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  • American Institute of Physics  (160,164)
  • Wiley-Blackwell  (79,531)
  • Annual Reviews
  • 2005-2009  (83,155)
  • 1995-1999  (106,103)
  • 1970-1974  (61,771)
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  • 1
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    An Intercomparison of Precipitable Water Vapor Measurements Obtained During the ECOWAR Field Campaign (2009)
    American Institute of Physics
    Details
    Publication Date: 2020-12-14
    Description: In this study we present an intercomparison of measurements of very low water vapor column content obtained with a Ground-Based Millimeter-wave Spectrometer (GBMS), Vaisala RS92k radiosondes, a Raman Lidar, and an IR Fourier Transform Spectrometer. These sets of measurements were carried out during the primary field campaign of the ECOWAR (Earth COoling by WAter vapor Radiation) project which took place on the Western Italian Alps from 3 to 16 March, 2007.
    Description: Published
    Description: 135-138
    Description: 1.8. Osservazioni di geofisica ambientale
    Description: N/A or not JCR
    Description: open
    Keywords: Precipitable Water Vapor ; ECOWAR ; IR and Millimeter-Wave Spectroscopy ; 01. Atmosphere::01.01. Atmosphere::01.01.01. Composition and Structure ; 01. Atmosphere::01.01. Atmosphere::01.01.02. Climate
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
    Type: article
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  • 2
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    Empirical H/V spectral ratios estimated in two deep sedimentary basins using microseisms recorded by short-period seismometers (2009)
    Wiley-Blackwell
    Details
    Publication Date: 2021-06-22
    Description: In this work, we analyse continuous measurements of microseisms to assess the reliability of the fundamental resonance frequency estimated by means of the horizontal-to-vertical (H/V) spectral ratio within the 0.1–1 Hz frequency range, using short-period sensors (natural period of 1 s). We apply the H/V technique to recordings of stations installed in two alluvial basins with different sedimentary cover thicknesses—the Lower Rhine Embayment (Germany) and the Gubbio Plain (Central Italy). The spectral ratios are estimated over the time–frequency domain, and we discuss the reliability of the results considering both the variability of the microseism activity and the amplitude of the instrumental noise. We show that microseisms measured by short period sensors allow the retrieval of fundamental resonance frequencies greater than about 0.1–0.2 Hz, with this lower frequency bound depending on the relative amplitude of themicroseism signal and the self-noise of the instruments. In particular,we show an examplewhere the considered short-period sensor is connected to instruments characterized by an instrumental noise level which allows detecting only fundamental frequencies greater than about 0.4 Hz. Since the frequency at which the peak of the H/V spectral ratio is biased depends upon the seismic signal-to-instrument noise ratio, the power spectral amplitude of instrumental self-noise should be always considered when interpreting the frequency of the peak as the fundamental resonance frequency of the investigated site.
    Description: Published
    Description: 175-184
    Description: 4.1. Metodologie sismologiche per l'ingegneria sismica
    Description: JCR Journal
    Description: open
    Keywords: site effects ; fourier analysis ; 04. Solid Earth::04.06. Seismology::04.06.01. Earthquake faults: properties and evolution
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 3
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    From COST 238 To COST 296: Four European COST Actions On Ionospheric Physics And Radio Propagation (2008)
    American Institute of Physics
    Details
    Publication Date: 2017-04-04
    Description: COST (Co-operation in the field of Scientific and Technical Research) is an important instrument supporting co-operation among scientists and researchers across Europe now joining 35 member countries. Scientific projects in the COST framework are called COST Actions and have the objectives embodied in their respective Memorandum of Understanding (MoU). The main objectives of the COST Actions within the European ionospheric and radio propagation community have been: to study the influence of upper atmospheric conditions on terrestrial and Earthspace communications, to develop methods and techniques to improve existing and generate new ionospheric and propagation models over Europe for telecommunication and navigation applications and to transfer the results to the appropriate national and international organizations, institutions and industry dealing with the modern communication systems. This paper summarises in brief the background and historical context of four ionospheric COST Actions and outlines their main objectives and results. In addition, the paper discusses the dissemination of the results and the collaboration among the participating institutions and researchers.
    Description: DRS Codem Systems Ball Aerospace Corporation University of Massachusetts Lowell
    Description: Published
    Description: Lowell, Massachusetts, U.S.A., April 29, 2007
    Description: 3.9. Fisica della magnetosfera, ionosfera e meteorologia spaziale
    Description: open
    Keywords: Physics of the Ionosphere ; 01. Atmosphere::01.02. Ionosphere::01.02.99. General or miscellaneous ; 05. General::05.07. Space and Planetary sciences::05.07.02. Space weather
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
    Type: Conference paper
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  • 4
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    Gas hazard assessment at the Monticchio Mt. Vulture, a volcano in Southern Italy (2009)
    Wiley-Blackwell
    Details
    Publication Date: 2017-04-04
    Description: Geochemical investigations have shown that there is a considerable inflow of gas into both crater lakes of Monticchio, Southern Italy. These lakes are located in two maars that formed 140 000 years ago during Mt. Vulture volcano s last eruptive activity. Isotopic analyses suggest that CO2 and helium are of magmatic origin; the latter displays 3He ⁄ 4He isotope ratios similar to those measured in olivines of the maar ejecta. In spite of the fact that the amount of dissolved gases in the water is less than that found in Lake Nyos (Cameroon), both the results obtained and the historical reports studied indicate that these crater lakes could be highly hazardous sites, even though they are located in a region currently considered inactive. This could be of special significance in very popular tourist areas such as the Monticchio lakes, which are visited by about 30 000 people throughout the summer, for the most part on Sundays.
    Description: Published
    Description: 83-87
    Description: 2.4. TTC - Laboratori di geochimica dei fluidi
    Description: JCR Journal
    Description: reserved
    Keywords: volcanic gases ; gas hazard ; crater lakes ; 04. Solid Earth::04.04. Geology::04.04.12. Fluid Geochemistry ; 04. Solid Earth::04.08. Volcanology::04.08.01. Gases ; 04. Solid Earth::04.08. Volcanology::04.08.08. Volcanic risk
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 5
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    Seismic moment tensors of the April 2009, L’Aquila (Central Italy), (2009)
    Wiley-Blackwell
    Details
    Publication Date: 2017-04-04
    Description: On 2009 April 6, the Central Apennines were hit by an Mw = 6.3 earthquake. The region had been shaken since 2008 October by seismic activity that culminated in two foreshocks with Mw 〉 4, 1 week and a few hours before the main shock. We computed seismic moment tensors for 26 events with Mw between 3.9 and 6.3, using the Regional Centroid Moment Tensor (RCMT) scheme. Most of these source parameters have been computed within 1 hr after the earthquake and rapidly revised successively. The focal mechanisms are all extensional, with a variable and sometimes significant strike-slip component. This geometry agrees with the NE–SW extensional deformation of the Apennines, known from previous seismic and geodetic observations. Events group into three clusters. Those located in the southern area have larger centroid depths and a wider distribution of T-axis directions. These differences suggest that towards south a different fault systemwas activated with respect to the SW-dipping normal faults beneath L’Aquila and more to the north.
    Description: In press
    Description: 1.1. TTC - Monitoraggio sismico del territorio nazionale
    Description: JCR Journal
    Description: open
    Keywords: moment tensor ; seismotectonics ; L'Aquila ; 04. Solid Earth::04.07. Tectonophysics::04.07.04. Plate boundaries, motion, and tectonics
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 6
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    The Mw 6.3, 2009 L’Aquila earthquake: source, path and site effects from spectral analysis of strong motion data (2009)
    Wiley-Blackwell
    Details
    Publication Date: 2017-04-04
    Description: The strong motion data of 2009 April 6 L’Aquila (Central Italy) earthquake (Mw = 6.3) and of 12 aftershocks (4.1 ≤ Mw ≤ 5.6) recorded by 56 stations of the Italian strong motion network are spectrally analysed to estimate the source parameters, the seismic attenuation, and the site amplification effects. The obtained source spectra for S wave have stress drop values ranging from 2.4 to 16.8 MPa, being the stress drop of the main shock equal to 9.2 MPa. The spectral curves describing the attenuation with distance show the presence of shoulders and bumps, mainly around 50 and 150 km, as consequence of significant reflected and refracted arrivals from crustal interfaces. The attenuation in the first 50 km is well described by a quality factor equal to Q( f ) = 59 f 0.56 obtained by fixing the geometrical spreading exponent to 1. Finally, the horizontal-to-vertical spectral ratio provides unreliable estimates of local site effects for those stations showing large amplifications over the vertical component of motion.
    Description: Published
    Description: 1573–1579
    Description: 4.1. Metodologie sismologiche per l'ingegneria sismica
    Description: JCR Journal
    Description: open
    Keywords: Generalized inversion ; strong-motion ; 04. Solid Earth::04.06. Seismology::04.06.04. Ground motion
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 7
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    Laser-slaved piezo-controlled Fabry–Perot interferometer (2008)
    American Institute of Physics
    Details
    Publication Date: 2020-02-24
    Description: A high-resolution Fabry–Perot interferometer was inserted in a feedback loop which, by monitoring elements of the fringe pattern, keeps the position of the transmitting window fixed with respect to a given line, taking into account the instability of the radiation source which would produce a wander of the line itself and the noise affecting the tuning of the receiving interferometer. The system, in this preliminary form, is able to lock itself and maintain its position indefinitely for slow and moderately fast varying disturbances.
    Description: Published
    Description: 2940-2944
    Description: 1.7. Osservazioni di alta e media atmosfera
    Description: JCR Journal
    Description: reserved
    Keywords: FABRY-PEROT ; INTERFEROMETER ; SERVOMECHANISMS ; FEEDBACK ; 01. Atmosphere::01.01. Atmosphere::01.01.08. Instruments and techniques
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 8
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    Role of carbon cycle observations and knowledge in carbon management (2005)
    Annual Reviews
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © Annual Reviews, 2003. This article is posted here by permission of Annual Reviews for personal use, not for redistribution. The definitive version was published in Annual Review of Environment and Resources 28 (2003): 521-558, doi:10.1146/annurev.energy.28.011503.163443.
    Description: Agriculture and industrial development have led to inadvertent changes in the natural carbon cycle. As a consequence, concentrations of carbon dioxide and other greenhouse gases have increased in the atmosphere and may lead to changes in climate. The current challenge facing society is to develop options for future management of the carbon cycle. A variety of approaches has been suggested: direct reduction of emissions, deliberate manipulation of the natural carbon cycle to enhance sequestration, and capture and isolation of carbon from fossil fuel use. Policy development to date has laid out some of the general principles to which carbon management should adhere. These are summarized as: how much carbon is stored, by what means, and for how long. To successfully manage carbon for climate purposes requires increased understanding of carbon cycle dynamics and improvement in the scientific capabilities available for measurement as well as for policy needs. The specific needs for scientific information to underpin carbon cycle management decisions are not yet broadly known. A stronger dialogue between decision makers and scientists must be developed to foster improved application of scientific knowledge to decisions. This review focuses on the current knowledge of the carbon cycle, carbon measurement capabilities (with an emphasis on the continental scale) and the relevance of carbon cycle science to carbon sequestration goals.
    Description: The National Center for Atmospheric Research is supported by the National Science Foundation.
    Keywords: Carbon sequestration ; Measurement techniques ; Climate ; Kyoto protocol
    Repository Name: Woods Hole Open Access Server
    Type: Article
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  • 9
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    Long nonlinear internal waves (2006)
    Annual Reviews
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © Annual Reviews, 2006. This article is posted here by permission of Annual Reviews for personal use, not for redistribution. The definitive version was published in Annual Review of Fluid Mechanics 38 (2006): 395-425, doi:10.1146/annurev.fluid.38.050304.092129.
    Description: Over the past four decades, the combination of in situ and remote sensing observations has demonstrated that long nonlinear internal solitary-like waves are ubiquitous features of coastal oceans. The following provides an overview of the properties of steady internal solitary waves and the transient processes of wave generation and evolution, primarily from the point of view of weakly nonlinear theory, of which the Korteweg-de Vries equation is the most frequently used example. However, the oceanographically important processes of wave instability and breaking, generally inaccessible with these models, are also discussed. Furthermore, observations often show strongly nonlinear waves whose properties can only be explained with fully nonlinear models.
    Description: KRH acknowledges support from NSF and ONR and an Independent Study Award from the Woods Hole Oceanographic Institution. WKM acknowledges support from NSF and ONR, which has made his work in this area possible, in close collaboration with former graduate students at Scripps Institution of Oceanography and MIT.
    Keywords: Solitary waves ; Nonlinear waves ; Stratified flow ; Physical Oceanography
    Repository Name: Woods Hole Open Access Server
    Type: Article
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  • 10
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    Design and function of superfast muscles : new insights into the physiology of skeletal muscle (2005)
    Annual Reviews
    Details
    Publication Date: 2022-05-25
    Description: First published online as a Review in Advance on October 24, 2005. (Some corrections may occur before final publication online and in print)
    Description: Author Posting. © Annual Reviews, 2005. This article is posted here by permission of Annual Reviews for personal use, not for redistribution. The definitive version was published in Annual Review of Physiology 68 (2006): 22.1-22.29, doi:10.1146/annurev.physiol.68.040104.105418.
    Description: Superfast muscles of vertebrates power sound production. The fastest, the swimbladder muscle of toadfish, generates mechanical power at frequencies in excess of 200 Hz. To operate at these frequencies, the speed of relaxation has had to increase approximately 50-fold. This increase is accomplished by modifications of three kinetic traits: (a) a fast calcium transient due to extremely high concentration of sarcoplasmic reticulum (SR)-Ca2+ pumps and parvalbumin, (b) fast off-rate of Ca2+ from troponin C due to an alteration in troponin, and (c) fast cross-bridge detachment rate constant (g, 50 times faster than that in rabbit fast-twitch muscle) due to an alteration in myosin. Although these three modifications permit swimbladder muscle to generate mechanical work at high frequencies (where locomotor muscles cannot), it comes with a cost: The high g causes a large reduction in attached force-generating cross-bridges, making the swimbladder incapable of powering low-frequency locomotory movements. Hence the locomotory and sound-producing muscles have mutually exclusive designs.
    Description: This work was made possible by support from NIH grants AR38404 and AR46125 as well as the University of Pennsylvania Research Foundation.
    Keywords: Parvalbumin ; Ca2+ release ; Ca2+ uptake ; Cross-bridges ; Adaptation ; Sound production ; Whitman Center
    Repository Name: Woods Hole Open Access Server
    Type: Article
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  • 11
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    Human-generated sound and marine mammals (2009)
    American Institute of Physics
    Details
    Publication Date: 2022-05-26
    Description: Author Posting. © American Institute of Physics, 2009. This article is posted here by permission of American Institute of Physics for personal use, not for redistribution. The definitive version was published in Physics Today 62 n.11 (2009): 39-44.
    Description: Most species of large whales are endangered because for centuries whaling fleets have decimated their populations. In the late 1960s, marine-mammal biologists discovered that fishermen setting nets for tuna in the Pacific Ocean were killing more than 100,000 dolphins a year. The cause of marine-mammal conservation became so popular at the dawn of the environmental movement that one of the first environmental accomplishments of the US Congress was to enact the Marine Mammal Protection Act of 1972, which prohibits the killing or injuring of marine mammals. Today, small remnant populations of whales, such as the North Atlantic right whale, are threatened by entanglement in fishing gear and collisions by ships. Indeed, marine biologists have estimated that hundreds of thousands of marine mammals are killed each year in fishing gear. Inadvertent effects of human activities can pose a serious risk to coastal populations, as evidenced by the recent extinction of the Chinese river dolphin due to fishing, pollution, and overdevelopment of the Yangtze River. A few decades ago, conservation efforts focused on reducing the intentional hunting of marine mammals. Nowadays, when hunts for marine mammals are better controlled, the slow degradation of habitat from a combination of sources may have a bigger impact. For example, biologists have documented cases in which the effects of coastal development—including noise, pollution, and dredging—have caused marine mammals to abandon critical breeding habitat. Noise in particular is at issue in legal actions that have been brought against the US Navy for sonar exercises that may have caused whales to strand and die.
    Repository Name: Woods Hole Open Access Server
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  • 12
    Electronic Resource
    Electronic Resource
    REGULATION OF MHC CLASS II GENES: Lessons from a Disease (1996)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 14 (1996), S. 301-331 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Precise regulation of major histocompatibility complex class II (MHC-II) gene expression plays a crucial role in the control of the immune response. A major breakthrough in the elucidation of the molecular mechanisms involved in MHC-II regulation has recently come from the study of patients that suffer from a primary immunodeficiency resulting from regulatory defects in MHC-II expression. A genetic complementation cloning approach has led to the isolation of CIITA and RFX5, two essential MHC-II gene transactivators. CIITA and RFX5 are mutated in these patients, and the wild-type genes are capable of correcting their defect in MHC-II expression. The identification of these regulatory factors has furthered our understanding of the molecular mechanisms that regulate MHC-II genes. CIITA was found to be a non-DNA binding transactivator that functions as a molecular switch controlling both constitutive and inducible MHC-II expression. The finding that RFX5 is a subunit of the nuclear RFX-complex has confirmed that a deficiency in the binding of this complex is indeed the molecular basis for MHC-II deficiency in the majority of patients. Furthermore, the study of RFX has demonstrated that MHC-II promoter activity is dependent on the binding of higher-order complexes that are formed by highly specific cooperative binding interactions between certain MHC-II promoter-binding proteins. Two of these proteins belong to families of which the other members, although capable of binding to the same DNA motifs, are probably not directly involved in the control of MHC-II expression. Finally, the facts that CIITA and RFX5 are both essential and highly specific for MHC-II genes make possible novel strategies designed to achieve immunomodulation via transcriptional intervention.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.14.1.301
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  • 13
    Electronic Resource
    Electronic Resource
    ROLE OF CYTOKINES IN RHEUMATOID ARTHRITIS (1996)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 14 (1996), S. 397-440 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNFalpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGFbeta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNFalpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNFalpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNFalpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNFalpha at its apex. This led to the hypothesis that TNFalpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNFalpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNFalpha antibody have shown marked clinical benefit, verifying the hypothesis that TNFalpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNFalpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.14.1.397
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  • 14
    Electronic Resource
    Electronic Resource
    RECOGNITION BY gamma/delta T CELLS (1996)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 14 (1996), S. 511-532 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract In contrast with the study of alphabeta T cells, that of gammadelta T cells is relatively recent and stems from the discovery of their rearranged genes, rather than from any knowledge of their biological function. Thus, experiments designed to characterize their specificity and function have drawn heavily on our knowledge of alphabeta T cells. During the past few years, many studies, especially with mice lacking either alphabeta or gammadelta T cells, have demonstrated that gammadelta T cells can contribute to immune competence, but they do so in a way that is distinct from alphabeta T cells. It is also evident that gammadelta T cells may not recognize antigen the same way as do alphabeta T cells. Analysis of three protein antigens-the murine MHC class II IEk, the nonclassical MHC T10/T22, and the Herpes virus glycoprotein gI-indicates that gammadelta T cell recognition does not require antigen processing and that the proteins are recognized directly. In all three cases, recognition by these T cell clones involves neither peptides bound to these proteins nor peptides derived from them. Moreover, a group of small phosphate-containing nonpeptide compounds derived from mycobacterial extracts has been found to stimulate a major population of human peripheral gammadelta T cells in a T cell receptor (TCR)-dependent manner. This indicates that gammadelta T cells can respond to ligands that are different from those of alphabeta T cells. Analysis of complementarity determining region (CDR3) length distributions of gamma and delta chains indicates that they are more similar to those of immunoglobulins than to TCR alpha and beta. This further supports the idea that gammadelta and alphabeta T cells recognize antigens differently and suggests that gammadelta T cells may be more like immunoglobulins in their recognition properties. gammadelta T cells share many cell surface proteins with alphabeta T cells and are able to secrete lymphokines and express cytolytic activities in response to antigenic stimulation. These, together with the results cited above, indicate that gammadelta T cells can mediate cellular immune functions without a requirement for antigen processing. Thus, pathogens, damaged tissues, or even B and T cells can be recognized directly, and cellular immune responses can be initiated without a requirement for antigen degradation or specialized antigen-presenting cells. This would give gammadelta T cells greater flexibility than the more classical type of alphabeta T cell-mediated cellular immunity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.14.1.511
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  • 15
    Electronic Resource
    Electronic Resource
    THE NF-kappaB AND IkappaB PROTEINS: New Discoveries and Insights (1996)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 14 (1996), S. 649-681 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The transcription factor NF-kappaB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-kappaB is through interactions with an inhibitor protein called IkappaB. Recent evidence confirms the existence of multiple forms of IkappaB that appear to regulate NF-kappaB by distinct mechanisms. NF-kappaB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-kappaB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IkappaB. Exciting new research has elaborated several important and unexpected findings that explain mechanisms involved in the activation of NF-kappaB. In the nucleus, NF-kappaB dimers bind to target DNA elements and activate transcription of genes encoding proteins involved with immune or inflammation responses and with cell growth control. Recent data provide evidence that NF-kappaB is constitutively active in several cell types, potentially playing unexpected roles in regulation of gene expression. In addition to advances in describing the mechanisms of NF-kappaB activation, excitement in NF-kappaB research has been generated by the first report of a crystal structure for one form of NF-kappaB, the first gene knockout studies for different forms of NF-kappaB and of IkappaB, and the implications for therapies of diseases thought to involve the inappropriate activation of NF-kappaB.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.14.1.649
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  • 16
    Electronic Resource
    Electronic Resource
    NATURALLY OCCURRING PRIMARY DEFICIENCIES OF THE IMMUNE SYSTEM (1997)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 15 (1997), S. 93-124 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Naturally occurring genetic disorders of the immune system provide many models for the study of its development and function. In a way, their analysis complements the information provided by the generation of genetic defects in mice created using homologous recombination techniques. In this review, the recent findings made in three areas are focused upon deficiencies in T cell differentiation and in T lymphocyte activation, and on the control process of peripheral immune response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.15.1.93
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  • 17
    Electronic Resource
    Electronic Resource
    Fc RECEPTOR BIOLOGY (1997)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 15 (1997), S. 203-234 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract This review deals with membrane Fc receptors (FcR) of the immunoglobulin superfamily. It is focused on the mechanisms by which FcR trigger and regulate biological responses of cells on which they are expressed. FcR deliver signals when they are aggregated at the cell surface. The aggregation of FcR having immunoreceptor tyrosine-based activation motifs (ITAMs) activates sequentially src family tyrosine kinases and syk family tyrosine kinases that connect transduced signals to common activation pathways shared with other receptors. FcR with ITAMs elicit cell activation, endocytosis, and phagocytosis. The nature of responses depends primarily on the cell type. The aggregation of FcR without ITAM does not trigger cell activation. Most of these FcR internalize their ligands, which can be endocytosed, phagocytosed, or transcytosed. The fate of internalized receptor-ligand complexes depends on defined sequences in the intracytoplasmic domain of the receptors. The coaggregation of different FcR results in positive or negative cooperation. Some FcR without ITAM use FcR with ITAM as signal transduction subunits. The coaggregation of antigen receptors or of FcR having ITAMs with FcR having immunoreceptor tyrosine-based inhibition motifs (ITIMs) negatively regulates cell activation. FcR therefore appear as the subunits of multichain receptors whose constitution is not predetermined and which deliver adaptative messages as a function of the environment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.15.1.203
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  • 18
    Electronic Resource
    Electronic Resource
    INDUCTION OF TH1 AND TH2 CD4+ T CELL RESPONSES:The Alternative Approaches (1997)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 15 (1997), S. 297-322 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract T helper lymphocytes can be divided into two distinct subsets of effector cells based on their functional capabilities and the profile of cytokines they produce. The Th1 subset of CD4+ T cells secretes cytokines usually associated with inflammation, such as IFN-gamma and TNF and induces cell-mediated immune responses. The Th2 subset produces cytokines such as IL-4 and IL-5 that help B cells to proliferate and differentiate and is associated with humoral-type immune responses. The selective differentiation of either subset is established during priming and can be significantly influenced by a variety of factors. One of these factors, the cytokine environment, has been put forward as the major variable influencing Th development and is already well reviewed by others. Instead, in the current review, we focus on some of the alternative approaches for skewing Th1/Th2 responses. Specifically, we discuss the effects on Th priming of (a) using altered peptide ligands as antigens, (b) varying the dose of antigen, and (c) altering costimulatory signals. The potential importance of each of these variables to influence immune responses to pathogens in vivo is discussed throughout.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.15.1.297
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    HUMAN CYTOTOXIC T LYMPHOCYTE RESPONSES TO EPSTEIN-BARR VIRUS INFECTION (1997)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 15 (1997), S. 405-431 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Epstein-Barr virus (EBV) provides one of the most informative systems with which to study cytotoxic T lymphocyte (CTL) responses in humans. The virus establishes a highly immunogenic growth-transforming infection of B lymphocytes, associated with the coordinate expression of six virus-coded nuclear antigens (EBNAs 1, 2, 3A, 3B, 3C, -LP) and two latent membrane proteins (LMPs 1 and 2). This elicits both primary and memory CT8+ CTL responses that are markedly skewed toward HLA allele-specific epitopes drawn from the EBNA3A, 3B, 3C subset of latent proteins, with reactivities to other antigens being generally much less frequent. This heirarchy of immunodominance among the different latent proteins may at least partly reflect their differential accessibility to the HLA class I-processing pathway. Furthermore, CTLs to some of the immunodominant epitopes involve highly conserved T cell receptor (TCR) usage, a level of focusing which evidence suggests could have immunopathological consequences from cross-reactive recognition of other target structures. EBV is associated with a range of human tumors, and there is increasing interest in the possibility of targeting such malignancies using virus-specific CTLs. The dramatic reversal of EBV-driven lymphoproliferations in bone marrow transplant patients following CTL infusion demonstrates the potential of this approach, and here we discuss prospects for its extension to other EBV-positive tumors in which the immunodominant EBNA3A, 3B, 3C proteins are not expressed.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.15.1.405
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    MOUSE CD1-SPECIFIC NK1 T CELLS:Development, Specificity, and Function (1997)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 15 (1997), S. 535-562 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract NK1 T cells are a specialized population of alpha/beta T cells that coexpress receptors of the NK lineage and have the unique potential to very rapidly secrete large amounts of cytokines, providing early help for effector cells and regulating the Th1 or Th2 differentiation of some immune responses. NK1 T cells express a restricted TCR repertoire made of an invariant TCR alpha chain, Valpha14-Jalpha281, associated with polyclonal Vbeta8, Vbeta7, and Vbeta2 TCR beta chains. NK1 T cells recognize the products of the conserved family of MHC class I-like CD1 genes, apparently in the absence of foreign antigens. Thus, this novel regulatory pathway, which straddles the innate and the adaptive immune systems, is unique in that its activation may not require associative recognition of antigen. Here, we review the specificity and function of mouse NK1 T cells, and we discuss the relationship of this lineage to mainstream T cells and NK cells.
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    gp130 AND THE INTERLEUKIN-6 FAMILY OF CYTOKINES (1997)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 15 (1997), S. 797-819 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Receptors for most interleukins and cytokines that regulate immune and hematopoietic systems belong to the class I cytokine receptor family. These molecules form multichain receptor complexes in order to exhibit high-affinity binding to, and mediate biological functions of, their respective cytokines. In most cases, these functional receptor complexes share common signal transducing receptor components that are also in the class I cytokine receptor family, i.e. gp130, common beta, and common gamma molecules. Interleukin-6 and related cytokines, interleukin-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1 are all pleiotropic and exhibit overlapping biological functions. Functional receptor complexes for this interleukin-6 family of cytokines share gp130 as a component critical for signal transduction. Unlike cytokines sharing common beta and common gamma chains that mainly function in hematopoietic and lymphoid cell systems, the interleukin-6 family of cytokines function extensively outside these systems as well, e.g. from the cardiovascular to the nervous system, owing to ubiquitously expressed gp130. Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. Although gp130 and its dimer partners possess no intrinsic tyrosine kinase domain, the dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. This paper reviews recent progress in the study of the interleukin-6 family of cytokines and gp130.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.15.1.797
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    EUREKA! AND OTHER PLEASURES* (1998)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 16 (1998), S. 1-25 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: At first one is very pleased at being invited to write a Prefatory Chapter, but as the delivery deadline draws closer one begins to think, "Oh my God! What on earth can I say that all but family members and few close friends will not find a great bore?" One solution is to write a scientific essay, but I concluded that that was a cop-out. I decided that perhaps the best tack to follow was to try to convey to the reader the personal characteristics I bring to my science and to other aspects of my professional career. The writing of this chapter has certainly convinced me that my particular background influenced what problems I chose to work on and how I approached their solution, but I hope that my results have a more ecumenical significance. There's been much written recently about how one's cultural background affects one's science, but I think that thesis can also be exaggerated. Science is a method of inquiry that by using certain guidelines permits rational individuals to observe Nature in a way that their findings will agree and have permanence. We shouldn't be diffident about defending that claim of objectivity.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.16.1.1
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    CD40 AND CD154 IN CELL-MEDIATED IMMUNITY (1998)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 16 (1998), S. 111-135 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract CD40-CD154-mediated contact-dependent signals between B and T cells are required for the generation of thymus dependent (TD) humoral immune responses. CD40-CD154 interactions are however also important in many other cell systems. CD40 is expressed by a large variety of cell types other than B cells, and these include dendritic cells, follicular dendritic cells, monocytes, macrophages, mast cells, fibroblasts, and endothelial cells. CD40- and CD154-knockout mice and antibodies to CD40 and CD154 have helped to elucidate the role of the CD40-CD154 system in immune responses. Recently published studies indicate that CD40-CD154 interactions can influence T cell priming and T cell-mediated effector functions; they can also upregulate costimulatory molecules and activate macrophages, NK cells, and endothelia as well as participate in organ-specific autoimmune disease, graft rejection, and even atherosclerosis. This review focuses on the role of the CD40-CD154 system in the regulation of many newly discovered functions important in inflammation and cell-mediated immunity.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.16.1.111
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    T CELL MEMORY (1998)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 16 (1998), S. 201-223 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Immunological memory can be defined as the faster and stronger response of an animal that follows reexposure to the same antigen. By this definition, it is an operational property of the whole animal or the immune system. Memory cells express a different pattern of cell surface markers, and they respond in several ways that are functionally different from those of naive cells. Murine memory cells are CD44 high and low in the expression of activation markers such as CD25 (IL-2R), whereas human memory cells are CD45RA-, CD45RO+. In contrast to naive cells, memory cells secrete a full range of T cell cytokines and can be polarized to secrete particular restricted patterns of secretion for both CD4 and CD8 T cells. The requirements for the activation of memory cells for proliferation and cytokine production are not quite as strict as those of naive cells, but costimulation in the broad sense is required for optimum responses and for responses to suboptimum antigen concentrations. It would appear that memory cells can persist in the absence of antigenic stimulation and persist as nondividing cells. Reencounter with the same antigen can expand the population to a new, stable, higher level and generate a separate population of CD44 high effectors that may be required for protection, while competition from other antigens can drive it down to a lower stable level. It is unclear how or where memory cells arise, but once generated they have different pathways of recirculation and homing.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.16.1.201
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    NK CELL RECEPTORS (1998)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 16 (1998), S. 359-393 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract NK cells are regulated by opposing signals from receptors that activate and inhibit effector function. While positive stimulation may be initiated by an array of co-stimulatory receptors, specificity is provided by inhibitory signals transduced by receptors for MHC class I. Three distinct receptor families, Ly49, CD94/NKG2, and KIR, are involved in NK cell recognition of polymorphic MHC class I molecules. A common pathway of inhibitory signaling is provided by ITIM sequences in the cytoplasmic domains of these otherwise structurally diverse receptors. Upon ligand binding and activation, the inhibitory NK cell receptors become tyrosine phosphorylated and recruit tyrosine phosphatases, SHP-1 and possibly SHP-2, resulting in inhibition of NK cell-mediated cytotoxicity and cytokine expression. Recent studies suggest these inhibitory NK cell receptors are members of a larger superfamily containing ITIM sequences, the inhibitory receptor superfamily (IRS).
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    URL: http://dx.doi.org/10.1146/annurev.immunol.16.1.359
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    XENOGENEIC TRANSPLANTATION (1998)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 16 (1998), S. 433-470 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract This review summarizes the clinical history and rationale for xenotransplantation; recent progress in understanding the physiologic, immunologic, and infectious obstacles to the procedure's success; and some of the strategies being pursued to overcome these obstacles. The problems of xenotransplantation are complex, and a combination of approaches is required. The earliest and most striking immunologic obstacle, that of hyperacute rejection, appears to be the closest to being solved. This phenomenon depends on the binding of natural antibody to the vascular endothelium, fixation of complement by that antibody, and finally, activation of the endothelium and initiation of coagulation. Therefore, these three pathways have been targeted as sites for intervention in the process. The mechanisms responsible for the next immunologic barrier, that of delayed xenograft/acute vascular rejection, remain to be fully elucidated. They probably also involve multiple pathways, including antibody and/or immune cell binding and endothelial cell activation. The final immunologic barrier, that of the cellular immune response, involves mechanisms that are similar to those involved in allograft rejection. However, the strength of the cellular immune response to xenografts is so great that it is unlikely to be controlled by the types of nonspecific immunosuppression used routinely to prevent allograft rejection. For this reason, it may be essential to induce specific immunologic unresponsiveness to at least some of the most antigenic xenogeneic molecules.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.16.1.433
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    THE ROLE OF COMPLEMENT AND COMPLEMENT RECEPTORS IN INDUCTION AND REGULATION OF IMMUNITY (1998)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 16 (1998), S. 545-568 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Covalent attachment of activated complement C3 (C3d) to antigen links innate and adaptive immunity by targeting antigen to follicular dendritic cells (FDC) and B cells via specific receptors CD21 and CD35. Recent characterization of knockout mice deficient in complement components C3, C4, or the receptors CD21 and CD35 as well as biochemical studies of the CD21/CD19/Tapa-1 coreceptor on B cells have helped to elucidate the mechanism of complement regulation of both B-1 and B-2 lymphocytes. Interestingly, natural antibody of the adaptive immune system provides a major recognition role in activation of the complement system, which in turn enhances activation of antigen-specific B cells. Enhancement of the primary and secondary immune response to T-dependent antigens is mediated by coligation of the coreceptor and the B cell antigen receptor, which dramatically increases follicular retention and B cell survival within the germinal center. Most recent evidence suggests that complement also regulates elimination of self-reactive B cells, as breeding of mice that are deficient in C4 or CD21/CD35 with the lupus-prone strain of lpr mice demonstrates an exacerbation of disease due to an increase in autoantibodies.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.16.1.545
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    DISCOVERING THE ORIGINS OF IMMUNOLOGICAL COMPETENCE (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 17 (1999), S. 1-17 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Work done in the late 1950s and in the 1960s revealed the role of the thymus in virus-induced leukemia in mice. Thymectomizing mice at birth to test whether the virus first multiplied in thymus tissue and then spread elsewhere ultimately led to the conclusion that the thymus was essential to the normal development of the immune system. Subsequent testing to try to understand how the thymus contributes to the pool of immunocompetent lymphocytes opened a new chapter in immunology and required a reappraisal of many immunological phenomena and an understanding of the molecular interactions that take place during cell-to-cell interactions.
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    THE MULTIFACETED REGULATION OF INTERLEUKIN-15 EXPRESSION AND THE ROLE OF THIS CYTOKINE IN NK CELL DIFFERENTIATION AND HOST RESPONSE TO INTRACELLULAR PATHOGENS1 (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 17 (1999), S. 19-49 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Interleukin-15 (IL-15) is a 14- to 15-kDa member of the 4 alpha-helix bundle family of cytokines. IL-15 expression is controlled at the levels of transcription, translation, and intracellular trafficking. In particular, IL-15 protein is posttranscriptionally regulated by multiple controlling elements that impede translation, including 12 upstream AUGs of the 5' UTR, 2 unusual signal peptides, and the C-terminus of the mature protein. IL-15 uses two distinct receptor and signaling pathways. In T and NK cells the IL-15 receptor includes IL-2/15Rbeta and gammac, subunits, which are shared with IL-2, and an IL-15-specific receptor subunit, IL-15Ralpha. Mast cells respond to IL-15 with a receptor system that does not share elements with the IL-2 receptor but uses a novel 60- to 65-kDa IL-15RX subunit. In mast cells IL-15 signaling involves Jak2/STAT5 activation rather than the Jak1/Jak3 and STAT5/STAT3 system used in activated T cells. In addition to its other functional activities in immune and nonimmune cells, IL-15 plays a pivotal role in the development, survival, and function of NK cells. Abnormalities of IL-15 expression have been described in patients with rheumatoid arthritis or inflammatory bowel disease and in diseases associated with the retroviruses HIV and HTLV-I. New approaches directed toward IL-15, its receptor, or its signaling pathway may be of value in the therapy of these disorders.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.17.1.19
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    NATURAL KILLER CELLS IN ANTIVIRAL DEFENSE: Function and Regulation by Innate Cytokines (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 17 (1999), S. 189-220 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Natural killer (NK) cells are populations of lymphocytes that can be activated to mediate significant levels of cytotoxic activity and produce high levels of certain cytokines and chemokines. NK cells respond to and are important in defense against a number of different infectious agents. The first indications for this function came from the observations that virus-induced interferons alpha/beta (IFN-alpha and -beta) are potent inducers of NK cell-mediated cytotoxicity, and that NK cells are important contributors to innate defense against viral infections. In addition to IFN-alpha/beta, a wide range of other innate cytokines can mediate biological functions regulating the NK cell responses of cytotoxicity, proliferation, and gamma interferon (IFN-gamma) production. Certain, but not all, viral infections induce interleukin 12 (IL-12) to elicit NK cell IFN-gamma production and antiviral mechanisms. However, high levels of IFN-alpha/beta appear to be unique and/or uniquely dominant in the context of viral infections and act to regulate other innate responses, including induction of NK cell proliferation in vivo and overall negative regulation of IL-12 production. A detailed picture is developing of particular innate cytokines activating NK cell responses and their consorted effects in providing unique endogenous milieus promoting downstream adaptive responses, most beneficial in defense against viral infections.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.17.1.189
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    TUMOR NECROSIS FACTOR RECEPTOR AND Fas SIGNALING MECHANISMS (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 17 (1999), S. 331-367 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Four members of the tumor necrosis factor (TNF) ligand family, TNF-alpha, LT-alpha, LT-beta, and LIGHT, interact with four receptors of the TNF/nerve growth factor family, the p55 TNF receptor (CD120a), the p75 TNF receptor (CD120b), the lymphotoxin beta receptor (LTbetaR), and herpes virus entry mediator (HVEM) to control a wide range of innate and adaptive immune response functions. Of these, the most thoroughly studied are cell death induction and regulation of the inflammatory process. Fas/Apo1 (CD95), a receptor of the TNF receptor family activated by a distinct ligand, induces death in cells through mechanisms shared with CD120a. The last four years have seen a proliferation in knowledge of the proteins participating in the signaling by the TNF system and CD95. The downstream signaling molecules identified so far-caspases, phospholipases, the three known mitogen activated protein (MAP) kinase pathways, and the NF-kappaB activation cascade-mediate the effects of other inducers as well. However, the molecules that initiate these signaling events, including the death domain- and TNF receptor associated factor (TRAF) domain-containing adapter proteins and the signaling enzymes associated with them, are largely unique to the TNF/nerve growth factor receptor family.
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    STRUCTURAL BASIS OF T CELL RECOGNITION (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 17 (1999), S. 369-397 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Exciting breakthroughs in the last two years have begun to elucidate the structural basis of cellular immune recognition. Crystal structures have been determined for full-length and truncated forms of alphabeta T cell receptor (TCR) heterodimers, both alone and in complex with their peptide-MHC (pMHC) ligands or with anti-TCR antibodies. In addition, a truncated CD8 coreceptor has been visualized with a pMHC. Aided in large part by the substantial body of knowledge accumulated over the last 25 years on antibody structure, a number of general conclusions about TCR structure and its recognition of antigen can already be derived from the relatively few TCR structures that have been determined. Small, but important, variations between TCR and antibody structures bear on their functional differences as well as on their specific antigen recognition requirements. As observed in antibodies, canonical CDR loop structures are already emerging for some of the TCR CDR loops. Highly similar docking orientations of the TCR Valpha domains in the TCR/pMHC complex appear to play a primary role in dictating orientation, but the Vbeta positions diverge widely. Similar TCR contact positions, but whose exact amino acid content can vary, coupled with relatively poor interface shape complementarity, may explain the flexibility and short half-lives of many TCR interactions with pMHC. Here we summarize the current state of this field, and suggest that the knowledge gap between the three-dimensional structure and the signaling function of the TCR can be bridged through a synthesis of molecular biological and biophysical techniques.
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    GENETIC ANALYSIS OF B CELL ANTIGEN RECEPTOR SIGNALING (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 17 (1999), S. 555-592 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract In B lymphocytes, a signaling complex that contributes to cell fate decisions is the B cell antigen receptor (BCR). Data from knockout experiments in cell lines and mice have revealed distinct functions for the intracellular protein tyrosine kinases (Lyn, Syk, Btk) in BCR signaling and B cell development. Combinations of intracellular signaling pathways downstream of these PTKs determine the quality and quantity of BCR signaling. For example, concerted actions of the PLC-gamma2 and PI3-K pathways are required for proper calcium responses. Similarly, the regulation of ERK and JNK responses involves both PLC-gamma2 and GTPases pathways. Since the immune response in vivo is regulated by alteration of these signaling outcomes, achieving a precise understanding of intracellular molecular events leading to B lymphocyte proliferation, deletion, anergy, receptor editing, and survival still remains a challenge for the future.
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    MECHANISMS OF PHAGOCYTOSIS IN MACROPHAGES (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 17 (1999), S. 593-623 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract Phagocytosis of pathogens by macrophages initiates the innate immune response, which in turn orchestrates the adaptive response. In order to discriminate between infectious agents and self, macrophages have evolved a restricted number of phagocytic receptors, like the mannose receptor, that recognize conserved motifs on pathogens. Pathogens are also phagocytosed by complement receptors after relatively nonspecific opsonization with complement and by Fc receptors after specific opsonization with antibodies. All these receptors induce rearrangements in the actin cytoskeleton that lead to the internalization of the particle. However, important differences in the molecular mechanisms underlying phagocytosis by different receptors are now being appreciated. These include differences in the cytoskeletal elements that mediate ingestion, differences in vacuole maturation, and differences in inflammatory responses. Infectious agents, such as M. tuberculosis, Legionella pneumophila, and Salmonella typhimurium, enter macrophages via heterogeneous pathways and modify vacuolar maturation in a manner that favors their survival. Macrophages also play an important role in the recognition and clearance of apoptotic cells; a notable feature of this process is the absence of an inflammatory response.
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    THE CENTRAL EFFECTORS OF CELL DEATH IN THE IMMUNE SYSTEM (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 17 (1999), S. 781-828 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The immune system relies on cell death to maintain lymphoid homeostasis and avoid disease. Recent evidence has indicated that the caspase family of cysteine proteases is a central effector in apoptotic cell death and is absolutely responsible for many of the morphological features of apoptosis. Cell death, however, can occur through caspase-independent and caspase-dependent pathways. In the case of cells that are irreversibly neglected or damaged, death occurs even in the absence of caspase activity. In contrast, healthy cells require caspase activation to undergo cell death induced by surface receptors. This review summarizes the current understanding of these two pathways of cell death in the immune system.
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    THE CRYSTAL STRUCTURE OF THE HUMAN HIGH-AFFINITY IgE RECEPTOR (FcepsilonRIalpha) (1999)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 17 (1999), S. 973-976 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
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    URL: http://dx.doi.org/10.1146/annurev.immunol.17.1.973
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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 
    Details
    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 
    Details
    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 
    Details
    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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    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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    THE B7 FAMILY REVISITED (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 23 (2005), S. 515-548 
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    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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    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 
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    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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    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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    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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    CYTOCHROME P450: Nature's Most Versatile Biological Catalyst (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 1-25 
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    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.
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    GLUTATHIONE TRANSFERASES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 51-88 
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    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.
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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 
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    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.
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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 
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    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.
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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 
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    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.
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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 
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    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.
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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 
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    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.
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    HUMAN FLAVIN-CONTAINING MONOOXYGENASES (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 65-100 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: This review summarizes recent information concerning the pharmacological and toxicological significance of the human flavin-containing monooxygenase (FMO, EC 1.14.13.8). The human FMO oxygenates nucleophilic heteroatom-containing chemicals and drugs and generally converts them into harmless, polar, readily excreted metabolites. Sometimes, however, FMO bioactivates chemicals into reactive materials that can cause toxicity. Most of the interindividual differences of FMO are due to genetic variability and allelic variation, and splicing variants may contribute to interindividual and interethnic variability observed for FMO-mediated metabolism. In contrast to cytochrome P450 (CYP), FMO is not easily induced nor readily inhibited, and potential adverse drug-drug interactions are minimized for drugs prominently metabolized by FMO. These properties may provide advantages in drug design and discovery, and by incorporating FMO detoxication pathways into drug candidates, more drug-like materials may be forthcoming. Although exhaustive examples are not available, physiological factors can influence FMO function, and this may have implications for the clinical significance of FMO and a role in human disease.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141043
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    Hepatitis B Virus Immunopathogenesis (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 13 (1995), S. 29-60 
    Details
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.iy.13.040195.000333
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    The Regulation of Immunity to Leishmania Major (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 13 (1995), S. 151-177 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.iy.13.040195.001055
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    Transcriptional Regulation of Complement Genes (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 13 (1995), S. 277-305 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.iy.13.040195.001425
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    Paracrine Cytokine Adjuvants in Cancer Immunotherapy (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 13 (1995), S. 399-415 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.iy.13.040195.002151
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    Superantigens of Mouse Mammary Tumor Virus (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 13 (1995), S. 459-486 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.iy.13.040195.002331
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    The Three-Dimensional Structure of Peptide-MHC Complexes (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 13 (1995), S. 587-622 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.iy.13.040195.003103
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    IMMUNOTOXINS: An Update (1996)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 14 (1996), S. 49-71 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract The use of immunotoxins (ITs) in the therapy of cancer, graft-vs-host disease (GvHD), autoimmune diseases, and AIDS has been ongoing for the past two decades. ITs contain a targeting moiety for delivery and a toxic moiety for cytotoxicity. Theoretically, one molecule of a toxin, routed to the appropriate cellular compartment, will be lethal to a cell. Newly developed MoAbs, toxins, and molecular biological technologies have enabled researchers to construct ITs that can effectively kill many different cell types. In fact, phase I/II clinical trials have given promising results. Although nonspecific toxicity and immunogenicity still limit the use of IT therapy, these agents hold enormous promise in an optimal setting to treat minimal disease.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.14.1.49
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    GENETIC ANALYSIS OF TYROSINE KINASE FUNCTION IN B CELL DEVELOPMENT (1996)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 14 (1996), S. 131-154 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract B lymphopoiesis is regulated by multiple signals from stromal cell contact, soluble cytokines, antigen, and T helper cells. In vitro and biochemical experiments have implicated tyrosine kinases as key components of many of these signaling pathways. Genetic analysis of the role of these tyrosine kinases has been facilitated by recent advances in transgenic and gene targeting technology as well as by the identification of the genetic basis of several human and murine immune deficiencies. This review discusses the effect of gain and loss of function mutations of selected tyrosine kinases and their regulators and substrates on B cell development and function.
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    URL: http://dx.doi.org/10.1146/annurev.immunol.14.1.131
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    CD28/B7 SYSTEM OF T CELL COSTIMULATION (1996)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 14 (1996), S. 233-258 
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    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Abstract T cells play a central role in the initiation and regulation of the immune response to antigen. Both the engagement of the TCR with MHC/Ag and a second signal are needed for the complete activation of the T cell. The CD28/B7 receptor/ligand system is one of the dominant costimulatory pathways. Interruption of this signaling pathway with CD28 antagonists not only results in the suppression of the immune response, but in some cases induces antigen-specific tolerance. However, the CD28/B7 system is increasingly complex due to the identification of multiple receptors and ligands with positive and negative signaling activities. This review summarizes the state of CD28/B7 immunobiology both in vitro and in vivo; summarizes the many experiments that have led to our current understanding of the participants in this complex receptor/ligand system; and illustrates the current models for CD28/B7-mediated T cell and B cell regulation. It is our hope and expectation that this review will provoke additional research that will unravel this important, yet complex, signaling pathway.
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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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    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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    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115616
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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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    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 
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    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.
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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 
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    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.
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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 
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    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.
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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 
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    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
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    PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS: How Their Effects on Macrophages Can Lead to the Development of a New Drug Therapy Against Atherosclerosis (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 1-39 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Peroxisome proliferator-activated receptors (PPARs) alpha (ʼ̛), beta/delta (?‚/??), and gamma (??) are members of the nuclear receptor superfamily, which also includes the estrogen, androgen, and glucocorticoid receptors. Recent evidence suggests that PPARs regulate genes involved in lipid metabolism, glucose homeostasis, and inflammation in various tissues; however, the mechanisms involved are not completely understood. Anti-diabetic drugs, called glitazones, can selectively activate PPAR??, and hypolipidemic drugs, called fibrates, can weakly activate PPARʼ̛. Both classes of drugs can decrease insulin resistance and dyslipidemias, which also makes them attractive for treating the metabolic syndrome. The metabolic syndrome exhibits a constellation of risk factors for atherosclerosis that include obesity, insulin resistance, dyslipidemias, and hypertension. Interestingly, all three PPARs are present in macrophages and can therefore have a profound effect on several disease processes, including atherosclerosis. Macrophages are key players in atherosclerotic lesion development. Currently, the first line of defense in reducing the risk of atherosclerosis is aimed at lowering low-density lipoproteins (LDL) and raising high-density lipoproteins (HDL), but a large percentage of patients on statins still succumb to coronary artery disease. However, with the development of drugs selectively activating PPARs, a new arsenal of drugs specifically targeting to the macrophage/foam cell may potentially have a profound impact on how we treat cardiovascular disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141247
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    THE REGULATION AND PHARMACOLOGY OF ENDOTHELIAL NITRIC OXIDE SYNTHASE (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 235-276 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Nitric oxide (NO) is a small, diffusible, lipophilic free radical gas that mediates significant and diverse signaling functions in nearly every organ system in the body. The endothelial isoform of nitric oxide synthase (eNOS) is a key source of NO found in the cardiovascular system. This review summarizes the pharmacology of NO and the cellular regulation of endothelial NOS (eNOS). The molecular intricacies of the chemistry of NO and the enzymology of NOSs are discussed, followed by a review of the biological activities of NO. This information is then used to develop a more global picture of the pharmacological control of NO synthesis by NOSs in both physiologic conditions and pathophysiologic states.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.44.101802.121844
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    CYTOCHROME P450 AND XENOBIOTIC RECEPTOR HUMANIZED MICE * (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 41-64 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Most xenobiotics that enter the body are subjected to metabolism that functions primarily to facilitate their elimination. Metabolism of certain xenobiotics can also result in the production of electrophilic derivatives that can cause cell toxicity and transformation. Many xenobiotics can also activate receptors that in turn induce the expression of genes encoding xenobiotic-metabolizing enzymes and xenobiotic transporters. However, there are marked species differences in the way mammals respond to xenobiotics, which are due in large part to molecular differences in receptors and xenobiotic-metabolizing enzymes. This presents a problem in extrapolating data obtained with rodent model systems to humans. There are also polymorphisms in xenobiotic-metabolizing enzymes that can impact drug therapy and cancer susceptibility. In an effort to generate more reliable in vivo systems to study and predict human response to xenobiotics, humanized mice are under development.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100007
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115653
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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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115835
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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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    URL: http://dx.doi.org/10.1146/annurev.immunol.23.021704.115633
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    My life in and Beyond the Laboratory (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 1-31 
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    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.000245
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    Design of Molecular Function: Channels of Communication (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 31-57 
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    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.000335
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    NMR Spectroscopic Studies of Paramagnetic Proteins: Iron-Sulfur Proteins (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 209-237 
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    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.001233
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    Applications of Parallel Computing to Biological Problems (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 239-267 
    Details
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.001323
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    The Cystine-Knot Growth-Factor Superfamily (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 269-292 
    Details
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.001413
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    Thermodynamics of Partly Folded Intermediates in Proteins (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 141-165 
    Details
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.001041
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    Membrane-Structure Studies Using X-Ray Standing Waves (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 351-377 
    Details
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.002031
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    Exceptionally Stable Nucleic Acid Hairpins (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 379-404 
    Details
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.002115
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    Fluorescent Protein Biosensors: Measurement of Molecular Dynamics in Living Cells (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 405-434 
    Details
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.002201
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    Site-Directed Mutagenesis with an Expanded Genetic Code (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 435-462 
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    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.002251
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    Complexes of the Minor Groove of DNA (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 463-493 
    Details
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.002335
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    Compact Intermediate States in Protein Folding (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 495-522 
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    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.002431
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    Structure-Function of the Channel-Forming Colicins (1995)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 24 (1995), S. 611-641 
    Details
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bb.24.060195.003143
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