annurev.immunol.20.082401.104914
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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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    Physiological Genetics (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 47-70 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.000403
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    Water Metabolism (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 145-178 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.001045
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    Blood Gas Transport (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 265-288 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.001405
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    Heart (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 345-368 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.002021
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    Physiology of Smell and Taste (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 469-484 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.002345
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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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    DATING THE TIME OF ORIGIN OF MAJOR CLADES: Molecular Clocks and the Fossil Record (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Earth and Planetary Sciences 30 (2002), S. 65-88 
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    ISSN: 0084-6597
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Geosciences , Physics
    Notes: Abstract Molecular and paleontological data provide independent means of estimating when groups of organisms evolved in the geological past, but neither approach can be considered straightforward. The single most fundamental obstacle to developing an accurate estimate of times of origination from gene sequence data is variation in rates of molecular evolution, both through time and among lineages. Although various techniques have been proposed to circumvent this problem, none unambiguously allow the components of time and rate to be separated. Furthermore, problems of establishing accurate calibration points, correctly rooted phylogenies, and accurate estimates of branch length remain formidable. Conversely, paleontological dates fix only the latest possible time of divergence, and so probabilistic methods are required to set a lower boundary on origination dates. Realistic confidence intervals that take preservational biases into account are only just becoming available. Although molecular and paleontological approaches to dating often agree reasonably well, there are two notable areas of disagreement; when mammal and bird orders originated and when the major phyla originated. The discrepancy in dating bird/mammal ordinal origins probably reflects a global rock-record bias. Paleontological sampling in the Late Cretaceous is still too restricted geographically to draw any firm conclusions about the existence of a pre-Tertiary record for modern orders of bird or mammal from anywhere other than North America. Dating the time of origin of phyla is more complicated, and is confounded by both preservational biases and problems of molecular clock estimation.
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    PETROLOGY OF SUBDUCTED SLABS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Earth and Planetary Sciences 30 (2002), S. 207-235 
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    ISSN: 0084-6597
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Geosciences , Physics
    Notes: Abstract The subducted lithosphere is composed of a complex pattern of chemical systems that undergo continuous and discontinuous phase transformation, through pressure and temperature variations. Volatile recycling plays a major geodynamic role in triggering mass transfer, melting, and volcanism. Although buoyancy forces are controlled by modal amounts of the most abundant phases, usually volatile-free, petrogenesis and chemical differentiation are controlled by the occurrence of minor phases, most of them volatile-bearing. Devolatilization of the subducted lithosphere is a continuous process distributed over more than 300 km of the slab-mantle interface. Melting of the subducted crust, if any, along sufficiently hot P-T paths, is governed by fluid-absent reactions, even though the difference between fluid and melt vanishes at pressures above the second critical end point. The density distribution at a depth of 660 km suggests episodic penetration in space and time of subducted slabs into the lower mantle and sinking down to the D" region at the core-mantle boundary.
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    PLUTO AND CHARON: Formation, Seasons, Composition (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Earth and Planetary Sciences 30 (2002), S. 307-345 
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    ISSN: 0084-6597
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Geosciences , Physics
    Notes: Abstract Pluto and Charon, once thought to be a singular system in an odd orbit at the edge of the solar system, are now known as members of a vast population of icy bodies beyond Neptune. Models for the occurrence of the odd orbit and formation of these bodies in the context of the total population are reviewed. Pluto's orbital characteristics, coupled with the existence of volatiles on the surface, suggest that large-scale seasonal change should occur on the surface. Models of seasonal variability are discussed, past and current observations are examined for evidence of variability, and a straw-man model of seasonal changes is proposed. Finally, recent observations of the surface composition of Charon are discussed and compared with observations of other similarly sized icy bodies in the outer Solar System.
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    PEPTIDE AGGREGATION IN NEURODEGENERATIVE DISEASE (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 155-174 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Abstract In the not-so-distant past, insoluble aggregated protein was considered as uninteresting and bothersome as yesterday's trash. More recently, protein aggregates have enjoyed considerable scientific interest, as it has become clear that these aggregates play key roles in many diseases. In this review, we focus attention on three polypeptides: beta-amyloid, prion, and huntingtin, which are linked to three feared neurodegenerative diseases: Alzheimer's, "mad cow," and Huntington's disease, respectively. These proteins lack any significant primary sequence homology, yet their aggregates possess very similar features, specifically, high beta-sheet content, fibrillar morphology, relative insolubility, and protease resistance. Because the aggregates are noncrystalline, secrets of their structure at nanometer resolution are only slowly yielding to X-ray diffraction, solid-state NMR, and other techniques. Besides structure, the aggregates may possess similar pathways of assembly. Two alternative assembly pathways have been proposed: the nucleation-elongation and the template-assisted mode. These two modes may be complementary, not mutually exclusive. Strategies for interfering with aggregation, which may provide novel therapeutic approaches, are under development. The structural similarities between protein aggregates of dissimilar origin suggest that therapeutic strategies successful against one disease may have broad utility in others.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.4.092801.094202
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    BIOMECHANICAL DYNAMICS OF THE HEART WITH MRI (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 321-347 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Abstract Magnetic resonance imaging (MRI) provides a noninvasive way to evaluate the biomechanical dynamics of the heart. MRI can provide spatially registered tomographic images of the heart in different phases of the cardiac cycle, which can be used to assess global cardiac function and regional endocardial surface motion. In addition, MRI can provide detailed information on the patterns of motion within the heart wall, permitting calculation of the evolution of regional strain and related motion variables within the wall. These show consistent patterns of spatial and temporal variation in normal subjects, which are affected by alterations of function due to disease. Although still an evolving technique, MRI shows promise as a new method for research and clinical evaluation of cardiac dynamics.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.4.020702.153434
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    HERMAN P. SCHWAN: A Scientist and Pioneer in Biomedical Engineering (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 1-27 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.4.092001.093625
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    ROLES FOR LEARNING SCIENCES AND LEARNING TECHNOLOGIES IN BIOMEDICAL ENGINEERING EDUCATION: A Review of Recent Advances (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 29-48 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Abstract Education in biomedical engineering offers a number of challenges to all constituents of the educational process-faculty, students, and employers of graduates. Although biomedical engineering educational systems have been under development for 40 years, interest in and the pace of development of these programs has accelerated in recent years. New advances in the learning sciences have provided a framework for the reexamination of instructional paradigms in biomedical engineering. This work shows that learning environments should be learner centered, knowledge centered, assessment centered, and community centered. In addition, learning technologies offer the potential to achieve this environment with efficiency. Biomedical engineering educators are in a position to design and implement new learning systems that can take advantage of advances in learning science, learning technology, and reform in engineering education.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.4.091701.125502
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    BIOENGINEERING OF THERAPEUTIC AEROSOLS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 93-107 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Abstract The new field of therapeutic aerosol bioengineering (TAB), driven primarily by the medical need for inhaled insulin, is now expanding to address medical needs ranging from respiratory to systemic diseases, including asthma, growth deficiency, and pain. Bioengineering of therapeutic aerosols involves a level of aerosol particle design absent in traditional therapeutic aerosols, which are created by conventionally spraying a liquid solution or suspension of drug or milling and mixing a dry drug form into respirable particles. Bioengineered particles may be created in liquid form from devices specially designed to create an unusually fine size distribution, possibly with special purity properties, or solid particles that possess a mixture of drug and excipient, with designed shape, size, porosity, and drug release characteristics. Such aerosols have enabled several high-visibility clinical programs of inhaled insulin, as well as earlier-stage programs involving inhaled morphine, growth hormone, beta-interferon, alpha-1-antitrypsin, and several asthma drugs. The design of these aerosols, limited by partial knowledge of the lungs' physiological environment, and driven largely at this stage by market forces, relies on a mixture of new and old science, pharmaceutical science intuition, and a degree of biological-impact empiricism that speaks to the importance of an increased level of academic involvement.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.4.100101.132311
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    MECHANO-ELECTROCHEMICAL PROPERTIES OF ARTICULAR CARTILAGE: Their Inhomogeneities and Anisotropies (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 175-209 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Abstract In this chapter, the recent advances in cartilage biomechanics and electromechanics are reviewed and summarized. Our emphasis is on the new experimental techniques in cartilage mechanical testing, new experimental and theoretical findings in cartilage biomechanics and electromechanics, and emerging theories and computational modeling of articular cartilage. The charged nature and depth-dependent inhomogeneity in mechano-electrochemical properties of articular cartilage are examined, and their importance in the normal and/or pathological structure-function relationships with cartilage is discussed, along with their pathophysiological implications. Developments in theoretical and computational models of articular cartilage are summarized, and their application in cartilage biomechanics and biology is reviewed. Future directions in cartilage biomechanics and mechano-biology research are proposed.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.4.110701.120309
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    ADVANCES IN IN VIVO BIOLUMINESCENCE IMAGING OF GENE EXPRESSION (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 235-260 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Abstract To advance our understanding of biological processes as they occur in living animals, imaging strategies have been developed and refined that reveal cellular and molecular features of biology and disease in real time. One rapid and accessible technology for in vivo analysis employs internal biological sources of light emitted from luminescent enzymes, luciferases, to label genes and cells. Combining this reporter system with the new generation of charge coupled device (CCD) cameras that detect the light transmitted through the animal's tissues has opened the door to sensitive in vivo measurements of mammalian gene expression in living animals. Here, we review the development and application of this imaging strategy, in vivo bioluminescence imaging (BLI), together with in vivo fluorescence imaging methods, which has enabled the real-time study of immune cell trafficking, of various genetic regulatory elements in transgenic mice, and of in vivo gene transfer. BLI has been combined with fluorescence methods that together offer access to in vivo measurements that were not previously available. Such studies will greatly facilitate the functional analysis of a wide range of genes for their roles in health and disease.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.4.111901.093336
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    PHYSICS AND APPLICATIONS OF MICROFLUIDICS IN BIOLOGY (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 261-286 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Abstract Fluid flow at the microscale exhibits unique phenomena that can be leveraged to fabricate devices and components capable of performing functions useful for biological studies. The physics of importance to microfluidics are reviewed. Common methods of fabricating microfluidic devices and systems are described. Components, including valves, mixers, and pumps, capable of controlling fluid flow by utilizing the physics of the microscale are presented. Techniques for sensing flow characteristics are described and examples of devices and systems that perform bioanalysis are presented. The focus of this review is microscale phenomena and the use of the physics of the scale to create devices and systems that provide functionality useful to the life sciences.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.4.112601.125916
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    ADVANCES IN PROTEOMIC TECHNOLOGIES (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 349-373 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Abstract Proteomics is a rapidly emerging set of key technologies that are being used to identify proteins and map their interactions in a cellular context. With the sequencing of the human genome, the scope of proteomics has shifted from protein identification and characterization to include protein structure, function and protein-protein interactions. Technologies used in proteomic research include two-dimensional gel electrophoresis, mass spectrometry, yeast two-hybrids screens, and computational prediction programs. While some of these technologies have been in use for a long time, they are currently being applied to study physiology and cellular processes in high-throughput formats. It is the high-throughput approach that defines and characterizes modern proteomics. In this review, we discuss the current status of these experimental and computational technologies relevant to the three major aspects of proteomics-characterization of proteomes, identification of proteins, and determination of protein function. We also briefly discuss the development of new proteomic technologies that are based on recent advances in analytical and biochemical techniques, engineering, microfabrication, and computational prowess. The integration of these advances with established technologies is invaluable for the drive toward a comprehensive understanding of protein structure and function in the cellular milieu.
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    The Physiology of Supporting Tissue (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 101-118 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.000533
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    Conduction and Synaptic Transmission in the Nervous System (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 399-420 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.002151
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    Physiology of Vision (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 485-502 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.002413
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    Metabolic Functions of the Endocrine Glands (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 503-536 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.002443
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    Reproduction (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 537-556 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.002541
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    Radiant Energy (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 27-46 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.000331
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    Digestive System (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 205-236 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.001225
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    Visceral Functions of the Nervous System (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 445-468 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.002305
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    Somatic Functions of the Nervous System (1950)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 12 (1950), S. 421-444 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
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    URL: http://dx.doi.org/10.1146/annurev.ph.12.030150.002225
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    A HUNDRED YEARS OF SODIUM PUMPING (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 1-18 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: This article gives a history of the evidence (a) that animal cell membranes contain pumps that expel sodium ions in exchange for potassium ions; (b) that the pump derives energy from the hydrolysis of ATP; (c) that it is thermodynamically reversible-artificially steep transmembrane ion gradients make it run backward synthesizing ATP from ADP and orthophosphate; (d) that its mechanism is a ping-pong one, in which phosphorylation of the pump by ATP is associated with an efflux of three sodium ions, and hydrolysis of the phosphoenzyme is associated with an influx of two potassium ions; (e) that each half of the working cycle involves both the transfer of a phosphate group and a conformational change-the phosphate transfer being associated with the occlusion of ions bound at one surface and the conformational change releasing the occluded ions at the opposite surface.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.64.081501.130716
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    FATTY ACID OXIDATION DISORDERS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 477-502 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Genetic disorders of mitochondrial fatty acid beta-oxidation have been recognized within the last 20 years as important causes of morbidity and mortality, highlighting the physiological significance of fatty acids as an energy source. Although the mammalian mitochondrial fatty acid-oxidizing system was recognized at the beginning of the last century, our understanding of its exact nature remains incomplete, and new components are being identified frequently. Originally described as a four-step enzymatic process located exclusively in the mitochondrial matrix, we now recognize that long-chain-specific enzymes are bound to the inner mitochondrial membrane, and some enzymes are expressed in a tissue-specific manner. Much of our new knowledge of fatty acid metabolism has come from the study of patients who were diagnosed with single-gene autosomal recessive defects, a situation that seems to be further evolving with the emergence of phenotypes determined by combinations of multiple genetic and environmental factors. This review addresses the normal process of mitochondrial fatty acid beta-oxidation and discusses the clinical, metabolic, and molecular aspects of more than 20 known inherited diseases of this pathway that have been described to date.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.64.082201.154705
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    THE RENIN ANGIOTENSIN SYSTEM AND KIDNEY DEVELOPMENT (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 551-561 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract When angiotensin II or AT1 receptor is experimentally inhibited during the perinatal period, either by pharmacological intervention or genetic manipulation, the kidney develops with profound structural abnormalities. Most prominent are hypertrophy of arterial vasculatures and atrophy of the papilla. Although the mechanism by which the vascular hypertrophy occurs remains unknown, study of the atrophic papilla gives us a new clue for understanding the physiological role of angiotensin. Mutant mice completely devoid of AT1 receptor fail to develop the renal pelvis and the ureteral peristaltic movement. Normally, angiotensin and AT1 receptor are transiently up-regulated around the renal outlet at birth. Thus angiotensin II induces the peristaltic machinery during the perinatal period in a timely fashion to accommodate the dramatic increase in urine production that occurs during the transition from intra- to extra-uterine life. Further studies revealed that in adult animals angiotensin augments the peristaltic movement when the urinary tract is partially obstructed, thereby protecting the kidney from hydronephrosis. This newly discovered function of angiotensin to protect kidney architecture at the time of urine outflow obstruction is reminiscent of its similar kidney structure-protecting function that is active during arterial blood flow obstruction.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.64.081501.155721
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    CHLORIDE CHANNELS AND HEPATOCELLULAR FUNCTION: Prospects for Molecular Identification (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 609-633 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Hepatocytes possess chloride channels at the plasma membrane and in multiple intracellular compartments. These channels are required for cell volume regulation and acidification of intracellular organelles. Evidence also supports a role of chloride channels in modulation of apoptosis and cell growth. Swelling- and Ca2+-activated chloride channels have been identified in hepatocyte plasma membranes, and chloride channels have been observed in the membranes of lysosomes, endosomes, Golgi, endoplasmic reticulum, mitochondria, and the nucleus. This review summarizes the functions of these channels and discusses the specific channel molecules they may represent. Chloride channel molecules shown to be expressed in hepatocytes include members of the ClC channel family (ClC-2, ClC-3, ClC-5, and ClC-7), members of the newly identified CLIC family of intracellular chloride channels (CLIC-1 and CLIC-4), the mitochondrial voltage-dependent anion channel, and a newly identified intracellular channel, MCLC (Mid-1 related chloride channel). Current understanding does not include a molecular identification of most of the observed channel functions, but details of the molecular properties of these channel molecules should allow future identification and further understanding of chloride channel function in hepatocytes.
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    MOLECULAR PATHOGENESIS OF LUNG CANCER (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 681-708 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Lung cancer is the most common cause of cancer death in the United States, killing more than 156,000 people every year. In the past two decades, significant progress has been made in understanding the molecular and cellular pathogenesis of lung cancer. Abnormalities of proto-oncogenes, genetic and epigenetic changes of tumor suppressor genes, the role of angiogenesis in the multistage development of lung cancer, as well as detection of molecular abnormalities in preinvasive respiratory lesions, have recently come into focus. Efforts are ongoing to translate these findings into new clinical strategies for risk assessment, chemoprevention, early diagnosis, treatment selection, and prognosis and to provide new targets and methods of treatment for lung cancer patients. All these strategies should aid in reducing the number of newly diagnosed lung cancer cases and in increasing the survival and quality of life of patients with lung cancer.
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    GM-CSF REGULATES PULMONARY SURFACTANT HOMEOSTASIS AND ALVEOLAR MACROPHAGE-MEDIATED INNATE HOST DEFENSE (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 64 (2002), S. 775-802 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Recent studies in transgenic mice have revealed important insights into the roles of GM-CSF in regulation of surfactant homeostasis and lung host defense. Interruption of the GM-CSF signaling pathway by targeted ablation of the GM-CSF gene or its receptor (GM-/- or GM Rbetac-/- mice, respectively) resulted in pulmonary alveolar proteinosis (PAP) but no hematologic abnormalities. Alveolar macrophages from GM-/- mice have reduced capacity for surfactant catabolism, cell adhesion, phagocytosis, bacterial killing, Toll-receptor signaling, and expression of various pathogen-associated molecular pattern recognition receptors, suggesting arrest at an early stage of differentiation. PAP and abnormalities of alveolar macrophage function were corrected by local expression of GM-CSF in the lung, and expression of the transcription factor PU.1 in alveolar macrophages of GM-/- mice rescued most defects. Recently, a strong association of auto-antibodies to GM-CSF or GM-CSF receptor gene mutations with PAP has implicated GM-CSF signaling abnormalities in the pathogenesis of PAP in humans. Together, these observations demonstrate that GM-CSF has a critical role in regulation of surfactant homeostasis and alveolar macrophage innate immune functions in the lung.
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    EARTHQUAKE PREDICTION: State-of-the-Art and Emerging Possibilities (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Earth and Planetary Sciences 30 (2002), S. 1-33 
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    ISSN: 0084-6597
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Geosciences , Physics
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    URL: http://dx.doi.org/10.1146/annurev.earth.30.100301.083856
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    IMPLICATIONS OF EXTRASOLAR PLANETS FOR UNDERSTANDING PLANET FORMATION (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Earth and Planetary Sciences 30 (2002), S. 113-148 
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    ISSN: 0084-6597
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Geosciences , Physics
    Notes: Abstract The observed properties of extrasolar planets and planetary systems are reviewed, including discussion of the mass, period, and eccentricity distributions; the presence of multiple systems; and the properties of the host stars. In all cases, the data refer to systems with ages in the Ga range. Some of the properties primarily reflect the formation mechanism, while others are determined by postformation dynamical evolutionary processes. The problem addressed here is the extraction of information relevant to the identification of the formation mechanism. The presumed formation sites, namely disks around young stars, therefore, must provide clues at times much closer to the actual formation time. The properties of such disks are briefly reviewed. The amount of material and its distribution in the disks provide a framework for the development of a model for planet formation. The strengths of, as well as the problems with, the two major planet formation mechanisms-gravitational instability and core accretion-gas capture-are then described. It is concluded that most of the known planetary systems are best explained by the accretion process. The timescales for the persistence of disks and for the formation time by this process are similar, and the mass range of the observed planets, up to approximately 10 Jupiter masses, is naturally explained. The mass range of 5-15 Jupiter masses probably represents an overlapping transition region, with planetary formation processes dominating below that range and star formation processes dominating above it.
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    URL: http://dx.doi.org/10.1146/annurev.earth.30.091201.140357
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    GEODYNAMO SIMULATIONS-HOW REALISTIC ARE THEY? (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Earth and Planetary Sciences 30 (2002), S. 237-257 
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    ISSN: 0084-6597
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Geosciences , Physics
    Notes: Abstract The past seven years have seen significant advances in computational simulations of convection and magnetic field generation in the Earth's core. Although dynamically self-consistent models of the geodynamo have simulated magnetic fields that appear in some ways quite similar to the geomagnetic field, none are able to run in an Earth-like parameter regime because of the considerable spatial resolution that is required. Here we discuss some of the subtle compromises that have been made in current models and propose a grand challenge for the future, requiring significant improvements in numerical methods and spatial resolution.
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    URL: http://dx.doi.org/10.1146/annurev.earth.30.091201.140817
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    GEOLOGIC STRUCTURE OF THE UPPERMOST OCEANIC CRUST CREATED AT FAST- TO INTERMEDIATE-RATE SPREADING CENTERS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Earth and Planetary Sciences 30 (2002), S. 347-384 
    Details
    ISSN: 0084-6597
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Geosciences , Physics
    Notes: Abstract Geological investigations of major fault scarps ("tectonic windows") and DSDP/ODP Drill Holes provide direct views of the uppermost oceanic crust generated at fast- to intermediate-rate spreading centers. These areas reveal a consistent upper crustal structural geometry with basaltic lava flows defining a pattern of downward increasing ("inward") dip toward the spreading center at which they formed and dikes in the lavas and underlying sheeted dike complex showing a similar degree of "outward" dip. Widespread fracturing, faulting, and hydrothermal metamorphism accompanied magmatic construction. These geological relationships can be interpreted in terms of dramatic, asymmetrical, subaxial subsidence of upper crustal rock units that diminishes across the very narrow (few kilometers wide) zone of lava accumulation and dike intrusion at the ridge axis. This type of crustal structure is in accord with some existing models of spreading but augments these idealized views with more realistic geological complexity.
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    URL: http://dx.doi.org/10.1146/annurev.earth.30.091201.141132
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    MANTLE MIXING: The Generation, Preservation, and Destruction of Chemical Heterogeneity (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Earth and Planetary Sciences 30 (2002), S. 493-525 
    Details
    ISSN: 0084-6597
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Geosciences , Physics
    Notes: Abstract Observations of the geochemical diversity of mid-oceanic ridge and ocean-island basalts have traditionally been attributed to the existence of large-scale mantle heterogeneity. In particular, the layered convection model has provided an important conceptual basis for discussing the chemical evolution of the Earth. In this model, a long-term boundary is assumed between a well-mixed and depleted upper mantle and a heterogeneous and more primitive lower mantle. The existence of high 3He/4He in ocean-island sources has been used to argue for the preservation of a primitive component in the deep mantle. Nevertheless, a primitive deep layer is difficult to reconcile with the abundant lithophile isotopic evidence for recycling of oceanic crust and the lack of preservation of primitive mantle. In addition, the widespread acceptance of geophysical evidence for whole mantle flow has made straightforward application of the layered convection model problematic. Model calculations show that whole mantle convection with present day heat flow and surface velocities is sufficiently vigorous to mix large-scale heterogeneity to an extent that is incompatible with the geochemical observations. Several concepts have been proposed in recent years to resolve the apparent conflicts between the various observational constraints and theoretical interpretations. The suggestions include the presence of deeper layering, preservation of highly viscous blobs, core mantle interaction, and strong temporal variations in mantle dynamics. Although these models generally appear to solve parts of the puzzle, at present no single model is able to account for all of the major observations. The reconciliation of conflicting evidence awaits improvements in observational and experimental techniques integrated with better model testing of hypotheses for the generation and destruction of mantle heterogeneity.
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    URL: http://dx.doi.org/10.1146/annurev.earth.30.091201.141236
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    AUDITORY SYSTEM DEVELOPMENT: Primary Auditory Neurons and Their Targets (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 51-101 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The neurons of the cochlear ganglion transmit acoustic information between the inner ear and the brain. These placodally derived neurons must produce a topographically precise pattern of connections in both the inner ear and the brain. In this review, we consider the current state of knowledge concerning the development of these neurons, their peripheral and central connections, and their influences on peripheral and central target cells. Relatively little is known about the cellular and molecular regulation of migration or the establishment of precise topographic connection to the hair cells or cochlear nucleus (CN) neurons. Studies of mice with neurotrophin deletions are beginning to yield increasing understanding of variations in ganglion cell survival and resulting innervation patterns, however. Finally, existing evidence suggests that while ganglion cells have little influence on the differentiation of their hair cell targets, quite the opposite is true in the brain. Ganglion cell innervation and synaptic activity are essential for normal development of neurons in the cochlear nucleus.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.25.112701.142849
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    AMPA RECEPTOR TRAFFICKING AND SYNAPTIC PLASTICITY (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 103-126 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Activity-dependent changes in synaptic function are believed to underlie the formation of memories. Two prominent examples are long-term potentiation (LTP) and long-term depression (LTD), whose mechanisms have been the subject of considerable scrutiny over the past few decades. Here we review the growing literature that supports a critical role for AMPA receptor trafficking in LTP and LTD, focusing on the roles proposed for specific AMPA receptor subunits and their interacting proteins. While much work remains to understand the molecular basis for synaptic plasticity, recent results on AMPA receptor trafficking provide a clear conceptual framework for future studies.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.25.112701.142758
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    INTENTIONAL MAPS IN POSTERIOR PARIETAL CORTEX (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 189-220 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The posterior parietal cortex (PPC), historically believed to be a sensory structure, is now viewed as an area important for sensory-motor integration. Among its functions is the forming of intentions, that is, high-level cognitive plans for movement. There is a map of intentions within the PPC, with different subregions dedicated to the planning of eye movements, reaching movements, and grasping movements. These areas appear to be specialized for the multisensory integration and coordinate transformations required to convert sensory input to motor output. In several subregions of the PPC, these operations are facilitated by the use of a common distributed space representation that is independent of both sensory input and motor output. Attention and learning effects are also evident in the PPC. However, these effects may be general to cortex and operate in the PPC in the context of sensory-motor transformations.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.25.112701.142922
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    BEYOND PHRENOLOGY: What Can Neuroimaging Tell Us About Distributed Circuitry? (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 221-250 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Unsupervised models of how the brain identifies and categorizes the causes of its sensory input can be divided into two classes: those that minimize the mutual information (i.e., redundancy) among evoked responses and those that minimize the prediction error. Although these models have the same goal, the way that goal is attained, and the functional architectures required, are fundamentally different. This review describes the differences, in the functional anatomy of sensory cortical hierarchies, implied by the two models. We then consider how neuroimaging can be used to disambiguate between them. The key distinction reduces to whether backward connections are employed by the brain to generate a prediction of sensory inputs. To ascertain whether backward influences are evident empirically requires a characterization of functional integration among brain systems. This review summarizes the approaches to measuring functional integration in terms of effective connectivity and proceeds to address the question posed by the theoretical considerations. In short, it will be shown that the conjoint manipulation of bottom-up and top-down inputs to an area can be used to test for interactions between them, in elaborating cortical responses. The conclusion, from these sorts of neuroimaging studies, points to the prevalence of top-down influences and the plausibility of generative models of sensory brain function.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.25.112701.142846
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    TRANSCRIPTIONAL CODES AND THE CONTROL OF NEURONAL IDENTITY (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 251-281 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The topographic assembly of neural circuits is dependent upon the generation of specific neuronal subtypes, each subtype displaying unique properties that direct the formation of selective connections with appropriate target cells. Studies of motor neuron development in the spinal cord have begun to elucidate the molecular mechanisms involved in controlling motor projections. In this review, we first describe the actions of transcription factors within motor neuron progenitors, which initiate a cascade of transcriptional interactions that lead to motor neuron specification. We next highlight the contribution of the LIM homeodomain (LIM-HD) transcription factors in establishing motor neuron subtype identity. Importantly, it has recently been shown that the combinatorial expression of LIM-HD transcription factors, the LIM code, confers motor neuron subtypes with the ability to select specific axon pathways to reach their distinct muscle targets. Finally, the downstream targets of the LIM code are discussed, especially in the context of subtype-specific motor axon pathfinding.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.25.112701.142916
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    THE ROLE OF HYPOCRETINS (OREXINS) IN SLEEP REGULATION AND NARCOLEPSY (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 283-313 
    Details
    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The hypocretins (orexins) are two novel neuropeptides (Hcrt-1 and Hcrt-2), derived from the same precursor gene, that are synthesized by neurons located exclusively in the lateral, posterior, and perifornical hypothalamus. Hypocretin-containing neurons have widespread projections throughout the CNS with particularly dense excitatory projections to monoaminergic centers such as the noradrenergic locus coeruleus, histaminergic tuberomammillary nucleus, serotoninergic raphe nucleus, and dopaminergic ventral tegmental area. The hypocretins were originally believed to be primarily important in the regulation of appetite; however, a major function emerging from research on these neuropeptides is the regulation of sleep and wakefulness. Deficiency in hypocretin neurotransmission results in the sleep disorder narcolepsy in mice, dogs, and humans. The hypocretins are also uniquely positioned to link sleep, appetite, and neuroendocrine control. The aim of this review is to describe and discuss the current knowledge regarding the hypocretin neurotransmitter system in narcolepsy and normal sleep.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.25.112701.142826
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    A DECADE OF MOLECULAR STUDIES OF FRAGILE X SYNDROME (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 315-338 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Fragile X syndrome is one of the most common forms of inherited mental retardation. In most cases the disease is caused by the methylation-induced transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene that occurs as a result of the expansion of a CGG repeat in the gene's 5'UTR and leads to the loss of protein product fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein that associates with translating polyribosomes as part of a large messenger ribonucleoprotein (mRNP) and modulates the translation of its RNA ligands. Pathological studies from the brains of patients and from Fmr1 knockout mice show abnormal dendritic spines implicating FMRP in synapse formation and function. Evidence from both in vitro and in vivo neuronal studies indicates that FMRP is located at the synapse and the loss of FMRP alters synaptic plasticity. As synaptic plasticity has been implicated in learning and memory, analysis of synapse abnormalities in patients and Fmr1 knockout mice should prove useful in studying the pathogenesis of fragile X syndrome and understanding learning and cognition in general. If an appreciable portion of the total variance (in IQ) is due to sex linked genes, it is of more importance that a boy should have a clever mother than a clever father. Hogben 1932 (quoted in Lehrke 1974)
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    URL: http://dx.doi.org/10.1146/annurev.neuro.25.112701.142909
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    LARGE-SCALE SOURCES OF NEURAL STEM CELLS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 381-407 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Large-scale sources of neural stem cells are crucial for both basic research and novel approaches toward treating neurological disorders. Three sources that produce neural cells closely resembling their normal counterparts are now available: oncogene immortalized stem cells, neurospheres, and embryonic stem cell (ES)-derived neural cells. Cells including multiple subtypes of CNS and PNS neurons, as well as oligodendrocytes, Schwann cells, and astrocytes, are modeled by these large-scale sources. Although most cell lines were originally from rodents, their human counterparts are being discovered and characterized.
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    CONTEXTUAL INFLUENCES ON VISUAL PROCESSING (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 339-379 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The visual image formed on the retina represents an amalgam of visual scene properties, including the reflectances of surfaces, their relative positions, and the type of illumination. The challenge facing the visual system is to extract the "meaning" of the image by decomposing it into its environmental causes. For each local region of the image, that extraction of meaning is only possible if information from other regions is taken into account. Of particular importance is a set of image cues revealing surface occlusion and/or lighting conditions. These information-rich cues direct the perceptual interpretation of other more ambiguous image regions. This context-dependent transformation from image to perception has profound-but frequently under-appreciated-implications for neurophysiological studies of visual processing: To demonstrate that neuronal responses are correlated with perception of visual scene properties, rather than visual image features, neuronal sensitivity must be assessed in varied contexts that differentially influence perceptual interpretation. We review a number of recent studies that have used this context-based approach to explore the neuronal bases of visual scene perception.
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    SCHIZOPHRENIA AS A DISORDER OF NEURODEVELOPMENT (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 409-432 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract A combination of genetic susceptibility and environmental perturbations appear to be necessary for the expression of schizophrenia. In addition, the pathogenesis of the disease is hypothesized to be neurodevelopmental in nature based on reports of an excess of adverse events during the pre- and perinatal periods, the presence of cognitive and behavioral signs during childhood and adolescence, and the lack of evidence of a neurodegenerative process in most individuals with schizophrenia. Recent studies of neurodevelopmental mechanisms strongly suggest that no single gene or factor is responsible for driving a highly complex biological process. Together, these findings suggest that combinatorial genetic and environmental factors, which disturb a normal developmental course early in life, result in molecular and histogenic responses that cumulatively lead to different developmental trajectories and the clinical phenotype recognized as schizophrenia.
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    THE ROLE OF NOTCH IN PROMOTING GLIAL AND NEURAL STEM CELL FATES (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 25 (2002), S. 471-490 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The Notch signaling pathway has long been known to influence cell fate in the developing nervous system. However, this pathway has generally been thought to inhibit the specification of certain cell types in favor of others, or to simply maintain a progenitor pool. Recently, this view has been challenged by numerous studies suggesting that Notch may play an instructive role in promoting glial development. This work has inspired a new look at the role of Notch signaling in specifying cell fate. It has also prompted further consideration of the emerging view that in some contexts glia may be multipotent progenitors. This review examines the role of Notch during gliogenesis in both fruit flies and vertebrates, as well as evidence in vertebrates that some glia may be stem cells.
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    URL: http://dx.doi.org/10.1146/annurev.neuro.25.030702.130823
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    THREE-DIMENSIONAL CONFOCAL MICROSCOPY OF THE LIVING HUMAN EYE (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 69-91 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Abstract Three-dimensional confocal microscopy of the living eye is a major development in instrumentation for biomicroscopy of the eye. This noninvasive optical technology has its roots in the application of optics to reflected light imaging of the eye. These instrument developments began with Leeuwenhoek's use of his single lens microscope to investigate the structure of the eye. There followed a series of connected instruments: the ophthalmoscope, the slit lamp, the specular microscope, and the clinical confocal microscope. In vivo confocal microscopy produces high contrast, reflected light images or optical sections through the depth of living ocular tissue. Stacks of registered optical sections can be transformed by computer visualization techniques into three-dimensional volume images of ocular tissues: cornea, ocular lens, retina, and optic nerve. The clinical confocal microscope has resulted in new diagnostic techniques and new cellular descriptions of ocular disorders and pathology.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.4.092701.132001
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    DENATURATION OF COLLAGEN VIA HEATING: An Irreversible Rate Process (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 4 (2002), S. 109-128 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Abstract Heating therapies are increasingly used in cardiology, dermatology, gynecology, neurosurgery, oncology, ophthalmology, orthopedics, and urology, among other medical specialties. This widespread use of heating is driven primarily by the availability of new technology, not by a detailed understanding of the biothermomechanics. Without basic quantification of the underlying physical and chemical processes in terms of parameters that can be controlled clinically, identification of preferred interventions will continue to be based primarily on trial and error, thus necessitating large clinical studies and years of accumulative experience. Perusal of the literature reveals that much has been learned over the past century about the response of cells, proteins, and tissues to supra-physiologic temperatures; yet, the associated findings are reported in diverse journals and the underlying basic processes remain unidentified. In this review, we seek to contrast various findings on the kinetics of the thermal denaturation of collagen and to encourage investigators to consider the many open problems in part via a synthesis of results from the diverse literatures.
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    THE BINDING SITE OF AMINERGIC G PROTEIN-COUPLED RECEPTORS: The Transmembrane Segments and Second Extracellular Loop (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 42 (2002), S. 437-467 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Abstract In the current chapter, we review approaches to the identification of the residues forming the binding sites for agonists, antagonists, and allosteric modulators in the family of aminergic G protein-coupled receptors (GPCRs). We then review the structural bases for ligand binding and pharmacological specificity based on the application of these methods to muscarinic cholinergic, adrenergic, dopaminergic, serotonergic, and histaminergic receptors, using the high resolution rhodopsin structure as a template. Furthermore, we propose a critical role of the second extracellular loop in forming the binding site for small molecular weight aminergic ligands, much as this loop dives down into the binding-site crevice and contacts retinal in rhodopsin.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.42.091101.144224
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    THE SPINAL PHOSPHOLIPASE-CYCLOOXYGENASE-PROSTANOID CASCADE IN NOCICEPTIVE PROCESSING (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 42 (2002), S. 553-583 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Abstract Intrathecal phospholipase A2 (PLA2) and cyclooxygenase-2 (COX-2), but not COX-1, inhibitors attenuate facilitated pain states generated by peripheral injury/inflammation and by direct activation of spinal glutamate and substance P receptors. These results are consistent with the constitutive expression of PLA2 and COX-2 in spinal cord, the spinal release of prostaglandins by persistent afferent input, and the effects of prostaglandins on spinal excitability. Whereas the acute actions of COX-2 inhibitors are clearly mediated by constitutively expressed spinal COX-2, studies of spinal COX-2 expression indicate that it is upregulated by neural input and circulating cytokines. Given the intrathecal potency of COX-2 inhibitors, the comparable efficacy of intrathecal versus systemic COX-2 inhibitors in hyperalgesic states not associated with inflammation, and the onset of antihyperalgesic activity prior to COX-2 upregulation, it is argued that a principal antihyperalgesic mechanism of COX-2 inhibitors lies with modulation of constitutive COX-2 present at the spinal level.
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    ALTERED DNA METHYLATION: A Secondary Mechanism Involved in Carcinogenesis (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 42 (2002), S. 501-525 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Abstract This review focuses on the role that DNA methylation plays in the regulation of normal and aberrant gene expression and on how, in a hypothesis-driven fashion, altered DNA methylation may be viewed as a secondary mechanism involved in carcinogenesis. Research aimed at discerning the mechanisms by which chemicals can transform normal cells into frank carcinomas has both theoretical and practical implications. Through an increased understanding of the mechanisms by which chemicals affect the carcinogenic process, we learn more about basic biology while, at the same time, providing the type of information required to make more rational safety assessment decisions concerning their actual potential to cause cancer under particular conditions of exposure. One key question is: does the mechanism of action of the chemical in question involve a secondary mechanism and, if so, what dose may be below its threshold?
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    MAP KINASES IN THE IMMUNE RESPONSE (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 55-72 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract MAP kinases are among the most ancient signal transduction pathways and are widely used throughout evolution in many physiological processes. In mammalian species, MAP kinases are involved in all aspects of immune responses, from the initiation phase of innate immunity, to activation of adaptive immunity, and to cell death when immune function is complete. In this review, we summarize recent progress in understanding the function and regulation of MAP kinase pathways in these phases of immune responses.
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    MOLECULAR MECHANISM OF CLASS SWITCH RECOMBINATION: Linkage with Somatic Hypermutation (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 165-196 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Class switch recombination (CSR) and somatic hypermutation (SHM) have been considered to be mediated by different molecular mechanisms because both target DNAs and DNA modification products are quite distinct. However, involvement of activation-induced cytidine deaminase (AID) in both CSR and SHM has revealed that the two genetic alteration mechanisms are surprisingly similar. Accumulating data led us to propose the following scenario: AID is likely to be an RNA editing enzyme that modifies an unknown pre-mRNA to generate mRNA encoding a nicking endonuclease specific to the stem-loop structure. Transcription of the S and V regions, which contain palindromic sequences, leads to transient denaturation, forming the stem-loop structure that is cleaved by the AID-regulated endonuclease. Cleaved single-strand tails will be processed by error-prone DNA polymerase-mediated gap-filling or exonuclease-mediated resection. Mismatched bases will be corrected or fixed by mismatch repair enzymes. CSR ends are then ligated by the NHEJ system while SHM nicks are repaired by another ligation system.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.20.090501.112049
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    LYMPHOCYTE-MEDIATED CYTOTOXICITY (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 323-370 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Virtually all of the measurable cell-mediated cytotoxicity delivered by cytotoxic T lymphocytes and natural killer cells comes from either the granule exocytosis pathway or the Fas pathway. The granule exocytosis pathway utilizes perforin to traffic the granzymes to appropriate locations in target cells, where they cleave critical substrates that initiate DNA fragmentation and apoptosis; granzymes A and B induce death via alternate, nonoverlapping pathways. The Fas/FasL system is responsible for activation-induced cell death but also plays an important role in lymphocyte-mediated killing under certain circumstances. The interplay between these two cytotoxic systems provides opportunities for therapeutic interventions to control autoimmune diseases and graft vs. host disease, but oversuppression of these pathways may also lead to increased viral susceptibility and/or decreased tumor cell killing.
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    PRODUCING NATURE'S GENE-CHIPS: The Generation of Peptides for Display by MHC Class I Molecules (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 463-493 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Gene-chips contain thousands of nucleotide sequences that allow simultaneous analysis of the complex mixture of RNAs transcribed in cells. Like these gene-chips, major histocompatibility complex (MHC) class I molecules display a large array of peptides on the cell surface for probing by the CD8+ T cell repertoire. The peptide mixture represents fragments of most, if not all, intracellular proteins. The antigen processing machinery accomplishes the daunting task of sampling these proteins and cleaving them into the precise set of peptides displayed by MHC I molecules. It has long been believed that antigenic peptides arose as by-products of normal protein turnover. Recent evidence, however, suggests that the primary source of peptides is newly synthesized proteins that arise from conventional as well as cryptic translational reading frames. It is increasingly clear that for many peptides the C-terminus is generated in the cytoplasm, and N-terminal trimming occurs in the endoplasmic reticulum in an MHC I-dependent manner. Nature's gene-chips are thus both parsimonious and elegant.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.20.100301.064819
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    ANTIGEN PRESENTATION AND T CELL STIMULATION BY DENDRITIC CELLS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 621-667 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Dendritic cells take up antigens in peripheral tissues, process them into proteolytic peptides, and load these peptides onto major histocompatibility complex (MHC) class I and II molecules. Dendritic cells then migrate to secondary lymphoid organs and become competent to present antigens to T lymphocytes, thus initiating antigen-specific immune responses, or immunological tolerance. Antigen presentation in dendritic cells is finely regulated: antigen uptake, intracellular transport and degradation, and the traffic of MHC molecules are different in dendritic cells as compared to other antigen-presenting cells. These specializations account for dendritic cells' unique role in the initiation of immune responses and the induction of tolerance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.20.100301.064828
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    PROTEIN KINASE Ctheta IN T CELL ACTIVATION (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 761-794 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The novel protein kinase C (PKC) isoform, PKCtheta, is selectively expressed in T lymphocytes and is a sine qua non for T cell antigen receptor (TCR)-triggered activation of mature T cells. Productive engagement of T cells by antigen-presenting cells (APCs) results in recruitment of PKCtheta to the T cell-APC contact area-the immunological synapse-where it interacts with several signaling molecules to induce activation signals essential for productive T cell activation and IL-2 production. The transcription factors NF-kappaB and AP-1 are the primary physiological targets of PKCtheta, and efficient activation of these transcription factors by PKCtheta requires integration of TCR and CD28 costimulatory signals. PKCtheta cooperates with the protein Ser/Thr phosphatase, calcineurin, in transducing signals leading to activation of JNK, NFAT, and the IL-2 gene. PKCtheta also promotes T cell cycle progression and regulates programmed T cell death. The exact mode of regulation and immediate downstream substrates of PKCtheta are still largely unknown. Identification of these molecules and determination of their mode of operation with respect to the function of PKCtheta will provide essential information on the mechanism of T cell activation. The selective expression of PKCtheta in T cells and its essential role in mature T cell activation establish it as an attractive drug target for immunosuppression in transplantation and autoimmune diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.20.100301.064807
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    RANK-L AND RANK: T Cells, Bone Loss, and Mammalian Evolution (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 795-823 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract TNF and TNFR family proteins play important roles in the control of cell death, proliferation, autoimmunity, the function of immune cells, or the organogenesis of lymphoid organs. Recently, novel members of this large family have been identified that have critical functions in immunity and that couple lymphoid cells with other organ systems such as bone morphogenesis and mammary gland formation in pregnancy. The TNF-family molecule RANK-L (RANK-L, TRANCE, ODF) and its receptor RANK are key regulators of bone remodeling, and they are essential for the development and activation of osteoclasts. Intriguingly, RANK-L/RANK interactions also regulate T cell/dendritic cell communications, dendritic cell survival, and lymph node formation; T cell-derived RANK-L can mediate bone loss in arthritis and periodontal disease. Moreover, RANK-L and RANK are expressed in mammary gland epithelial cells, and they control the development of a lactating mammary gland during pregnancy and the propagation of mammalian species. Modulation of these systems provides us with a unique opportunity to design novel therapeutics to inhibit bone loss in arthritis, periodontal disease, and osteoporosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.20.100301.064753
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    PROSPECTS FOR VACCINE PROTECTION AGAINST HIV-1 INFECTION AND AIDS (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 73-99 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The rapid and devastating spread of the AIDS epidemic in the developing world as well as the difficulties associated with delivering antiretroviral drugs in affected countries underscore the urgent need for the development of a safe and effective AIDS vaccine. In this review, we discuss recent advances in our understanding of the cellular and humoral immune responses to human immunodeficiency virus type 1 (HIV-1) infection. We then describe vaccine strategies that have been explored and discuss the evidence suggesting that cellular immune responses elicited by novel vaccine modalities may attenuate clinical disease caused by HIV-1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.20.081501.094854
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    T CELL RESPONSE IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE): Role of Self and Cross-Reactive Antigens in Shaping, Tuning, and Regulating the Autopathogenic T Cell Repertoire (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 101-123 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract T cells that can respond to self-antigens are present in the peripheral immune repertoire of all healthy individuals. Recently we have found that unmanipulated SJL mice that are highly susceptible to EAE also maintain a very high frequency of T cells responding to an encephalitogenic epitope of a myelin antigen proteolipid protein (PLP) 139-151 in the peripheral repertoire. This is not due to lack of expression of myelin antigens in the thymus resulting in escape of PLP 139-151 reactive cells from central tolerance, but is due to expression of a splice variant of PLP named DM20, which lacks the residues 116-150. In spite of this high frequency, the PLP 139-151 reactive cells remain undifferentiated in the periphery and do not induce spontaneous EAE. In contrast, SJL TCR transgenic mice expressing a receptor derived from a pathogenic T cell clone do develop spontaneous disease. This may be because in normal mice, autoreactive cells are kept in check by an alternate PLP 139-151 reactive nonpathogenic repertoire, which maintains a balance that keeps them healthy. If this is the case, selective activation of one repertoire or the other may alter susceptibility to autoimmune disease. Since T cells are generally cross-reactive, besides responding to nonself-antigens, they also maintain significant responses to self-antigens. Based on the PLP 139-151 system, we propose a model in which activation with foreign antigens can result in the generation of pathogenic memory T cells that mediate autoimmunity. We also outline circumstances under which activation of self-reactive T cells with foreign antigens can generate selective tolerance and thus generate protective/regulatory memory against self while still maintaining significant responses against foreign antigens. This provides a mechanism by which the fidelity and specificity of the immune system against foreign antigens is improved without increasing the potential for developing an autoimmune disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.20.081701.141316
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    ORIGINS AND FUNCTIONS OF B-1 CELLS WITH NOTES ON THE ROLE OF CD5 (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 253-300 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Whether B-1a (CD5+) cells are a distinct lineage derived from committed fetal/neonatal precursors or arise from follicular B-2 cells in response to BCR ligation and other, unknown signals remains controversial. Recent evidence indicates that B-1a cells can derive from adult precursors expressing an appropriate specificity when the (self-) antigen is present. Antibody specificity determines whether a B cell expressing immunoglobulin transgenes has a B-2, B-1a or marginal zone (MZ) phenotype. MZ cells share many phenotypic characteristics of B-1 cells and, like them, appear to develop in response to T independent type 2 antigens. Because fetal-derived B cell progenitors fail to express terminal deoxynucleotidyl transferase (TdT) and for other reasons, they are likely to express a repertoire that allows selection into the B-1a population. As it is selected by self-antigen, the B-1 repertoire tends to be autoreactive. This potentially dangerous repertoire is also useful, as B-1 cells are essential for resistance to several pathogens and they play an important role in mucosal immunity. The CD5 molecule can function as a negative regulator of BCR signaling that may help prevent inappropriate activation of autoreactive B-1a cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.20.100301.064833
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    CHROMATIN STRUCTURE AND GENE REGULATION IN THE IMMUNE SYSTEM (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 427-462 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The development of the immune system and the host response to microbial infection rely on the activation and silencing of numerous, differentially expressed genes. Since the mid-1980s, a primary goal has been to identify transcription factors that regulate specific genes and specific immunological processes. More recently, there has been a growing appreciation of the role of chromatin structure in gene regulation. Before most activators of a gene access their binding sites, a transition from a condensed to a decondensed chromatin structure appears to take place. The activation of transcription is then accompanied by the remodeling of specific nucleosomes. Conversely, the acquisition of a more condensed chromatin structure is often associated with gene silencing. Chromatin structure is a particularly significant contributor to gene regulation because it is likely to be a major determinant of cell identity and cell memory. That is, the propagation of decondensed chromatin at specific loci through DNA replication and cell division helps a cell remember which genes are expressed constitutively in that cell type or are poised for expression upon exposure to a stimulus. Here we review recent progress toward understanding the role of chromatin in the immune system. The interleukin-4 gene serves as a primary model for exploring the events involved in the acquisition and heritable maintenance of a decondensed chromatin structure. Studies of the interleukin-12 p40 and interferon-beta genes are then reviewed for insight into the mechanisms by which the remodeling of specific nucleosomes in the vicinity of a promoter can contribute to rapid activation following cell stimulation. Finally, basic principles of gene silencing are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.20.100301.064739
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    NEGATIVE REGULATION OF IMMUNORECEPTOR SIGNALING (2002)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 20 (2002), S. 669-707 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Immune cells are activated as a result of productive interactions between ligands and various receptors known as immunoreceptors. These receptors function by recruiting cytoplasmic protein tyrosine kinases, which trigger a unique phosphorylation signal leading to cell activation. In the recent past, there has been increasing interest in elucidating the processes involved in the negative regulation of immunoreceptor-mediated signal transduction. Evidence is accumulating that immunoreceptor signaling is inhibited by complex and highly regulated mechanisms that involve receptors, protein tyrosine kinases, protein tyrosine phosphatases, lipid phosphatases, ubiquitin ligases, and inhibitory adaptor molecules. Genetic evidence indicates that this inhibitory machinery is crucial for normal immune cell homeostasis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.20.081501.130710
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