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  • Articles  (48,620)
  • National Academy of Sciences  (19,923)
  • BioMed Central  (14,035)
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  • 1945-1949  (2,773)
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  • 1
    Publication Date: 2021-06-08
    Description: The Aegean water masses and circulation structure are studied via two large-scale surveys performed during the late winters of 1988 and 1990 by the R/V Yakov Gakkel of the former Soviet Union. The analysis of these data sheds light on the mechanisms of water mass formation in the Aegean Sea that triggered the outflow of Cretan Deep Water (CDW) from the Cretan Sea into the abyssal basins of the eastern Mediterranean Sea (the so-called Eastern Mediterranean Transient). It is found that the central Aegean Basin is the site of the formation of Aegean Intermediate Water, which slides southward and, depending on their density, renews either the intermediate or the deep water of the Cretan Sea. During the winter of 1988, the Cretan Sea waters were renewed mainly at intermediate levels, while during the winter of 1990 it was mainly the volume of CDW that increased. This Aegean water mass redistribution and formation process in 1990 differed from that in 1988 in two major aspects: (i) during the winter of 1990 the position of the front between the Black Sea Water and the Levantine Surface Water was displaced farther north than during the winter of 1988 and (ii) heavier waters were formed in 1990 as a result of enhanced lateral advection of salty Levantine Surface Water that enriched the intermediate waters with salt. In 1990 the 29.2 isopycnal rose to the surface of the central basin and a large volume of CDW filled the Cretan Basin. It is found that, already in 1988, the 29.2 isopycnal surface, which we assume is the lowest density of the CDW, was shallower than the Kassos Strait sill and thus CDW egressed into the Eastern Mediterranean.
    Description: Published
    Description: 1841-1859
    Description: JCR Journal
    Description: reserved
    Keywords: Aegean Sea ; Water Masses ; 03. Hydrosphere::03.03. Physical::03.03.03. Interannual-to-decadal ocean variability
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 2
    Publication Date: 2021-06-01
    Description: Five non-eddy-resolving oceanic general circulation models driven by atmospheric fluxes derived from the NCEP reanalysis are used to investigate the link between the Gulf Stream (GS) variability, the atmospheric circulation, and the Atlantic meridional overturning circulation (AMOC). Despite the limited model resolution, the temperature at the 200-m depth along the mean GS axis behaves similarly in most models to that observed, and it is also well correlated with the North Atlantic Oscillation (NAO), indicating that a northward (southward) GS shift lags a positive (negative) NAO phase by 0–2 yr. The northward shift is accompanied by an increase in the GS transport, and conversely the southward shift with a decrease in the GS transport. Two dominant time scales appear in the response of the GS transport to the NAO forcing: a fast time scale (less than 1 month) for the barotropic component, and a slower one (about 2 yr) for the baroclinic component. In addition, the two components are weakly coupled. The GS response seems broadly consistent with a linear adjustment to the changes in the wind stress curl, and evidence for baroclinic Rossby wave propagation is found in the southern part of the subtropical gyre. However, the GS shifts are also affected by basin-scale changes in the oceanic conditions, and they are well correlated in most models with the changes in the AMOC. A larger AMOC is found when the GS is stronger and displaced northward, and a higher correlation is found when the observed changes of the GS position are used in the comparison. The relation between the GS and the AMOC could be explained by the inherent coupling between the thermohaline and the wind-driven circulation, or by the NAO variability driving them on similar time scales in the models.
    Description: This research was supported by the PREDICATE project of the European Community, and for M. Bentsen by the Research Council of Norway through RegClim, NOClim, and the Programme of Supercomputing.
    Description: Published
    Description: 2119–2135
    Description: 3.7. Dinamica del clima e dell'oceano
    Description: JCR Journal
    Description: reserved
    Keywords: ocean modelling ; gulf stream variability ; 03. Hydrosphere::03.01. General::03.01.03. Global climate models
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 3
    Publication Date: 2020-11-19
    Description: A land surface model (LSM) has been included in the ECMWF Hamburg version 4 (ECHAM4) atmospheric general circulation model (AGCM). The LSM is an early version of the Organizing Carbon and Hydrology in Dynamic Ecosystems (ORCHIDEE) and it replaces the simple land surface scheme previously included in ECHAM4. The purpose of this paper is to document how a more exhaustive consideration of the land surface–vegetation processes affects the simulated boreal summer surface climate. To investigate the impacts on the simulated climate, different sets of Atmospheric Model Intercomparison Project (AMIP)-type simulations have been performed with ECHAM4 alone and with the AGCM coupled with ORCHIDEE. Furthermore, to assess the effects of the increase in horizontal resolution the coupling of ECHAM4 with the LSM has been implemented at different horizontal resolutions. The analysis reveals that the LSM has large effects on the simulated boreal summer surface climate of the atmospheric model. Considerable impacts are found in the surface energy balance due to changes in the surface latent heat fluxes over tropical and midlatitude areas covered with vegetation. Rainfall and atmospheric circulation are substantially affected by these changes. In particular, increased precipitation is found over evergreen and summergreen vegetated areas. Because of the socioeconomical relevance, particular attention has been devoted to the Indian summer monsoon (ISM) region. The results of this study indicate that precipitation over the Indian subcontinent is better simulated with the coupled ECHAM4–ORCHIDEE model compared to the atmospheric model alone.
    Description: Published
    Description: 255–278
    Description: 3.7. Dinamica del clima e dell'oceano
    Description: JCR Journal
    Description: partially_open
    Keywords: Land Atmosphere interactions ; Global climate models ; 01. Atmosphere::01.01. Atmosphere::01.01.02. Climate
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 4
    Publication Date: 2017-04-04
    Description: In this paper results from the application of an ocean data assimilation (ODA) system, combining a multivariate reduced-order optimal interpolator (OI) scheme with a global ocean general circulation model (OGCM), are described. The present ODA system, designed to assimilate in situ temperature and salinity observations, has been used to produce ocean reanalyses for the 1962–2001 period. The impact of assimilating observed hydrographic data on the ocean mean state and temporal variability is evaluated. A special focus of this work is on the ODA system skill in reproducing a realistic ocean salinity state. Results from a hierarchy of different salinity reanalyses, using varying combinations of assimilated data and background error covariance structures, are described. The impact of the space and time resolution of the background error covariance parameterization on salinity is addressed.
    Description: This work has been funded by the ENACT Project (Contract EVK2-CT2001-00117) for A. Bellucci and P. Di Pietro, and partially by the ENSEMBLES Project (Contract GOCE-CT-2003-505539) for A. Bellucci.
    Description: Published
    Description: 3785-3807
    Description: 3.7. Dinamica del clima e dell'oceano
    Description: JCR Journal
    Description: reserved
    Keywords: ocean modelling ; data assimilation ; reanalysis ; upper ocean variability ; temperature ; Salinity ; 03. Hydrosphere::03.01. General::03.01.04. Ocean data assimilation and reanalysis
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 5
    Publication Date: 2017-04-04
    Description: The effect of horizontal resolution on tropical variability is investigated within the modified SINTEX model, SINTEX-F, developed jointly at INGV, IPSL and at the Frontier Research System. The horizontal resolutions T30 and T106 are investigated in terms of the coupling characteristics, frequency and variability of the tropical ocean-atmosphere interactions. It appears that the T106 resolution is generally beneficial even if it does not eliminate all the major systematic errors of the coupled model. There is an excessive shift west of the cold tongue and ENSO variability, and high resolution has also a somewhat negative impact to the variability in the East Indian Ocean. A dominant two-year peak for the NINO3 variabilty in the T30 model is moderated in the T106 as it shifts to longer time scale. At high resolution new processes come into play, as the coupling of tropical instability waves, the resolution of coastal flows at the Pacific Mexican coasts and improved coastal forcing along the coast of South America. The delayed oscillator seems the main mechanism that generates the interannual variability in both models, but the models realize it in different ways. In the T30 model it is confined close to the equator, involving relatively fast equatorial and near-equatorial modes, in the high resolution, it involves a wider latitudinal region and slower waves. It is speculated that the extent of the region that is involved in the interannual variability may be linked to the time scale of the variability itself.
    Description: This research was partially supported by the Italy–USA Cooperation Program of the Italian Ministry of Environment and by the EU projects ENSEMBLES and DYNAMITE.
    Description: Published
    Description: 730-750
    Description: 3.7. Dinamica del clima e dell'oceano
    Description: JCR Journal
    Description: reserved
    Keywords: coupled models ; tropical variability ; ENSO system ; 03. Hydrosphere::03.01. General::03.01.03. Global climate models
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 6
    Publication Date: 2017-04-04
    Description: The Indian Summer Monsoon (ISM) is one of the main components of the Asian summer monsoon. It is well known that one of the starting mechanisms of a summer monsoon is the thermal contrast between land and ocean and that sea surface temperature (SST) and moisture are crucial factors for its evolution and intensity. The Indian Ocean, therefore, may play a very important role in the generation and evolution of the ISM itself. A coupled general circulation model, implemented with a high resolution atmospheric component, appears to be able to simulate the Indian summer monsoon in a realistic way. In particular, the features of the simulated ISM variability are similar to the observations. In this study, the relationships between ISM and Tropical Indian Ocean (TIO) SST anomalies are investigated, as well as the ability of the coupled model to capture those connections. The recent discovery of the Indian Ocean Dipole Mode (IODM) may suggest new perspectives in the relationship between ISM and TIO SST. A new statistical technique, the Coupled Manifold, is used to investigate the TIO SST variability and its relation with the Tropical Pacific Ocean (TPO). The analysis shows that the SST variability in the TIO contains a significant portion that is independent from the TPO variability. The same technique is used to estimate the amount of Indian rainfall variability that can be explained by the Tropical Indian Ocean SST. Indian Ocean SST anomalies are separated in a part remotely forced from the Tropical Pacific Ocean variability and a part independent from that. The relationships between the two SSTA components and the Indian monsoon variability are then investigated in detail.
    Description: Published
    Description: 3083-3105
    Description: 3.7. Dinamica del clima e dell'oceano
    Description: JCR Journal
    Description: reserved
    Keywords: Indian Ocean ; monsoon ; 01. Atmosphere::01.01. Atmosphere::01.01.02. Climate
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 7
    Publication Date: 2017-04-04
    Description: An assessment of the present European operational marine monitoring and forecasting systems shows how observations, atmospheric forcing fields and ocean models combine to make useful oceanographic products possible.
    Description: Published
    Description: 1081-1090
    Description: open
    Keywords: MARINE ENVIRONMENT ; 03. Hydrosphere::03.01. General::03.01.05. Operational oceanography
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 8
    Publication Date: 2017-04-04
    Description: Ensemble experiments are performed with five coupled atmosphere–ocean models to investigate the potential for initial-value climate forecasts on interannual to decadal time scales. Experiments are started from similar model-generated initial states, and common diagnostics of predictability are used. We find that variations in the ocean meridional overturning circulation (MOC) are potentially predictable on interannual to decadal time scales, a more consistent picture of the surface temperature impact of decadal variations in the MOC is now apparent, and variations of surface air temperatures in the North Atlantic Ocean are also potentially predictable on interannual to decadal time scales, albeit with potential skill levels that are less than those seen for MOC variations. This intercomparison represents a step forward in assessing the robustness of model estimates of potential skill and is a prerequisite for the development of any operational forecasting system.
    Description: Published
    Description: 1195-1203
    Description: JCR Journal
    Description: reserved
    Keywords: Decadal Climate ; North Atlantic ; 03. Hydrosphere::03.01. General::03.01.03. Global climate models ; 03. Hydrosphere::03.02. Hydrology::03.02.05. Models and Forecasts ; 03. Hydrosphere::03.03. Physical::03.03.03. Interannual-to-decadal ocean variability
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 9
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    American Meteorological Society
    In:  EPIC3Journal of Atmospheric and Oceanic Technology, American Meteorological Society, 25(2), pp. 149-166, ISSN: 0739-0572
    Publication Date: 2019-07-17
    Description: The accuracy of all types of Vaisala radiosondes and two types of Snow White chilled-mirror hygrosondes was assessed in an intensive in situ comparison with reference hygrometers. Fourteen nighttime reference comparisons were performed to determine a working reference for the radiosonde comparisons. These showed that the night version of the Snow White agreed best with the references [i.e., the NOAA frost-point hygrometer (FPH) and University of Colorado cryogenic frost-point hygrometer (CFH)], but that the daytime version had severe problems with contamination in the humid upper troposphere. Since the RS92 performance was superior to the other radiosondes and to the day version of the Snow White, it was selected to be the working reference. According to the reference comparison, the RS92 has no bias in the mid- and lower troposphere, with deviations 〈±5% in relative humidity (RH). In the upper troposphere, the RS92 has a 5% RH wet bias, which is partly due to the RS92 time lag error and the termination of the heating cycle. It was shown that the time lag effects relating to Vaisala radiosondes can be corrected. Because these were nighttime comparisons, they can be considered to be free from solar radiation effects. Neither the radiosondes nor the Snow White succeeded in reproducing reference class hygrometer profiles in the stratosphere. According to the 29 radiosonde intercomparisons, the RS92 and the modified RS90 (FN) had the best mutual agreement and no bias. The disagreement is largest (〈±10% RH) at low temperatures (T ≪ −30°C), where the FN underestimated (overestimated) in high (low) ambient RH. In comparison with the RS92, the RS90 had a semilinearly increasing wet bias with decreasing temperature, where the bias was 10% RH at −60°C. The RS80-A suffers from a large temperature-dependent dry bias in high RH conditions, being over 30% RH at −60°C and 5% RH near 0°C. The RS80-A dry bias can be almost totally removed with the correction algorithm by Leiterer et al., which was chosen as the best available. The other approach tested tends to overcorrect in high RH conditions when T 〈 −50°C. For T 〉 −30°C it is ineffective and does not correct the RS80-A dry bias in high ambient RH.
    Repository Name: EPIC Alfred Wegener Institut
    Type: Article , isiRev
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  • 10
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    American Meteorological Society
    Publication Date: 2021-05-19
    Description: In this study we show a teleconnection pattern relating Outgoing Longwave Radiation (OLR) anomalies over the western Pacific Ocean and sea surface temperature anomalies (SSTA) over the western Indian Ocean over two seasons (Sept-Oct-Nov and Dec-Jan-Feb) at zero lag from observations and atmospheric general circulation model (AGCM) integrations. This teleconnection pattern suggests that a positive SSTA in Sept-Oct-Nov (SON) and Dec-Jan-Feb (DJF) seasons over the western Indian Ocean increases the contemporaneous positive OLR anomalies over the western Pacific Ocean. This teleconnection pattern is also simulated by the Center for Ocean-Land- Atmosphere studies (COLA) AGCM forced with observed SST’s. From the experimental COLA AGCM runs (wherein the Pacific Ocean SST variability is suppressed except for the climatological annual cycle) it is diagnosed that the interannual variability of OLR over the western Pacific Ocean persists because of this teleconnection. In relation to this teleconnection pattern it is shown that there is a significant linear response of the SON and DJF equatorial zonal wind anomaly over the Pacific Ocean to contemporaneous SSTA over the western Indian Ocean which is comparable to that of the eastern and western Pacific Oceans. The experimental AGCM runs clearly show that this response of the equatorial zonal wind anomaly to the western Indian Ocean forcing shifts westward towards the Indian Ocean in the absence of Pacific SST variability.
    Description: Published
    Keywords: Sea surface temperature ; Atmospheric conditions ; Teleconnections
    Repository Name: AquaDocs
    Type: Journal Contribution , Refereed , Article
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  • 11
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    American Meteorological Society
    Publication Date: 2021-05-19
    Description: Skill in ensemble-mean dynamical seasonal climate hindcasts with a coupled land-atmosphere model and specified observed sea surface temperature is compared to that for long multi-decade integrations of the same model where the initial conditions are far removed from the seasons of validation. The evaluations are performed for surface temperature and compared among all seasons. Skill is found to be higher in the seasonal simulations than the multi-decadal integrations except during boreal winter. The higher skill is prominent even beyond the first month when the direct influence of the atmospheric initial state elevates model skill. Skill is generally found to be lowest during the winter season for the dynamical seasonal forecasts, equal to that of the long integrations, which show some of the highest skill during winter. The reason for the differences in skill during the non-winter months is attributed to the severe climate drift in the long simulations, manifest through errors in downward fluxes of water and energy over land and evident in soil wetness. The drift presses the land surface to extreme dry or wet states over much of the globe, into a range where there is little sensitivity of evaporation to fluctuations in soil moisture. Thus, the land-atmosphere feedback is suppressed, which appears to lessen the model’s ability to respond correctly over land to remote ocean temperature anomalies.
    Description: Center for Ocean-Land-Atmosphere Studies
    Description: Published
    Keywords: Atmosphere-ocean system
    Repository Name: AquaDocs
    Type: Journal Contribution , Refereed , Article
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  • 12
    Publication Date: 2021-05-19
    Description: In this paper, the circulations driven by deep heating and shallow heating are investigated through analytically solving a set of linear equations and examining circulations simulated by a dry primitive equation model. Special emphasis is placed on the low-level mass (moisture) convergence associated with the forced circulation and the maintenance of the shallow and deep heat sources. It is found that the forced circulation driven by shallow heating is more likely to be trapped horizontally near the heating area but relatively extended in the vertical. As a consequence, diabatic heating can not balance adiabatic cooling due to upward motion. At the levels slightly above the top of the heating, a negative vertical gradient of temperature perturbation appears. For the atmosphere driven by deep heating, however, the temperature perturbation cannot accumulate because the heating signals propagate away very fast, allowing an approximate equilibrium between the convective diabatic heating and adiabatic cooling due to upward motion. The converged moisture associated with circulation driven by shallow heating exceeds the amount needed to maintain the heat source. However, the circulation driven by deep heating does not feed back effectively to the moisture convergence, and thus can not be self-sustaining.
    Description: Center for Ocean-Land-Atmosphere Studies - Calverton
    Description: Published
    Keywords: Atmospheric circulation
    Repository Name: AquaDocs
    Type: Journal Contribution , Refereed , Article
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  • 13
    Publication Date: 2022-05-25
    Description: Author Posting. © National Academy of Sciences, 2006. This article is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 103 (2006): 3675-3680, doi:10.1073/pnas.0600160103.
    Description: We investigated whether the evolution of electric organs and electric signal diversity in two independently evolved lineages of electric fishes was accompanied by convergent changes on the molecular level. We found that a sodium channel gene (Nav1.4a) that is expressed in muscle in nonelectric fishes has lost its expression in muscle and is expressed instead in the evolutionarily novel electric organ in both lineages of electric fishes. This gene appears to be evolving under positive selection in both lineages, facilitated by its restricted expression in the electric organ. This view is reinforced by the lack of evidence for selection on this gene in one electric species in which expression of this gene is retained in muscle. Amino acid replacements occur convergently in domains that influence channel inactivation, a key trait for shaping electric communication signals. Some amino acid replacements occur at or adjacent to sites at which disease-causing mutations have been mapped in human sodium channel genes, emphasizing that these replacements occur in functionally important domains. Selection appears to have acted on the final step in channel inactivation, but complementarily on the inactivation "ball" in one lineage, and its receptor site in the other lineage. Thus, changes in the expression and sequence of the same gene are associated with the independent evolution of signal complexity.
    Description: This work was funded by National Institutes of Health Grant R01 NS025513 (to H.H.Z. and Y.L.) and National Science Foundation Integrative Graduate Education and Research Traineeship Program DGE-0114387 (to D.J.Z. and D.M.H.).
    Keywords: Animal communication ; Electric organ ; Channel inactivation ; Protein evolution ; Positive selection
    Repository Name: Woods Hole Open Access Server
    Type: Article
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  • 14
    Publication Date: 2022-05-25
    Description: Author Posting. © National Academy of Sciences, 2006. This article is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 103 (2006): 6448-6453, doi:10.1073/pnas.0600830103.
    Description: Submersible exploration of the Samoan hotspot revealed a new, 300-m-tall, volcanic cone, named Nafanua, in the summit crater of Vailulu'u seamount. Nafanua grew from the 1,000-m-deep crater floor in 〈4 years and could reach the sea surface within decades. Vents fill Vailulu'u crater with a thick suspension of particulates and apparently toxic fluids that mix with seawater entering from the crater breaches. Low-temperature vents form Fe oxide chimneys in many locations and up to 1-m-thick layers of hydrothermal Fe floc on Nafanua. High-temperature (81°C) hydrothermal vents in the northern moat (945-m water depth) produce acidic fluids (pH 2.7) with rising droplets of (probably) liquid CO2. The Nafanua summit vent area is inhabited by a thriving population of eels (Dysommina rugosa) that feed on midwater shrimp probably concentrated by anticyclonic currents at the volcano summit and rim. The moat and crater floor around the new volcano are littered with dead metazoans that apparently died from exposure to hydrothermal emissions. Acid-tolerant polychaetes (Polynoidae) live in this environment, apparently feeding on bacteria from decaying fish carcasses. Vailulu'u is an unpredictable and very active underwater volcano presenting a potential long-term volcanic hazard. Although eels thrive in hydrothermal vents at the summit of Nafanua, venting elsewhere in the crater causes mass mortality. Paradoxically, the same anticyclonic currents that deliver food to the eels may also concentrate a wide variety of nektonic animals in a death trap of toxic hydrothermal fluids.
    Description: This work was supported by the National Oceanic and Atmospheric Administration (NOAA) Oceans Exploration and the Hawaii Undersea Research Laboratory–NOAA Undersea Research Program, the National Science Foundation, the Australian Research Council, and the SERPENT program.
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  • 15
    Publication Date: 2022-05-25
    Description: © 2008 Hutt et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License 2.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in BMC Developmental Biology 8 (2008): 1, doi:10.1186/1471-213X-8-1.
    Description: Environmental toxicants, whose actions are often mediated through the aryl hydrocarbon receptor (AhR) pathway, pose risks to the health and well-being of exposed species, including humans. Of particular concern are exposures during the earliest stages of development that while failing to abrogate embryogenesis, may have long term effects on newborns or adults. The purpose of this study was to evaluate the effect of maternal exposure to the AhR-specific ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the development of rat pre-implantation embryos with respect to nuclear and cytoskeletal architecture and cell lineage allocation. We performed a systematic 3 dimensional (3D) confocal microscopy analysis of rat pre-implantation embryos following maternal exposure to environmentally relevant doses of TCDD. Both chronic (50 ng/kg/wk for 3 months) and acute (50 ng/kg and 1 μg/kg at proestrus) maternal TCDD exposure disrupted morphogenesis at the compaction stage (8–16 cell), with defects including monopolar spindle formation, f-actin capping and fragmentation due to aberrant cytokinesis. Additionally, the size, shape and position of nuclei were modified in compaction stage pre-implantation embryos collected from treated animals. Notably, maternal TCDD exposure did not compromise survival to blastocyst, which with the exception of nuclear shape, were morphologically similar to control blastocysts. We have identified the compaction stage of pre-implantation embryogenesis as critically sensitive to the effects of TCDD, while survival to the blastocyst stage is not compromised. To the best of our knowledge this is the first in vivo study to demonstrate a critical window of pre-implantation mammalian development that is vulnerable to disruption by an AhR ligand at environmentally relevant doses.
    Description: This research was supported by NIH/NIEHS-012916 (BKP), ESHE Fund (DFA), Hall Family Foundation (DFA and KJH) and Biomedical Research Training Grant KUMC (KJH).
    Repository Name: Woods Hole Open Access Server
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  • 16
    Publication Date: 2022-05-25
    Description: © 2007 Ioannidis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in BMC Genomics 8 (2007): 182, doi:10.1186/1471-2164-8-182.
    Description: Background: The annotated genomes of two closely related strains of the intracellular bacterium Wolbachia pipientis have been reported without the identifications of the putative origin of replication (ori). Identifying the ori of these bacteria and related alpha-Proteobacteria as well as their patterns of sequence evolution will aid studies of cell replication and cell density, as well as the potential genetic manipulation of these widespread intracellular bacteria. Results: Using features that have been previously experimentally verified in the alpha-Proteobacterium Caulobacter crescentus, the origin of DNA replication (ori) regions were identified in silico for Wolbachia strains and eleven other related bacteria belonging to Ehrlichia, Anaplasma, and Rickettsia genera. These features include DnaA-, CtrA- and IHF-binding sites as well as the flanking genes in C. crescentus. The Wolbachia ori boundary genes were found to be hemE and COG1253 protein (CBS domain protein). Comparisons of the putative ori region among related Wolbachia strains showed higher conservation of bases within binding sites. Conclusion: The sequences of the ori regions described here are only similar among closely related bacteria while fundamental characteristics like presence of DnaA and IHF binding sites as well as the boundary genes are more widely conserved. The relative paucity of CtrA binding sites in the ori regions, as well as the absence of key enzymes associated with DNA replication in the respective genomes, suggest that several of these obligate intracellular bacteria may have altered replication mechanisms. Based on these analyses, criteria are set forth for identifying the ori region in genome sequencing projects.
    Description: PI, PS, SS, GT and KB acknowledge support of their work from intramural funding from the University of Ioannina. SB, JDH, LB and JW acknowledge support of their work from the U.S. National Science Foundation grant EF-0328363. SB also acknowledges the support from the NASA Astrobiology Institute (NNA04CC04A)
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  • 17
    Publication Date: 2022-05-25
    Description: © 2007 Huse et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in Genome Biology 8 (2007): R143, doi:10.1186/gb-2007-8-7-r143.
    Description: Additional data file 1 is a fasta file of the 43 known sequences used. Additional data file 2 is a gzip-compressed fasta file of the sequences output by the GS20. These sequences correspond to those included in Additional data files 3, 4, 5 but include only the final sequence information. Additional data files 3, 4, 5 are three compressed text files representing the text translations of the original GS20 binary output (sff) files for all of the sequencing used in the analysis, including sequence, flowgram and other run information. GS20 data are reported by region of the PicoTiterPlate™; we sequenced three plate regions.
    Description: Massively parallel pyrosequencing systems have increased the efficiency of DNA sequencing, although the published per-base accuracy of a Roche GS20 is only 96%. In genome projects, highly redundant consensus assemblies can compensate for sequencing errors. In contrast, studies of microbial diversity that catalogue differences between PCR amplicons of ribosomal RNA genes (rDNA) or other conserved gene families cannot take advantage of consensus assemblies to detect and minimize incorrect base calls. We performed an empirical study of the per-base error rate for the Roche GS20 system using sequences of the V6 hypervariable region from cloned microbial ribosomal DNA (tag sequencing). We calculated a 99.5% accuracy rate in unassembled sequences, and identified several factors that can be used to remove a small percentage of low-quality reads, improving the accuracy to 99.75% or better. By using objective criteria to eliminate low quality data, the quality of individual GS20 sequence reads in molecular ecological applications can surpass the accuracy of traditional capillary methods.
    Description: This work was supported by National Aeronautics and Space Administration Astrobiology Institute Cooperative Agreement NNA04CC04A (to MLS), subcontracts from the Woods Hole Center for Oceans and Human Health from the National Institutes of Health and National Science Foundation (NIH/NIEHS 1 P50 ES012742-01 and NSF/OCE 0430724-J Stegeman PI to HGM and MLS), grants from the WM Keck Foundation and the G Unger Vetlesen Foundation (to MLS), and a National Research Council Research Associateship Award (to JAH).
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  • 18
    Publication Date: 2022-05-25
    Description: © 2008 Salvador-Recatalà et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License. The definitive version was published in BMC Physiology 8 (2008): 6, doi:10.1186/1472-6793-8-6.
    Description: The function of voltage-gated calcium (Cav) channels greatly depends on coupling to cytoplasmic accessory β subunits, which not only promote surface expression, but also modulate gating and kinetic properties of the α1 subunit. Schistosomes, parasitic platyhelminths that cause schistosomiasis, express two β subunit subtypes: a structurally conventional β subunit and a variant β subunit with unusual functional properties. We have previously characterized the functional properties of the variant Cavβ subunit. Here, we focus on the modulatory phenotype of the conventional Cavβ subunit (SmCavβ) using the human Cav2.3 channel as the substrate for SmCavβ and the whole-cell patch-clamp technique. The conventional Schistosoma mansoni Cavβ subunit markedly increases Cav2.3 currents, slows macroscopic inactivation and shifts steady state inactivation in the hyperpolarizing direction. However, currents produced by Cav2.3 in the presence of SmCavβ run-down to approximately 75% of their initial amplitudes within two minutes of establishing the whole-cell configuration. This suppressive effect was independent of Ca2+, but dependent on intracellular Mg2+-ATP. Additional experiments revealed that SmCavβ lends the Cav2.3/SmCavβ complex sensitivity to Na+ ions. A mutant version of the Cavβ subunit lacking the first forty-six amino acids, including a string of twenty-two acidic residues, no longer conferred sensitivity to intracellular Mg2+-ATP and Na+ ions, while continuing to show wild type modulation of current amplitude and inactivation of Cav2.3. The data presented in this article provide insights into novel mechanisms employed by platyhelminth Cavβ subunits to modulate voltage-gated Ca2+ currents that indicate interactions between the Ca2+ channel complex and chelated forms of ATP as well as Na+ ions. These results have potentially important implications for understanding previously unknown mechanisms by which platyhelminths and perhaps other organisms modulate Ca2+ currents in excitable cells.
    Description: This work was supported by NIH grant #s R01 AI-40522 and R01 AI-73660 to RMG and by NIH-NCRR grant # P41 RR001395 to the Biocurrents Research Center (BRC) at MBL.
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  • 19
    Publication Date: 2022-05-25
    Description: © 2008 Riley et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in BMC Genomics 9 (2008): 210, doi:10.1186/1471-2164-9-210.
    Description: The genome sequence of the sea-ice bacterium Psychromonas ingrahamii 37, which grows exponentially at -12C, may reveal features that help to explain how this extreme psychrophile is able to grow at such low temperatures. Determination of the whole genome sequence allows comparison with genes of other psychrophiles and mesophiles. Correspondence analysis of the composition of all P. ingrahamii proteins showed that (1) there are 6 classes of proteins, at least one more than other bacteria, (2) integral inner membrane proteins are not sharply separated from bulk proteins suggesting that, overall, they may have a lower hydrophobic character, and (3) there is strong opposition between asparagine and the oxygen-sensitive amino acids methionine, arginine, cysteine and histidine and (4) one of the previously unseen clusters of proteins has a high proportion of "orphan" hypothetical proteins, raising the possibility these are cold-specific proteins. Based on annotation of proteins by sequence similarity, (1) P. ingrahamii has a large number (61) of regulators of cyclic GDP, suggesting that this bacterium produces an extracellular polysaccharide that may help sequester water or lower the freezing point in the vicinity of the cell. (2) P. ingrahamii has genes for production of the osmolyte, betaine choline, which may balance the osmotic pressure as sea ice freezes. (3) P. ingrahamii has a large number (11) of three-subunit TRAP systems that may play an important role in the transport of nutrients into the cell at low temperatures. (4) Chaperones and stress proteins may play a critical role in transforming nascent polypeptides into 3-dimensional configurations that permit low temperature growth. (5) Metabolic properties of P. ingrahamii were deduced. Finally, a few small sets of proteins of unknown function which may play a role in psychrophily have been singled out as worthy of future study. The results of this genomic analysis provide a springboard for further investigations into mechanisms of psychrophily. Focus on the role of asparagine excess in proteins, targeted phenotypic characterizations and gene expression investigations are needed to ascertain if and how the organism regulates various proteins in response to growth at lower temperatures.
    Description: MR acknowledges support from DE-FG02-04ER63940. JTS acknowledges the support from the University of Washington NASA NAI program and the NSF Astrobiology IGERT program. TZW acknowledges support from a grant from the Fondation Fourmentin-Guilbert and AD acknowledges support from the European Union BioSapiens Network of Excellence, Grant LSHG CT-2003-503265
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    Publication Date: 2022-05-25
    Description: © 2009 The Authors. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in BMC Genomics 10 (2009): 11, doi:10.1186/1471-2164-10-11.
    Description: Cold adapted or psychrophilic organisms grow at low temperatures, where most of other organisms cannot grow. This adaptation requires a vast array of sequence, structural and physiological adjustments. To understand the molecular basis of cold adaptation of proteins, we analyzed proteomes of psychrophilic and mesophilic bacterial species and compared the differences in amino acid composition and substitution patterns to investigate their likely association with growth temperatures. In psychrophilic bacteria, serine, aspartic acid, threonine and alanine are overrepresented in the coil regions of secondary structures, whilst glutamic acid and leucine are underrepresented in the helical regions. Compared to mesophiles, psychrophiles comprise a significantly higher proportion of amino acids that contribute to higher protein flexibility in the coil regions of proteins, such as those with tiny/small or neutral side chains. Amino acids with aliphatic, basic, aromatic and hydrophilic side chains are underrepresented in the helical regions of proteins of psychrophiles. The patterns of amino acid substitutions between the orthologous proteins of psychrophiles versus mesophiles are significantly different for several amino acids when compared to their substitutions in orthologous proteins of within the mesophiles or psychrophiles. Current results provide quantitative substitution preferences (or avoidance) of amino acids that lead to the adaptation of proteins to cold temperatures. These finding would help future efforts in selecting mutations for rational design of proteins with enhanced psychrophilic properties.
    Description: This work was supported by a grant from Howard Hughes Medical Institute to Queens College, CUNY, and Queens College Research Enhancement Grant.
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  • 21
    Publication Date: 2022-05-25
    Description: © 2009 Sarkar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License. The definitive version was published in BMC Research Notes 2 (2009): 101, doi:10.1186/1756-0500-2-101.
    Description: GenBank(R) is a public repository of all publicly available molecular sequence data from a range of sources. In addition to relevant metadata (e.g., sequence description, source organism and taxonomy), publication information is recorded in the GenBank data file. The identification of literature associated with a given molecular sequence may be an essential first step in developing research hypotheses. Although many of the publications associated with GenBank records may not be linked into or part of complementary literature databases (e.g., PubMed), GenBank records associated with literature indexed in Medline are identifiable as they contain PubMed identifiers (PMIDs). Here we show that an analysis of 87,116,501 GenBank sequence files reveals that 42% are associated with a publication or patent. Of these, 71% are associated with PMIDs, and can therefore be linked to a citation record in the PubMed database. The remaining (29%) of publication-associated GenBank entries either do not have PMIDs or cite a publication that is not currently indexed by PubMed. We also identify the journal titles that are linked through citations in the GenBank files to the largest number of sequences. Our analysis suggests that GenBank contains molecular sequences from a range of disciplines beyond biomedicine, the initial scope of PubMed. The findings thus suggest opportunities to develop mechanisms for integrating biological knowledge beyond the biomedical field.
    Description: INS and HM are funded in part by a research grant from the Ellison Medical Foundation and National Library of Medicine award R01LM009725 to INS.
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    Publication Date: 2022-05-25
    Description: © 2009 Reitzel and Tarrant. This is an open-access article distributed under the terms of the Creative Commons Attribution License. The definitive version was published in BMC Evolutionary Biology 9 (2009): 230, doi:10.1186/1471-2148-9-230.
    Description: Nuclear receptors are a superfamily of metazoan transcription factors that regulate diverse developmental and physiological processes. Sequenced genomes from an increasing number of bilaterians have provided a more complete picture of duplication and loss of nuclear receptors in protostomes and deuterostomes but have left open the question of which nuclear receptors were present in the cnidarian-bilaterian ancestor. In addition, nuclear receptor expression and function are largely uncharacterized within cnidarians, preventing determination of conserved and novel nuclear receptor functions in the context of animal evolution. Here we report the first complete set of nuclear receptors from a cnidarian, the starlet sea anemone Nematostella vectensis. Genomic searches using conserved DNA- and ligand-binding domains revealed seventeen nuclear receptors in N. vectensis. Phylogenetic analyses support N. vectensis orthologs of bilaterian nuclear receptors in four nuclear receptor subfamilies within nuclear receptor family 2 (COUP-TF, TLL, HNF4, TR2/4) and one putative ortholog of GCNF (nuclear receptor family 6). Other N. vectensis genes grouped well with nuclear receptor family 2 but represented lineage-specific duplications somewhere within the cnidarian lineage and were not clear orthologs of bilaterian genes. Three nuclear receptors were not well-supported within any particular nuclear receptor family. The seventeen nuclear receptors exhibited distinct developmental expression patterns, with expression of several nuclear receptors limited to a subset of developmental stages. N. vectensis contains a diverse complement of nuclear receptors including orthologs of several bilaterian nuclear receptors. Novel nuclear receptors in N. vectensis may be ancient genes lost from triploblastic lineages or may represent cnidarian-specific radiations. Nuclear receptors exhibited distinct developmental expression patterns, which are consistent with diverse regulatory roles for these genes. Understanding the evolutionary relationships and developmental expression of the N. vectensis nuclear receptor complement provides insight into the evolution of the nuclear receptor superfamily and a foundation for mechanistic characterization of cnidarian nuclear receptor function.
    Description: We are grateful for financial support from the Woods Hole Oceanographic Institution (WHOI) through the Tropical Research Initiative, the Ocean Life Institute (AMT), the Academic Programs Office, and to the Beacon Institute for Rivers and Estuaries (AMR).
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    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
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    Publication Date: 2022-05-25
    Description: Author Posting. © 2001 Serres et al. The definitive version was published in Genome Biology 2 (2001): research0035.1–0035.7, doi:10.1186/gb-2001-2-9-research0035.
    Description: Background: Since the genome of Escherichia coli K-12 was initially annotated in 1997, additional functional information based on biological characterization and functions of sequence-similar proteins has become available. On the basis of this new information, an updated version of the annotated chromosome has been generated. Results: The E. coli K-12 chromosome is currently represented by 4,401 genes encoding 116 RNAs and 4,285 proteins. The boundaries of the genes identified in the GenBank Accession U00096 were used. Some protein-coding sequences are compound and encode multimodular proteins. The coding sequences (CDSs) are represented by modules (protein elements of at least 100 amino acids with biological activity and independent evolutionary history). There are 4,616 identified modules in the 4,285 proteins. Of these, 48.9% have been characterized, 29.5% have an imputed function, 2.1% have a phenotype and 19.5% have no function assignment. Only 7% of the modules appear unique to E. coli, and this number is expected to be reduced as more genome data becomes available. The imputed functions were assigned on the basis of manual evaluation of functions predicted by BLAST and DARWIN analyses and by the MAGPIE genome annotation system. Conclusions: Much knowledge has been gained about functions encoded by the E. coli K-12 genome since the 1997 annotation was published. The data presented here should be useful for analysis of E. coli gene products as well as gene products encoded by other genomes.
    Description: This work was supported by NIH grant RO1 RR07861, the NASA Astrobiology Institute grant NCC2-1054, grants from the Edward Mallinckrodt, Jr Foundation and the Sinsheimer Foundation, and NSF grants NSF DBI - 9984882 and NSF IIS - 9996304.
    Keywords: Escherichia coli K-12
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    Annual Reviews
    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
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    Publication Date: 2022-05-25
    Description: Author Posting. © National Academy of Sciences, 2006. This article is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 103 (2006): 3846-3851, doi:10.1073/pnas.0600035103.
    Description: Studies of deeply buried, sedimentary microbial communities and associated biogeochemical processes during Ocean Drilling Program Leg 201 showed elevated prokaryotic cell numbers in sediment layers where methane is consumed anaerobically at the expense of sulfate. Here, we show that extractable archaeal rRNA, selecting only for active community members in these ecosystems, is dominated by sequences of uncultivated Archaea affiliated with the Marine Benthic Group B and the Miscellaneous Crenarchaeotal Group, whereas known methanotrophic Archaea are not detectable. Carbon flow reconstructions based on stable isotopic compositions of whole archaeal cells, intact archaeal membrane lipids, and other sedimentary carbon pools indicate that these Archaea assimilate sedimentary organic compounds other than methane even though methanotrophy accounts for a major fraction of carbon cycled in these ecosystems. Oxidation of methane by members of Marine Benthic Group B and the Miscellaneous Crenarchaeotal Group without assimilation of methane–carbon provides a plausible explanation. Maintenance energies of these subsurface communities appear to be orders of magnitude lower than minimum values known from laboratory observations, and ecosystem-level carbon budgets suggest that community turnover times are on the order of 100–2,000 years. Our study provides clues about the metabolic functionality of two cosmopolitan groups of uncultured Archaea.
    Description: This work was supported by Deutsche Forschungsgemeinschaft (to J.S.L., R.A., M.E., and K.-U.H. at Research Center for Ocean Margins and Grant Hi 616/4 to K.U.-H.); National Aeronautics and Space Administration Astrobiology Institute Grants NNA04CC06A (to J.E.B. and C.H.H. at Pennsylvania State University), NCC 2-1275 (to M.A.L., K.G.L., K.B.S., H.F.F., A.T., and K.-U.H. at the University of Rhode Island), and NCC 2-1054 (to M.L.S. and A.T. at the Marine Biological Laboratory); the G. Unger Vetlesen Foundation; U.S. Department of Energy Grant DE-FG02-93ER20117; and NSF Grant MCB03-48492. J.F.B. was supported by NSF Integrative Graduate Education and Research Traineeship Program Grant DGE-9972759 and a Schlanger fellowship from the Joint Oceanographic Institutions (JOI). M.A.L. was supported in part by postcruise support from JOI.
    Keywords: Anaerobic methanotrophy ; Deep biosphere ; FISH–secondary ion MS ; Intact polar lipids ; Stable carbon isotopes
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    Publication Date: 2022-05-25
    Description: From The Third Annual Conference of the MidSouth Computational Biology and Bioinformatics Society Baton Rouge, Louisiana. 2–4 March, 2006.
    Description: © 2006 Nahum et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    Description: EGenBio is a system for manipulation and filtering of large numbers of sequences, integrating curated sequence alignments and phylogenetic trees, managing evolutionary analyses, and visualizing their output. EGenBio is organized into three conceptual divisions, Evolution, Genomics, and Biodiversity. The Genomics division includes tools for selecting pre-aligned sequences from different genes and species, and for modifying and filtering these alignments for further analysis. Species searches are handled through queries that can be modified based on a tree-based navigation system and saved. The Biodiversity division contains tools for analyzing individual sequences or sequence alignments, whereas the Evolution division contains tools involving phylogenetic trees. Alignments are annotated with analytical results and modification history using our PRAED format. A miscellaneous Tools section and Help framework are also available. EGenBio was developed around our comparative genomic research and a prototype database of mtDNA genomes. It utilizes MySQL-relational databases and dynamic page generation, and calls numerous custom programs.
    Description: This work was partly funded by the National Institutes of Health (R22/R33 Innovation and Development grant to David Pollock), the National Science Foundation (CBM2/EPSCOR), and the State of Louisiana (Biological Computation and Visualization Center, Governor's iotechnology Initiative, and startup funds to David Pollock).
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    Publication Date: 2022-05-25
    Description: © 2006 Erdner and Anderson. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in BMC Genomics 7 (2006): 88, doi:10.1186/1471-2164-7-88.
    Description: Dinoflagellates are one of the most important classes of marine and freshwater algae, notable both for their functional diversity and ecological significance. They occur naturally as free-living cells, as endosymbionts of marine invertebrates and are well known for their involvement in "red tides". Dinoflagellates are also notable for their unusual genome content and structure, which suggests that the organization and regulation of dinoflagellate genes may be very different from that of most eukaryotes. To investigate the content and regulation of the dinoflagellate genome, we performed a global analysis of the transcriptome of the toxic dinoflagellate Alexandrium fundyense under nitrate- and phosphate-limited conditions using Massively Parallel Signature Sequencing (MPSS).
    Description: This work was funded by National Science Foundation OCE-0136861 and OCE-0430724, National Institute of Environmental Health Sciences 1 P50 ES012742-01, and a grant from the Woods Hole Oceanographic Institution Ocean Life Institute.
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  • 29
    Publication Date: 2022-05-25
    Description: © 2003 BioMed Central. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in Genome Biology 4 (2003): 235, doi:10.1186/gb-2003-4-11-235.
    Description: One of the challenges for ‘post-genomic’ biology is the integration of data from many different sources. Two recent studies independently take steps towards this goal for Escherichia coli, using mathematical modeling and a combination of gene expression and protein levels to predict new gene functions and metabolic behaviors.
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    Publication Date: 2022-05-25
    Description: © 2006 Hutt and Albertini. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in Journal of Experimental & Clinical Assisted Reproduction 3 (2006): 6, doi:10.1186/1743-1050-3-6.
    Description: The publication of a report in Nature in 2004 by the Tilly group suggesting that mouse ovaries are capable of generating oocytes de novo post-natally, has sparked interest in a problem long thought to have been resolved from classical studies in a variety of mammalian species. Within a nearly two year time period, laboratories around the world have taken up the challenge to dogma raised by this initial report, either to test this concept in an experimental basic science setting or give direction to clinical applications that could result, were the original premises of this work in the mouse valid for extrapolation to humans. This review provides a status report for this promising area of research, (1) to summarize recent findings in the literature with respect to the validity of the original hypothesis proffered by the Tilly group, and, (2) to gauge the potential utility of ovarian stem cells as a treatment for certain forms of human infertility.
    Description: Support and the funding provided from the Hall Family Foundation.
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  • 31
    Publication Date: 2022-05-25
    Description: © 2008 Author et al. This is an open access article distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Environmental Health 7 (2008): S3, doi:10.1186/1476-069X-7-S2-S3.
    Description: Innovative research relating oceans and human health is advancing our understanding of disease-causing organisms in coastal ecosystems. Novel techniques are elucidating the loading, transport and fate of pathogens in coastal ecosystems, and identifying sources of contamination. This research is facilitating improved risk assessments for seafood consumers and those who use the oceans for recreation. A number of challenges still remain and define future directions of research and public policy. Sample processing and molecular detection techniques need to be advanced to allow rapid and specific identification of microbes of public health concern from complex environmental samples. Water quality standards need to be updated to more accurately reflect health risks and to provide managers with improved tools for decision-making. Greater discrimination of virulent versus harmless microbes is needed to identify environmental reservoirs of pathogens and factors leading to human infections. Investigations must include examination of microbial community dynamics that may be important from a human health perspective. Further research is needed to evaluate the ecology of non-enteric water-transmitted diseases. Sentinels should also be established and monitored, providing early warning of dangers to ecosystem health. Taken together, this effort will provide more reliable information about public health risks associated with beaches and seafood consumption, and how human activities can affect their exposure to disease-causing organisms from the oceans.
    Description: The Oceans and Human Health Initiative research described within this paper is supported by the National Science Foundation, The National Institute for Environmental Health Sciences and the National Oceanic and Atmospheric Administration. Grant numbers are: NIEHS P50 ES012742 and NSF OCE- 043072 (RJG, LAA-Z, MFP), NSF OCE04-32479 and NIEHS P50 ES012740 (RSF), NSF OCE-0432368 and NIEHS P50 ES12736 (HMS-G), NIEHS P50 ES012762 and NSF OCE-0434087 (JSM).
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    Publication Date: 2022-05-25
    Description: © 2008 Author et al. This is an open access article distributed under the terms of the Creative Commons Attribution License The definitive version was published in Environmental Health 7 (2008): S6, doi:10.1186/1476-069X-7-S2-S6.
    Description: We review the major linkages between the oceans and public health, focusing on exposures and potential health effects due to anthropogenic and natural factors including: harmful algal blooms, microbes, and chemical pollutants in the oceans; consumption of seafood; and flooding events. We summarize briefly the current state of knowledge about public health effects and their economic consequences; and we discuss priorities for future research. We find that: • There are numerous connections between the oceans, human activities, and human health that result in both positive and negative exposures and health effects (risks and benefits); and the study of these connections comprises a new interdisciplinary area, "oceans and human health." • The state of present knowledge about the linkages between oceans and public health varies. Some risks, such as the acute health effects caused by toxins associated with shellfish poisoning and red tide, are relatively well understood. Other risks, such as those posed by chronic exposure to many anthropogenic chemicals, pathogens, and naturally occurring toxins in coastal waters, are less well quantified. Even where there is a good understanding of the mechanism for health effects, good epidemiological data are often lacking. Solid data on economic and social consequences of these linkages are also lacking in most cases. • The design of management measures to address these risks must take into account the complexities of human response to warnings and other guidance, and the economic tradeoffs among different risks and benefits. Future research in oceans and human health to address public health risks associated with marine pathogens and toxins, and with marine dimensions of global change, should include epidemiological, behavioral, and economic components to ensure that resulting management measures incorporate effective economic and risk/benefit tradeoffs.
    Description: Funding was provided in part by the NSF-NIEHS Oceans Centers at Woods Hole, University of Hawaii, University of Miami, and University of Washington, and the NOAA Oceans and Human Health Initiative Centers of Excellent in Charleston, Seattle and Milwaukee, the National Center for Environmental Health (NCEH) of the Centers for Disease Control and Prevention (CDC), and the WHOI Marine Policy Center. Grant numbers are: NIEHS P50 ES012742 and NSF OCE-043072 (HLKP, RJG, PH); NSF OCE 0432368 and NIEHS P50 ES12736 (LEF); NIEHS P50 ES012762 and NSF OCE-0434087 (EMF, AT, LRY); NSF OCE04-32479 and NIEHS P50 ES012740 (BAW)
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  • 33
    Publication Date: 2022-05-25
    Description: Author Posting. © National Academy of Sciences, 2002. This article is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 99 (2002): 14694-14699, doi:10.1073/pnas.232562899.
    Description: The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is best known because it mediates the actions of polycyclic and halogenated aromatic hydrocarbon environmental toxicants such as 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. We report here the successful identification of an endogenous ligand for this receptor; {approx}20 µg was isolated in pure form from 35 kg of porcine lung. Its structure was deduced as 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester from extensive physical measurements and quantum mechanical calculations. In a reporter gene assay, this ligand activates the AHR with a potency five times greater than that of {beta}-naphthoflavone, a prototypical synthetic AHR ligand. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester competes with 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin for binding to human, murine, and fish AHRs, thus showing that AHR activation is caused by direct receptor binding, and that recognition of this endogenous ligand is conserved from early vertebrates (fish) to humans.
    Description: This work was supported by the Wisconsin Alumni Research Foundation, the University of Wisconsin Sea Grant Institute, and the National Institutes of Health.
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  • 34
    Publication Date: 2022-05-25
    Description: Author Posting. © National Academy of Sciences, 2006. This article is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 103 (2006): 6252-6257, doi:10.1073/pnas.0509950103.
    Description: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons (HAHs) are highly toxic to most vertebrate animals, but there are dramatic differences in sensitivity among species and strains. Aquatic birds including the common tern (Sterna hirundo) are highly exposed to HAHs in the environment, but are up to 250-fold less sensitive to these compounds than the typical avian model, the domestic chicken (Gallus gallus). The mechanism of HAH toxicity involves altered gene expression subsequent to activation of the aryl hydrocarbon receptor (AHR), a basic helix–loop–helix-PAS transcription factor. AHR polymorphisms underlie mouse strain differences in sensitivity to HAHs and polynuclear aromatic hydrocarbons, but the role of the AHR in species differences in HAH sensitivity is not well understood. Here, we show that although chicken and tern AHRs both exhibit specific binding of [3H]TCDD, the tern AHR has a lower binding affinity and exhibits a reduced ability to support TCDD-dependent transactivation as compared to AHRs from chicken or mouse. We further show through use of chimeric AHR proteins and site-directed mutagenesis that the difference between the chicken and tern AHRs resides in the ligand-binding domain and that two amino acids (Val-325 and Ala-381) are responsible for the reduced activity of the tern AHR. Other avian species with reduced sensitivity to HAHs also possess these residues. These studies provide a molecular understanding of species differences in sensitivity to dioxin-like compounds and suggest an approach to using the AHR as a marker of dioxin susceptibility in wildlife.
    Description: This research was supported by the National Oceanographic and Atmospheric Administration National Sea Grant College Program, Department of Commerce, under Grants NA46RG0470 and NA16RG2273.
    Keywords: Basic helix–loop–helix-PAS ; Comparative toxicology ; Mechanisms ; Risk assessment ; Susceptibility
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  • 35
    Publication Date: 2022-05-25
    Description: This paper is not subject to U.S. copyright. The definitive version was published in Journal of Atmospheric and Oceanic Technology 21 (2004): 1448–1461, doi:10.1175/1520-0426(2004)021〈1448:AOAPAD〉2.0.CO;2.
    Description: The accuracy of velocities measured by a pulse-coherent acoustic Doppler profiler (PCADP) in the bottom boundary layer of a wave-dominated inner-shelf environment is evaluated. The downward-looking PCADP measured velocities in eight 10-cm cells at 1 Hz. Velocities measured by the PCADP are compared to those measured by an acoustic Doppler velocimeter for wave orbital velocities up to 95 cm s−1 and currents up to 40 cm s−1. An algorithm for correcting ambiguity errors using the resolution velocities was developed. Instrument bias, measured as the average error in burst mean speed, is −0.4 cm s−1 (standard deviation = 0.8). The accuracy (root-mean-square error) of instantaneous velocities has a mean of 8.6 cm s−1 (standard deviation = 6.5) for eastward velocities (the predominant direction of waves), 6.5 cm s−1 (standard deviation = 4.4) for northward velocities, and 2.4 cm s−1 (standard deviation = 1.6) for vertical velocities. Both burst mean and root-mean-square errors are greater for bursts with ub ≥ 50 cm s−1. Profiles of burst mean speeds from the bottom five cells were fit to logarithmic curves: 92% of bursts with mean speed ≥ 5 cm s−1 have a correlation coefficient R2 〉 0.96. In cells close to the transducer, instantaneous velocities are noisy, burst mean velocities are biased low, and bottom orbital velocities are biased high. With adequate blanking distances for both the profile and resolution velocities, the PCADP provides sufficient accuracy to measure velocities in the bottom boundary layer under moderately energetic inner-shelf conditions.
    Description: This work was funded by the U.S. Geological Survey as part of the Southwest Washington Coastal Erosion Study
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  • 36
    Publication Date: 2022-05-25
    Description: © 2007 Dietz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 2.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in BMC Ecology 7 (2007): 14, doi:10.1186/1472-6785-7-14.
    Description: Free-ranging narwhals (Monodon monoceros) were instrumented in Admiralty Inlet, Canada with both satellite tags to study migration and stock separation and short-term, high-resolution digital archival tags to explore diving and feeding behaviour. Three narwhals were equipped with an underwater camera pod (Crittercam), another individual was equipped with a digital archival tag (DTAG), and a fifth with both units during August 2003 and 2004. Crittercam footage indicated that of the combined 286 minutes of recordings, 12% of the time was spent along the bottom. When the bottom was visible in the camera footage, the narwhals were oriented upside-down 80% of the time (range: 61 100%). The DTAG data (14.6 hours of recordings) revealed that during time spent below the surface, the two tagged narwhals were supine an average of 13% (range: 9–18%) of the time. Roughly 70% of this time spent in a supine posture occurred during the descent. Possible reasons for this upside-down swimming behaviour are discussed. No preference for a clockwise or counter-clockwise direction of roll was observed, discounting the possibility that rolling movements contribute to the asymmetric left-handed helical turns of the tusk.
    Description: This study was funded by the National Environmental Research Institute, the Greenland Institute of Natural Resources (organized by Mads Peter Heide-Jørgensen), the Department of Fisheries and Oceans, the Nunavut Wildlife Research Trust Fund and the Danish Cooperation for the Environment in the Arctic (DANCEA). Ari D. Shapiro received financial support from the WHOI Academic Programs Office, the National Science Foundation Research Fellowship and the National Defense Science & Engineering Graduate Fellowship.
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  • 37
    Publication Date: 2022-05-25
    Description: © 2008 Author et al. This is an open access article distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Environmental Health 7 (2008): S1, doi:10.1186/1476-069X-7-S2-S1.
    Description: The oceans are the dominant feature of the planet and are fundamentally linked to human history and to human health. Concerns about the impact of the oceans on human health can be traced to ancient times. Jewish law prohibited the consumption of shellfish, probably reflecting the fact that filter-feeding bivalves can accumulate pathogens and toxins. The Portuguese explorer Pedro Fernandes de Queirós described symptoms associated with ciguatera fish poisoning after eating Caribbean sea bream in 1606, and several of British explorer James Cook's crew experienced similar symptoms after eating fish off the coast of Vanuatu in 1774 [1]. Roughly 1,200 people died from the consumption of fish and shellfish contaminated with methyl mercury in Minamata (Japan) during the 20th century; an even larger number were affected by chronic long-term neurotoxicological impacts [2]. A tsunami caused by an undersea earthquake on December 26, 2004 killed more than 225,000 people in eleven countries bordering the Indian Ocean; and more than 1,400 people died within a single day when the storm surge generated by Hurricane Katrina overwhelmed the New Orleans levee system on August 29, 2005 [3]. Looking ahead, the International Panel on Climate Change has projected a sea level rise of as much as 88 cm during the 21st century as a result of global warming [4], with major implications for the welfare and sustainability of coastal communities.
    Description: The support of the National Science Foundation (US) and the National Institute of Environmental Health Sciences (US) is gratefully acknowledged: Grant numbers NSF OCE04- 32479 and NIEHS P50 ES012740 (EAL), NSF OCE-0432368 and NIEHS P50 ES12736 (LEB), and NIEHS P50 ES012742 and NSF OCE-043072 (JJS).
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  • 38
    Publication Date: 2022-05-25
    Description: © 2008 Author et al. This is an open access article distributed under the terms of the Creative Commons Attribution License The definitive version was published in Environmental Health 7 (2008): S2, doi:10.1186/1476-069X-7-S2-S2.
    Description: Harmful algal blooms (HABs) are one focus of the national research initiatives on Oceans and Human Health (OHH) at NIEHS, NOAA and NSF. All of the OHH Centers, from the east coast to Hawaii, include one or more research projects devoted to studying HAB problems and their relationship to human health. The research shares common goals for understanding, monitoring and predicting HAB events to protect and improve human health: understanding the basic biology of the organisms; identifying how chemistry, hydrography and genetic diversity influence blooms; developing analytical methods and sensors for cells and toxins; understanding health effects of toxin exposure; and developing conceptual, empirical and numerical models of bloom dynamics. In the past several years, there has been significant progress toward all of the common goals. Several studies have elucidated the effects of environmental conditions and genetic heterogeneity on bloom dynamics. New methods have been developed or implemented for the detection of HAB cells and toxins, including genetic assays for Pseudo-nitzschia and Microcystis, and a biosensor for domoic acid. There have been advances in predictive models of blooms, most notably for the toxic dinoflagellates Alexandrium and Karenia. Other work is focused on the future, studying the ways in which climate change may affect HAB incidence, and assessing the threat from emerging HABs and toxins, such as the cyanobacterial neurotoxin β-N-methylamino-L-alanine. Along the way, many challenges have been encountered that are common to the OHH Centers and also echo those of the wider HAB community. Long-term field data and basic biological information are needed to develop accurate models. Sensor development is hindered by the lack of simple and rapid assays for algal cells and especially toxins. It is also critical to adequately understand the human health effects of HAB toxins. Currently, we understand best the effects of acute toxicity, but almost nothing is known about the effects of chronic, subacute toxin exposure. The OHH initiatives have brought scientists together to work collectively on HAB issues, within and across regions. The successes that have been achieved highlight the value of collaboration and cooperation across disciplines, if we are to continue to advance our understanding of HABs and their relationship to human health.
    Description: This work was funded through grants from the NSF/NIEHS Centers for Oceans and Human Health, NIEHS P50 ES012742 and NSF OCE-043072 (DLE and DMA), NSF OCE04-32479 and NIEHS P50 ES012740 (PB and RRB), NSF OCE-0432368 and NIEHS P50 ES12736 (LEB), NIEHS P50 ES012762 and NSF OCE-0434087 (RCS, KAL, MSP, MLW, and KAH). Additional support was provided by the ECOHAB Grant program NSF Grant OCE-9808173 and NOAA Grant NA96OP0099 (DMA), NOAA OHHI NA04OAR4600206 (RRB) and Washington State Sea Grant NA16RG1044 (RCS). KAL and VLT were supported in part by the West Coast Center for Oceans and Human Health (WCCOHH) as part of the NOAA Oceans and Human Health Initiative.
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  • 39
    Publication Date: 2022-05-25
    Description: © 2008 Author et al. This is an open access article distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Environmental Health 7 (2008): S5, doi:10.1186/1476-069X-7-S2-S5.
    Description: Coupled physical-biological models are capable of linking the complex interactions between environmental factors and physical hydrodynamics to simulate the growth, toxicity and transport of infectious pathogens and harmful algal blooms (HABs). Such simulations can be used to assess and predict the impact of pathogens and HABs on human health. Given the widespread and increasing reliance of coastal communities on aquatic systems for drinking water, seafood and recreation, such predictions are critical for making informed resource management decisions. Here we identify three challenges to making this connection between pathogens/HABs and human health: predicting concentrations and toxicity; identifying the spatial and temporal scales of population and ecosystem interactions; and applying the understanding of population dynamics of pathogens/HABs to management strategies. We elaborate on the need to meet each of these challenges, describe how modeling approaches can be used and discuss strategies for moving forward in addressing these challenges.
    Description: The authors acknowledge the financial support for the NSF/NIEHS and NOAA Centers for Oceans and Human Health
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  • 40
    Publication Date: 2022-05-25
    Description: © 2009 The Authors. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Biology Direct 4 (2009): 46, doi:10.1186/1745-6150-4-46.
    Description: Sequence related families of genes and proteins are common in bacterial genomes. In Escherichia coli they constitute over half of the genome. The presence of families and superfamilies of proteins suggest a history of gene duplication and divergence during evolution. Genome encoded protein families, their size and functional composition, reflect metabolic potentials of the organisms they are found in. Comparing protein families of different organisms give insight into functional differences and similarities. Equivalent enzyme families with metabolic functions were selected from the genomes of four experimentally characterized bacteria belonging to separate genera. Both similarities and differences were detected in the protein family memberships, with more similarities being detected among the more closely related organisms. Protein family memberships reflected known metabolic characteristics of the organisms. Differences in divergence of functionally characterized enzyme family members accounted for characteristics of taxa known to differ in those biochemical properties and capabilities. While some members of the gene families will have been acquired by lateral exchange and other former family members will have been lost over time, duplication and divergence of genes and functions appear to have been a significant contributor to the functional diversity of today’s microbes. Protein families seem likely to have arisen during evolution by gene duplication and divergence where the gene copies that have been retained are the variants that have led to distinct bacterial physiologies and taxa. Thus divergence of the duplicate enzymes has been a major process in the generation of different kinds of bacteria.
    Description: This research was supported by the Office of Science (BER), U.S. Department of Energy, Grant No. DE-FG02-08ER64511.
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  • 41
    Publication Date: 2022-05-25
    Description: © 2005 Serres and Riley. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in BMC Genomics 6 (2005): 33, doi:10.1186/1471-2164-6-33.
    Description: Background: Escherichia coli a model organism provides information for annotation of other genomes. Our analysis of its genome has shown that proteins encoded by fused genes need special attention. Such composite (multimodular) proteins consist of two or more components (modules) encoding distinct functions. Multimodular proteins have been found to complicate both annotation and generation of sequence similar groups. Previous work overstated the number of multimodular proteins in E. coli. This work corrects the identification of modules by including sequence information from proteins in 50 sequenced microbial genomes. Results: Multimodular E. coli K-12 proteins were identified from sequence similarities between their component modules and non-fused proteins in 50 genomes and from the literature. We found 109 multimodular proteins in E. coli containing either two or three modules. Most modules had standalone sequence relatives in other genomes. The separated modules together with all the single (un-fused) proteins constitute the sum of all unimodular proteins of E. coli. Pairwise sequence relationships among all E. coli unimodular proteins generated 490 sequence similar, paralogous groups. Groups ranged in size from 92 to 2 members and had varying degrees of relatedness among their members. Some E. coli enzyme groups were compared to homologs in other bacterial genomes. Conclusion: The deleterious effects of multimodular proteins on annotation and on the formation of groups of paralogs are emphasized. To improve annotation results, all multimodular proteins in an organism should be detected and when known each function should be connected with its location in the sequence of the protein. When transferring functions by sequence similarity, alignment locations must be noted, particularly when alignments cover only part of the sequences, in order to enable transfer of the correct function. Separating multimodular proteins into module units makes it possible to generate protein groups related by both sequence and function, avoiding mixing of unrelated sequences. Organisms differ in sizes of groups of sequence-related proteins. A sample comparison of orthologs to selected E. coli paralogous groups correlates with known physiological and taxonomic relationships between the organisms.
    Description: The research was supported by the Office of Science (BER), U.S. Department of Energy, Grant No. DE-FG02-01ER63202 and by National Aeronautics and Space Administration Astrobiology grant NCC2-1054.
    Keywords: Escherichia coli ; Multimodular proteins
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  • 42
    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
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  • 43
    Publication Date: 2022-05-25
    Description: © 2007 Huang and Gogarten. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in Genome Biology 8 (2007): R99, doi:10.1186/gb-2007-8-6-r99.
    Description: Ancient endosymbioses are responsible for the origins of mitochondria and plastids, and they contribute to the divergence of several major eukaryotic groups. Although chlamydiae, a group of obligate intracellular bacteria, are not found in plants, an unexpected number of chlamydial genes are most similar to plant homologs, which, interestingly, often contain a plastid-targeting signal. This observation has prompted several hypotheses, including gene transfer between chlamydiae and plant-related groups and an ancestral relationship between chlamydiae and cyanobacteria. We conducted phylogenomic analyses of the red alga Cyanidioschyzon merolae to identify genes specifically related to chlamydial homologs. We show that at least 21 genes were transferred between chlamydiae and primary photosynthetic eukaryotes, with the donor most similar to the environmental Protochlamydia. Such an unusually high number of transferred genes suggests an ancient chlamydial endosymbiosis with the ancestral primary photosynthetic eukaryote. We hypothesize that three organisms were involved in establishing the primary photosynthetic lineage: the eukaryotic host cell, the cyanobacterial endosymbiont that provided photosynthetic capability, and a chlamydial endosymbiont or parasite that facilitated the establishment of the cyanobacterial endosymbiont. Our findings provide a glimpse into the complex interactions that were necessary to establish the primary endosymbiotic relationship between plastid and host cytoplasms, and thereby explain the rarity with which long-term successful endosymbiotic relationships between heterotrophs and photoautotrophs were established. Our data also provide strong and independent support for a common origin of all primary photosynthetic eukaryotes and of the plastids they harbor.
    Description: This work was performed while JH held a National Research Council Associateship Award at the NASA Astrobiology Institute at the Marine Biological Laboratory in Woods Hole, Massachusetts (NCC2-1054). Additional support was provided through NSF (MCB-0237197) and NASA AISR (NNG04GP90G) grants to JPG.
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  • 44
    Publication Date: 2022-05-26
    Description: This is an Open Access article distributed under the terms of the Creative Commons Attribution License 2.0 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in BMC Evolutionary Biology 8 (2008): 14, doi:10.1186/1471-2148-8-14.
    Description: Our understanding of the eukaryotic tree of life and the tremendous diversity of microbial eukaryotes is in flux as additional genes and diverse taxa are sampled for molecular analyses. Despite instability in many analyses, there is an increasing trend to classify eukaryotic diversity into six major supergroups: the 'Amoebozoa', 'Chromalveolata', 'Excavata', 'Opisthokonta', 'Plantae', and 'Rhizaria'. Previous molecular analyses have often suffered from either a broad taxon sampling using only single-gene data or have used multigene data with a limited sample of taxa. This study has two major aims: (1) to place taxa represented by 72 sequences, 61 of which have not been characterized previously, onto a well-sampled multigene genealogy, and (2) to evaluate the support for the six putative supergroups using two taxon-rich data sets and a variety of phylogenetic approaches.
    Description: This project was made possible by a collaborative grant from the National Science Foundation Assembling the Tree of Life program (EF 04-31117) that was awarded to L.A.K., D.B., J.L., D.J.P., and to the ATCC
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  • 45
    Publication Date: 2022-05-26
    Description: © 2009 The Authors. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in BMC Biology 7 (2009): 72, doi:10.1186/1741-7007-7-72.
    Description: Recent advances in sequencing strategies make possible unprecedented depth and scale of sampling for molecular detection of microbial diversity. Two major paradigm-shifting discoveries include the detection of bacterial diversity that is one to two orders of magnitude greater than previous estimates, and the discovery of an exciting 'rare biosphere' of molecular signatures ('species') of poorly understood ecological significance. We applied a high-throughput parallel tag sequencing (454 sequencing) protocol adopted for eukaryotes to investigate protistan community complexity in two contrasting anoxic marine ecosystems (Framvaren Fjord, Norway; Cariaco deep-sea basin, Venezuela). Both sampling sites have previously been scrutinized for protistan diversity by traditional clone library construction and Sanger sequencing. By comparing these clone library data with 454 amplicon library data, we assess the efficiency of high-throughput tag sequencing strategies. We here present a novel, highly conservative bioinformatic analysis pipeline for the processing of large tag sequence data sets.The analyses of ca. 250,000 sequence reads revealed that the number of detected Operational Taxonomic Units (OTUs) far exceeded previous richness estimates from the same sites based on clone libraries and Sanger sequencing. More than 90% of this diversity was represented by OTUs with less than 10 sequence tags. We detected a substantial number of taxonomic groups like Apusozoa, Chrysomerophytes, Centroheliozoa, Eustigmatophytes, hyphochytriomycetes, Ichthyosporea, Oikomonads, Phaeothamniophytes, and rhodophytes which remained undetected by previous clone library-based diversity surveys of the sampling sites. The most important innovations in our newly developed bioinformatics pipeline employ (i) BLASTN with query parameters adjusted for highly variable domains and a complete database of public ribosomal RNA (rRNA) gene sequences for taxonomic assignments of tags; (ii) a clustering of tags at k differences (Levenshtein distance) with a newly developed algorithm enabling very fast OTU clustering for large tag sequence data sets; and (iii) a novel parsing procedure to combine the data from individual analyses. Our data highlight the magnitude of the under-sampled 'protistan gap' in the eukaryotic tree of life. This study illustrates that our current understanding of the ecological complexity of protist communities, and of the global species richness and genome diversity of protists, is severely limited. Even though 454 pyrosequencing is not a panacea, it allows for more comprehensive insights into the diversity of protistan communities, and combined with appropriate statistical tools, enables improved ecological interpretations of the data and projections of global diversity.
    Description: The International Census of Marine Microbes and the W.M. Keck Foundation award to the Marine Biological Laboratory at Woods Hole (MA) supported the pyrosequencing part of this study. Further financial support came from a grant from the Deutsche Forschungsgemeinschaft to TS (STO414/3-1). Support for the unpublished work on Cariaco Basin protists came from NSF MCB-0348407 to VE (collaborative project with S Epstein at Northeastern University, Boston, MA, USA). Financial support to AC was provided by NSF MCB-0348045. Financial support to RC was provided by the ANR-Biodiversité project Aquaparadox.
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  • 46
    Publication Date: 2022-05-26
    Description: © 2009 The Authors. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in BMC Microbiology 9 (2009): 16, doi:10.1186/1471-2180-9-16.
    Description: The Euglenozoa is a large group of eukaryotic flagellates with diverse modes of nutrition. The group consists of three main subclades – euglenids, kinetoplastids and diplonemids – that have been confirmed with both molecular phylogenetic analyses and a combination of shared ultrastructural characteristics. Several poorly understood lineages of putative euglenozoans live in anoxic environments, such as Calkinsia aureus, and have yet to be characterized at the molecular and ultrastructural levels. Improved understanding of these lineages is expected to shed considerable light onto the ultrastructure of prokaryote-eukaryote symbioses and the associated cellular innovations found within the Euglenozoa and beyond. We collected Calkinsia aureus from core samples taken from the low-oxygen seafloor of the Santa Barbara Basin (580 – 592 m depth), California. These biflagellates were distinctively orange in color and covered with a dense array of elongated epibiotic bacteria. Serial TEM sections through individually prepared cells demonstrated that C. aureus shares derived ultrastructural features with other members of the Euglenozoa (e.g. the same paraxonemal rods, microtubular root system and extrusomes). However, C. aureus also possessed several novel ultrastructural systems, such as modified mitochondria (i.e. hydrogenosome-like), an "extrusomal pocket", a highly organized extracellular matrix beneath epibiotic bacteria and a complex flagellar transition zone. Molecular phylogenies inferred from SSU rDNA sequences demonstrated that C. aureus grouped strongly within the Euglenozoa and with several environmental sequences taken from low-oxygen sediments in various locations around the world. Calkinsia aureus possesses all of the synapomorphies for the Euglenozoa, but lacks traits that are specific to any of the three previously recognized euglenozoan subgroups. Molecular phylogenetic analyses of C. aureus demonstrate that this lineage is a member of a novel euglenozoan subclade consisting of uncharacterized cells living in low-oxygen environments. Our ultrastructural description of C. aureus establishes the cellular identity of a fourth group of euglenozoans, referred to as the "Symbiontida".
    Description: This work was supported by grants to BSL from the Tula Foundation (Centre for Microbial Diversity and Evolution), the National Science and Engineering Research Council of Canada (NSERC 283091-04) and the Canadian Institute for Advanced Research, Program in Integrated Microbial Biodiversity. Funding for the collection of sediments and participation of VPE and JMB in this research was provided by the US National Science Foundation grant MCB-060484.
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  • 47
    Publication Date: 2022-05-26
    Description: © 2001 Samuel et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. The definitive version was published in BMC Microbiology 1 (2001): 4, doi:10.1186/1471-2180-1-4.
    Description: Many bacteria swim by rotating helical flagellar filaments. Waterbury et al. discovered an exception, strains of the cyanobacterium Synechococcus that swim without flagella or visible changes in shape. Other species of cyanobacteria glide on surfaces. The hypothesis that Synechococcus might swim using traveling surface waves prompted this investigation. Results Using quick-freeze electron microscopy, we have identified a crystalline surface layer that encloses the outer membrane of the motile strain Synechococcus sp. WH8113, the components of which are arranged in a rhomboid lattice. Spicules emerge in profusion from the layer and extend up to 150 nm into the surrounding fluid. These spicules also send extensions inwards to the inner cell membrane where motility is powered by an ion-motive force. Conclusion The envelope structure of Synechococcus sp. WH8113 provides new constraints on its motile mechanism. The spicules are well positioned to transduce energy at the cell membrane into mechanical work at the cell surface. One model is that an unidentified motor embedded in the cell membrane utilizes the spicules as oars to generate a traveling wave external to the surface layer in the manner of ciliated eukaryotes.
    Description: ADTS was supported by the Rowland Institute for Science and is an Amgen Fellow of the Life Sciences Research Foundation.
    Keywords: Synechococcus sp. ; Motile mechanism
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    Description: © 2008 Sarkar et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License. The definitive version was published in BMC Evolutionary Biology 8 (2008): 144, doi:10.1186/1471-2148-8-144.
    Description: Authority and year information have been attached to taxonomic names since Linnaean times. The systematic structure of taxonomic nomenclature facilitates the ability to develop tools that can be used to explore historical trends that may be associated with taxonomy. From the over 10.7 million taxonomic names that are part of the uBio system, approximately 3 million names were identified to have taxonomic authority information from the years 1750 to 2004. A pipe-delimited file was then generated, organized according to a Linnaean hierarchy and by years from 1750 to 2004, and imported into an Excel workbook. A series of macros were developed to create an Excel-based tool and a complementary Web site to explore the taxonomic data. A cursory and speculative analysis of the data reveals observable trends that may be attributable to significant events that are of both taxonomic (e.g., publishing of key monographs) and societal importance (e.g., world wars). The findings also help quantify the number of taxonomic descriptions that may be made available through digitization initiatives. Temporal organization of taxonomic data can be used to identify interesting biological epochs relative to historically significant events and ongoing efforts. We have developed an Excel workbook and complementary Web site that enables one to explore taxonomic trends for Linnaean taxonomic groupings, from Kingdoms to Families.
    Description: The work presented here was funded in part by the MBLWHOI Library and the DAB Lindberg Research Fellowship from the Medical Library Association to INS.
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    Description: Author Posting. © National Academy of Sciences, 1997. This article is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 94 (1997): 13743-13748.
    Description: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor through which halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cause altered gene expression and toxicity. The AHR belongs to the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of transcriptional regulatory proteins, whose members play key roles in development, circadian rhythmicity, and environmental homeostasis; however, the normal cellular function of the AHR is not yet known. As part of a phylogenetic approach to understanding the function and evolutionary origin of the AHR, we sequenced the PAS homology domain of AHRs from several species of early vertebrates and performed phylogenetic analyses of these AHR amino acid sequences in relation to mammalian AHRs and 24 other members of the PAS family. AHR sequences were identified in a teleost (the killifish Fundulus heteroclitus), two elasmobranch species (the skate Raja erinacea and the dogfish Mustelus canis), and a jawless fish (the lamprey Petromyzon marinus). Two putative AHR genes, designated AHR1 and AHR2, were found both in Fundulus and Mustelus. Phylogenetic analyses indicate that the AHR2 genes in these two species are orthologous, suggesting that an AHR gene duplication occurred early in vertebrate evolution and that multiple AHR genes may be present in other vertebrates. Database searches and phylogenetic analyses identified four putative PAS proteins in the nematode Caenorhabditis elegans, including possible AHR and ARNT homologs. Phylogenetic analysis of the PAS gene family reveals distinct clades containing both invertebrate and vertebrate PAS family members; the latter include paralogous sequences that we propose have arisen by gene duplication early in vertebrate evolution. Overall, our analyses indicate that the AHR is a phylogenetically ancient protein present in all living vertebrate groups (with a possible invertebrate homolog), thus providing an evolutionary perspective to the study of dioxin toxicity and AHR function.
    Description: This work was supported in part by the National Institute of Environmental Health Sciences (Grants R29 ES06272, F32 ES05644, and P42 ES07381), the Donaldson Charitable Trust, and a Christopher Haebler Frantz Fellowship (to M.A.S.).
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    Description: © 2008 Sarkar et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License 2.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The definitive version was published in BMC Bioinformatics 9 (2008): 103, doi:10.1186/1471-2105-9-103.
    Description: The availability of sequences from whole genomes to reconstruct the tree of life has the potential to enable the development of phylogenomic hypotheses in ways that have not been before possible. A significant bottleneck in the analysis of genomic-scale views of the tree of life is the time required for manual curation of genomic data into multi-gene phylogenetic matrices. To keep pace with the exponentially growing volume of molecular data in the genomic era, we have developed an automated technique, ASAP (Automated Simultaneous Analysis Phylogenetics), to assemble these multigene/multi species matrices and to evaluate the significance of individual genes within the context of a given phylogenetic hypothesis. Applications of ASAP may enable scientists to re-evaluate species relationships and to develop new phylogenomic hypotheses based on genome-scale data.
    Description: This work is funded in part by NSF DBI-0421604 to GC and RD. INS is supported in part by the Ellison Medical Foundation.
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    Annual Review of Immunology 23 (2005), S. 161-196 
    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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    Annual Review of Immunology 23 (2005), S. 487-513 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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    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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    Annual Review of Immunology 23 (2005), S. 415-445 
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    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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    Annual Review of Immunology 23 (2005), S. 683-747 
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    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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    Annual Review of Immunology 23 (2005), S. 651-682 
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    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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    Annual Review of Immunology 23 (2005), S. 945-974 
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    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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    Annual Review of Immunology 23 (2005), S. 975-1028 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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    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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    Annual Review of Immunology 23 (2005), S. 515-548 
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    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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    Annual Review of Immunology 26 (2005), S. 877-900 
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    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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    Annual Review of Immunology 23 (2005), S. 549-600 
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    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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    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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    Annual Review of Immunology 23 (2005), S. 23-68 
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    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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    Annual Review of Immunology 23 (2005), S. 447-485 
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    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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    Annual Review of Immunology 23 (2005), S. 101-125 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
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    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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    Annual Review of Pharmacology 45 (2005), S. 1-25 
    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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    Annual Review of Pharmacology 45 (2005), S. 51-88 
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    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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    Annual Review of Pharmacology 45 (2005), S. 177-202 
    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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    Annual Review of Pharmacology 45 (2005), S. 291-310 
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    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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    Annual Review of Pharmacology 45 (2005), S. 335-355 
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    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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    Annual Review of Pharmacology 45 (2005), S. 385-412 
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    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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    Annual Review of Pharmacology 45 (2005), S. 657-687 
    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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    Annual Review of Pharmacology 46 (2006), S. 65-100 
    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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    Annual Review of Immunology 23 (2005), S. 367-386 
    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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    Annual Review of Immunology 23 (2005), S. 337-366 
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: C reactive protein, the first innate immunity receptor identified, and serum amyloid P component are classic short pentraxins produced in the liver. Long pentraxins, including the prototype PTX3, are expressed in a variety of tissues. Some long pentraxins are expressed in the brain and some are involved in neuronal plasticity and degeneration. PTX3 is produced by a variety of cells and tissues, most notably dendritic cells and macrophages, in response to Toll-like receptor (TLR) engagement and inflammatory cytokines. PTX3 acts as a functional ancestor of antibodies, recognizing microbes, activating complement, and facilitating pathogen recognition by phagocytes, hence playing a nonredundant role in resistance against selected pathogens. In addition, PTX3 is essential in female fertility because it acts as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional soluble pattern recognition receptor at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility.
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    Annual Review of Immunology 23 (2005), S. 225-274 
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    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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    Annual Review of Immunology 23 (2005), S. 787-819 
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    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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    Annual Review of Immunology 23 (2005), S. 387-414 
    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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    Annual Review of Immunology 23 (2005), S. 901-944 
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    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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    Annual Review of Immunology 23 (2005), S. 601-649 
    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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    Annual Review of Immunology 23 (2005), S. 307-335 
    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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    Annual Review of Immunology 23 (2005), S. 127-159 
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    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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    Annual Review of Immunology 23 (2005), S. 749-786 
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    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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    Annual Review of Immunology 23 (2005), S. 1-21 
    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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    Annual Review of Immunology 23 (2005), S. 853-875 
    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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    Annual Review of Pharmacology 45 (2005), S. 465-476 
    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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    Annual Review of Pharmacology 45 (2005), S. 565-585 
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    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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    Annual Review of Pharmacology 46 (2006), S. 1-39 
    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.
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    Annual Review of Pharmacology 46 (2006), S. 235-276 
    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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    Annual Review of Pharmacology 46 (2006), S. 41-64 
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    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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    Annual Review of Immunology 23 (2005), S. 197-223 
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: Neutrophils provide the first line of defense of the innate immune system by phagocytosing, killing, and digesting bacteria and fungi. Killing was previously believed to be accomplished by oxygen free radicals and other reactive oxygen species generated by the NADPH oxidase, and by oxidized halides produced by myeloperoxidase. We now know this is incorrect. The oxidase pumps electrons into the phagocytic vacuole, thereby inducing a charge across the membrane that must be compensated. The movement of compensating ions produces conditions in the vacuole conducive to microbial killing and digestion by enzymes released into the vacuole from the cytoplasmic granules.
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    Annual Review of Immunology 23 (2005), S. 821-852 
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Notes: The complement system not only represents an effective innate immune mechanism of host defense to eradicate microbial pathogens, but it is also widely involved in many forms of acute and chronic inflammatory diseases including sepsis, acute lung injury, ischemia-reperfusion injury, and asthma, to give just a few examples. The complement-activated product, C5a, displays powerful biological activities that lead to inflammatory sequelae. C5a is a strong chemoattractant and is involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, in activation of phagocytic cells and release of granule-based enzymes and generation of oxidants, all of which may contribute to innate immune functions or tissue damage. Accumulating data suggest that C5a provides a vital bridge between innate and adaptive immune functions, extending the roles of C5a in inflammation. Herein, we review human and animal data describing the cellular and molecular mechanisms of C5a in the development of inflammatory disorders, sepsis, acute lung injury, ischemia-reperfusion injury, and asthma.
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    Annual Review of Immunology 23 (2005), S. 275-306 
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    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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    Annual Review of Biophysics and Biomolecular Structure 34 (2005), S. 267-294 
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Notes: With genome sequencing nearing completion for the model organisms used in biomedical research, there is a rapidly growing appreciation that proteomics, the study of covalent modification to proteins, and transcriptional regulation will likely dominate the research headlines in the next decade. Protein methylation plays a central role in both of these fields, as several different residues (Arg, Lys, Gln) are methylated in cells and methylation plays a central role in the "histone code" that regulates chromatin structure and impacts transcription. In some cases, a single lysine can be mono-, di-, or trimethylated, with different functional consequences for each of the three forms. This review describes structural aspects of methylation of histone lysine residues by two enzyme families with entirely different structural scaffolding (the SET proteins and Dot1p) and methylation of protein arginine residues by PRMTs.
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    Annual Review of Biophysics and Biomolecular Structure 34 (2005), S. 153-171 
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Notes: Potassium (K+) channels are tetrameric membrane-spanning proteins that provide a selective pore for the conductance of K+ across the cell membranes. These channels are most remarkable in their ability to discriminate K+ from Na+ by more than a thousandfold and conduct at a throughput rate near diffusion limit. The recent progress in the structural characterization of K+ channel provides us with a unique opportunity to understand their function at the atomic level. With their ability to go beyond static structures, molecular dynamics simulations based on atomic models can play an important role in shaping our view of how ion channels carry out their function. The purpose of this review is to summarize the most important findings from experiments and computations and to highlight a number of fundamental mechanistic questions about ion conduction and selectivity that will require further work.
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    Annual Review of Biophysics and Biomolecular Structure 34 (2005), S. 91-118 
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Notes: Proteins have become accessible targets for chemical synthesis. The basic strategy is to use native chemical ligation, Staudinger ligation, or other orthogonal chemical reactions to couple synthetic peptides. The ligation reactions are compatible with a variety of solvents and proceed in solution or on a solid support. Chemical synthesis enables a level of control on protein composition that greatly exceeds that attainable with ribosome-mediated biosynthesis. Accordingly, the chemical synthesis of proteins is providing previously unattainable insight into the structure and function of proteins.
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    Annual Review of Biophysics and Biomolecular Structure 34 (2005), S. 71-90 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Notes: Despite the central importance of peripheral membrane proteins to cellular signaling and metabolic pathways, the structures of protein-membrane interfaces remain largely inaccessible to high-resolution structural methods. In recent years a number of laboratories have contributed to the development of an electron paramagnetic resonance (EPR) power saturation approach that utilizes site-directed spin labeling to determine the key geometric parameters of membrane-docked proteins, including their penetration depths and angular orientations relative to the membrane surface. Representative applications to Ca2+-activated, membrane-docking C2 domains are described.
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    Annual Review of Biophysics and Biomolecular Structure 34 (2005), S. 119-151 
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Notes: Research in the past decade has revealed that many cytosolic proteins are recruited to different cellular membranes to form protein-protein and lipid-protein interactions during cell signaling and membrane trafficking. Membrane recruitment of these peripheral proteins is mediated by a growing number of modular membrane-targeting domains, including C1, C2, PH, FYVE, PX, ENTH, ANTH, BAR, FERM, and tubby domains, that recognize specific lipid molecules in the membranes. Structural studies of these membrane-targeting domains demonstrate how they specifically recognize their cognate lipid ligands. However, the mechanisms by which these domains and their host proteins are recruited to and interact with various cell membranes are only beginning to unravel with recent computational studies, in vitro membrane binding studies using model membranes, and cellular translocation studies using fluorescent protein-tagged proteins. This review summarizes the recent progress in our understanding of how the kinetics and energetics of membrane-protein interactions are regulated during the cellular membrane targeting and activation of peripheral proteins.
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    Annual Review of Biophysics and Biomolecular Structure 34 (2005), S. 173-199 
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Notes: Water plays a central role in the structures and properties of biomoleculesĐ??proteins, nucleic acids, and membranesĐ??and in their interactions with ligands and drugs. Over the past half century, our understanding of water has been advanced significantly owing to theoretical and computational modeling. However, like the blind men and the elephant, different models describe different aspects of water's behavior. The trend in water modeling has been toward finer-scale properties and increasing structural detail, at increasing computational expense. Recently, our labs and others have moved in the opposite direction, toward simpler physical models, focusing on more global propertiesĐ??water's thermodynamics, phase diagram, and solvation properties, for exampleĐ??and toward less computational expense. Simplified models can guide a better understanding of water in ways that complement what we learn from more complex models. One ultimate goal is more tractable models for computer simulations of biomolecules. This review gives a perspective from simple models on how the physical properties of waterĐ??as a pure liquid and as a solventĐ??derive from the geometric and hydrogen bonding properties of water.
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  • 99
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 34 (2005), S. 379-398 
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Notes: Structural data on protein-DNA complexes provide clues for understanding the mechanism of protein-DNA recognition. Although the structures of a large number of protein-DNA complexes are known, the mechanisms underlying their specific binding are still only poorly understood. Analysis of these structures has shown that there is no simple one-to-one correspondence between bases and amino acids within protein-DNA complexes; nevertheless, the observed patterns of interaction carry important information on the mechanisms of protein-DNA recognition. In this review, we show how the patterns of interaction, either observed in known structures or derived from computer simulations, confer recognition specificity, and how they can be used to examine the relationship between structure and specificity and to predict target DNA sequences used by regulatory proteins.
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  • 100
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biophysics and Biomolecular Structure 34 (2005), S. 319-349 
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Notes: Progress in experimental and theoretical biology is likely to provide us with the opportunity to assemble detailed predictive models of mammalian cells. Using a functional format to describe the organization of mammalian cells, we describe current approaches for developing qualitative and quantitative models using data from a variety of experimental sources. Recent developments and applications of graph theory to biological networks are reviewed. The use of these qualitative models to identify the topology of regulatory motifs and functional modules is discussed. Cellular homeostasis and plasticity are interpreted within the framework of balance between regulatory motifs and interactions between modules. From this analysis we identify the need for detailed quantitative models on the basis of the representation of the chemistry underlying the cellular process. The use of deterministic, stochastic, and hybrid models to represent cellular processes is reviewed, and an initial integrated approach for the development of large-scale predictive models of a mammalian cell is presented.
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