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  • Articles  (3,573)
  • Springer  (3,081)
  • Annual Reviews  (298)
  • Blackwell Publishing Ltd  (194)
  • American Institute of Physics
  • 2005-2009  (3,573)
  • 1980-1984
  • 2005  (3,573)
  • Medicine  (3,573)
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  • Articles  (3,573)
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  • 2005-2009  (3,573)
  • 1980-1984
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Journal
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  • 1
    Electronic Resource
    Electronic Resource
    THE LYMPHATIC VASCULATURE: Recent Progress and Paradigms (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 457-483 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The field of lymphatic research has been recently invigorated by the identification of genes and mechanisms that control various aspects of lymphatic development. We are beginning to understand how, starting from a subgroup of embryonic venous endothelial cells, the whole lymphatic system forms in a stepwise manner. The generation of genetically engineered mice with defects in different steps of the lymphangiogenic program has provided models that are increasing our understanding of the lymphatic system in health and disease. This knowledge, in turn, should lead to the development of better diagnostic methods and treatments of lymphatic disorders and tumor metastasis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.012704.132338
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  • 2
    Electronic Resource
    Electronic Resource
    IN AWE OF SUBCELLULAR COMPLEXITY: 50 Years of Trespassing Boundaries Within the Cell (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 1-33 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: In this review I describe the several stages of my research career, all of which were driven by a desire to understand the basic mechanisms responsible for the complex and beautiful organization of the eukaryotic cell. I was originally trained as an electron microscopist in Argentina, and my first major contribution was the introduction of glutaraldehyde as a fixative that preserved the fine structure of cells, which opened the way for cytochemical studies at the EM level. My subsequent work on membrane-bound ribosomes illuminated the process of cotranslational translocation of polypeptides across the ER membrane and led to the formulation, with Gunter Blobel, of the signal hypothesis. My later studies with many talented colleagues contributed to an understanding of ER structure and function and aspects of the mechanisms that generate and maintain the polarity of epithelial cells. For this work my laboratory introduced the now widely adopted Madin-Darby canine kidney (MDCK) cell line, and demonstrated the polarized budding of envelope viruses from those cells, providing a powerful new system that further advanced the field of protein traffic.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.020904.151711
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  • 3
    Electronic Resource
    Electronic Resource
    ASSEMBLY OF VARIANT HISTONES INTO CHROMATIN (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 133-153 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Chromatin can be differentiated by the deposition of variant histones at centromeres, active genes, and silent loci. Variant histones are assembled into nucleosomes in a replication-independent manner, in contrast to assembly of bulk chromatin that is coupled to replication. Recent in vitro studies have provided the first glimpses of protein machines dedicated to building and replacing alternative nucleosomes. They deposit variant H2A and H3 histones and are targeted to particular functional sites in the genome. Differences between variant and canonical histones can have profound consequences, either for delivery of the histones to sites of assembly or for their function after incorporation into chromatin. Recent studies have also revealed connections between assembly of variant nucleosomes, chromatin remodeling, and histone post-translational modification. Taken together, these findings indicate that chromosome architecture can be highly dynamic at the most fundamental level, with epigenetic consequences.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.012704.133518
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  • 4
    Electronic Resource
    Electronic Resource
    ANISOTROPIC EXPANSION OF THE PLANT CELL WALL (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 203-222 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Plants shape their organs with a precision demanded by optimal function; organ shaping requires control over cell wall expansion anisotropy. Focusing on multicellular organs, I survey the occurrence of expansion anisotropy and discuss its causes and proposed controls. Expansion anisotropy of a unit area of cell wall is characterized by the direction and degree of anisotropy. The direction of maximal expansion rate is usually regulated by the direction of net alignment among cellulose microfibrils, which overcomes the prevailing stress anisotropy. In some stems, the directionality of expansion of epidermal cells is controlled by that of the inner tissue. The degree of anisotropy can vary widely as a function of position and of treatment. The degree of anisotropy is probably controlled by factors in addition to the direction of microfibril alignment. I hypothesize that rates of expansion in maximal and minimal directions are regulated by distinct molecular mechanisms that regulate interactions between matrix and microfibrils.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.082503.103053
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  • 5
    Electronic Resource
    Electronic Resource
    IN VIVO IMAGING OF LYMPHOCYTE TRAFFICKING (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 581-603 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Over the past decades, intravital microscopy (IVM), the imaging of cells in living organisms, has become a valuable tool for studying the molecular determinants of lymphocyte trafficking. Recent advances in microscopy now make it possible to image cell migration and cell-cell interactions in vivo deep within intact tissues. Here, we summarize the principal techniques that are currently used in IVM, discuss options and tools for fluorescence-based visualization of lymphocytes in microvessels and tissues, and describe IVM models used to explore lymphoid and non-lymphoid organs. The latter will be introduced according to the physiologic itinerary of developing and differentiating T and B lymphocytes as they traffic through the body, beginning with their development in bone marrow and thymus and continuing with their migration to secondary lymphoid organs and peripheral tissues.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.122303.133159
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  • 6
    Electronic Resource
    Electronic Resource
    CENTROSOMES IN CELLULAR REGULATION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 411-434 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Centrosomes, spindle pole bodies, and related structures in other organisms are a morphologically diverse group of organelles that share a common ability to nucleate and organize microtubules and are thus referred to as microtubule organizing centers or MTOCs. Features associated with MTOCs include organization of mitotic spindles, formation of primary cilia, progression through cytokinesis, and self-duplication once per cell cycle. Centrosomes bind more than 100 regulatory proteins, whose identities suggest roles in a multitude of cellular functions. In fact, recent work has shown that MTOCs are required for several regulatory functions including cell cycle transitions, cellular responses to stress, and organization of signal transduction pathways. These new liaisons between MTOCs and cellular regulation are the focus of this review. Elucidation of these and other previously unappreciated centrosome functions promises to yield exciting scientific discovery for some time to come.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.122303.120418
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  • 7
    Electronic Resource
    Electronic Resource
    THE GREAT ESCAPE: When Cancer Cells Hijack the Genes for Chemotaxis and Motility (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 695-718 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The combined use of the new technologies of multiphoton-based intravital imaging, the chemotaxis-mediated collection of invasive cells, and high sensitivity expression profiling has allowed the correlation of the behavior of invasive tumor cells in vivo with their gene expression patterns. New insights have resulted including a gene expression signature for invasive cells and the tumor microenvironment invasion model. This model proposes that tumor invasion and metastasis can be studied as a problem resembling normal morphogenesis. We discuss how these new insights may lead to a better understanding of the molecular basis of the invasive behavior of tumor cells in vivo, which may result in new strategies for the diagnosis and treatment of metastasis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.122303.120306
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  • 8
    Electronic Resource
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    ENDOPLASMIC RETICULUMĐ??ASSOCIATED DEGRADATION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 435-456 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Secretory and transmembrane proteins enter the secretory pathway through the protein-conducting Sec61 channel in the membrane of the endoplasmic reticulum. In the endoplasmic reticulum, proteins fold, are frequently covalently modified, and oligomerize before they are packaged into transport vesicles that shuttle them to the Golgi complex. Proteins that misfold in the endoplasmic reticulum are selectively transported back across the endoplasmic reticulum membrane to the cytosol for degradation by proteasomes. Depending on the topology of the defect in the protein, cytosolic or lumenal chaperones are involved in its targeting to degradation. The export channel for misfolded proteins is likely also formed by Sec61p. Export may be powered by AAA-ATPases of the proteasome 19S regulatory particle or Cdc48p/p97. Exported proteins are frequently ubiquitylated prior to degradation and are escorted to the proteasome by polyubiquitin-binding proteins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.012704.133250
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  • 9
    Electronic Resource
    Electronic Resource
    PHAGOCYTOSIS: At the Crossroads of Innate and Adaptive Immunity (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 511-527 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Phagocytosis, the process by which cells engulf large particles, requires a substantial contribution of membranes. Recent studies have revealed that intracellular compartments, including endocytic organelles and the endoplasmic reticulum (ER), can engage in fusion events with the plasma membrane at the sites of nascent phagosomes. The finding that ER proteins are delivered to phagosomes, where degraded peptides are loaded onto major histocompatibility complex (MHC) class II molecules, has significantly enhanced our understanding of the immune functions associated with these organelles. Although it is well known that pathogens are killed in phagosomes, the contribution of ER proteins to phagosomes has provided a novel pathway for the loading of exogenous peptides onto MHC class I molecules, a process known as cross-presentation. Thus, phagocytosis has evolved from a nutritional function in unicellular organisms to play key roles in both innate and adaptive immunity in vertebrates.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.010403.102755
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  • 10
    Electronic Resource
    Electronic Resource
    RETINOTECTAL MAPPING: New Insights from Molecular Genetics (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 551-580 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The sensory and motor components of nervous systems are connected topographically and contain neural maps of the external world. The paradigm for such maps is the precisely ordered wiring of the output cells of the eye to their synaptic targets in the tectum of the midbrain. The retinotectal map is organized in development through the graded activity of Eph receptor tyrosine kinases and their ephrin ligands. These signaling proteins are arrayed in complementary expression gradients along the orthogonal axes of the retina and tectum, and provide both input and recipient cells with Cartesian coordinates that specify their location. Molecular genetic studies in the mouse indicate that these coordinates are interpreted in the context of neuronal competition for termination sites in the tectum. They further suggest that order in the retinotectal map is determined by ratiometric rather than absolute difference comparisons in Eph signaling along the temporal-nasal and dorsal-ventral axes of the eye.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.022403.093702
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  • 11
    Electronic Resource
    Electronic Resource
    SPATIAL CONTROL OF CELL EXPANSION BY THE PLANT CYTOSKELETON (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 271-295 
    Details
    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The cytoskeleton plays important roles in plant cell shape determination by influencing the patterns in which cell wall materials are deposited. Cortical microtubules are thought to orient the direction of cell expansion primarily via their influence on the deposition of cellulose into the wall, although the precise nature of the microtubule-cellulose relationship remains unclear. In both tip-growing and diffusely growing cell types, F-actin promotes growth and also contributes to the spatial regulation of growth. F-actin has been proposed to play a variety of roles in the regulation of secretion in expanding cells, but its functions in cell growth control are not well understood. Recent work highlighted in this review on the morphogenesis of selected cell types has yielded substantial new insights into mechanisms governing the dynamics and organization of cytoskeletal filaments in expanding plant cells and how microtubules and F-actin interact to direct patterns of cell growth. Nevertheless, many important questions remain to be answered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.122303.114901
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  • 12
    Electronic Resource
    Electronic Resource
    REGULATION OF ROOT APICAL MERISTEM DEVELOPMENT (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 485-509 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The establishment of the Angiosperm root apical meristem is dependent on the specification of a stem cell niche and the subsequent development of the quiescent center at the presumptive root pole. Distribution of auxin and the establishment of auxin maxima are early formative steps in niche specification that depend on the expression and distribution of auxin carriers. Auxin specifies stem cell niche formation by directly and indirectly affecting gene activities. Part of the indirect regulation by auxin may involve changes in redox, favoring local, oxidized microenvironments. Formation of a QC is required for root meristem development and elaboration. Many signals likely pass between the QC and the adjacent root meristem tissues. Disappearance of the QC is associated with roots becoming determinate. Given the many auxin feedback loops, we hypothesize that roots evolved as part of an auxin homeostasis mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.122303.114753
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  • 13
    Electronic Resource
    Electronic Resource
    PLANAR CELL POLARIZATION: An Emerging Model Points in the Right Direction (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 155-176 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Polarization is a feature common to many cell types. Epithelial cells, for example, exhibit a characteristic apical-basolateral polarity that is critical for their function. In addition to this ubiquitous form of polarity, whole fields of cells are often polarized in a plane perpendicular to the apical-basal axis. This form of polarity, referred to as planar cell polarity (PCP), exists in all adult Drosophila cuticular tissues, as well as in numerous vertebrate tissues, including the mammalian skin and inner ear epithelia. Recent advances in the study of PCP establishment are beginning to unravel the molecular mechanisms underlying this cellular process. This review discusses new developments in the molecular understanding of PCP in Drosophila and vertebrates and integrates the current data in a model to illustrate how interactions between PCP factors might function to generate planar polarity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.012704.132806
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  • 14
    Electronic Resource
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    DOCOSAHEXAENOIC ACID, FATTY ACIDĐ??INTERACTING PROTEINS, AND NEURONAL FUNCTION: Breastmilk and Fish Are Good for You (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 633-657 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: In contrast to other tissues, the nervous system is enriched in the polyunsaturated fatty acids (PUFAs): arachidonic acid (AA, 20:4 n-6) and docosahexaenoic acid (DHA, 22:6 n-3). Despite their abundance in the nervous system, AA and DHA cannot be synthesized de novo by mammals; they, or their precursors, must be ingested from dietary sources and transported to the brain. During late gestation and the early postnatal period, neurodevelopment is exceptionally rapid, and substantial amounts of PUFAs, especially DHA, are critical to ensure neurite outgrowth as well as proper brain and retina development. Here, we review the various functions of DHA in the nervous system, the proteins involved in its internalization and metabolism into phospholipids, and its relationship to several neurological disorders, including Alzheimer's disease and depression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.122303.120624
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  • 15
    Electronic Resource
    Electronic Resource
    QUORUM SENSING: Cell-to-Cell Communication in Bacteria (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 319-346 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Bacteria communicate with one another using chemical signal molecules. As in higher organisms, the information supplied by these molecules is critical for synchronizing the activities of large groups of cells. In bacteria, chemical communication involves producing, releasing, detecting, and responding to small hormone-like molecules termed autoinducers . This process, termed quorum sensing, allows bacteria to monitor the environment for other bacteria and to alter behavior on a population-wide scale in response to changes in the number and/or species present in a community. Most quorum-sensing-controlled processes are unproductive when undertaken by an individual bacterium acting alone but become beneficial when carried out simultaneously by a large number of cells. Thus, quorum sensing confuses the distinction between prokaryotes and eukaryotes because it enables bacteria to act as multicellular organisms. This review focuses on the architectures of bacterial chemical communication networks; how chemical information is integrated, processed, and transduced to control gene expression; how intra- and interspecies cell-cell communication is accomplished; and the intriguing possibility of prokaryote-eukaryote cross-communication.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.012704.131001
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  • 16
    Electronic Resource
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    MOLECULAR MECHANISMS OF STEROID HORMONE SIGNALING IN PLANTS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 177-201 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Brassinosteroids (BRs), the polyhydroxylated steroid hormones of plants, regulate the growth and differentiation of plants throughout their life cycle. Over the past several years, genetic and biochemical approaches have yielded great progress in understanding BR signaling. Unlike their animal counterparts, BRs are perceived at the plasma membrane by direct binding to the extracellular domain of the BRI1 receptor S/T kinase. BR perception initiates a signaling cascade, acting through a GSK3 kinase, BIN2, and the BSU1 phosphatase, which in turn modulates the phosphorylation state and stability of the nuclear transcription factors BES1 and BZR1. Microarray technology has been used extensively to provide a global view of BR genomic effects, as well as a specific set of target genes for BES1 and BZR1. These gene products thus provide a framework for how BRs regulate the growth of plants.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.090704.151241
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  • 17
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    INTEGRIN STRUCTURE, ALLOSTERY, AND BIDIRECTIONAL SIGNALING (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 381-410 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: ʼ̛?‚ heterodimeric integrins mediate dynamic adhesive cell-cell and cell-extracellular matrix (ECM) interactions in metazoa that are critical in growth and development, hemostasis, and host defense. A central feature of these receptors is their capacity to change rapidly and reversibly their adhesive functions by modulating their ligand-binding affinity. This is normally achieved through interactions of the short cytoplasmic integrin tails with intracellular proteins, which trigger restructuring of the ligand-binding site through long-range conformational changes in the ectodomain. Ligand binding in turn elicits conformational changes that are transmitted back to the cell to regulate diverse responses. The publication of the integrin ʼ̛V?‚3 crystal structure has provided the context for interpreting decades-old biochemical studies. Newer NMR, crystallographic, and EM data, reviewed here, are providing a better picture of the dynamic integrin structure and the allosteric changes that guide its diverse functions.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.090704.151217
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  • 18
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    CAJAL BODIES: A Long History of Discovery (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 105-131 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: This review surveys what is known about the structure and function of the subnuclear domains called Cajal bodies (CBs). The major focus is on CBs in mammalian cells but we provide an overview of homologous CB structures in other organisms. We discuss the protein and RNA components of CBs, including factors recently found to associate in a cell cycle-dependent fashion or under specific metabolic or stress conditions. We also consider the dynamic properties of both CBs and their molecular components, based largely on recent data obtained thanks to the advent of improved in vivo detection and imaging methods. We discuss how these data contribute to an understanding of CB functions and highlight major questions that remain to be answered. Finally, we consider the interesting links that have emerged between CBs and alterations in nuclear structure apparent in a range of human pathologies, including cancer and inherited neurodegenerative diseases. We speculate on the relationship between CB function and molecular disease.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.20.010403.103738
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  • 19
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    REGULATION OF PROTEIN ACTIVITIES BY PHOSPHOINOSITIDE PHOSPHATES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 57-79 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Phosphoinositide phosphates (PIPs) correspond to phosphorylated derivatives of phosphatidylinositol (PI). Despite their relatively low abundance in the plasma membrane, PIPs play a crucial role as precursors of second messengers and are themselves important signaling and targeting molecules. Indeed, modulation of levels of PIPs affects, for example, cortical actin organization, membrane dynamics, and cell migration. The focus of this review is on selected interesting targets of PIPs. Those proteins that bind PIPs and are involved in regulation of actin assembly, actin membrane linkage, and actin contractility are discussed, as well as those that are involved in signaling, such as small GTPases, protein kinases, and phosphatases, or in regulation of membrane dynamics.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.021704.102317
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  • 20
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    RNA TRANSPORT AND LOCAL CONTROL OF TRANSLATION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 223-245 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: In eukaryotes, the entwined pathways of RNA transport and local translational regulation are key determinants in the spatio-temporal articulation of gene expression. One of the main advantages of this mechanism over transcriptional control in the nucleus lies in the fact that it endows local sites with independent decision-making authority, a consideration that is of particular relevance in cells with complex cellular architecture such as neurons. Localized RNAs typically contain codes, expressed within cis-acting elements, that specify subcellular targeting. Such codes are recognized by trans-acting factors, adaptors that mediate translocation along cytoskeletal elements by molecular motors. Most transported mRNAs are assumed translationally dormant while en route. In some cell types, especially in neurons, it is considered crucial that translation remains repressed after arrival at the destination site (e.g., a postsynaptic microdomain) until an appropriate activation signal is received. Several candidate mechanisms have been suggested to participate in the local implementation of translational repression and activation, and such mechanisms may target translation at the level of initiation and/or elongation. Recent data indicate that untranslated RNAs may play important roles in the local control of translation.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.122303.120653
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  • 21
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    RHO GTPASES: Biochemistry and Biology (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 247-269 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Approximately one percent of the human genome encodes proteins that either regulate or are regulated by direct interaction with members of the Rho family of small GTPases. Through a series of complex biochemical networks, these highly conserved molecular switches control some of the most fundamental processes of cell biology common to all eukaryotes, including morphogenesis, polarity, movement, and cell division. In the first part of this review, we present the best characterized of these biochemical pathways; in the second part, we attempt to integrate these molecular details into a biological context.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.020604.150721
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  • 22
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    PROTEIN TRANSLOCATION BY THE SEC61/SECY CHANNEL (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 529-550 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The conserved protein-conducting channel, referred to as the Sec61 channel in eukaryotes or the SecY channel in eubacteria and archaea, translocates proteins across cellular membranes and integrates proteins containing hydrophobic transmembrane segments into lipid bilayers. Structural studies illustrate how the protein-conducting channel accomplishes these tasks. Three different mechanisms, each requiring a different set of channel binding partners, are employed to move polypeptide substrates: The ribosome feeds the polypeptide chain directly into the channel, a ratcheting mechanism is used by the eukaryotic endoplasmic reticulum chaperone BiP, and a pushing mechanism is utilized by the bacterial ATPase SecA. We review these translocation mechanisms, relating biochemical and genetic observations to the structures of the protein-conducting channel and its binding partners.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.012704.133214
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    MECHANISMS OF APOPTOSIS THROUGH STRUCTURAL BIOLOGY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 35-56 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Apoptosis plays a central role in the development and homeostasis of metazoans. Research in the past two decades has led to the identification of hundreds of genes that govern the initiation, execution, and regulation of apoptosis. An earlier focus on the genetic and cell biological characterization has now been complemented by systematic biochemical and structural investigation, giving rise to an unprecedented level of clarity in many aspects of apoptosis. In this review, we focus on the molecular mechanisms of apoptosis by synthesizing available biochemical and structural information. We discuss the mechanisms of ligand binding to death receptors, actions of the Bcl-2 family of proteins, and caspase activation, inhibition, and removal of inhibition. Although an emphasis is given to the mammalian pathways, a comparative analysis is applied to related mechanistic information in Drosophila and Caenorhabditis elegans.
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    PUSHING THE ENVELOPE: Structure, Function, and Dynamics of the Nuclear Periphery (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 347-380 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The nuclear envelope (NE) is a highly specialized membrane that delineates the eukaryotic cell nucleus. It is composed of the inner and outer nuclear membranes, nuclear pore complexes (NPCs) and, in metazoa, the lamina. The NE not only regulates the trafficking of macromolecules between nucleoplasm and cytosol but also provides anchoring sites for chromatin and the cytoskeleton. Through these interactions, the NE helps position the nucleus within the cell and chromosomes within the nucleus, thereby regulating the expression of certain genes. The NE is not static, rather it is continuously remodeled during cell division. The most dramatic example of NE reorganization occurs during mitosis in metazoa when the NE undergoes a complete cycle of disassembly and reformation. Despite the importance of the NE for eukaryotic cell life, relatively little is known about its biogenesis or many of its functions. We thus are far from understanding the molecular etiology of a diverse group of NE-associated diseases.
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    STEM CELL NICHE: Structure and Function (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 605-631 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Adult tissue-specific stem cells have the capacity to self-renew and generate functional differentiated cells that replenish lost cells throughout an organism's lifetime. Studies on stem cells from diverse systems have shown that stem cell function is controlled by extracellular cues from the niche and by intrinsic genetic programs within the stem cell. Here, we review the remarkable progress recently made in research regarding the stem cell niche. We compare the differences and commonalities of different stem cell niches in Drosophila ovary/testis and Caenorhabditis elegans distal tip, as well as in mammalian bone marrow, skin/hair follicle, intestine, brain, and testis. On the basis of this comparison, we summarize the common features, structure, and functions of the stem cell niche and highlight important niche signals that are conserved from Drosophila to mammals. We hope this comparative summary defines the basic elements of the stem cell niche, providing guiding principles for identification of the niche in other systems and pointing to areas for future studies.
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    SPECIFICITY AND VERSATILITY IN TGF-?‚ SIGNALING THROUGH SMADS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 659-693 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The TGF-?‚ family comprises many structurally related differentiation factors that act through a heteromeric receptor complex at the cell surface and an intracellular signal transducing Smad complex. The receptor complex consists of two type II and two type I transmembrane serine/threonine kinases. Upon phosphorylation by the receptors, Smad complexes translocate into the nucleus, where they cooperate with sequence-specific transcription factors to regulate gene expression. The vertebrate genome encodes many ligands, fewer type II and type I receptors, and only a few Smads. In contrast to the perceived simplicity of the signal transduction mechanism with few Smads, the cellular responses to TGF-?‚ ligands are complex and context dependent. This raises the question of how the specificity of the ligand-induced signaling is achieved. We review the molecular basis for the specificity and versatility of signaling by the many ligands through this conceptually simple signal transduction mechanism.
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    URL: http://dx.doi.org/10.1146/annurev.cellbio.21.022404.142018
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    PRINCIPLES OF LYSOSOMAL MEMBRANE DIGESTION: Stimulation of Sphingolipid Degradation by Sphingolipid Activator Proteins and Anionic Lysosomal Lipids (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 81-103 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Sphingolipids and glycosphingolipids are membrane components of eukaryotic cell surfaces. Their constitutive degradation takes place on the surface of intra-endosomal and intra-lysosomal membrane structures. During endocytosis, these intra-lysosomal membranes are formed and prepared for digestion by a lipid-sorting process during which their cholesterol content decreases and the concentration of the negatively charged bis(monoacylglycero)phosphate (BMP)Đ??erroneously also called lysobisphosphatidic acid (LBPA)Đ??increases. Glycosphingolipid degradation requires the presence of water-soluble acid exohydrolases, sphingolipid activator proteins, and anionic phospholipids like BMP. The lysosomal degradation of sphingolipids with short hydrophilic head groups requires the presence of sphingolipid activator proteins (SAPs). These are the saposins (Saps) and the GM2 activator protein. Sphingolipid activator proteins are membrane-perturbing and lipid-binding proteins with different specificities for the bound lipid and the activated enzyme-catalyzed reaction. Their inherited deficiency leads to sphingolipid- and membrane-storage diseases. Sphingolipid activator proteins not only facilitate glycolipid digestion but also act as glycolipid transfer proteins facilitating the association of lipid antigens with immunoreceptors of the CD1 family.
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    RNA SILENCING SYSTEMS AND THEIR RELEVANCE TO PLANT DEVELOPMENT (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Cell and Developmental Biology 21 (2005), S. 297-318 
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    ISSN: 1081-0706
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: RNA silencing refers to a broad range of phenomena sharing the common feature that large, double-stranded RNAs or stem-loop precursors are processed to ca. 21Đ??26 nucleotide small RNAs, which then guide the cleavage of cognate RNAs, block productive translation of these RNAs, or induce methylation of specific target DNAs. Although the core mechanisms are evolutionarily conserved, epigenetic maintenance of silencing by amplification of small RNAs and the elaboration of mobile, RNA-based silencing signals occur predominantly in plants. Plant RNA silencing systems are organized into a network with shared components and overlapping functions. MicroRNAs, and probably trans-acting small RNAs, help regulate development at the posttranscriptional level. Small interfering RNAs associated with transgene- and virus-induced silencing function primarily in defending against foreign nucleic acids. Another system, which is concerned with RNA-directed methylation of DNA repeats, seems to have roles in epigenetic silencing of certain transposable elements and genes under their control.
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    MARGINAL ZONE B CELLS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 161-196 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Our views regarding the origins and functions of splenic marginal zone B cells have changed considerably over the past few years. Perspectives regarding the development and function of these cells vary considerably between investigators studying human and rodent immunology. Marginal zone B cells are now recognized to constitute a distinct naive B lymphoid lineage. Considerable progress has been made regarding the mechanisms involved in marginal zone B cell development in the mouse. Many of the molecular events that participate in the retention of this lineage of B cells in the marginal zone have been identified. Here, we discuss the functions of these cells in both innate and adaptive immunity. We also attempt to reconcile differing viewpoints regarding the generation and function of marginal zone B cells in rodents and primates.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115728
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    ANTIGEN-SPECIFIC MEMORY B CELL DEVELOPMENT (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 487-513 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Helper T (Th) cellĐ??regulated B cell immunity progresses in an ordered cascade of cellular development that culminates in the production of antigen-specific memory B cells. The recognition of peptide MHC class II complexes on activated antigen-presenting cells is critical for effective Th cell selection, clonal expansion, and effector Th cell function development (Phase I). Cognate effector Th cellĐ??B cell interactions then promote the development of either short-lived plasma cells (PCs) or germinal centers (GCs) (Phase II). These GCs expand, diversify, and select high-affinity variants of antigen-specific B cells for entry into the long-lived memory B cell compartment (Phase III). Upon antigen rechallenge, memory B cells rapidly expand and differentiate into PCs under the cognate control of memory Th cells (Phase IV). We review the cellular and molecular regulators of this dynamic process with emphasis on the multiple memory B cell fates that develop in vivo.
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    B CELL SIGNALING AND Tumorigenesis (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 415-445 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The proliferation and differentiation of lymphocytes are regulated by receptors localized on the cell surface. Engagement of these receptors induces the activation of intracellular signaling proteins that transmit the receptor signals to distinct targets and control the cellular responses. The first signaling proteins to be discovered in higher organisms were the products of oncogenes. For example, the kinases Src and Abelson (Abl) were originally identified as oncogenes and were later characterized as important proteins for signal transduction in various cell types, including lymphocytes. Now, as many cellular signaling molecules have been discovered and ordered into certain pathways, we can better understand why particular signaling proteins are associated with tumorigenesis. In this review, we discuss recent progress in unraveling the molecular mechanisms of signaling pathways that control the proliferation and differentiation of early B cells. We point out the concepts of auto-inhibition and subcellular localization as crucial aspects in the regulation of B cell signaling.
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    IMMUNOLOGY OF MULTIPLE SCLEROSIS * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 683-747 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future.
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    UNDERSTANDING PRESENTATION OF VIRAL ANTIGENS TO CD8+ T CELLS IN VIVO: The Key to Rational Vaccine Design * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 651-682 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: CD8+ T cells play a critical role in antiviral immunity by exerting direct antiviral activity against infected cells. Because of their ability to recognize all types of viral proteins, they offer the promise of providing broad immunity to viruses that evade humoral immunity by varying their surface proteins. Consequently, there is considerable interest in developing vaccines that elicit effective antiviral TCD8+ responses. Generating optimal vaccines ultimately requires rational design based on detailed knowledge of how TCD8+ are activated in vivo under natural circumstances. Here we review recent progress obtained largely by in vivo studies in mice to understand the mechanistic basis for activation of naive TCD8+ in virus infections. These studies point the way to detailed understanding and provide some key information for vaccine development, although much remains to be learned to enable truly rational vaccine design.
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    REGULATION OF LYMPHOID DEVELOPMENT, DIFFERENTIATION, AND FUNCTION BY THE NOTCH PATHWAY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 945-974 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The Notch pathway is gaining increasing recognition as a key regulator of developmental choices, differentiation, and function throughout the hematolymphoid system. Notch controls the generation of hematopoietic stem cells during embryonic development and may affect their subsequent homeostasis. Commitment to the T??cell lineage and subsequent stages of early thymopoiesis is critically regulated by Notch. Recent data indicate that Notch can also direct the differentiation and activity of peripheral T and B cells. Thus, the full spectrum of Notch effects is just beginning to be understood. In this review, we discuss this explosion of knowledge as well as current controversies and challenges in the field.
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    PETER HOCHACHKA: Adventures in Biochemical Adaptation (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 25-37 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Peter Hochachka was one of the most creative forces in the field of comparative physiology during the past half-century. His career was truly an exploratory adventure, in both intellectual and geographic senses. His broad comparative studies of metabolism in organisms as diverse as trout, tunas, oysters, squid, turtles, locusts, hummingbirds, seals, and humans revealed the adaptable features of enzymes and metabolic pathways that provide the biochemical bases for diverse lifestyles and environments. In its combined breadth and depth, no other corpus of work better illustrates the principle of "unity in diversity" that marks comparative physiology. Through his publications, his stimulating mentorship, his broad editorial services, and his continuousĐ??and highly infectiousĐ??enthusiasm for his field, Peter Hochachka served as one of the most influential leaders in the transformation of comparative physiology.
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    UNLOCKING THE SECRETS OF CELL SIGNALING (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 1-21 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: My scientific life has been spent trying to understand how cells communicate with each other. This interest in cell signaling began with studies on the control of fluid secretion by an insect salivary gland, and the subsequent quest led to the discovery of inositol trisphosphate (IP3) and its role in calcium signaling, which effectively divided my scientific career into two distinct parts. The first part was primarily experimental and culminated in the discovery of IP3, which set the agenda for the second half during which I have enjoyed exploring the many functions of this remarkably versatile signaling system. It has been particularly exciting to find out how this IP3/Ca2+ signaling pathway has been adapted to control processes as diverse as fertilization, proliferation, cell contraction, secretion, and information processing in neuronal cells.
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    RNAI AS AN EXPERIMENTAL AND THERAPEUTIC TOOL TO STUDY AND REGULATE PHYSIOLOGICAL AND DISEASE PROCESSES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 147-173 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Over the past four years RNA interference (RNAi) has exploded onto the research scene as a new approach to manipulate gene expression in mammalian systems. More recently, RNAi has garnered much interest as a potential therapeutic strategy. In this review, we briefly summarize the current understanding of RNAi biology and examine how RNAi has been used to study the genetic basis of physiological and disease processes in mammalian systems. We also explore some of the new developments in the use of RNAi for disease therapy and highlight the key challenges that currently limit its application in the laboratory, as well as in the clinical setting.
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    ENDOCRINOLOGY OF THE STRESS RESPONSE 1 (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 259-284 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery. The principal effectors of the stress system include corticotropin-releasing hormone (CRH); arginine vasopressin; the proopiomelanocortin-derived peptides ʼ̛-melanocyte-stimulating hormone and ?‚-endorphin, the glucocorticoids; and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of the stressful events, given that prenatal life, infancy, childhood, and adolescence are critical periods characterized by increased vulnerability to stressors.
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    LESSONS IN ESTROGEN BIOLOGY FROM KNOCKOUT AND TRANSGENIC ANIMALS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 285-308 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Tremendous progress has been made in elucidating numerous critical aspects of estrogen signaling. New tools and techniques have enabled detailed molecular analysis of components that direct estrogen responses. At the other end of the spectrum, generation of a multiplicity of transgenic animals has allowed analysis of the physiological roles of the estrogen-signaling components in biologically relevant models. Here, we review the ever-increasing body of knowledge in the field of estrogen biology, especially as applied to the female reproductive processes.
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    MECHANISMS OF BICARBONATE SECRETION IN THE PANCREATIC DUCT (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 377-409 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: In many species the pancreatic duct epithelium secretes HCO3 ions at a concentration of around 140 mM by a mechanism that is only partially understood. We know that HCO3 uptake at the basolateral membrane is achieved by Na+-HCO3 cotransport and also by a H+-ATPase and Na+/H+ exchanger operating together with carbonic anhydrase. At the apical membrane, the secretion of moderate concentrations of HCO3 can be explained by the parallel activity of a Cl/HCO3 exchanger and a Cl conductance, either the cystic fibrosis transmembrane conductance regulator (CFTR) or a Ca2+-activated Cl channel (CaCC). However, the sustained secretion of HCO3 into a HCO3 -rich luminal fluid cannot be explained by conventional Cl/HCO3 exchange. HCO3 efflux across the apical membrane is an electrogenic process that is facilitated by the depletion of intracellular Cl, but it remains to be seen whether it is mediated predominantly by CFTR or by an electrogenic SLC26 anion exchanger.
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    SECRETION AND ABSORPTION BY COLONIC CRYPTS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 471-490 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The intestines play an important role in the absorption and secretion of nutrients. The colon is the final area for recapturing electrolytes and water prior to excretion, and in order to maintain this electrolyte homeostasis, a complex interaction between secretory and absorptive processes is necessary. Until recently it was thought that secretion and absorption were two distinct processes associated with either crypts or surface cells, respectively. Recently it was demonstrated that both the surface and crypt cells can perform secretory and absorptive functions and that, in fact, these functions can be going on simultaneously. This issue is important in the complexities associated with secretory diarrhea and also in attempting to develop treatment strategies for intestinal disorders. Here, we update the model of colonic secretion and absorption, discuss new issues of transporter activation, and identify some important new receptor pathways that are important modulators of the secretory and absorptive functions of the colon.
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    NOVEL RENAL AMINO ACID TRANSPORTERS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 557-572 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Reabsorption of amino acids, similar to that of glucose, is a major task of the proximal kidney tubule. Various amino acids are actively transported across the luminal brush border membrane into proximal tubule epithelial cells, most of which by cotransport. An important player is the newly identified cotransporter (symporter) B0AT1 (SLC6A19), which imports a broad range of neutral amino acids together with Na+ across the luminal membrane and which is defective in Hartnup disorder. In contrast, cationic amino acids and cystine are taken up in exchange for recycled neutral amino acids by the heterodimeric cystinuria transporter. The basolateral release of some neutral amino acids into the extracellular space is mediated by unidirectional efflux transporters, analogous to GLUT2, that have not yet been definitively identified. Additionally, cationic amino acids and some other neutral amino acids leave the cell basolaterally via heterodimeric obligatory exchangers.
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    SURFACTANT PROTEIN C BIOSYNTHESIS AND ITS EMERGING ROLE IN CONFORMATIONAL LUNG DISEASE (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 663-696 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Surfactant protein C (SP-C) is a hydrophobic 35-amino acid peptide that co-isolates with the phospholipid fraction of lung surfactant. SP-C represents a structurally and functionally challenging protein for the alveolar type 2 cell, which must synthesize, traffic, and process a 191Đ??197-amino acid precursor protein through the regulated secretory pathway. The current understanding of SP-C biosynthesis considers the SP-C proprotein (proSP-C) as a hybrid molecule that incorporates structural and functional features of both bitopic integral membrane proteins and more classically recognized luminal propeptide hormones, which are subject to post-translational processing and regulated exocytosis. Adding to the importance of a detailed understanding of SP-C biosynthesis has been the recent association of mutations in the proSP-C sequence with chronic interstitial pneumonias in children and adults. Many of these mutations involve either missense or deletion mutations located in a region of the proSP-C molecule that has structural homology to the BRI family of proteins linked to inherited degenerative dementias. This review examines the current state of SP-C biosynthesis with a focus on recent developments related to molecular and cellular mechanisms implicated in the emerging role of SP-C mutations in the pathophysiology of diffuse parenchymal lung disease.
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    EXOCYTOSIS OF LUNG SURFACTANT: From the Secretory Vesicle to the Air-Liquid Interface (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 595-621 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Exocytosis is fundamental in biology and requires an orchestra of proteins and other constituents to fuse a vesicle with the plasma membrane. Although the molecular fusion machinery appears to be well conserved in evolution, the process itself varies considerably with regard to the diversity of physico-chemical and structural factors that govern the delay between stimulus and fusion, the expansion of the fusion pore, the release of vesicle content, and, finally, its extracellular dispersion. Exocytosis of surfactant is unique in many of these aspects. This review deals with the secretory pathway of pulmonary surfactant from the type II cell to the air-liquid interface, with focus on the distinct mechanisms and regulation of lamellar body (LB) fusion and release. We also discuss the fate of secreted material until it is rearranged into units that finally function to reduce the surface tension in the lung.
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    FUNCTION OF CHLORIDE CHANNELS IN THE KIDNEY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 759-778 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Numerous Cl channels have been identified in the kidney using physiological approaches and thus are thought to be involved in a range of physiological processes, including vectorial transepithelial Cl transport, cell volume regulation, and vesicular acidification. In addition, expression of genes from several Cl channel gene families has also been observed. However, the molecular characteristics of a number of Cl channels within the kidney are still unknown, and the physiological roles of Cl channels identified by molecular means remain to be determined. A gene knockout approach using mice might shed further light on the characteristics of these various Cl channels. In addition, study of diseases involving Cl channels (channelopathies) might clarify the physiological role of specific Cl channels. To date, more is known about CLC Cl channels than any other Cl channels within the kidney. This review focuses on the physiological roles of CLC Cl channels within the kidney, particularly kidney-specific ClC-K Cl channels, as well as the recently identified maxi anion channel in macula densa, which is involved in tubulo-glomerular feedback.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.67.032003.153547
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    CALCIUM, THIN FILAMENTS, AND THE INTEGRATIVE BIOLOGY OF CARDIAC CONTRACTILITY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 39-67 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Although well known as the location of the mechanism by which the cardiac sarcomere is activated by Ca2+ to generate force and shortening, the thin filament is now also recognized as a vital component determining the dynamics of contraction and relaxation. Molecular signaling in the thin filament involves steric, allosteric, and cooperative mechanisms that are modified by protein phosphorylation, sarcomere length and load, the chemical environment, and isoform composition. Approaches employing transgenesis and mutagenesis now permit investigation of these processes at the level of the systems biology of the heart. These studies reveal that the thin filaments are not merely slaves to the levels of Ca2+ determined by membrane channels, transporters and exchangers, but are actively involved in beat to beat control of cardiac function by neural and hormonal factors and by the Frank-Starling mechanism.
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    BIOPHYSICS, PHYSIOLOGICAL ECOLOGY, AND CLIMATE CHANGE: Does Mechanism Matter? (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 177-201 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Recent meta-analyses have shown that the effects of climate change are detectable and significant in their magnitude, but these studies have emphasized the utility of looking for large-scale patterns without necessarily understanding the mechanisms underlying these changes. Using a series of case studies, we explore the potential pitfalls when one fails to incorporate aspects of physiological performance when predicting the consequences of climate change on biotic communities. We argue that by considering the mechanistic details of physiological performance within the context of biophysical ecology (engineering methods of heat, mass and momentum exchange applied to biological systems), such approaches will be better poised to predict where and when the impacts of climate change will most likely occur.
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    URL: http://dx.doi.org/10.1146/annurev.physiol.67.040403.105027
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    RETINAL PROCESSING NEAR ABSOLUTE THRESHOLD: From Behavior to Mechanism (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 491-514 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Vision at absolute threshold is based on signals produced in a tiny fraction of the rod photoreceptors. This requires that the rods signal the absorption of single photons, and that the resulting signals are transmitted across the retina and encoded in the activity sent from the retina to the brain. Behavioral and ganglion cell sensitivity has often been interpreted to indicate that these biophysical events occur noiselessly, i.e., that vision reaches limits to sensitivity imposed by the division of light into discrete photons and occasional photon-like noise events generated in the rod photoreceptors. We argue that this interpretation is not unique and provide a more conservative view of the constraints behavior and ganglion cell experiments impose on phototransduction and retinal processing. We summarize what is known about how these constraints are met and identify some of the outstanding open issues.
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    LUNG VASCULAR DEVELOPMENT: Implications for the Pathogenesis of Bronchopulmonary Dysplasia (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 623-661 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Past studies have primarily focused on how altered lung vascular growth and development contribute to pulmonary hypertension. Recently, basic studies of vascular growth have led to novel insights into mechanisms underlying development of the normal pulmonary circulation and the essential relationship of vascular growth to lung alveolar development. These observations have led to new concepts underlying the pathobiology of developmental lung disease, especially the inhibition of lung growth that characterizes bronchopulmonary dysplasia (BPD). We speculate that understanding basic mechanisms that regulate and determine vascular growth will lead to new clinical strategies to improve the long-term outcome of premature babies with BPD.
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    CALCIUM-ACTIVATED CHLORIDE CHANNELS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 719-758 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Calcium-activated chloride channels (CaCCs) play important roles in cellular physiology, including epithelial secretion of electrolytes and water, sensory transduction, regulation of neuronal and cardiac excitability, and regulation of vascular tone. This review discusses the physiological roles of these channels, their mechanisms of regulation and activation, and the mechanisms of anion selectivity and conduction. Despite the fact that CaCCs are so broadly expressed in cells and play such important functions, understanding these channels has been limited by the absence of specific blockers and the fact that the molecular identities of CaCCs remains in question. Recent status of the pharmacology and molecular identification of CaCCs is evaluated.
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    ASSEMBLY OF FUNCTIONAL CFTR CHLORIDE CHANNELS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 701-718 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The assembly of the cystic fibrosis transmembrane regulator (CFTR) chloride channel is of interest from the broad perspective of understanding how ion channels and ABC transporters are formed as well as dealing with the mis-assembly of CFTR in cystic fibrosis. CFTR is functionally distinct from other ABC transporters because it permits bidirectional permeation of anions rather than vectorial transport of solutes. This adaptation of the ABC transporter structure can be rationalized by considering CFTR as a hydrolyzable-ligand-gated channel with cytoplasmic ATP as ligand. Channel gating is initiated by ligand binding when the protein is also phosphorylated by protein kinase A and made reversible by ligand hydrolysis. The two nucleotide-binding sites play different roles in channel activation. CFTR self-associates, possibly as a function of its activation, but most evidence, including the low-resolution three-dimensional structure, indicates that the channel is monomeric. Domain assembly and interaction within the monomer is critical in maturation, stability, and function of the protein. Disease-associated mutations, including the most common, ??F508, interfere with domain folding and association, which occur both co- and post-translationally. Intermolecular interactions of mature CFTR have been detected primarily with the N- and C-terminal tails, and these interactions have some impact not only on channel function but also on localization and processing within the cell. The biosynthetic processing of the nascent polypeptide leading to channel assembly involves transient interactions with numerous chaperones and enzymes on both sides of the endoplasmic reticulum membrane.
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    STRUCTURE AND FUNCTION OF CLC CHANNELS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 809-839 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The CLC family comprises a group of integral membrane proteins whose major action is to translocate chloride (Cl) ions across the cell membranes. Recently, the structures of CLC orthologues from two bacterial species, Salmonella typhimurium and Escherichia coli, were solved, providing the first framework for understanding the operating mechanisms of these molecules. However, most of the previous mechanistic understanding of CLC channels came from electrophysiological studies of a branch of the channel family, the muscle-type CLC channels in vertebrate species. These vertebrate CLC channels were predicted to contain two identical but independent pores, and this hypothesis was confirmed by the solved bacterial CLC structures. The opening and closing of the vertebrate CLC channels are also known to couple to the permeant ions via their binding sites in the ion-permeation pathway. The bacterial CLC structures can probably serve as a structural model to explain the gating-permeation coupling mechanism. However, the CLC-ec1 protein in E. coli was most recently shown to be a Cl-H+ antiporter, but not an ion channel. The molecular basis to explain the difference between vertebrate and bacterial CLCs, especially the distinction between an ion channel and a transporter, remains a challenge in the structure/function studies for the CLC family.
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    THE PLASTIC HUMAN BRAIN CORTEX (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 28 (2005), S. 377-401 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Plasticity is an intrinsic property of the human brain and represents evolution's invention to enable the nervous system to escape the restrictions of its own genome and thus adapt to environmental pressures, physiologic changes, and experiences. Dynamic shifts in the strength of preexisting connections across distributed neural networks, changes in task-related cortico-cortical and cortico-subcortical coherence and modifications of the mapping between behavior and neural activity take place in response to changes in afferent input or efferent demand. Such rapid, ongoing changes may be followed by the establishment of new connections through dendritic growth and arborization. However, they harbor the danger that the evolving pattern of neural activation may in itself lead to abnormal behavior. Plasticity is the mechanism for development and learning, as much as a cause of pathology. The challenge we face is to learn enough about the mechanisms of plasticity to modulate them to achieve the best behavioral outcome for a given subject.
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    QUANTUM DOTS AS CELLULAR PROBES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 7 (2005), S. 55-76 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Robust and bright light emitters, semiconductor nanocrystals [quantum dots (QDs)] have been adopted as a new class of fluorescent labels. Six years after the first experiments of their uses in biological applications, there have been dramatic improvements in understanding surface chemistry, biocompatibility, and targeting specificity. Many studies have shown the great potential of using quantum dots as new probes in vitro and in vivo. This review summarizes the recent advances of quantum dot usage at the cellular level, including immunolabeling, cell tracking, in situ hybridization, FRET, in vivo imaging, and other related technologies. Limitations and potential future uses of quantum dot probes are also discussed.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.7.060804.100432
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    INSTRUMENTATION ASPECTS OF ANIMAL PET (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 7 (2005), S. 255-285 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Biological research has been accelerated by the development of noninvasive imaging techniques and by use of genetically engineered mice to model human diseases and normal development. Because these mice can be expensive, noninvasive imaging techniques, such as high-resolution positron emission tomography (PET), that permit longitudinal studies of the same animals are very attractive. Such studies reduce the number of animals used, reduce intersubject variability, and improve the accuracy of biological models. PET provides quantitative measurements of the spatiotemporal distribution of radiotracers and is an extremely powerful tool in using molecular imaging to study biology, to monitor disease intervention, and to establish pharmacokinetics for new drugs. The design of animal PET scanners has improved significantly in the past decade and can provide adequate image resolution and sensitivity to study transgenic mice. This article reviews the fundamental and technical challenges of small-animal PET imaging, with a particular focus on the latest developments and future directions of detector technologies and system design.
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    DETERMINISTIC AND STOCHASTIC ELEMENTS OF AXONAL GUIDANCE (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 7 (2005), S. 187-221 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: An enormous literature has been developed on investigations of the growth and guidance of axons during development and after injury. In this review, we provide a guide to this literature as a resource for biomedical investigators. We first review briefly the molecular biology that is known to regulate migration of the growth cone and branching of axonal arbors. We then outline some important fundamental considerations that are important to the modeling of the phenomenology of these guidance effects and of what is known of their underlying internal mechanisms. We conclude by providing some thoughts on the outlook for future biomedical modeling in the field.
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    BIOCHEMISTRY AND BIOMECHANICS OF CELL MOTILITY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 7 (2005), S. 105-150 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Cell motility is an essential cellular process for a variety of biological events. The process of cell migration requires the integration and coordination of complex biochemical and biomechanical signals. The protrusion force at the leading edge of a cell is generated by the cytoskeleton, and this force generation is controlled by multiple signaling cascades. The formation of new adhesions at the front and the release of adhesions at the rear involve the outside-in and inside-out signaling mediated by integrins and other adhesion receptors. The traction force generated by the cell on the extracellular matrix (ECM) regulates cell-ECM adhesions, and the counter force exerted by ECM on the cell drives the migration. The polarity of cell migration can be amplified and maintained by the feedback loop between the cytoskeleton and cell-ECM adhesions. Cell migration in three-dimensional ECM has characteristics distinct from that on two-dimensional ECM. The migration of cells is initiated and modulated by external chemical and mechanical factors, such as chemoattractants and the mechanical forces acting on the cells and ECM, as well as the surface density, distribution, topography, and rigidity of the ECM.
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    FUNCTIONAL ELECTRICAL STIMULATION FOR NEUROMUSCULAR APPLICATIONS * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 7 (2005), S. 327-360 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Paralyzed or paretic muscles can be made to contract by applying electrical currents to the intact peripheral motor nerves innervating them. When electrically elicited muscle contractions are coordinated in a manner that provides function, the technique is termed functional electrical stimulation (FES). In more than 40 years of FES research, principles for safe stimulation of neuromuscular tissue have been established, and methods for modulating the strength of electrically induced muscle contractions have been discovered. FES systems have been developed for restoring function in the upper extremity, lower extremity, bladder and bowel, and respiratory system. Some of these neuroprostheses have become commercialized products, and others are available in clinical research settings. Technological developments are expected to produce new systems that have no external components, are expandable to multiple applications, are upgradable to new advances, and are controlled by a combination of signals, including biopotential signals from nerve, muscle, and the brain.
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    RENAL TUBULE ALBUMIN TRANSPORT (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 573-594 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Albumin is the most abundant protein in serum and contributes to the maintenance of oncotic pressure as well as to transport of hydrophobic molecules. Although albumin is a large anionic protein, it is not completely retained by the glomerular filtration barrier. In order to prevent proteinuria, albumin is reabsorbed along the proximal tubules by receptor-mediated endocytosis, which involves the binding proteins megalin and cubilin. Endocytosis depends on proper vesicle acidification. Disturbance of endosomal acidification or loss of the binding proteins leads to tubular proteinuria. Furthermore, endocytosis is subject to modulation by different signaling systems, such as protein kinase A (PKA), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3-K) and transforming growth factor beta (TGF-?‚). In addition to being reabsorbed in the proximal tubule, albumin can also act as a profibrotic and proinflammatory stimulus, thereby initiating or promoting tubulo-interstitial diseases.
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    PHYSIOLOGICAL FUNCTIONS OF CLC ClCHANNELS GLEANED FROM HUMAN GENETIC DISEASE AND MOUSE MODELS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 779-807 
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    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The CLC gene family encodes nine different Cl channels in mammals. These channels perform their functions in the plasma membrane or in intracellular organelles such as vesicles of the endosomal/lysosomal pathway or in synaptic vesicles. The elucidation of their cellular roles and their importance for the organism were greatly facilitated by mouse models and by human diseases caused by mutations in their respective genes. Human mutations in CLC channels are known to cause diseases as diverse as myotonia (muscle stiffness), Bartter syndrome (renal salt loss) with or without deafness, Dent's disease (proteinuria and kidney stones), osteopetrosis and neurodegeneration, and possibly epilepsy. Mouse models revealed blindness and infertility as further consequences of CLC gene disruptions. These phenotypes firmly established the roles CLC channels play in stabilizing the plasma membrane voltage in muscle and possibly in neurons, in the transport of salt and fluid across epithelia, in the acidification of endosomes and synaptic vesicles, and in the degradation of bone by osteoclasts.
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    DENDRITIC COMPUTATION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Neuroscience 28 (2005), S. 503-532 
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    ISSN: 0147-006X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: One of the central questions in neuroscience is how particular tasks, or computations, are implemented by neural networks to generate behavior. The prevailing view has been that information processing in neural networks results primarily from the properties of synapses and the connectivity of neurons within the network, with the intrinsic excitability of single neurons playing a lesser role. As a consequence, the contribution of single neurons to computation in the brain has long been underestimated. Here we review recent work showing that neuronal dendrites exhibit a range of linear and nonlinear mechanisms that allow them to implement elementary computations. We discuss why these dendritic properties may be essential for the computations performed by the neuron and the network and provide theoretical and experimental examples to support this view.
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    FAT CELLS: Afferent and Efferent Messages Define New Approaches to Treat Obesity (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 119-146 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: For a long time neural and endocrine messages were studied for their impact on adipocyte metabolism and control of storage/release of fatty acids. In fact, bidirectional communication exists between adipocytes and other tissues. Several molecules secreted from adipocytes are involved in fat cell signaling to other tissues. Adipocyte products could initiate antagonistic effects on target tissues. Fat cells produce peptides that can elicit insulin resistance, such as tumor necrosis factor-ʼ̛ and resistin, as well as hormones that can improve insulin resistance, such as leptin and adiponectin. Secretion of complement proteins, proinflammatory cytokines, procoagulant, and acute phase reactant proteins have also been observed in adipocytes. There is much to learn about how these signals function. It is unlikely that all the adipocyte's endocrine and paracrine signals have been identified. Putative pharmacological strategies aiming at modulation of afferent and efferent fat cell messages are reviewed and discussed.
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    NATURAL HEALTH PRODUCTS AND DRUG DISPOSITION * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 203-226 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Botanicals such as herbal products (HPs) and nutraceuticals (NCs) are often regarded as low risk because of their long history of human use. Anecdotal and literature reports of adverse drug events (ADEs) and clinical studies with HPs are increasing, but many of the reports are incomplete and contradictory. These reports need to identify confounding factors and explain contradictory findings if they are to help health care professionals or patients understand what risks are involved. HPs are complex botanicals, not single-active ingredient (SAI) products. Studies can be confounded by different manufacturing processes and formulations, including cosmetics and food supplements; environment; chemotypes; misidentification or adulteration; and factors associated with the patient or user population such as use, total drug load, and genetics. Future studies need to be conducted with characterized product that includes all commercially available related products. Clinical trials should be relevant to the user population and take into account the confounding factors that may influence the interpretation of the findings.
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    EPOXIDE HYDROLASES: Mechanisms, Inhibitor Designs, and Biological Roles (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 311-333 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Organisms are exposed to epoxide-containing compounds from both exogenous and endogenous sources. In mammals, the hydration of these compounds by various epoxide hydrolases (EHs) can not only regulate their genotoxicity but also, for lipid-derived epoxides, their endogenous roles as chemical mediators. Recent findings suggest that the EHs as a family represent novel drug discovery targets for regulation of blood pressure, inflammation, cancer progression, and the onset of several other diseases. Knowledge of the EH mechanism provides a solid foundation for the rational design of inhibitors, and this review summarizes the current understanding of the catalytic mechanism of the EHs. Although the overall EH mechanism is now known, the molecular basis of substrate selectivity, possible allosteric regulation, and many fine details of the catalytic mechanism remain to be solved. Finally, recent development in the design of EH inhibitors and the EH biological role are discussed.
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    CELL BIOLOGY OF ANTIGEN PROCESSING IN VITRO AND IN VIVO (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 975-1028 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The conversion of exogenous and endogenous proteins into immunogenic peptides recognized by T lymphocytes involves a series of proteolytic and other enzymatic events culminating in the formation of peptides bound to MHC class I or class II molecules. Although the biochemistry of these events has been studied in detail, only in the past few years has similar information begun to emerge describing the cellular context in which these events take place. This review thus concentrates on the properties of antigen-presenting cells, especially those aspects of their overall organization, regulation, and intracellular transport that both facilitate and modulate the processing of protein antigens. Emphasis is placed on dendritic cells and the specializations that help account for their marked efficiency at antigen processing and presentation both in vitro and, importantly, in vivo. How dendritic cells handle antigens is likely to be as important a determinant of immunogenicity and tolerance as is the nature of the antigens themselves.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104538
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    THE B7 FAMILY REVISITED (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 515-548 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The discovery of new functions for the original B7 family members, together with the identification of additional B7 and CD28 family members, have revealed new ways in which the B7:CD28 family regulates T cell activation and tolerance. B7-1/B7-2:CD28 interactions not only promote initial T cell activation but also regulate self-tolerance by supporting CD4+CD25+ T regulatory cell homeostasis. CTLA-4 can exert its inhibitory effects in both B7-1/B7-2 dependent and independent fashions. B7-1 and B7-2 can signal bidirectionally by engaging CD28 and CTLA-4 on T cells and by delivering signals into B7-expressing cells. The five new B7 family members, ICOS ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1) are expressed on professional antigen-presenting cells as well as on cells within nonlymphoid organs, providing new means for regulating T cell activation and tolerance in peripheral tissues. The new CD28 families members, ICOS, PD-1, and BTLA, are inducibly expressed on T cells, and they have important roles in regulating previously activated T cells. PD-1 and BTLA also are expressed on B cells and may have broader immunoregulatory functions. The ICOS:ICOSL pathway appears to be particularly important for stimulating effector T cell responses and T cellĐ??dependent B cell responses, but it also has an important role in regulating T cell tolerance. In addition, the PD-1:PD-L1/PD-L2 pathway plays a critical role in regulating T cell activation and tolerance. In this review, we revisit the roles of the B7:CD28 family members in regulating immune responses, and we discuss their therapeutic potential.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115611
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    TOWARD AN UNDERSTANDING OF NKT CELL BIOLOGY: Progress and Paradoxes (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 26 (2005), S. 877-900 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Natural killer T (NKT) cells constitute a conserved T cell sublineage with unique properties, including reactivity for a synthetic glycolipid presented by CD1d, expression of an invariant T cell antigen receptor (TCR) ʼ̛ chain, and unusual requirements for thymic selection. They rapidly produce many cytokines after stimulation and thus influence diverse immune responses and pathogenic processes. Because of intensive research effort, we have learned much about factors promoting the development and survival of NKT cells, regulation of their cytokine production, and the means by which they influence dendritic cells and other cell types. Despite this progress, knowledge of the natural antigen(s) they recognize and their physiologic role remain incomplete. The activation of NKT cells paradoxically can lead either to suppression or stimulation of immune responses, and we cannot predict which will occur. Despite this uncertainty, many investigators are hopeful that immune therapies can be developed based on NKT cell stimulation.
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    TEC FAMILY KINASES IN T LYMPHOCYTE DEVELOPMENT AND FUNCTION * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 549-600 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The Tec family tyrosine kinases are now recognized as important mediators of antigen receptor signaling in lymphocytes. Three members of this family, Itk, Rlk, and Tec, are expressed in T cells and activated in response to T cell receptor (TCR) engagement. Although initial studies demonstrated a role for these proteins in TCR-mediated activation of phospholipase C-??, recent data indicate that Tec family kinases also regulate actin cytoskeletal reorganization and cellular adhesion following TCR stimulation. In addition, Tec family kinases are activated downstream of G proteinĐ??coupled chemokine receptors, where they play parallel roles in the regulation of Rho GTPases, cell polarization, adhesion, and migration. In all these systems, however, Tec family kinases are not essential signaling components, but instead function to modulate or amplify signaling pathways. Although they quantitatively reduce proximal signaling, mutations that eliminate Tec family kinases in T cells nonetheless qualitatively alter T cell development and differentiation.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.22.012703.104743
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    DEVELOPMENT AND REGULATION OF CELL-MEDIATED IMMUNE RESPONSES TO THE BLOOD STAGES OF MALARIA: Implications for Vaccine Research (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 69-99 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The immune response to the malaria parasite is complex and poorly understood. Although antibodies and T cells can control parasite growth in model systems, natural immunity to malaria in regions of high endemicity takes several years to develop. Variation and polymorphism of antibody target antigens are known to impede immune responses, but these factors alone cannot account for the slow acquisition of immunity. In human and animal model systems, cell-mediated responses can control parasite growth effectively, but such responses are regulated by parasite load via direct effects on dendritic cells and possibly on T and B cells as well. Furthermore, high parasite load is associated with pathology, and cell-mediated responses may also harm the host. Inflammatory cytokines have been implicated in the pathogenesis of cerebral malaria, anemia, weight loss, and respiratory distress in malaria. Immunity without pathology requires rapid parasite clearance, effective regulation of the inflammatory antiparasite effects of cellular responses, and the eventual development of a repertoire of antibodies effective against multiple strains. Data suggest that this may be hastened by exposure to malaria antigens in low dose, leading to augmented cellular immunity and rapid parasite clearance.
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    TNF/TNFR FAMILY MEMBERS IN COSTIMULATION OF T CELL RESPONSES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 23-68 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Several members of the tumor necrosis factor receptor (TNFR) family function after initial T cell activation to sustain T cell responses. This review focuses on CD27, 4-1BB (CD137), OX40 (CD134), HVEM, CD30, and GITR, all of which can have costimulatory effects on T cells. The effects of these costimulatory TNFR family members can often be functionally, temporally, or spatially segregated from those of CD28 and from each other. The sequential and transient regulation of T cell activation/survival signals by different costimulators may function to allow longevity of the response while maintaining tight control of T cell survival. Depending on the disease condition, stimulation via costimulatory TNF family members can exacerbate or ameliorate disease. Despite these complexities, stimulation or blockade of TNFR family costimulators shows promise for several therapeutic applications, including cancer, infectious disease, transplantation, and autoimmunity.
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    THE NOD MOUSE: A Model of Immune Dysregulation (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 447-485 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Autoimmunity is a complex process that likely results from the summation of multiple defective tolerance mechanisms. The NOD mouse strain is an excellent model of autoimmune disease and an important tool for dissecting tolerance mechanisms. The strength of this mouse strain is that it develops spontaneous autoimmune diabetes, which shares many similarities to autoimmune or type 1a diabetes (T1D) in human subjects, including the presence of pancreas-specific autoantibodies, autoreactive CD4+ and CD8+ T cells, and genetic linkage to disease syntenic to that found in humans. During the past ten years, investigators have used a wide variety of tools to study these mice, including immunological reagents and transgenic and knockout strains; these tools have tremendously enhanced the study of the fundamental disease mechanisms. In addition, investigators have recently developed a number of therapeutic interventions in this animal model that have now been translated into human therapies. In this review, we summarize many of the important features of disease development and progression in the NOD strain, emphasizing the role of central and peripheral tolerance mechanisms that affect diabetes in these mice. The information gained from this highly relevant model of human disease will lead to potential therapies that may alter the development of the disease and its progression in patients with T1D.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115643
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    THE T CELL RECEPTOR: Critical Role of the Membrane Environment in Receptor Assembly and Function (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 101-125 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Recent studies have demonstrated that cell membranes provide a unique environment for protein-protein and protein-lipid interactions that are critical for the assembly and function of the T cell receptor (TCR)-CD3 complex. Highly specific polar interactions among transmembrane (TM) domains that are uniquely favorable in the lipid environment organize the association of the three signaling dimers with the TCR. Each of these three assembly steps depends on the formation of a three-helix interface between one basic and two acidic residues in the membrane environment. The same polar TM residues that drive assembly also play a central role in quality control and export by directing the retention and degradation of free subunits and partial complexes, while membrane proximal cytoplasmic signals control recycling and degradation of surface receptors. Recent studies also suggest that interactions between the membrane and the cytoplasmic domains of CD3 proteins may be important for receptor triggering.
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    MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 901-944 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Macrophages express a broad range of plasma membrane receptors that mediate their interactions with natural and altered-self components of the host as well as a range of microorganisms. Recognition is followed by surface changes, uptake, signaling, and altered gene expression, contributing to homeostasis, host defense, innate effector mechanisms, and the induction of acquired immunity. This review covers recent studies of selected families of structurally defined molecules, studies that have improved understanding of ligand discrimination in the absence of opsonins and differential responses by macrophages and related myeloid cells.
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    MOLECULAR GENETICS OF T CELL DEVELOPMENT (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 601-649 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: T cell development is guided by a complex set of transcription factors that act recursively, in different combinations, at each of the developmental choice points from T-lineage specification to peripheral T cell specialization. This review describes the modes of action of the major T-lineage-defining transcription factors and the signal pathways that activate them during intrathymic differentiation from pluripotent precursors. Roles of Notch and its effector RBPSuh (CSL), GATA-3, E2A/HEB and Id proteins, c-Myb, TCF-1, and members of the Runx, Ets, and Ikaros families are critical. Less known transcription factors that are newly recognized as being required for T cell development at particular checkpoints are also described. The transcriptional regulation of T cell development is contrasted with that of B cell development, in terms of their different degrees of overlap with the stem-cell program and the different roles of key transcription factors in gene regulatory networks leading to lineage commitment.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115737
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    MAINTENANCE OF SERUM ANTIBODY LEVELS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 367-386 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: In vertebrates, serum antibodies are an essential component of innate and adaptive immunity and immunological memory. They also can contribute significantly to immunopathology. Their composition is the result of tightly regulated differentiation of B lymphocytes into antibody-secreting plasma blasts and plasma cells. The survival of antibody-secreting cells determines their contribution to the immune response in which they were generated and to long-lasting immunity, as provided by stable serum antibody levels. Short-lived plasma blasts and/or plasma cells secrete antibodies for a reactive immune response. Short-lived plasma blasts can become long-lived plasma cells, probably by competition with preexisting plasma cells for occupation of a limited number of survival niches in the body, in a process not yet fully understood. Limitation of the number of long-lived plasma cells allows the immune system to maintain a stable humoral immunological memory over long periods, to react to new pathogenic challenges, and to adapt the humoral memory in response to these antigens.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115723
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    PENTRAXINS AT THE CROSSROADS BETWEEN INNATE IMMUNITY, INFLAMMATION, MATRIX DEPOSITION, AND FEMALE FERTILITY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 337-366 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: C reactive protein, the first innate immunity receptor identified, and serum amyloid P component are classic short pentraxins produced in the liver. Long pentraxins, including the prototype PTX3, are expressed in a variety of tissues. Some long pentraxins are expressed in the brain and some are involved in neuronal plasticity and degeneration. PTX3 is produced by a variety of cells and tissues, most notably dendritic cells and macrophages, in response to Toll-like receptor (TLR) engagement and inflammatory cytokines. PTX3 acts as a functional ancestor of antibodies, recognizing microbes, activating complement, and facilitating pathogen recognition by phagocytes, hence playing a nonredundant role in resistance against selected pathogens. In addition, PTX3 is essential in female fertility because it acts as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional soluble pattern recognition receptor at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility.
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    NK CELL RECOGNITION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 225-274 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The integrated processing of signals transduced by activating and inhibitory cell surface receptors regulates NK cell effector functions. Here, I review the structure, function, and ligand specificity of the receptors responsible for NK cell recognition.
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    NETWORK COMMUNICATIONS: Lymphotoxins, LIGHT, and TNF (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 787-819 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Lymphotoxins (LT) provide essential communication links between lymphocytes and the surrounding stromal and parenchymal cells and together with the two related cytokines, tumor necrosis factor (TNF) and LIGHT (LT-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells), form an integrated signaling network necessary for efficient innate and adaptive immune responses. Recent studies have identified signaling pathways that regulate several genes, including chemokines and interferons, which participate in the development and function of microenvironments in lymphoid tissue and host defense. Disruption of the LT/TNF/LIGHT network alleviates inflammation in certain autoimmune disease models, but decreases resistance to selected pathogens. Pharmacological disruption of this network in human autoimmune diseases such as rheumatoid arthritis alleviates inflammation in a significant number of patients, but not in other diseases, a finding that challenges our molecular paradigms of autoimmunity and perhaps will reveal novel roles for this network in pathogenesis.
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    CATERPILLER: A Novel Gene Family Important in Immunity, Cell Death, and Diseases (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 387-414 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The newly discovered CATERPILLER (CLR) gene family encodes proteins with a variable but limited number of N-terminal domains, followed by a nucleotide-binding domain (NBD) and leucine-rich repeats (LRR). The N-terminal domain consists of transactivation, CARD, Pyrin, or BIR domains, with a minority containing undefined domains. These proteins are remarkably similar in structure to the TIR-NBD-LRR and CC-NBD-LRR disease resistance (R) proteins that mediate immune responses in plants. The NBD-LRR architecture is conserved in plants and vertebrates, but only remnants are found in worms and flies. The CLRs regulate inflammatory and apoptotic responses, and some act as sensors that detect pathogen products. Several CLR genes have been genetically linked to susceptibility to immunologic disorders. We describe prominent family members, including CIITA, CARD4/NOD1, NOD2/CARD15, CIAS1, CARD7/NALP1, and NAIP, in more detail. We also discuss implied roles of these proteins in diversifying immune detection and in providing a check-and-balance during inflammation.
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    HOW NEUTROPHILS KILL MICROBES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 197-223 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Neutrophils provide the first line of defense of the innate immune system by phagocytosing, killing, and digesting bacteria and fungi. Killing was previously believed to be accomplished by oxygen free radicals and other reactive oxygen species generated by the NADPH oxidase, and by oxidized halides produced by myeloperoxidase. We now know this is incorrect. The oxidase pumps electrons into the phagocytic vacuole, thereby inducing a charge across the membrane that must be compensated. The movement of compensating ions produces conditions in the vacuole conducive to microbial killing and digestion by enzymes released into the vacuole from the cytoplasmic granules.
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    ROLE OF C5A IN INFLAMMATORY RESPONSES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 821-852 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The complement system not only represents an effective innate immune mechanism of host defense to eradicate microbial pathogens, but it is also widely involved in many forms of acute and chronic inflammatory diseases including sepsis, acute lung injury, ischemia-reperfusion injury, and asthma, to give just a few examples. The complement-activated product, C5a, displays powerful biological activities that lead to inflammatory sequelae. C5a is a strong chemoattractant and is involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, in activation of phagocytic cells and release of granule-based enzymes and generation of oxidants, all of which may contribute to innate immune functions or tissue damage. Accumulating data suggest that C5a provides a vital bridge between innate and adaptive immune functions, extending the roles of C5a in inflammation. Herein, we review human and animal data describing the cellular and molecular mechanisms of C5a in the development of inflammatory disorders, sepsis, acute lung injury, ischemia-reperfusion injury, and asthma.
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    IPC: Professional Type 1 Interferon-Producing Cells and Plasmacytoid Dendritic Cell Precursors (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 275-306 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Type 1 interferon-(ʼ̛, ?‚, ?)-producing cells (IPCs), also known as plasmacytoid dendritic cell precursors (pDCs), represent 0.2%Đ??0.8% of peripheral blood mononuclear cells in both humans and mice. IPCs display plasma cell morphology, selectively express Toll-like receptor (TLR)-7 and TLR9, and are specialized in rapidly secreting massive amounts of type 1 interferon following viral stimulation. IPCs can promote the function of natural killer cells, B cells, T cells, and myeloid DCs through type 1 interferons during an antiviral immune response. At a later stage of viral infection, IPCs differentiate into a unique type of mature dendritic cell, which directly regulates the function of T cells and thus links innate and adaptive immune responses. After more than two decades of effort by researchers, IPCs finally claim their place in the hematopoietic chart as the most important cell type in antiviral innate immunity. Understanding IPC biology holds future promise for developing cures for infectious diseases, cancer, and autoimmune diseases.
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    TYPE I INTERFERONS (ʼ̛/?‚) IN IMMUNITY AND AUTOIMMUNITY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 307-335 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The significance of type I interferons (IFN-ʼ̛/?‚) in biology and medicine renders research on their activities continuously relevant to our understanding of normal and abnormal (auto) immune responses. This relevance is bolstered by discoveries that unambiguously establish IFN-ʼ̛/?‚, among the multitude of cytokines, as dominant in defining qualitative and quantitative characteristics of innate and adaptive immune processes. Recent advances elucidating the biology of these key cytokines include better definition of their complex signaling pathways, determination of their importance in modifying the effects of other cytokines, the role of Toll-like receptors in their induction, their major cellular producers, and their broad and diverse impact on both cellular and humoral immune responses. Consequently, the role of IFN-ʼ̛/?‚ in the pathogenesis of autoimmunity remains at the forefront of scientific inquiry and has begun to illuminate the mechanisms by which these molecules promote or inhibit systemic and organ-specific autoimmune diseases.
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    CHEMOKINES, SPHINGOSINE-1-PHOSPHATE, AND CELL MIGRATION IN SECONDARY LYMPHOID ORGANS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 127-159 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Secondary lymphoid organs serve as hubs for the adaptive immune system, bringing together antigen, antigen-presenting cells, and lymphocytes. Two families of G proteinĐ??coupled receptors play essential roles in lymphocyte migration through these organs: chemokine receptors and sphingosine-1-phosphate (S1P) receptors. Chemokines expressed by lymphoid stromal cells guide lymphocyte and dendritic cell movements during antigen surveillance and the initiation of adaptive immune responses. S1P receptor-1 is required for lymphocyte egress from thymus and secondary lymphoid organs and is downregulated by the immunosuppressive drug FTY720. Here, we review the steps associated with the initiation of adaptive immune responses in secondary lymphoid organs, highlighting the roles of chemokines and S1P.
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    MAST CELLS AS "TUNABLE" EFFECTOR AND IMMUNOREGULATORY CELLS: Recent Advances (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 749-786 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: This review focuses on recent progress in our understanding of how mast cells can contribute to the initiation, development, expression, and regulation of acquired immune responses, both those associated with IgE and those that are apparently expressed independently of this class of Ig. We emphasize findings derived from in vivo studies in mice, particularly those employing genetic approaches to influence mast cell numbers and/or to alter or delete components of pathways that can regulate mast cell development, signaling, or function. We advance the hypothesis that mast cells not only can function as proinflammatory effector cells and drivers of tissue remodeling in established acquired immune responses, but also may contribute to the initiation and regulation of such responses. That is, we propose that mast cells can also function as immunoregulatory cells. Finally, we show that the notion that mast cells have primarily two functional configurations, off (or resting) or on (or activated for extensive mediator release), markedly oversimplifies reality. Instead, we propose that mast cells are "tunable," by both genetic and environmental factors, such that, depending on the circumstances, the cell can be positioned phenotypically to express a wide spectrum of variation in the types, kinetics, and/or magnitude of its secretory functions.
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    INTERLEUKIN-6: From Basic Science to MedicineĐ??40 Years in Immunology (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 1-21 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: This essay summarizes my 40 years of research in immunology. As a young physician, I encountered a patient with Waldenstro?m's macroglobulinemia, and this inspired me to study the structure of IgM. I began to ask how antibody responses are regulated. In the late 1960s, the essential role of T cells in antibody production had been reported. In search of molecules mediating T cell helper function, I discovered activities in the culture supernatant of T cells that induced proliferation and differentiation of B cells. This led to my life's work: studying one of those factors, interleukin-6 (IL-6). To my surprise, IL-6 turned out to play additional roles, including myeloma growth factor and hepatocyte-stimulating factor activities. More importantly, it was involved in a number of diseases, such as rheumatoid arthritis and Castleman's disease. I feel exceptionally fortunate that my work not only revealed the framework of cytokine signaling, including identification of the IL-6 receptor, gp130, NF-IL6, STAT3, and SOCS-1, but also led to the development of a new therapy for chronic inflammatory diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115806
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    DNA DEGRADATION IN DEVELOPMENT AND PROGRAMMED CELL DEATH (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 853-875 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Most mammalian cells have nuclei that contain DNA, which replicates during cell proliferation. DNA is destroyed by various developmental processes in mammals. It is degraded during programmed cell death that accompanies mammalian development. The nuclei of erythrocytes and eye lens fiber cells are also removed during their differentiation into mature cells. If DNA is not properly degraded in these processes, it can cause various diseases, including tissue atrophy, anemia, cataract, and autoimmune diseases, which indicates that DNA can be a pathogenic molecule. Here, I present how DNA is degraded during programmed cell death, erythroid cell differentiation, and lens cell differentiation. I discuss what might be or will be learned from understanding the molecular mechanisms of DNA degradation that occurs during mammalian development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115811
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    CYTOCHROME P450: Nature's Most Versatile Biological Catalyst (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 1-25 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The author describes studies that led to the resolution and reconstitution of the cytochrome P450 enzyme system in microsomal membranes. The review indicates how purification and characterization of the cytochromes led to rigorous evidence for multiple isoforms of the oxygenases with distinct chemical and physical properties and different but somewhat overlapping substrate specificities. Present knowledge of the individual steps in the P450 and reductase reaction cycles is summarized, including evidence for the generation of multiple functional oxidants that may contribute to the exceptional diversity of the reactions catalyzed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100030
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    GLUTATHIONE TRANSFERASES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 51-88 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous ʼ̛,?‚-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-??12,14-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor ?? (PPAR??) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-?”B (NF-?”B). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095857
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    THE ROLE OF METABOLIC ACTIVATION IN DRUG-INDUCED HEPATOTOXICITY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 177-202 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The importance of reactive metabolites in the pathogenesis of drug-induced toxicity has been a focus of research interest since pioneering investigations in the 1950s revealed the link between toxic metabolites and chemical carcinogenesis. There is now a great deal of evidence that shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, but how these toxic species initiate and propagate tissue damage is still poorly understood. This review summarizes the evidence for reactive metabolite formation from hepatotoxic drugs, such as acetaminophen, tamoxifen, diclofenac, and troglitazone, and the current hypotheses of how this leads to liver injury. Several hepatic proteins can be modified by reactive metabolites, but this in general equates poorly with the extent of toxicity. Much more important may be the identification of the critical proteins modified by these toxic species and how this alters their function. It is also important to note that the toxicity of reactive metabolites may be mediated by noncovalent binding mechanisms, which may also have profound effects on normal liver physiology. Technological developments in the wake of the genomic revolution now provide unprecedented power to characterize and quantify covalent modification of individual target proteins and their functional consequences; such information should dramatically improve our understanding of drug-induced hepatotoxic reactions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100058
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    NON-MICHAELIS-MENTEN KINETICS IN CYTOCHROME P450-CATALYZED REACTIONS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 291-310 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The cytochrome P450 monooxygenases (CYPs) are the dominant enzyme system responsible for xenobiotic detoxification and drug metabolism. Several CYP isoforms exhibit non-Michaelis-Menten, or "atypical," steady state kinetic patterns. The allosteric kinetics confound prediction of drug metabolism and drug-drug interactions, and they challenge the theoretical paradigms of allosterism. Both homotropic and heterotropic ligand effects are now widely documented. It is becoming apparent that multiple ligands can simultaneously bind within the active sites of individual CYPs, and the kinetic parameters change with ligand occupancy. In fact, the functional effect of any specific ligand as an activator or inhibitor can be substrate dependent. Divergent approaches, including kinetic modeling and X-ray crystallography, are providing new information about how multiple ligand binding yields complex CYP kinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100004
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    NITROXYL (HNO): Chemistry, Biochemistry, and Pharmacology (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 335-355 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Recent discoveries of novel and potentially important biological activity have spurred interest in the chemistry and biochemistry of nitroxyl (HNO). It has become clear that, among all the nitrogen oxides, HNO is unique in its chemistry and biology. Currently, the intimate chemical details of the biological actions of HNO are not well understood. Moreover, many of the previously accepted chemical properties of HNO have been recently revised, thus requiring reevaluation of possible mechanisms of biological action. Herein, we review these developments in HNO chemistry and biology.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095959
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    ACTIONS OF ADENOSINE AT ITS RECEPTORS IN THE CNS: Insights from Knockouts and Drugs (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 385-412 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Adenosine and its receptors have been the topic of many recent reviews ( 1Đ??26 ). These reviews provide a good summary of much of the relevant literatureĐ??including the older literature. We have, therefore, chosen to focus the present review on the insights gained from recent studies on genetically modified mice, particularly with respect to the function of adenosine receptors and their potential as therapeutic targets. The information gained from studies of drug effects is discussed in this context, and discrepancies between genetic and pharmacological results are highlighted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095731
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    PROTEASOME INHIBITION IN MULTIPLE MYELOMA: Therapeutic Implication (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 465-476 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Normal cellular functioning requires processing of proteins regulating cell cycle, growth, and apoptosis. The ubiquitin-proteasome pathway (UBP) modulates intracellular protein degradation. Specifically, the 26S proteasome is a multienzyme protease that degrades misfolded or redundant proteins; conversely, blockade of the proteasomal degradation pathways results in accumulation of unwanted proteins and cell death. Because cancer cells are more highly proliferative than normal cells, their rate of protein translation and degradation is also higher. This notion led to the development of proteasome inhibitors as therapeutics in cancer. The FDA recently approved the first proteasome inhibitor bortezomib (VelcadeĐ?„), formerly known as PS-341, for the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Ongoing studies are examining other novel proteasome inhibitors, in addition to bortezomib, for the treatment of MM and other cancers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100037
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    MOLECULAR MECHANISMS OF RESISTANCE IN ANTIMALARIAL CHEMOTHERAPY: The Unmet Challenge (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 565-585 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The enormous public health problem posed by malaria has been substantially worsened in recent years by the emergence and worldwide spread of drug-resistant parasites. The utility of two major therapies, chloroquine and the synergistic combination of pyrimethamine/sulfadoxine, is now seriously compromised. Although several genetic mechanisms have been described, the major source of drug resistance appears to be point mutations in protein target genes. Clinically significant resistance to these agents requires the accumulation of multiple mutations, which genetic studies of parasite populations suggest arise focally and sweep through the population. Efforts to circumvent resistance range from the use of combination therapy with existing agents to laboratory studies directed toward discovering novel targets and therapies. The prevention and management of drug resistance are among the most important practical problems of tropical medicine and public health. Leonard J. Bruce-Chwatt, 1972
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095946
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    THE CARDIAC FIBROBLAST: Therapeutic Target in Myocardial Remodeling and Failure (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 657-687 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Cardiac fibroblasts play a central role in the maintenance of extracellular matrix in the normal heart and as mediators of inflammatory and fibrotic myocardial remodeling in the injured and failing heart. In this review, we evaluate the cardiac fibroblast as a therapeutic target in heart disease. Unique features of cardiac fibroblast cell biology are discussed in relation to normal and pathophysiological cardiac function. The contribution of cardiac fibrosis as an independent risk factor in the outcome of heart failure is considered. Candidate drug therapies that derive benefit from actions on cardiac fibroblasts are summarized, including inhibitors of angiotensin-aldosterone systems, endothelin receptor antagonists, statins, anticytokine therapies, matrix metalloproteinase inhibitors, and novel antifibrotic/anti-inflammatory agents. These findings point the way to future challenges in cardiac fibroblast biology and pharmacotherapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095802
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    INTRACELLULAR CALCIUM RELEASE AND CARDIAC DISEASE (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 69-98 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Intracellular calcium release channels are present on sarcoplasmic and endoplasmic reticuli (SR, ER) of all cell types. There are two classes of these channels: ryanodine receptors (RyR) and inositol 1,4,5-trisphosphate receptors (IP3R). RyRs are required for excitation-contraction (EC) coupling in striated (cardiac and skeletal) muscles. RyRs are made up of macromolecular signaling complexes that contain large cytoplasmic domains, which serve as scaffolds for proteins that regulate the function of the channel. These regulatory proteins include calstabin1/calstabin2 (FKBP12/FKBP12.6), a 12/12.6 kDa subunit that stabilizes the closed state of the channel and prevents aberrant calcium leak from the SR. Kinases and phosphatases are targeted to RyR2 channels and modulate RyR2 function in response to extracellular signals. In the classic fight or flight stress response, phosphorylation of RyR channels by protein kinase A reduces the affinity for calstabin and activates the channels leading to increased SR calcium release. In heart failure, a cardiac insult causes a mismatch between blood supply and metabolic demands of organs. The chronically activated fight or flight response leads to leaky channels, altered calcium signaling, and contractile dysfunction and cardiac arrhythmias.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.040403.114521
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    COMPARATIVE DEVELOPMENTAL PHYSIOLOGY:An Interdisciplinary Convergence (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 203-223 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Comparative developmental physiology spans genomics to physiological ecology and evolution. Although not a new discipline, comparative developmental physiology's position at the convergence of development, physiology and evolution gives it prominent new significance. The contributions of this discipline may be particularly influential as physiologists expand beyond genomics to a true systems synthesis, integrating molecular through organ function in multiple organ systems. This review considers how developing physiological systems are directed by genes yet respond to environment and how these characteristics both constrain and enable evolution of physiological characters. Experimental approaches and methodologies of comparative developmental physiology include studying event sequences (heterochrony and heterokairy), describing the onset and progression of physiological regulation, exploiting scaling, expanding the list of animal models, using genetic engineering, and capitalizing on new miniaturized technologies for physiological investigation down to the embryonic level. A synthesis of these approaches is likely to generate a more complete understanding of how physiological systems and, indeed, whole animals develop and how populations evolve.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.040403.104223
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    LIGAND CONTROL OF COREGULATOR RECRUITMENT TO NUCLEAR RECEPTORS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 309-333 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Nuclear receptors modulate transcription through ligand-mediated recruitment of transcriptional coregulator proteins. The structural connection between ligand and coregulator is mediated by a molecular switch, made up of the most carboxy-terminal helix in the ligand-binding domain, helix 12. The dynamics of this switch are thought to underlie ligand specificity of nuclear receptor signaling, but the details of this control mechanism have remained elusive. This review highlights recent structural work on how the ligand controls this molecular switch and the modulation of this signaling pathway by receptor subtype and dimer partner.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.66.032802.154710
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    REGULATION OF SIGNAL TRANSDUCTION PATHWAYS BY ESTROGEN AND PROGESTERONE (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 67 (2005), S. 335-376 
    Details
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The female sex steroid hormones 17?‚-estradiol and progesterone mediate their biological effects on development, differentiation, and maintenance of reproductive tract and other target tissues through gene regulation by nuclear steroid receptors that function as ligand-dependent transcription factors. However, not all effects of 17?‚-estradiol and progesterone are mediated by direct control of gene expression. These hormones also have rapid stimulatory effects on the activities of a variety of signal transduction molecules and pathways and, in many cases, these effects appear to be initiated from the plasma cell membrane. There is growing evidence that a subpopulation of the conventional nuclear steroid receptor localized at the cell membrane mediates many of the rapid signaling actions of steroid hormones; however, novel membrane receptors unrelated to conventional steroid receptors have also been implicated. This chapter reviews the nature of the receptors that mediate rapid signaling actions of estrogen and progesterone and describes the signaling molecules and pathways involved, the mechanisms by which receptors couple with components of signaling complexes and trigger responses, and the target tissues and cell functions regulated by this mode of steroid hormone action.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physiol.67.040403.120151
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