Sample records for source receptor relationships

  1. Historical and Future Trends in Global Source-receptor Relationships of Mercury

    NASA Astrophysics Data System (ADS)

    Chen, L.; Zhang, W.; Wang, X.

    2017-12-01

    Growing concerns about the risk associated with increasing environmental Mercury (Hg) levels have resulted in a focus on the relationships between intercontinental emitted and accumulated Hg. We use a global biogeochemical Hg model with eight continental regions and a global ocean to evaluate the legacy impacts of historical anthropogenic releases (2000 BC to 2008 AD) on global source-receptor relationships of Hg. The legacy impacts of historical anthropogenic releases are confirmed to be significant on the source-receptor relationships according to our results. Historical anthropogenic releases from Asia account for 8% of total soil Hg in North America, which is smaller than the proportion ( 17%) from previous studies. The largest contributors to the global oceanic Hg are historical anthropogenic releases from North America (26%), Asia (16%), Europe (14%) and South America (14%). Although anthropogenic releases from Asia have exceeded North America since the 1970s, source contributions to global Hg receptors from Asia have not exceeded North America so far. Future projections indicate that if Hg emissions are not effectively controlled, Asia will exceed North America as the largest contributor to the global ocean in 2019 and this has a long-term adverse impact on the future environment. For the Arctic Ocean, historical anthropogenic release from North America contributes most to the oceanic Hg reservoir and future projections reveal that the legacy impacts of historical releases from mid-latitudes would lead to the potential of rising Hg in the Arctic Ocean in the future decades, which calls for more effective Hg controls on mid-latitude releases.

  2. Historical and future trends in global source-receptor relationships of mercury.

    PubMed

    Chen, Long; Zhang, Wei; Zhang, Yanxu; Tong, Yindong; Liu, Maodian; Wang, Huanhuan; Xie, Han; Wang, Xuejun

    2018-01-01

    Growing concern about the risk associated with increasing environmental mercury (Hg) concentrations has resulted in a focus on the relationships between intercontinental emitted and accumulated Hg. We use a global biogeochemical Hg model with 8 continental regions and a global ocean to evaluate the legacy impacts of historical anthropogenic releases (2000BCE to 2008AD) on global source-receptor relationships of Hg. Legacy impacts of historical anthropogenic releases are confirmed to be significant on the source-receptor relationships according to our results. Historical anthropogenic releases from Asia account for 8% of total soil Hg in North America, which is smaller than the proportion (~17%) from previous studies. The largest contributors to the global oceanic Hg are historical anthropogenic releases from North America (26%), Asia (16%), Europe (14%) and South America (14%). Although anthropogenic releases from Asia have exceeded North America since the 1970s, source contributions to global Hg receptors from Asia have not exceeded North America so far. Future projections indicate that if Hg emissions are not effectively controlled, Asia will exceed North America as the largest contributor to the global ocean in 2019 and this has a long-term adverse impact on the future environment. For the Arctic Ocean, historical anthropogenic release from North America contributes most to the oceanic Hg reservoir and future projections reveal that the legacy impacts of historical releases from mid-latitudes would lead to the potential of rising Hg in the Arctic Ocean in the future decades, which calls for more effective Hg controls on mid-latitude releases. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Aerosol Source Attributions and Source-Receptor Relationships Across the Northern Hemisphere

    NASA Technical Reports Server (NTRS)

    Bian, Huisheng; Chin, Mian; Kucsera, Tom; Pan, Xiaohua; Darmenov, Anton; Colarco, Peter; Torres, Omar; Shults, Michael

    2014-01-01

    Emissions and long-range transport of air pollution pose major concerns on air quality and climate change. To better assess the impact of intercontinental transport of air pollution on regional and global air quality, ecosystems, and near-term climate change, the UN Task Force on Hemispheric Transport of Air Pollution (HTAP) is organizing a phase II activity (HTAP2) that includes global and regional model experiments and data analysis, focusing on ozone and aerosols. This study presents the initial results of HTAP2 global aerosol modeling experiments. We will (a) evaluate the model results with surface and aircraft measurements, (b) examine the relative contributions of regional emission and extra-regional source on surface PM concentrations and column aerosol optical depth (AOD) over several NH pollution and dust source regions and the Arctic, and (c) quantify the source-receptor relationships in the pollution regions that reflect the sensitivity of regional aerosol amount to the regional and extra-regional emission reductions.

  4. Air Pollution Source/receptor Relationships in South Coast Air Basin, CA

    NASA Astrophysics Data System (ADS)

    Gao, Ning

    This research project includes the application of some existing receptor models to study the air pollution source/receptor relationships in the South Coast Air Basin (SoCAB) of southern California, the development of a new receptor model and the testing and the modifications of some existing models. These existing receptor models used include principal component factor analysis (PCA), potential source contribution function (PSCF) analysis, Kohonen's neural network combined with Prim's minimal spanning tree (TREE-MAP), and direct trilinear decomposition followed by a matrix reconstruction. The ambient concentration measurements used in this study are a subset of the data collected during the 1987 field exercise of Southern California Air Quality Study (SCAQS). It consists of a number of gaseous and particulate pollutants analyzed from samples collected by SCAQS samplers at eight sampling sites, Anaheim, Azusa, Burbank, Claremont, Downtown Los Angeles, Hawthorne, Long Beach, and Rubidoux. Based on the information of emission inventories, meteorology and ambient concentrations, this receptor modeling study has revealed mechanisms that influence the air quality in SoCAB. Some of the mechanisms affecting the air quality in SoCAB that were revealed during this study include the following aspects. The SO_2 collected at sampling sites is mainly contributed by refineries in the coastal area and the ships equipped with oil-fired boilers off shore. Combustion of fossil fuel by automobiles dominates the emission of NO_{rm x} that is subsequently transformed and collected at sampling sites. Electric power plants also contribute HNO_3 to the sampling sites. A large feedlot in the eastern region of SoCAB has been identified as the major source of NH_3. Possible contributions from other industrial sources such as smelters and incinerators were also revealed. The results of this study also suggest the possibility of DMS (dimethylsulfide) and NH_3 emissions from off-shore sediments

  5. Global Source-Receptor Relationships for Mercury Deposition Under Present-Day and 2050 Emissions Scenarios

    PubMed Central

    Corbitt, Elizabeth S.; Jacob, Daniel J.; Holmes, Christopher D.; Streets, David G.; Sunderland, Elsie M.

    2011-01-01

    Global policies regulating anthropogenic mercury require an understanding of the relationship between emitted and deposited mercury on intercontinental scales. Here we examine source-receptor relationships for present-day conditions and for four 2050 IPCC scenarios encompassing a range of economic development and environmental regulation projections. We use the GEOS-Chem global model to track mercury from its point of emission through rapid cycling in surface ocean and land reservoirs to its accumulation in longer-lived ocean and soil pools. Deposited mercury has a local component (emitted HgII, lifetime of 3.7 days against deposition) and a global component (emitted Hg0, lifetime of 6 months against deposition). Fast recycling of deposited mercury through photoreduction of HgII and re-emission of Hg0 from surface reservoirs (ice, land, surface ocean) increases the effective lifetime of anthropogenic mercury to 9 months against loss to legacy reservoirs (soil pools and the subsurface ocean). This lifetime is still sufficiently short that source-receptor relationships have a strong hemispheric signature. Asian emissions are the largest source of anthropogenic deposition to all ocean basins, though there is also regional source influence from upwind continents. Current anthropogenic emissions account for only about one-third of mercury deposition to the global ocean with the remainder from natural and legacy sources. However, controls on anthropogenic emissions would have the added benefit of reducing the legacy mercury re-emitted to the atmosphere. Better understanding is needed of the timescales for transfer of mercury from active pools to stable geochemical reservoirs. PMID:22050654

  6. Source-receptor matrix calculation with a Source-receptor matrix calculation with a backward mode

    NASA Astrophysics Data System (ADS)

    Seibert, P.; Frank, A.

    2003-08-01

    The possibility to calculate linear-source receptor relationships for the transport of atmospheric trace substances with a Lagrangian particle dispersion model (LPDM) running in backward mode is shown and presented with many tests and examples. The derivation includes the action of sources and of any first-order processes (transformation with prescribed rates, dry and wet deposition, radioactive decay, ...). The backward mode is computationally advantageous if the number of receptors is less than the number of sources considered. The combination of an LPDM with the backward (adjoint) methodology is especially attractive for the application to point measurements, which can be handled without artificial numerical diffusion. Practical hints are provided for source-receptor calculations with different settings, both in forward and backward mode. The equivalence of forward and backward calculations is shown in simple tests for release and sampling of particles, pure wet deposition, pure convective redistribution and realistic transport over a short distance. Furthermore, an application example explaining measurements of Cs-137 in Stockholm as transport from areas contaminated heavily in the Chernobyl disaster is included.

  7. Source contribution analysis of surface particulate polycyclic aromatic hydrocarbon concentrations in northeastern Asia by source-receptor relationships.

    PubMed

    Inomata, Yayoi; Kajino, Mizuo; Sato, Keiichi; Ohara, Toshimasa; Kurokawa, Jun-ichi; Ueda, Hiromasa; Tang, Ning; Hayakawa, Kazuichi; Ohizumi, Tsuyoshi; Akimoto, Hajime

    2013-11-01

    We analyzed the source-receptor relationships for particulate polycyclic aromatic hydrocarbon (PAH) concentrations in northeastern Asia using an aerosol chemical transport model. The model successfully simulated the observed concentrations. In Beijing (China) benzo[a]pyren (BaP) concentrations are due to emissions from its own domain. In Noto, Oki and Tsushima (Japan), transboundary transport from northern China (>40 °N, 40-60%) and central China (30-40 °N, 10-40%) largely influences BaP concentrations from winter to spring, whereas the relative contribution from central China is dominant (90%) in Hedo. In the summer, the contribution from Japanese domestic sources increases (40-80%) at the 4 sites. Contributions from Japan and Russia are additional source of BaP over the northwestern Pacific Ocean in summer. The contribution rates for the concentrations from each domain are different among PAH species depending on their particulate phase oxidation rates. Reaction with O3 on particulate surfaces may be an important component of the PAH oxidation processes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Adding spatial flexibility to source-receptor relationships for air quality modeling.

    PubMed

    Pisoni, E; Clappier, A; Degraeuwe, B; Thunis, P

    2017-04-01

    To cope with computing power limitations, air quality models that are used in integrated assessment applications are generally approximated by simpler expressions referred to as "source-receptor relationships (SRR)". In addition to speed, it is desirable for the SRR also to be spatially flexible (application over a wide range of situations) and to require a "light setup" (based on a limited number of full Air Quality Models - AQM simulations). But "speed", "flexibility" and "light setup" do not naturally come together and a good compromise must be ensured that preserves "accuracy", i.e. a good comparability between SRR results and AQM. In this work we further develop a SRR methodology to better capture spatial flexibility. The updated methodology is based on a cell-to-cell relationship, in which a bell-shape function links emissions to concentrations. Maintaining a cell-to-cell relationship is shown to be the key element needed to ensure spatial flexibility, while at the same time the proposed approach to link emissions and concentrations guarantees a "light set-up" phase. Validation has been repeated on different areas and domain sizes (countries, regions, province throughout Europe) for precursors reduced independently or contemporarily. All runs showed a bias around 10% between the full AQM and the SRR. This methodology allows assessing the impact on air quality of emission scenarios applied over any given area in Europe (regions, set of regions, countries), provided that a limited number of AQM simulations are performed for training.

  9. PM SOURCE APPORTIONMENT/RECEPTOR MODELING

    EPA Science Inventory

    Source apportionment (receptor) models are mathematical procedures for identifying and quantifying the sources of ambient air pollutants and their effects at a site (the receptor), primarily on the basis of species concentration measurements at the receptor, and generally without...

  10. A Novel Approach for Determining Source-Receptor Relationships of Aerosols in Model Simulations

    NASA Astrophysics Data System (ADS)

    Ma, P.; Gattiker, J.; Liu, X.; Rasch, P. J.

    2013-12-01

    The climate modeling community usually performs sensitivity studies in the 'one-factor-at-a-time' fashion. However, owing to the a-priori unknown complexity and nonlinearity of the climate system and simulation response, it is computationally expensive to systematically identify the cause-and-effect of multiple factors in climate models. In this study, we use a Gaussian Process emulator, based on a small number of Community Atmosphere Model Version 5.1 (CAM5) simulations (constrained by meteorological reanalyses) using a Latin Hypercube experimental design, to demonstrate that it is possible to characterize model behavior accurately and very efficiently without any modifications to the model itself. We use the emulator to characterize the source-receptor relationships of black carbon (BC), focusing specifically on describing the constituent burden and surface deposition rates from emissions in various regions. Our results show that the emulator is capable of quantifying the contribution of aerosol burden and surface deposition from different source regions, finding that most of current Arctic BC comes from remote sources. We also demonstrate that the sensitivity of the BC burdens to emission perturbations differs for various source regions. For example, the emission growth in Africa where dry convections are strong results in a moderate increase of BC burden over the globe while the same emission growth in the Arctic leads to a significant increase of local BC burdens and surface deposition rates. These results provide insights into the dynamical, physical, and chemical processes of the climate model, and the conclusions may have policy implications for making cost-effective global and regional pollution management strategies.

  11. Source-receptor matrix calculation with a Lagrangian particle dispersion model in backward mode

    NASA Astrophysics Data System (ADS)

    Seibert, P.; Frank, A.

    2003-04-01

    A method for the calculation of source-receptor (s-r) relationships (sensitivity of a trace substance concentration at some place and time to emission at some place and time) with Lagrangian particle models has been derived and presented previously (Air Pollution Modeling and its Application XIV, Proc. of ITM Boulder 2000). Now, the generalisation to any linear s-r relationship, including dry and wet deposition, decay etc., is presented. It was implemented in the model FLEXPART and tested extensively in idealised set-ups. These tests turned out to be very useful for finding minor model bugs and inaccuracies, and can be recommended generally for model testing. Recently, a convection scheme has been integrated in FLEXPART which was also tested. Both source and receptor can be specified in mass mixing ratio or mass units. Properly taking care of this is quite relevant for sources and receptors at different levels in the atmosphere. Furthermore, we present a test with the transport of aerosol-bound Caesium-137 from the areas contaminated by the Chernobyl disaster to Stockholm during one month.

  12. Using air quality modeling to study source-receptor relationships between nitrogen oxides emissions and ozone exposures over the United States.

    PubMed

    Tong, Daniel Q; Muller, Nicholas Z; Kan, Haidong; Mendelsohn, Robert O

    2009-11-01

    Human exposure to ambient ozone (O(3)) has been linked to a variety of adverse health effects. The ozone level at a location is contributed by local production, regional transport, and background ozone. This study combines detailed emission inventory, air quality modeling, and census data to investigate the source-receptor relationships between nitrogen oxides (NO(x)) emissions and population exposure to ambient O(3) in 48 states over the continental United States. By removing NO(x) emissions from each state one at a time, we calculate the change in O(3) exposures by examining the difference between the base and the sensitivity simulations. Based on the 49 simulations, we construct state-level and census region-level source-receptor matrices describing the relationships among these states/regions. We find that, for 43 receptor states, cumulative NO(x) emissions from upwind states contribute more to O(3) exposures than the state's own emissions. In-state emissions are responsible for less than 15% of O(3) exposures in 90% of U.S. states. A state's NO(x) emissions can influence 2 to 40 downwind states by at least a 0.1 ppbv change in population-averaged O(3) exposure. The results suggest that the U.S. generally needs a regional strategy to effectively reduce O(3) exposures. But the current regional emission control program in the U.S. is a cap-and-trade program that assumes the marginal damage of every ton of NO(x) is equal. In this study, the average O(3) exposures caused by one ton of NO(x) emissions ranges from -2.0 to 2.3 ppm-people-hours depending on the state. The actual damage caused by one ton of NO(x) emissions varies considerably over space.

  13. Source-Receptor Relationship Analysis of the Atmospheric Deposition of PAHs Subject to Long-Range Transport in Northeast Asia.

    PubMed

    Inomata, Yayoi; Kajino, Mizuo; Sato, Keiichi; Kurokawa, Junichi; Tang, Ning; Ohara, Toshimasa; Hayakawa, Kazuichi; Ueda, Hiromasa

    2017-07-18

    The source-receptor relationship analysis of PAH deposition in Northeast Asia was investigated using an Eulerian regional-scale aerosol chemical transport model. Dry deposition (DD) of PAH was controlled by wind flow patterns, whereas wet deposition (WD) depended on precipitation in addition to wind flow patterns. The contribution of WD was approximately 50-90% of the total deposition, except during winter in Northern China (NCHN) and Eastern Russia (ERUS) because of the low amount of precipitation. The amount of PAH deposition showed clear seasonal variation and was high in winter and low in summer in downwind (South Korea, Japan) and oceanic-receptor regions. In the downwind region, the contributions from NCHN (WD 28-52%; DD 54-55%) and Central China (CCHN) (WD 43-65%; DD 33-38%) were large in winter, whereas self-contributions (WD 20-51%; DD 79-81%) were relatively high in summer. In the oceanic-receptor region, the deposition amount decreased with distance from the Asian continent. The amount of DD was strongly influenced by emissions from neighboring domains. The contributions of WD from NCHN (16-20%) and CCHN (28-35%) were large. The large contributions from China in summer to the downwind region were linked to vertical transport of PAHs over the Asian continent associated with convection.

  14. Source-receptor matrix calculation with a Lagrangian particle dispersion model in backward mode

    NASA Astrophysics Data System (ADS)

    Seibert, P.; Frank, A.

    2004-01-01

    The possibility to calculate linear-source receptor relationships for the transport of atmospheric trace substances with a Lagrangian particle dispersion model (LPDM) running in backward mode is shown and presented with many tests and examples. This mode requires only minor modifications of the forward LPDM. The derivation includes the action of sources and of any first-order processes (transformation with prescribed rates, dry and wet deposition, radioactive decay, etc.). The backward mode is computationally advantageous if the number of receptors is less than the number of sources considered. The combination of an LPDM with the backward (adjoint) methodology is especially attractive for the application to point measurements, which can be handled without artificial numerical diffusion. Practical hints are provided for source-receptor calculations with different settings, both in forward and backward mode. The equivalence of forward and backward calculations is shown in simple tests for release and sampling of particles, pure wet deposition, pure convective redistribution and realistic transport over a short distance. Furthermore, an application example explaining measurements of Cs-137 in Stockholm as transport from areas contaminated heavily in the Chernobyl disaster is included.

  15. Atmospheric Aerosol Source-Receptor Relationships: The Role of Coal-Fired Power Plants

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Allen L. Robinson; Spyros N. Pandis; Cliff I. Davidson

    2005-12-01

    This report describes the technical progress made on the Pittsburgh Air Quality Study (PAQS) during the period of March 2005 through August 2005. Significant progress was made this project period on the source characterization, source apportionment, and deterministic modeling activities. This report highlights new data on road dust, vegetative detritus and motor vehicle emissions. For example, the results show significant differences in the composition in urban and rural road dust. A comparison of the organic of the fine particulate matter in the tunnel with the ambient provides clear evidence of the significant contribution of vehicle emissions to ambient PM. Themore » source profiles developed from this work are being used by the source-receptor modeling activities. The report presents results on the spatial distribution of PMF-factors. The results can be grouped into three different categories: regional sources, local sources, or potentially both regional and local sources. Examples of the regional sources are the sulfate and selenium PMF-factors which most likely-represent coal fired power plants. Examples of local sources are the specialty steel and lead factors. There is reasonable correspondence between these apportionments and data from the EPA TRI and AIRS emission inventories. Detailed comparisons between PMCAMx predictions and measurements by the STN and IMPROVE measurements in the Eastern US are presented. Comparisons were made for the major aerosol components and PM{sub 2.5} mass in July 2001, October 2001, January 2002, and April 2002. The results are encouraging with average fraction biases for most species less than 0.25. The improvement of the model performance during the last two years was mainly due to the comparison of the model predictions with the continuous measurements in the Pittsburgh Supersite. Major improvements have included the descriptions: of ammonia emissions (CMU inventory), night time nitrate chemistry, EC emissions and their

  16. Using an Explicit Emission Tagging Method in Global Modeling of Source-Receptor Relationships for Black Carbon in the Arctic: Variations, Sources and Transport Pathways

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Hailong; Rasch, Philip J.; Easter, Richard C.

    2014-11-27

    We introduce an explicit emission tagging technique in the Community Atmosphere Model to quantify source-region-resolved characteristics of black carbon (BC), focusing on the Arctic. Explicit tagging of BC source regions without perturbing the emissions makes it straightforward to establish source-receptor relationships and transport pathways, providing a physically consistent and computationally efficient approach to produce a detailed characterization of the destiny of regional BC emissions and the potential for mitigation actions. Our analysis shows that the contributions of major source regions to the global BC burden are not proportional to the respective emissions due to strong region-dependent removal rates and lifetimes,more » while the contributions to BC direct radiative forcing show a near-linear dependence on their respective contributions to the burden. Distant sources contribute to BC in remote regions mostly in the mid- and upper troposphere, having much less impact on lower-level concentrations (and deposition) than on burden. Arctic BC concentrations, deposition and source contributions all have strong seasonal variations. Eastern Asia contributes the most to the wintertime Arctic burden. Northern Europe emissions are more important to both surface concentration and deposition in winter than in summer. The largest contribution to Arctic BC in the summer is from Northern Asia. Although local emissions contribute less than 10% to the annual mean BC burden and deposition within the Arctic, the per-emission efficiency is much higher than for major non-Arctic sources. The interannual variability (1996-2005) due to meteorology is small in annual mean BC burden and radiative forcing but is significant in yearly seasonal means over the Arctic. When a slow aging treatment of BC is introduced, the increase of BC lifetime and burden is source-dependent. Global BC forcing-per-burden efficiency also increases primarily due to changes in BC vertical

  17. A Novel Approach for Determining Source–Receptor Relationships in Model Simulations: A Case Study of Black Carbon Transport in Northern Hemisphere Winter

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ma, Po-Lun; Gattiker, J. R.; Liu, Xiaohong

    2013-06-27

    A Gaussian process (GP) emulator is applied to quantify the contribution of local and remote emissions of black carbon (BC) on the BC concentrations in different regions using a Latin Hypercube sampling strategy for emission perturbations in the offline version of the Community Atmosphere Model Version 5.1 (CAM5) simulations. The source-receptor relationships are computed based on simulations constrained by a standard free-running CAM5 simulation and the ERA-Interim reanalysis product. The analysis demonstrates that the emulator is capable of retrieving the source-receptor relationships based on a small number of CAM5 simulations. Most regions are found susceptible to their local emissions. Themore » emulator also finds that the source-receptor relationships retrieved from the model-driven and the reanalysis-driven simulations are very similar, suggesting that the simulated circulation in CAM5 resembles the assimilated meteorology in ERA-Interim. The robustness of the results provides confidence for applying the emulator to detect dose-response signals in the climate system.« less

  18. Multi-model Estimates of Intercontinental Source-Receptor Relationships for Ozone Pollution

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Fiore, A M; Dentener, F J; Wild, O

    2008-10-16

    Understanding the surface O{sub 3} response over a 'receptor' region to emission changes over a foreign 'source' region is key to evaluating the potential gains from an international approach to abate ozone (O{sub 3}) pollution. We apply an ensemble of 21 global and hemispheric chemical transport models to estimate the spatial average surface O{sub 3} response over East Asia (EA), Europe (EU), North America (NA) and South Asia (SA) to 20% decreases in anthropogenic emissions of the O{sub 3} precursors, NO{sub x}, NMVOC, and CO (individually and combined), from each of these regions. We find that the ensemble mean surfacemore » O{sub 3} concentrations in the base case (year 2001) simulation matches available observations throughout the year over EU but overestimates them by >10 ppb during summer and early fall over the eastern U.S. and Japan. The sum of the O{sub 3} responses to NO{sub x}, CO, and NMVOC decreases separately is approximately equal to that from a simultaneous reduction of all precursors. We define a continental-scale 'import sensitivity' as the ratio of the O{sub 3} response to the 20% reductions in foreign versus 'domestic' (i.e., over the source region itself) emissions. For example, the combined reduction of emissions from the 3 foreign regions produces an ensemble spatial mean decrease of 0.6 ppb over EU (0.4 ppb from NA), less than the 0.8 ppb from the reduction of EU emissions, leading to an import sensitivity ratio of 0.7. The ensemble mean surface O{sub 3} response to foreign emissions is largest in spring and late fall (0.7-0.9 ppb decrease in all regions from the combined precursor reductions in the 3 foreign regions), with import sensitivities ranging from 0.5 to 1.1 (responses to domestic emission reductions are 0.8-1.6 ppb). High O{sub 3} values are much more sensitive to domestic emissions than to foreign emissions, as indicated by lower import sensitivities of 0.2 to 0.3 during July in EA, EU, and NA when O{sub 3} levels are typically

  19. Development of Source-Receptor matrix over South Korea in support of GAINS-Korea model

    NASA Astrophysics Data System (ADS)

    Choi, K. C.; Woo, J. H.; Kim, H. K.; Lee, Y. M.; Kim, Y.; Heyes, C.; Lee, J. B.; Song, C. K.; Han, J.

    2014-12-01

    A comprehensive and combined analysis of air pollution and climate change could reveal important synergies of emission control measures, which could be of high policy relevance. IIASA's GAINS model (The Greenhouse gas - Air pollution Interactions and Synergies) has been developed as a tool to identify emission control strategies that achieve given targets on air quality and greenhouse gas emissions at least costs. The GAINS-Korea Model, which is being jointly developed by Konkuk University and IIASA, should play an important role in understanding the impact of air quality improvements across the regions in Korea. Source-Receptor relationships (S-R) is an useful methodology in air pollution studies to determine the areas of origin of chemical compounds at receptor point, and thus be able to target actions to reduce pollutions. The GAINS model can assess the impact of emission reductions of sources on air quality in receptor regions based on S-R matrix, derived from chemical transport model. In order to develop S-R matrix for GAINS-Korea, the CAMx model with PSAT/OSAT tools was applied in this study. The coarse domain covers East Asia, and a nesting domain as main research area was used for Korea peninsula. To evaluate of S-R relationships, a modeling domain is divided into sixteen regions over South Korea with three outside of S. Korea countries (China, N. Korea and Japan) for estimating transboundary contributions. The results of our analysis will be presented at the conference.

  20. A study on the uncertainty based on Meteorological fields on Source-receptor Relationships for Total Nitrate in the Northeast Asia

    NASA Astrophysics Data System (ADS)

    Sunwoo, Y.; Park, J.; Kim, S.; Ma, Y.; Chang, I.

    2010-12-01

    Northeast Asia hosts more than one third of world population and the emission of pollutants trends to increase rapidly, because of economic growth and the increase of the consumption in high energy intensity. In case of air pollutants, especially, its characteristics of emissions and transportation become issued nationally, in terms of not only environmental aspects, but also long-range transboundary transportation. In meteorological characteristics, westerlies area means what air pollutants that emitted from China can be delivered to South Korea. Therefore, considering meteorological factors can be important to understand air pollution phenomena. In this study, we used MM5(Fifth-Generation Mesoscale Model) and WRF(Weather Research and Forecasting Model) to produce the meteorological fields. We analyzed the feature of physics option in each model and the difference due to characteristic of WRF and MM5. We are trying to analyze the uncertainty of source-receptor relationships for total nitrate according to meteorological fields in the Northeast Asia. We produced the each meteorological fields that apply the same domain, same initial and boundary conditions, the best similar physics option. S-R relationships in terms of amount and fractional number for total nitrate (sum of N from HNO3, nitrate and PAN) were calculated by EMEP method 3.

  1. Receptor modeling for source apportionment of polycyclic aromatic hydrocarbons in urban atmosphere.

    PubMed

    Singh, Kunwar P; Malik, Amrita; Kumar, Ranjan; Saxena, Puneet; Sinha, Sarita

    2008-01-01

    This study reports source apportionment of polycyclic aromatic hydrocarbons (PAHs) in particulate depositions on vegetation foliages near highway in the urban environment of Lucknow city (India) using the principal components analysis/absolute principal components scores (PCA/APCS) receptor modeling approach. The multivariate method enables identification of major PAHs sources along with their quantitative contributions with respect to individual PAH. The PCA identified three major sources of PAHs viz. combustion, vehicular emissions, and diesel based activities. The PCA/APCS receptor modeling approach revealed that the combustion sources (natural gas, wood, coal/coke, biomass) contributed 19-97% of various PAHs, vehicular emissions 0-70%, diesel based sources 0-81% and other miscellaneous sources 0-20% of different PAHs. The contributions of major pyrolytic and petrogenic sources to the total PAHs were 56 and 42%, respectively. Further, the combustion related sources contribute major fraction of the carcinogenic PAHs in the study area. High correlation coefficient (R2 > 0.75 for most PAHs) between the measured and predicted concentrations of PAHs suggests for the applicability of the PCA/APCS receptor modeling approach for estimation of source contribution to the PAHs in particulates.

  2. WRF dynamically downscaling PCM data for climate change impacts in California & application of a signal technique to the source-receptor relationship in WRF

    NASA Astrophysics Data System (ADS)

    Zhao, Zhan

    2009-12-01

    My dissertation consists of three parts. Parts I and II are focused on the climate change impacts on meteorology and air quality conditions in California (CA), while Part III is focused on the source-receptor relationship. The WRF model is applied to dynamically downscaled PCM data, with a horizontal resolution of approximately 2.8°x2.8°, to 4km resolution under the Business as Usual (BAU) scenario. The dynamical downscaling method could retain the large-scale features of the global simulations with more meso-scale details. A seven year simulation is conducted for both present (2000˜2006) and future (2047˜2053) in order to avoid the El Nino related inter-annual variation. In order to assess the PCM data quality and estimate the simulation error inherited from the PCM data bias, the present seven year simulations are driven by NCEP's Global Forecast System (GFS) data with the same model configuration. Part I is focused on the comparisons of the present time climatology from the two sets of simulations and the driving global datasets (i.e., PCM vs. GFS), which illustrate that the biases of the downscaling results are mostly inherited from the driving GCM. The imprecise prediction for the location and strength of the Pacific Subtropical High (PSH) is a main source of the PCM data bias. The analysis also implies that using the simulation results driven by PCM data as the input of the air quality model will underrate the air pollution problems in CA. The regional averaged statistics of the downscaling results compared to observational data show that both the surface temperature and wind speed were overestimate for most times of the year, and WRF preformed better during summer than winter. The low summer PBLH in the San Joaquin Valley (SJV) is addressed, and two reasons causing this are the dominance of a high pressure system over the valley and, to a lesser extent, the valley wind at daytime during summer. Part II is focused on the future change of meteorology and

  3. α1b-Adrenergic Receptor Localization and Relationship to the D1-Dopamine Receptor in the Rat Nucleus Accumbens.

    PubMed

    Mitrano, Darlene A; Jackson, Kelsey; Finley, Samantha; Seeley, Allison

    2018-02-10

    The α1-adrenergic receptors (α1ARs) have been implicated in numerous actions of the brain, including attention and wakefulness. Additionally, they have been identified as contributing to disorders of the brain, such as drug addiction, and recent work has shown a role of these receptors in relapse to psychostimulants. While some functionality is known, the actual subcellular localization of the subtypes of the α1ARs remains to be elucidated. Further, their anatomical relationship to receptors for other neurotransmitters, such as dopamine (DA), remains unclear. Therefore, using immunohistochemistry and electron microscopy techniques, this study describes the subcellular localization of the α1b-adrenergic receptor (α1bAR), the subtype most tied to relapse behaviors, as well as its relationship to the D1-dopamine receptor (D1R) in both the shell and core of the rat nucleus accumbens (NAc). Overall, α1bARs were found in unmyelinated axons and axon terminals with some labeling in dendrites. In accordance with other studies of the striatum, the D1R was found mainly in dendrites and spines; therefore, colocalization of the D1R with the α1bAR was rare postsynaptically. However, in the NAc shell, when the receptors were co-expressed in the same neuronal elements there was a trend for both receptors to be found on the plasma membrane, as opposed to the intracellular compartment. This study provides valuable anatomical information about the α1bAR and its relationship to the D1R and the regulation of DA and norepinephrine (NE) neurotransmission in the brain which have been examined previously. Published by Elsevier Ltd.

  4. Source-receptor relationships for PM2.5 during typical pollution episodes in the Pearl River Delta city cluster, China.

    PubMed

    Liu, Yiming; Hong, Yingying; Fan, Qi; Wang, Xuemei; Chan, Pakwai; Chen, Xiaoyang; Lai, Anqi; Wang, Mingjie; Chen, Xunlai

    2017-10-15

    Located in the Southern China monsoon region, pollution days in Pearl River Delta (PRD) were classified into "Western type", "Central type" or "Eastern type", with a relative percentage of 67%, 24% and 9%, respectively. Using this classification system, three typical pollution events were selected for numerical simulations using the WRF-Chem model. The source sensitivity method for anthropogenic emissions of PM 2.5 and its precursors was applied to identify the source-receptor relationships for PM 2.5 among 9 cities in PRD. For "Western type" case, the PRD region was under control of a high-pressure system with easterly prevailing winds. The PM 2.5 concentrations in the western PRD region were higher than those in the eastern region, with emissions from cities in the eastern PRD region having higher contributions. Within the PRD's urban cluster, PM 2.5 in Huizhou, Dongguan and Shenzhen was mainly derived from local emissions, whereas the PM 2.5 in the other cities was primarily derived from external transport. For "Eastern type" case, the PRD was influenced by Typhoon Soulik with westerly prevailing winds. Emissions from cities in the western PRD region had the highest impacts on the overall PM 2.5 concentration. PM 2.5 in Jiangmen and Foshan was primarily derived from local emissions. Regarding "Central type" case, the PRD region was under control of a uniform pressure field with low wind speed. PM 2.5 concentrations of each city were primarily caused by local emissions. Overall, wind flows played a significant role in the transport and spatial distribution of PM 2.5 across the PRD region. Ideally, local governments would be wise to establish joint prevention and control measures to reduce regional atmospheric pollution, especially for "Western type" pollution. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Source-receptor relationships for PM2.5 during typical pollution episodes in the Pearl River Delta city cluster, China

    NASA Astrophysics Data System (ADS)

    Fan, Q.; Liu, Y.; Hong, Y.; Wang, X.; Chan, P.; Chen, X.; Lai, A.; Wang, M.; Chen, X.

    2017-12-01

    Located in the Southern China monsoon region, pollution days in Pearl River Delta (PRD) were classified into "Western type", "Central type" or "Eastern type", with a relative percentage of 67%, 24% and 9%, respectively. Using this classification system, three typical pollution events were selected for numerical simulations using the WRF-Chem model. The source sensitivity method for anthropogenic emissions of PM2.5 and its precursors was applied to identify the source-receptor relationships for PM2.5 among 9 cities in PRD. For "Western type" case, the PRD region was under control of a high-pressure system with easterly prevailing winds. The PM2.5 concentrations in the western PRD region were higher than those in the eastern region, with emissions from cities in the eastern PRD region having higher contributions. Within the PRD's urban cluster, PM2.5 in Huizhou, Dongguan and Shenzhen was mainly derived from local emissions, whereas the PM2.5 in the other cities was primarily derived from external transport. For "Eastern type" case, the PRD was influenced by Typhoon Soulik with westerly prevailing winds. Emissions from cities in the western PRD region had the highest impacts on the overall PM2.5 concentration. PM2.5 in Jiangmen and Foshan was primarily derived from local emissions. Regarding "Central type" case, the PRD region was under control of a uniform pressure field with low wind speed. PM2.5 concentrations of each city were primarily caused by local emissions. Overall, wind flows played a significant role in the transport and spatial distribution of PM2.5 across the PRD region. Ideally, local governments would be wise to establish joint prevention and control measures to reduce regional atmospheric pollution, especially for "Western type" pollution.

  6. A shift in emission time profiles of fossil fuel combustion due to energy transitions impacts source receptor matrices for air quality.

    PubMed

    Hendriks, Carlijn; Kuenen, Jeroen; Kranenburg, Richard; Scholz, Yvonne; Schaap, Martijn

    2015-03-01

    Effective air pollution and short-lived climate forcer mitigation strategies can only be designed when the effect of emission reductions on pollutant concentrations and health and ecosystem impacts are quantified. Within integrated assessment modeling source-receptor relationships (SRRs) based on chemistry transport modeling are used to this end. Currently, these SRRs are made using invariant emission time profiles. The LOTOS-EUROS model equipped with a source attribution module was used to test this assumption for renewable energy scenarios. Renewable energy availability and thereby fossil fuel back up are strongly dependent on meteorological conditions. We have used the spatially and temporally explicit energy model REMix to derive time profiles for backup power generation. These time profiles were used in LOTOS-EUROS to investigate the effect of emission timing on air pollutant concentrations and SRRs. It is found that the effectiveness of emission reduction in the power sector is significantly lower when accounting for the shift in the way emissions are divided over the year and the correlation of emissions with synoptic situations. The source receptor relationships also changed significantly. This effect was found for both primary and secondary pollutants. Our results indicate that emission timing deserves explicit attention when assessing the impacts of system changes on air quality and climate forcing from short lived substances.

  7. Preliminary Results of the first European Source Apportionment intercomparison for Receptor and Chemical Transport Models

    NASA Astrophysics Data System (ADS)

    Belis, Claudio A.; Pernigotti, Denise; Pirovano, Guido

    2017-04-01

    Source Apportionment (SA) is the identification of ambient air pollution sources and the quantification of their contribution to pollution levels. This task can be accomplished using different approaches: chemical transport models and receptor models. Receptor models are derived from measurements and therefore are considered as a reference for primary sources urban background levels. Chemical transport model have better estimation of the secondary pollutants (inorganic) and are capable to provide gridded results with high time resolution. Assessing the performance of SA model results is essential to guarantee reliable information on source contributions to be used for the reporting to the Commission and in the development of pollution abatement strategies. This is the first intercomparison ever designed to test both receptor oriented models (or receptor models) and chemical transport models (or source oriented models) using a comprehensive method based on model quality indicators and pre-established criteria. The target pollutant of this exercise, organised in the frame of FAIRMODE WG 3, is PM10. Both receptor models and chemical transport models present good performances when evaluated against their respective references. Both types of models demonstrate quite satisfactory capabilities to estimate the yearly source contributions while the estimation of the source contributions at the daily level (time series) is more critical. Chemical transport models showed a tendency to underestimate the contribution of some single sources when compared to receptor models. For receptor models the most critical source category is industry. This is probably due to the variety of single sources with different characteristics that belong to this category. Dust is the most problematic source for Chemical Transport Models, likely due to the poor information about this kind of source in the emission inventories, particularly concerning road dust re-suspension, and consequently the

  8. Comparison of receptor models for source apportionment of the PM10 in Zaragoza (Spain).

    PubMed

    Callén, M S; de la Cruz, M T; López, J M; Navarro, M V; Mastral, A M

    2009-08-01

    Receptor models are useful to understand the chemical and physical characteristics of air pollutants by identifying their sources and by estimating contributions of each source to receptor concentrations. In this work, three receptor models based on principal component analysis with absolute principal component scores (PCA-APCS), Unmix and positive matrix factorization (PMF) were applied to study for the first time the apportionment of the airborne particulate matter less or equal than 10microm (PM10) in Zaragoza, Spain, during 1year sampling campaign (2003-2004). The PM10 samples were characterized regarding their concentrations in inorganic components: trace elements and ions and also organic components: polycyclic aromatic hydrocarbons (PAH) not only in the solid phase but also in the gas phase. A comparison of the three receptor models was carried out in order to do a more robust characterization of the PM10. The three models predicted that the major sources of PM10 in Zaragoza were related to natural sources (60%, 75% and 47%, respectively, for PCA-APCS, Unmix and PMF) although anthropogenic sources also contributed to PM10 (28%, 25% and 39%). With regard to the anthropogenic sources, while PCA and PMF allowed high discrimination in the sources identification associated with different combustion sources such as traffic and industry, fossil fuel, biomass and fuel-oil combustion, heavy traffic and evaporative emissions, the Unmix model only allowed the identification of industry and traffic emissions, evaporative emissions and heavy-duty vehicles. The three models provided good correlations between the experimental and modelled PM10 concentrations with major precision and the closest agreement between the PMF and PCA models.

  9. SOURCE APPORTIONMENT OF PHOENIX PM2.5 AEROSOL WITH THE UNMIX RECEPTOR MODEL

    EPA Science Inventory

    The multivariate receptor model Unmix has been used to analyze a 3-yr PM2.5 ambient aerosol data set collected in Phoenix, AZ, beginning in 1995. The analysis generated source profiles and overall percentage source contribution estimates (SCE) for five source categories: ga...

  10. Sex- and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor.

    PubMed

    Mirabito, Katrina M; Hilliard, Lucinda M; Kett, Michelle M; Brown, Russell D; Booth, Sean C; Widdop, Robert E; Moritz, Karen M; Evans, Roger G; Denton, Kate M

    2014-10-15

    Sex hormones regulate the renin-angiotensin system. For example, estrogen enhances expression of the angiotensin type 2 receptor. We hypothesized that activation of the angiotensin type 2 receptor shifts the chronic pressure-natriuresis relationship leftward in females compared with males and that this effect is lost with age. Mean arterial pressure was measured by radiotelemetry in adult (4 mo old) and aged (14 mo old) wild-type and angiotensin type 2 receptor knockout male and female mice. Chronic pressure-natriuresis curves were constructed while mice were maintained on a normal-salt (0.26%) diet and following 6 days of high salt (5.0%) diet. Mean arterial pressure was lower in adult wild-type females than males (88 ± 1 and 97 ± 1 mmHg, respectively), a difference that was maintained with age, but was absent in adult knockout mice. In wild-type females, the chronic pressure-natriuresis relationship was shifted leftward compared with knockout females, an effect that was lost with age. In males, the chronic pressure-natriuresis relationship was not influenced by angiotensin type 2 receptor deficiency. Compared with age-matched females, the chronic pressure-natriuresis relationships in male mice were shifted rightward. Renal expression of the angiotensin type 2 receptor was fourfold greater in adult wild-type females than males. With age, the angiotensin type 2 receptor-to-angiotensin type 1 receptor balance was reduced in females. Conversely, in males, angiotensin receptor expression did not vary significantly with age. In conclusion, the angiotensin type 2 receptor modulates the chronic pressure-natriuresis relationship in an age- and sex-dependent manner. Copyright © 2014 the American Physiological Society.

  11. Source-sink-storage relationships of conifers

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Luxmoore, R.J.; Oren, R.; Sheriff, D.W.

    1995-07-01

    Irradiance, air temperature, saturation vapor pressure deficit, and soil temperature vary in association with Earth`s daily rotation, inducing significant hourly changes in the rates of plant physiological processes. These processes include carbon fixation in photosynthesis, sucrose translocation, and carbon utilization in growth, storage, and respiration. The sensitivity of these physiological processes to environmental factors such as temperature, soil water availability, and nutrient supply reveals differences that must be viewed as an interactive whole in order to comprehend whole-plant responses to the environment. Integrative frameworks for relationships between plant physiological processes are needed to provide syntheses of plant growth and development.more » Source-sink-storage relationships, addressed in this chapter, provide one framework for synthesis of whole-plant responses to external environmental variables. To address this issue, some examples of carbon assimilation and utilization responses of five conifer species to environmental factors from a range of field environments are first summarized. Next, the interactions between sources, sinks, and storages of carbon are examined at the leaf and tree scales, and finally, the review evaluates the proposition that processes involved with carbon utilization (sink activity) are more sensitive to the supply of water and nutrients (particularly nitrogen) than are the processes of carbon gain (source activity) and carbon storage. The terms {open_quotes}sink{close_quotes} and {open_quotes}source{close_quotes} refer to carbon utilization and carbon gain, respectively. The relative roles of stored carbon reserves and of current photosynthate in meeting sink demand are addressed. Discussions focus on source-sink-storage relationships within the diurnal, wetting-drying, and annual cycles of conifer growth and development, and some discussion of life cycle aspects is also presented.« less

  12. Relationship between ploidy and steroid hormone receptors in primary invasive breast cancer.

    PubMed Central

    Horsfall, D. J.; Tilley, W. D.; Orell, S. R.; Marshall, V. R.; Cant, E. L.

    1986-01-01

    The relationship between ploidy, as measured by flow cytometry, and the presence of oestrogen and progesterone receptors was investigated in 145 primary invasive breast cancers. The tumours were considered as an integral group, and as subgroups of lobular and ductal carcinomas. An association was found between the presence of aneuploid stemlines and an absence of oestrogen receptors (ER), for the total tumour population (P less than 0.02), and for the ductal carcinoma group (P less than 0.05). An association between aneuploidy and an absence of progesterone receptors (PR) was observed for the total tumour group (P less than 0.05). Evaluation of a combined oestrogen and progesterone receptor status indicated that the association between aneuploidy and an absence of both receptors was highly significant. The probability of such an association was P less than 0.001 for the total tumour population, and P less than 0.01 for the ductal tumour group. Assessment of progesterone receptor expression by breast cancers containing oestrogen receptors indicated that aneuploid tumours were as likely to express PR as were diploid tumours. Hence, the biological activity of oestrogen receptors appears unmodified by the presence of aneuploid nuclei. PMID:3004547

  13. Spatial patterns of mobile source particulate matter emissions-to-exposure relationships across the United States

    NASA Astrophysics Data System (ADS)

    Greco, Susan L.; Wilson, Andrew M.; Spengler, John D.; Levy, Jonathan I.

    Assessing the public health benefits from air pollution control measures is assisted by understanding the relationship between mobile source emissions and subsequent fine particulate matter (PM 2.5) exposure. Since this relationship varies by location, we characterized its magnitude and geographic distribution using the intake fraction (iF) concept. We considered emissions of primary PM 2.5 as well as particle precursors SO 2 and NO x from each of 3080 counties in the US. We modeled the relationship between these emissions and total US population exposure to PM 2.5, making use of a source-receptor matrix developed for health risk assessment. For primary PM 2.5, we found a median iF of 1.2 per million, with a range of 0.12-25. Half of the total exposure was reached by a median distance of 150 km from the county where mobile source emissions originated, though this spatial extent varied across counties from within the county borders to 1800 km away. For secondary ammonium sulfate from SO 2 emissions, the median iF was 0.41 per million (range: 0.050-10), versus 0.068 per million for secondary ammonium nitrate from NO x emissions (range: 0.00092-1.3). The median distance to half of the total exposure was greater for secondary PM 2.5 (450 km for sulfate, 390 km for nitrate). Regression analyses using exhaustive population predictors explained much of the variation in primary PM 2.5 iF ( R2=0.83) as well as secondary sulfate and nitrate iF ( R2=0.74 and 0.60), with greater near-source contribution for primary than for secondary PM 2.5. We conclude that long-range dispersion models with coarse geographic resolution are appropriate for risk assessments of secondary PM 2.5 or primary PM 2.5 emitted from mobile sources in rural areas, but that more resolved dispersion models are warranted for primary PM 2.5 in urban areas due to the substantial contribution of near-source populations.

  14. Sources of perceived responsiveness in family relationships.

    PubMed

    Cook, William L; Dezangré, Marie; De Mol, Jan

    2018-05-10

    Perceived responsiveness has become one of the most important constructs in the relationship sciences. It is central to the development of a secure attachment style, the experience of social support, an internal locus of control, and the sense of control in close relationships. Conversely, an unresponsive environment is associated with learned helplessness and depression. Viewed through the lens of the social relations model (SRM), perceived responsiveness in family relationships could have multiple sources: the perceiver; the target or partner; the perceiver-target relationship; and the family group. This study used the SRM to determine the relative importance of these sources of perceived responsiveness in the relationships of 207 two-parent two-child families. Characteristics of the perceiver and the target each accounted for about 25% of the systematic variance in perceived responsiveness, whereas the perceiver-target relationship accounted for approximately 48%. At the individual level of analysis, reciprocity of perceived responsiveness was pervasive in the family relationships of the two children. Regardless of age, young people who generally perceived others as responsive were generally perceived by others as responsive. At the dyadic level of analysis, reciprocity was present in two dyads: mother-father and older child-younger child. Reliable target variances support the view that perceived responsiveness is not just "inside the head" of the perceiver, and reciprocity correlations suggest potentially useful systemic interventions. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  15. Inter-comparison of receptor models for PM source apportionment: Case study in an industrial area

    NASA Astrophysics Data System (ADS)

    Viana, M.; Pandolfi, M.; Minguillón, M. C.; Querol, X.; Alastuey, A.; Monfort, E.; Celades, I.

    2008-05-01

    Receptor modelling techniques are used to identify and quantify the contributions from emission sources to the levels and major and trace components of ambient particulate matter (PM). A wide variety of receptor models are currently available, and consequently the comparability between models should be evaluated if source apportionment data are to be used as input in health effects studies or mitigation plans. Three of the most widespread receptor models (principal component analysis, PCA; positive matrix factorization, PMF; chemical mass balance, CMB) were applied to a single PM10 data set (n=328 samples, 2002-2005) obtained from an industrial area in NE Spain, dedicated to ceramic production. Sensitivity and temporal trend analyses (using the Mann-Kendall test) were applied. Results evidenced the good overall performance of the three models (r2>0.83 and α>0.91×between modelled and measured PM10 mass), with a good agreement regarding source identification and high correlations between input (CMB) and output (PCA, PMF) source profiles. Larger differences were obtained regarding the quantification of source contributions (up to a factor of 4 in some cases). The combined application of different types of receptor models would solve the limitations of each of the models, by constructing a more robust solution based on their strengths. The authors suggest the combined use of factor analysis techniques (PCA, PMF) to identify and interpret emission sources, and to obtain a first quantification of their contributions to the PM mass, and the subsequent application of CMB. Further research is needed to ensure that source apportionment methods are robust enough for application to PM health effects assessments.

  16. Quantitative structure-activity relationships of selective antagonists of glucagon receptor using QuaSAR descriptors.

    PubMed

    Manoj Kumar, Palanivelu; Karthikeyan, Chandrabose; Hari Narayana Moorthy, Narayana Subbiah; Trivedi, Piyush

    2006-11-01

    In the present paper, quantitative structure activity relationship (QSAR) approach was applied to understand the affinity and selectivity of a novel series of triaryl imidazole derivatives towards glucagon receptor. Statistically significant and highly predictive QSARs were derived for glucagon receptor inhibition by triaryl imidazoles using QuaSAR descriptors of molecular operating environment (MOE) employing computer-assisted multiple regression procedure. The generated QSAR models revealed that factors related to hydrophobicity, molecular shape and geometry predominantly influences glucagon receptor binding affinity of the triaryl imidazoles indicating the relevance of shape specific steric interactions between the molecule and the receptor. Further, QSAR models formulated for selective inhibition of glucagon receptor over p38 mitogen activated protein (MAP) kinase of the compounds in the series highlights that the same structural features, which influence the glucagon receptor affinity, also contribute to their selective inhibition.

  17. Amylin structure–function relationships and receptor pharmacology: implications for amylin mimetic drug development

    PubMed Central

    Bower, Rebekah L

    2016-01-01

    Amylin is an important, but poorly understood, 37 amino acid glucoregulatory hormone with great potential to target metabolic diseases. A working example that the amylin system is one worth developing is the FDA‐approved drug used in insulin‐requiring diabetic patients, pramlintide. However, certain characteristics of pramlintide pharmacokinetics and formulation leave considerable room for further development of amylin‐mimetic compounds. Given that amylin‐mimetic drug design and development is an active area of research, surprisingly little is known about the structure/function relationships of amylin. This is largely due to the unfavourable aggregative and solubility properties of the native peptide sequence, which are further complicated by the composition of amylin receptors. These are complexes of the calcitonin receptor with receptor activity‐modifying proteins. This review explores what is known of the structure–function relationships of amylin and provides insights that can be drawn from the closely related peptide, CGRP. We also describe how this information is aiding the development of more potent and stable amylin mimetics, including peptide hybrids. PMID:27061187

  18. ATMOSPHERIC AEROSOL SOURCE-RECEPTOR RELATIONSHIPS: THE ROLE OF COAL-FIRED POWER PLANTS

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Allen L. Robinson; Spyros N. Pandis; Cliff I. Davidson

    2004-12-01

    This report describes the technical progress made on the Pittsburgh Air Quality Study (PAQS) during the period of March 2004 through August 2004. Significant progress was made this project period on the analysis of ambient data, source apportionment, and deterministic modeling activities. Results highlighted in this report include evaluation of the performance of PMCAMx+ for an air pollution episode in the Eastern US, an emission profile for a coke production facility, ultrafine particle composition during a nucleation event, and a new hybrid approach for source apportionment. An agreement was reached with a utility to characterize fine particle and mercury emissionsmore » from a commercial coal fired power. Research in the next project period will include source testing of a coal fired power plant, source apportionment analysis, emission scenario modeling with PMCAMx+, and writing up results for submission as journal articles.« less

  19. Source apportionment of PM2.5 at the Lin'an regional background site in China with three receptor models

    NASA Astrophysics Data System (ADS)

    Deng, Junjun; Zhang, Yanru; Qiu, Yuqing; Zhang, Hongliang; Du, Wenjiao; Xu, Lingling; Hong, Youwei; Chen, Yanting; Chen, Jinsheng

    2018-04-01

    Source apportionment of fine particulate matter (PM2.5) were conducted at the Lin'an Regional Atmospheric Background Station (LA) in the Yangtze River Delta (YRD) region in China from July 2014 to April 2015 with three receptor models including principal component analysis combining multiple linear regression (PCA-MLR), UNMIX and Positive Matrix Factorization (PMF). The model performance, source identification and source contribution of the three models were analyzed and inter-compared. Source apportionment of PM2.5 was also conducted with the receptor models. Good correlations between the reconstructed and measured concentrations of PM2.5 and its major chemical species were obtained for all models. PMF resolved almost all masses of PM2.5, while PCA-MLR and UNMIX explained about 80%. Five, four and seven sources were identified by PCA-MLR, UNMIX and PMF, respectively. Combustion, secondary source, marine source, dust and industrial activities were identified by all the three receptor models. Combustion source and secondary source were the major sources, and totally contributed over 60% to PM2.5. The PMF model had a better performance on separating the different combustion sources. These findings improve the understanding of PM2.5 sources in background region.

  20. PM2.5 pollution from household solid fuel burning practices in Central India: 2. Application of receptor models for source apportionment.

    PubMed

    Matawle, Jeevan Lal; Pervez, Shamsh; Deb, Manas Kanti; Shrivastava, Anjali; Tiwari, Suresh

    2018-02-01

    USEPA's UNMIX, positive matrix factorization (PMF) and effective variance-chemical mass balance (EV-CMB) receptor models were applied to chemically speciated profiles of 125 indoor PM 2.5 measurements, sampled longitudinally during 2012-2013 in low-income group households of Central India which uses solid fuels for cooking practices. Three step source apportionment studies were carried out to generate more confident source characterization. Firstly, UNMIX6.0 extracted initial number of source factors, which were used to execute PMF5.0 to extract source-factor profiles in second step. Finally, factor analog locally derived source profiles were supplemented to EV-CMB8.2 with indoor receptor PM 2.5 chemical profile to evaluate source contribution estimates (SCEs). The results of combined use of three receptor models clearly describe that UNMIX and PMF are useful tool to extract types of source categories within small receptor dataset and EV-CMB can pick those locally derived source profiles for source apportionment which are analog to PMF-extracted source categories. The source apportionment results have also shown three fold higher relative contribution of solid fuel burning emissions to indoor PM 2.5 compared to those measurements reported for normal households with LPG stoves. The previously reported influential source marker species were found to be comparatively similar to those extracted from PMF fingerprint plots. The comparison between PMF and CMB SCEs results were also found to be qualitatively similar. The performance fit measures of all three receptor models were cross-verified and validated and support each other to gain confidence in source apportionment results.

  1. Comparison of source apportionments of PM2.5 using three receptor models (CMB, PMF, and SMP) in Seoul, Korea

    NASA Astrophysics Data System (ADS)

    Heo, J.; Kim, J. Y.; Kim, S. W.

    2017-12-01

    We compared source apportionments of PM2.5 in Seoul, Korea by three receptor models, Chemical Mass Balance (CMB), Positive Matrix Factorization (PMF), and Solver for Mixture Problem (SMP). The CMB model can estimate source apportionment with suitable source profiles of emissions, but it is difficult to find location-specific source profiles. In contrary, the multivariate receptor model does not need source profiles, but fundamental natural physical constraints (FNPCs) required for aerosol source apportionment are different in PMF and SMP. Ninety-six PM2.5 daily samples collected at Korea Institute of Science and Technology (KIST) in Seoul, Korea from October 2012 to September 2013 were analyzed in this study. The average PM2.5 mass concentration over the study period was 41.5 ± 27.7 mg m-3 and secondary inorganic species and organic matter were the main chemical species occupying about 73.7% - 87.9% of the PM2.5 mass concentration in all seasons. Secondary sulfate (18.0% - 26.1%), secondary nitrate (12.1% - 28.5%), vehicle (2.9% - 32.9%), biomass burning (13.2% - 21.3%) were identified by all three receptor models as the major sources accounting for approximately 76.3%-82.7% of the total PM2.5 and contributions of main sources represented their seasonality. However, three receptor models showed significant differences, especially for vehicle emission due to their measured/estimated source profiles. In this presentation, more detailed comparisons among CMB, PMF and SMP models will be presented focusing on the source profiles and contributions.

  2. The Sources of the Relationship between Sustained Attention and Reasoning

    ERIC Educational Resources Information Center

    Ren, Xuezhu; Schweizer, Karl; Xu, Fen

    2013-01-01

    Although a substantial relationship of sustained attention and reasoning was consistently found, little is known about what drives this relationship. The present study aims at revealing the underlying sources that are responsible for the relationship by means of an integrative approach combining experimental manipulation and psychometric modeling.…

  3. Receptor model-based source apportionment of particulate pollution in Hyderabad, India.

    PubMed

    Guttikunda, Sarath K; Kopakka, Ramani V; Dasari, Prasad; Gertler, Alan W

    2013-07-01

    Air quality in Hyderabad, India, often exceeds the national ambient air quality standards, especially for particulate matter (PM), which, in 2010, averaged 82.2 ± 24.6, 96.2 ± 12.1, and 64.3 ± 21.2 μg/m(3) of PM10, at commercial, industrial, and residential monitoring stations, respectively, exceeding the national ambient standard of 60 μg/m(3). In 2005, following an ordinance passed by the Supreme Court of India, a source apportionment study was conducted to quantify source contributions to PM pollution in Hyderabad, using the chemical mass balance (version 8.2) receptor model for 180 ambient samples collected at three stations for PM10 and PM2.5 size fractions for three seasons. The receptor modeling results indicated that the PM10 pollution is dominated by the direct vehicular exhaust and road dust (more than 60%). PM2.5 with higher propensity to enter the human respiratory tracks, has mixed sources of vehicle exhaust, industrial coal combustion, garbage burning, and secondary PM. In order to improve the air quality in the city, these findings demonstrate the need to control emissions from all known sources and particularly focus on the low-hanging fruits like road dust and waste burning, while the technological and institutional advancements in the transport and industrial sectors are bound to enhance efficiencies. Andhra Pradesh Pollution Control Board utilized these results to prepare an air pollution control action plan for the city.

  4. Molecular characterization of the receptor binding structure-activity relationships of influenza B virus hemagglutinin.

    PubMed

    Carbone, V; Kim, H; Huang, J X; Baker, M A; Ong, C; Cooper, M A; Li, J; Rockman, S; Velkov, T

    2013-01-01

    Selectivity of α2,6-linked human-like receptors by B hemagglutinin (HA) is yet to be fully understood. This study integrates binding data with structure-recognition models to examine the impact of regional-specific sequence variations within the receptor-binding pocket on selectivity and structure activity relationships (SAR). The receptor-binding selectivity of influenza B HAs corresponding to either B/Victoria/2/1987 or the B/Yamagata/16/88 lineages was examined using surface plasmon resonance, solid-phase ELISA and gel-capture assays. Our SAR data showed that the presence of asialyl sugar units is the main determinant of receptor preference of α2,6 versus α2,3 receptor binding. Changes to the type of sialyl-glycan linkage present on receptors exhibit only a minor effect upon binding affinity. Homology-based structural models revealed that structural properties within the HA pocket, such as a glyco-conjugate at Asn194 on the 190-helix, sterically interfere with binding to avian receptor analogs by blocking the exit path of the asialyl sugars. Similarly, naturally occurring substitutions in the C-terminal region of the 190-helix and near the N-terminal end of the 140-loop narrows the horizontal borders of the binding pocket, which restricts access of the avian receptor analog LSTa. This study helps bridge the gap between ligand structure and receptor recognition for influenza B HA; and provides a consensus SAR model for the binding of human and avian receptor analogs to influenza B HA.

  5. Positive Modulators of the N-Methyl-d-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters.

    PubMed

    Krausova, Barbora; Slavikova, Barbora; Nekardova, Michaela; Hubalkova, Pavla; Vyklicky, Vojtech; Chodounska, Hana; Vyklicky, Ladislav; Kudova, Eva

    2018-05-24

    Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure-activity relationship (SAR) for their modulation of N-methyl-d-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC 50 varying from 1.8 to 151.4 μM and E max varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC 50 = 21.7 μM). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABA A R responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs.

  6. Source apportionment of exposures to volatile organic compounds. I. Evaluation of receptor models using simulated exposure data

    NASA Astrophysics Data System (ADS)

    Miller, Shelly L.; Anderson, Melissa J.; Daly, Eileen P.; Milford, Jana B.

    Four receptor-oriented source apportionment models were evaluated by applying them to simulated personal exposure data for select volatile organic compounds (VOCs) that were generated by Monte Carlo sampling from known source contributions and profiles. The exposure sources modeled are environmental tobacco smoke, paint emissions, cleaning and/or pesticide products, gasoline vapors, automobile exhaust, and wastewater treatment plant emissions. The receptor models analyzed are chemical mass balance, principal component analysis/absolute principal component scores, positive matrix factorization (PMF), and graphical ratio analysis for composition estimates/source apportionment by factors with explicit restriction, incorporated in the UNMIX model. All models identified only the major contributors to total exposure concentrations. PMF extracted factor profiles that most closely represented the major sources used to generate the simulated data. None of the models were able to distinguish between sources with similar chemical profiles. Sources that contributed <5% to the average total VOC exposure were not identified.

  7. The Bi-directional Relationship between Source Characteristics and Message Content

    PubMed Central

    Collins, Peter J.; Hahn, Ulrike; von Gerber, Ylva; Olsson, Erik J.

    2018-01-01

    Much of what we believe we know, we know through the testimony of others (Coady, 1992). While there has been long-standing evidence that people are sensitive to the characteristics of the sources of testimony, for example in the context of persuasion, researchers have only recently begun to explore the wider implications of source reliability considerations for the nature of our beliefs. Likewise, much remains to be established concerning what factors influence source reliability. In this paper, we examine, both theoretically and empirically, the implications of using message content as a cue to source reliability. We present a set of experiments examining the relationship between source information and message content in people's responses to simple communications. The results show that people spontaneously revise their beliefs in the reliability of the source on the basis of the expectedness of a source's claim and, conversely, adjust message impact by perceived reliability; hence source reliability and message content have a bi-directional relationship. The implications are discussed for a variety of psychological, philosophical and political issues such as belief polarization and dual-route models of persuasion. PMID:29441029

  8. Curvilinear relationships between mu-opioid receptor labeling and undirected song in male European starlings (Sturnus vulgaris).

    PubMed

    Kelm-Nelson, Cynthia A; Riters, Lauren V

    2013-08-21

    Female-directed communication in male songbirds has been reasonably well studied; yet, relatively little is known about communication in other social contexts. Songbirds also produce song that is not clearly directed towards another individual (undirected song) when alone or in flocks. Although the precise functions of undirected song may differ across species, this type of song is considered important for flock maintenance, song learning or practice. Past studies show that undirected song is tightly coupled to analgesia and positive affective state, which are both mediated by opioid activity. Furthermore, labeling for the opioid met-enkephalin in the medial preoptic nucleus (POM) correlates positively with undirected song production. We propose that undirected song is facilitated and maintained by opioid receptor activity in the POM and other brain regions involved in affective state, analgesia, and social behavior. To provide insight into this hypothesis, we used immunohistochemistry to examine relationships between undirected song and mu-opioid receptors in male starlings. Polynomial regression analyses revealed significant inverted-U shaped relationships between measures of undirected song and mu-opioid receptor labeling in the POM, medial bed nucleus of the stria terminalis (BSTm), and periaqueductal gray (PAG). These results suggest that low rates of undirected song may stimulate and/or be maintained by mu-opioid receptor activity; however, it may be that sustained levels of mu-opioid receptor activity associated with high rates of undirected song cause mu-opioid receptor down-regulation. The results indicate that mu-opioid receptor activity in POM, BSTm, and PAG may underlie previous links identified between undirected song, analgesia, and affective state. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. A novel in vivo receptor occupancy methodology for the glucocorticoid receptor: toward an improved understanding of lung pharmacokinetic/pharmacodynamic relationships.

    PubMed

    Boger, Elin; Ewing, Pär; Eriksson, Ulf G; Fihn, Britt-Marie; Chappell, Michael; Evans, Neil; Fridén, Markus

    2015-05-01

    Investigation of pharmacokinetic/pharmacodynamic (PK/PD) relationships for inhaled drugs is challenging because of the limited possibilities of measuring tissue exposure and target engagement in the lung. The aim of this study was to develop a methodology for measuring receptor occupancy in vivo in the rat for the glucocorticoid receptor (GR) to allow more informative inhalation PK/PD studies. From AstraZeneca's chemical library of GR binders, compound 1 [N-(2-amino-2-oxo-ethyl)-3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-methyl-benzamide] was identified to have properties that are useful as a tracer for GR in vitro. When given at an appropriate dose (30 nmol/kg) to rats, compound 1 functioned as a tracer in the lung and spleen in vivo using liquid chromatography-tandem mass spectrometry bioanalysis. The methodology was successfully used to show the dose-receptor occupancy relationship measured at 1.5 hours after intravenous administration of fluticasone propionate (20, 150, and 750 nmol/kg) as well as to characterize the time profile for receptor occupancy after a dose of 90 nmol/kg i.v. The dose giving 50% occupancy was estimated as 47 nmol/kg. The methodology is novel in terms of measuring occupancy strictly in vivo and by using an unlabeled tracer. This feature confers key advantages, including occupancy estimation not being influenced by drug particle dissolution or binding/dissociation taking place postmortem. In addition, the tracer may be labeled for use in positron emission tomography imaging, thus enabling occupancy estimation in humans as a translatable biomarker of target engagement. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  10. ATMOSPHERIC AEROSOL SOURCE-RECEPTOR RELATIONSHIPS: THE ROLE OF COAL-FIRED POWER PLANTS

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Allen L. Robinson; Spyros N. Pandis; Cliff I. Davidson

    2005-04-01

    This report describes the technical progress made on the Pittsburgh Air Quality Study (PAQS) during the period of September 2004 through February 2005. Significant progress was made this project period on the analysis of ambient data, source apportionment, and deterministic modeling activities. The major experimental achievement this project period was the characterization of the mercury and fine particle emissions from two modern, large, commercial pulverized coal boilers. This testing completes the field work component of the Source Characterization Activity. This report highlights results from mercury emission measurements made using a dilution sampler. The measurements clearly indicate that mercury is beingmore » transformed from an oxidized to an elemental state within the dilution. However, wall effects are significant making it difficult to determine whether or not these changes occur in the gas phase or due to some interaction with the sampler walls. This report also presents results from an analysis that uses spherical aluminum silicate (SAS) particles as a marker for primary PM{sub 2.5} emitted from coal combustion. Primary emissions from coal combustion contribute only a small fraction of the PM{sub 2.5} mass (less than 1.5% in the summer and less than 3% in the winter) at the Pittsburgh site. Ambient SAS concentrations also appear to be reasonably spatially homogeneous. Finally, SAS emission factors measured at pilot-scale are consistent with measurements made at full-scale. This report also presents results from applying the Unmix and PMF models to estimate the contribution of different sources to the PM{sub 2.5} mass concentrations in Pittsburgh using aerosol composition information. Comparison of the two models shows similar source composition and contribution for five factors: crustal material, nitrate, an Fe, Mn, and Zn factor, specialty steel production, and a cadmium factor. PMF found several additional factors. Comparison between source

  11. Source apportionment of PM10 and PM2.5 in major urban Greek agglomerations using a hybrid source-receptor modeling process.

    PubMed

    Argyropoulos, G; Samara, C; Diapouli, E; Eleftheriadis, K; Papaoikonomou, K; Kungolos, A

    2017-12-01

    A hybrid source-receptor modeling process was assembled, to apportion and infer source locations of PM 10 and PM 2.5 in three heavily-impacted urban areas of Greece, during the warm period of 2011, and the cold period of 2012. The assembled process involved application of an advanced computational procedure, the so-called Robotic Chemical Mass Balance (RCMB) model. Source locations were inferred using two well-established probability functions: (a) the Conditional Probability Function (CPF), to correlate the output of RCMB with local wind directional data, and (b) the Potential Source Contribution Function (PSCF), to correlate the output of RCMB with 72h air-mass back-trajectories, arriving at the receptor sites, during sampling. Regarding CPF, a higher-level conditional probability function was defined as well, from the common locus of CPF sectors derived for neighboring receptor sites. With respect to PSCF, a non-parametric bootstrapping method was applied to discriminate the statistically significant values. RCMB modeling showed that resuspended dust is actually one of the main barriers for attaining the European Union (EU) limit values in Mediterranean urban agglomerations, where the drier climate favors build-up. The shift in the energy mix of Greece (caused by the economic recession) was also evidenced, since biomass burning was found to contribute more significantly to the sampling sites belonging to the coldest climatic zone, particularly during the cold period. The CPF analysis showed that short-range transport of anthropogenic emissions from urban traffic to urban background sites was very likely to have occurred, within all the examined urban agglomerations. The PSCF analysis confirmed that long-range transport of primary and/or secondary aerosols may indeed be possible, even from distances over 1000km away from study areas. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Immunocytochemical assessment of sigma-1 receptor and human sterol isomerase in breast cancer and their relationship with a series of prognostic factors

    PubMed Central

    Simony-Lafontaine, J; Esslimani, M; Bribes, E; Gourgou, S; Lequeux, N; Lavail, R; Grenier, J; Kramar, A; Casellas, P

    2000-01-01

    The purpose of this study was to immunocytochemically investigate two new markers, the sigma-1 receptor and the human sterol isomerase (hSI), in comparison with a series of clinicopathological and immunocytochemical prognostic factors in a trial including 95 patients with operable primary breast cancers. Our results showed no statistically significant relationship between these two markers and the age of the patients, their menopausal status, the tumour size and its histological grade, the nodal status and the expression of the Ki-67 proliferative marker. However, we evidenced a close correlation between the sigma-1 receptor expression and the hormonal receptor positivity (P = 0.008), essentially due to a link with the progesterone receptor status (P = 0.01). By contrast there was an inverse relationship between hSI expression and the oestrogen receptor and/or progesterone receptor positivity (P = 0.098). A significant relationship was shown between both the sigma-1 receptor, hSI expressions and Bcl2 expression, with P = 0.017 and 0.035 respectively. We also assessed whether the expression of the sigma-1 receptor or hSI might be linked with disease-free survival (DFS) and found that the presence of hSI and the absence of sigma-1 receptor expression were associated with a poorer disease-free survival (P = 0.007). Altogether these results suggest that in primary breast carcinomas in association with the evaluation of the steroid receptor status, the sigma-1 receptor and hSI may be interesting new markers useful to identify those patients who might be able to benefit from an adjuvant therapy. © 2000 Cancer Research Campaign PMID:10864204

  13. Source-receptor probability of atmospheric long-distance dispersal of viruses to Israel from the eastern Mediterranean area.

    PubMed

    Klausner, Z; Klement, E; Fattal, E

    2018-02-01

    Viruses that affect the health of humans and farm animals can spread over long distances via atmospheric mechanisms. The phenomenon of atmospheric long-distance dispersal (LDD) is associated with severe consequences because it may introduce pathogens into new areas. The introduction of new pathogens to Israel was attributed to LDD events numerous times. This provided the motivation for this study which is aimed to identify all the locations in the eastern Mediterranean that may serve as sources for pathogen incursion into Israel via LDD. This aim was achieved by calculating source-receptor relationship probability maps. These maps describe the probability that an infected vector or viral aerosol, once airborne, will have an atmospheric route that can transport it to a distant location. The resultant probability maps demonstrate a seasonal tendency in the probability of specific areas to serve as sources for pathogen LDD into Israel. Specifically, Cyprus' season is the summer; southern Turkey and the Greek islands of Crete, Karpathos and Rhodes are associated with spring and summer; lower Egypt and Jordan may serve as sources all year round, except the summer months. The method used in this study can easily be implemented to any other geographic region. The importance of this study is the ability to provide a climatologically valid and accurate risk assessment tool to support long-term decisions regarding preparatory actions for future outbreaks long before a specific outbreak occurs. © 2017 Blackwell Verlag GmbH.

  14. Discovering relationships between nuclear receptor signaling pathways, genes, and tissues in Transcriptomine.

    PubMed

    Becnel, Lauren B; Ochsner, Scott A; Darlington, Yolanda F; McOwiti, Apollo; Kankanamge, Wasula H; Dehart, Michael; Naumov, Alexey; McKenna, Neil J

    2017-04-25

    We previously developed a web tool, Transcriptomine, to explore expression profiling data sets involving small-molecule or genetic manipulations of nuclear receptor signaling pathways. We describe advances in biocuration, query interface design, and data visualization that enhance the discovery of uncharacterized biology in these pathways using this tool. Transcriptomine currently contains about 45 million data points encompassing more than 2000 experiments in a reference library of nearly 550 data sets retrieved from public archives and systematically curated. To make the underlying data points more accessible to bench biologists, we classified experimental small molecules and gene manipulations into signaling pathways and experimental tissues and cell lines into physiological systems and organs. Incorporation of these mappings into Transcriptomine enables the user to readily evaluate tissue-specific regulation of gene expression by nuclear receptor signaling pathways. Data points from animal and cell model experiments and from clinical data sets elucidate the roles of nuclear receptor pathways in gene expression events accompanying various normal and pathological cellular processes. In addition, data sets targeting non-nuclear receptor signaling pathways highlight transcriptional cross-talk between nuclear receptors and other signaling pathways. We demonstrate with specific examples how data points that exist in isolation in individual data sets validate each other when connected and made accessible to the user in a single interface. In summary, Transcriptomine allows bench biologists to routinely develop research hypotheses, validate experimental data, or model relationships between signaling pathways, genes, and tissues. Copyright © 2017, American Association for the Advancement of Science.

  15. SOURCE APPORTIONMENT OF EXPOSURES TO VOLATILE ORGANIC COMPOUNDS: I. EVALUATION OF RECEPTOR MODELS USING SIMULATED EXPOSURE DATA. (R826788)

    EPA Science Inventory

    Four receptor-oriented source apportionment models were evaluated by applying them to simulated personal exposure data for select volatile organic compounds (VOCs) that were generated by Monte Carlo sampling from known source contributions and profiles. The exposure sources mo...

  16. Structure-activity relationship study of spider polyamine toxins as inhibitors of ionotropic glutamate receptors.

    PubMed

    Xiong, Xiao-Feng; Poulsen, Mette H; Hussein, Rama A; Nørager, Niels G; Strømgaard, Kristian

    2014-12-01

    The spider polyamine toxins Joro spider toxin-3 (JSTX-3) and Nephila polyamine toxins-1 and -8 (NPTX-1 and NPTX-8) are isolated from the venom of the orb-weaver spider Nephila clavata (Joro spider). They share a high degree of structural resemblance, their aromatic head groups being the only difference, and were recently found to be very potent open-channel blockers of ionotropic glutamate (iGlu) receptors. In this study we designed and synthesized a collection of 24 analogues of these toxins using a recently developed solid-phase synthetic methodology. Systematic variation in two regions of the toxins and subsequent evaluation of biological activity at AMPA and NMDA subtypes of iGlu receptors provided succinct information on structure-activity relationships. In particular, one set of analogues were found to display exquisite selectivity and potency for AMPA receptors relative to the natural products. Thus, this systematic SAR study has provided new pharmacological tools for studies of iGlu receptors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Comparison of hybrid receptor models to locate PCB sources in Chicago

    NASA Astrophysics Data System (ADS)

    Hsu, Ying-Kuang; Holsen, Thomas M.; Hopke, Philip K.

    Results of three hybrid receptor models, potential source contribution function (PSCF), concentration weighted trajectory (CWT), and residence time weighted concentration (RTWC), were compared for locating polychlorinated biphenyl (PCB) sources contributing to the atmospheric concentrations in Chicago. Variations of these models, including PSCF using mean and 75% criterion concentrations, joint probability PSCF (JP-PSCF), changes of point filters and grid cell sizes for RTWC, and PSCF using wind trajectories started at different altitudes, are also discussed. Modeling results were relatively consistent between models. However, no single model provided as complete information as was obtained by using all of them. CWT and 75% PSCF appears to be able to distinguish between larger sources and moderate ones. RTWC resolved high potential source areas. RTWC and JP-PSCF pooling data from all sampling sites removed the trailing effect often seen in PSCF modeling. PSCF results using average concentration criteria, appears to identify both moderate and major sources. Each model has advantages and disadvantages. However, used in combination, they provide information that is not available if only one of them is used. For short-range atmospheric transport, PSCF results were consistent when using wind trajectories starting at different heights. Based on the archived PCB data, the modeling results indicate there is a large potential source area between Joliet and Kankakee, IL, and two moderate sources to the northwest and south of Chicago. On the south side of Chicago in the neighborhood of Lake Calumet, several PCB sources were identified. Other unidentified potential source location(s) will require additional upwind/downwind field sampling to verify modeling results.

  18. The Relationship Between Gene Polymorphism of Leptin and Leptin Receptor and Growth Hormone Deficiency.

    PubMed

    He, Jinshui; Fang, Yanling; Lin, Xinfu; Zhou, Huowang; Zhu, Shaobo; Zhang, Yugui; Yang, Huicong; Ye, Xiaoling

    2016-02-26

    BACKGROUND Growth hormone deficiency (GHD) is a major cause of congenital short stature. GHD patients have significantly decreased serum leptin levels, which are regulated by gene polymorphism of leptin and leptin receptor. This study thus investigated the relationship between gene polymorphism and susceptibility to GHD. MATERIAL AND METHODS A case-control study was performed using 180 GHD children in addition to 160 healthy controls. After the extraction of whole genomic DNA, the genotypes of leptin and leptin receptor gene loci were analyzed by sequencing for single-nucleotide polymorphism. RESULTS The frequency distribution of all alleles identified in leptin gene (loci rs7799039) and leptin receptor gene (loci rs1137100 and rs1137101) fit Hardy-Weinberg equilibrium. There was a significant difference in allele frequency at loci rs7799039 or rs1137101, as individuals with heterozygous GA allele had lower (rs7799039) or higher (rs1137101) GHD risk. No significant difference in allele frequency was discovered at loci rs1137100 (p>0.05), which was unrelated to GHD susceptibility. CONCLUSIONS Gene polymorphism of leptin (loci rs7799039) and leptin receptor (loci rs1137101) are correlated with GHD susceptibility.

  19. The Relationship of Body Size and Adiposity to Source of Self-Esteem in College Women

    ERIC Educational Resources Information Center

    Moncur, Breckann; Bailey, Bruce W.; Lockhart, Barbara D.; LeCheminant, James D.; Perkins, Annette E.

    2013-01-01

    Background: Studies looking at self-esteem and body size or adiposity generally demonstrate a negative relationship. However, the relationship between the source of self-esteem and body size has not been examined in college women. Purpose: The purpose of this study was to evaluate the relationship of body size and adiposity to source of…

  20. Can Concentration - Discharge Relationships Diagnose Material Source During Extreme Events?

    NASA Astrophysics Data System (ADS)

    Karwan, D. L.; Godsey, S.; Rose, L.

    2017-12-01

    Floods can carry >90% of the basin material exported in a given year as well as alter flow pathways and material sources. In turn, sediment and solute fluxes can increase flood damages and negatively impact water quality and integrate physical and chemical weathering of landscapes and channels. Concentration-discharge (C-Q) relationships are used to both describe export patterns as well as compute them. Metrics for describing C-Q patterns and inferring their controls are vulnerable to infrequent sampling that affects how C-Q relationships are interpolated and interpreted. C-Q relationships are typically evaluated from multiple samples, but because hydrological extremes are rare, data are often unavailable for extreme events. Because solute and sediment C-Q relationships likely respond to changes in hydrologic extremes in different ways, there is a pressing need to define their behavior under extreme conditions, including how to properly sample to capture these patterns. In the absence of such knowledge, improving load estimates in extreme floods will likely remain difficult. Here we explore the use of C-Q relationships to determine when an event alters a watershed system such that it enters a new material source/transport regime. We focus on watersheds with sediment and discharge time series include low-frequency and/or extreme events. For example, we compare solute and sediment patterns in White Clay Creek in southeastern Pennsylvania across a range of flows inclusive of multiple hurricanes for which we have ample ancillary hydrochemical data. TSS is consistently mobilized during high flow events, even during extreme floods associated with hurricanes, and sediment fingerprinting indicates different sediment sources, including in-channel remobilization and landscape erosion, are active at different times. In other words, TSS mobilization in C-Q space is not sensitive to the source of material being mobilized. Unlike sediments, weathering solutes in this watershed

  1. Toll-like receptor 4-related immunostimulatory polysaccharides: Primary structure, activity relationships, and possible interaction models.

    PubMed

    Zhang, Xiaorui; Qi, Chunhui; Guo, Yan; Zhou, Wenxia; Zhang, Yongxiang

    2016-09-20

    Toll-like receptor (TLR) 4 is an important polysaccharide receptor; however, the relationships between the structures and biological activities of TLR4 and polysaccharides remain unknown. Many recent findings have revealed the primary structure of TLR4/MD-2-related polysaccharides, and several three-dimensional structure models of polysaccharide-binding proteins have been reported; and these models provide insights into the mechanisms through which polysaccharides interact with TLR4. In this review, we first discuss the origins of polysaccharides related to TLR4, including polysaccharides from higher plants, fungi, bacteria, algae, and animals. We then briefly describe the glucosidic bond types of TLR4-related heteroglycans and homoglycans and describe the typical molecular weights of TLR4-related polysaccharides. The primary structures and activity relationships of polysaccharides with TLR4/MD-2 are also discussed. Finally, based on the existing interaction models of LPS with TLR4/MD-2 and linear polysaccharides with proteins, we provide insights into the possible interaction models of polysaccharide ligands with TLR4/MD-2. To our knowledge, this review is the first to summarize the primary structures and activity relationships of TLR4-related polysaccharides and the possible mechanisms of interaction for TLR4 and TLR4-related polysaccharides. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Selective CB2 receptor agonists. Part 2: Structure-activity relationship studies and optimization of proline-based compounds.

    PubMed

    Riether, Doris; Zindell, Renee; Wu, Lifen; Betageri, Raj; Jenkins, James E; Khor, Someina; Berry, Angela K; Hickey, Eugene R; Ermann, Monika; Albrecht, Claudia; Ceci, Angelo; Gemkow, Mark J; Nagaraja, Nelamangala V; Romig, Helmut; Sauer, Achim; Thomson, David S

    2015-02-01

    Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. The relationship between reward and punishment processing and the 5-HT1A receptor as shown by PET.

    PubMed

    Faulkner, Paul; Selvaraj, Sudhakar; Pine, Alex; Howes, Oliver D; Roiser, Jonathan P

    2014-07-01

    The serotonin (5-HT) system has been reported to be involved in decision-making. A key component of this neurotransmitter system is the 5-HT1A receptor, and research is beginning to show how this receptor can influence decision-making. However, this relationship has rarely been studied in humans. This study assessed whether individual variability in 5-HT1A availability correlates with decision-making in healthy volunteers. We measured regional availability of the 5-HT1A receptor in the hippocampal complex and striatum using positron emission tomography and correlated this with performance on two decision-making tasks measuring sensitivity to probability, rewards and punishments and temporal discounting, respectively. No relationship between decision-making behaviour and 5-HT1A availability in the striatum was found. However, a positive correlation was detected between participants' 5-HT1A availability in the hippocampal complex and their sensitivity to the probability of winning. Furthermore, there was a negative correlation between the degree to which participants discounted future rewards and 5-HT1A availability in the hippocampal complex. These data support a role for the 5-HT1A receptor in the aberrant decision-making that can occur in neuropsychiatric disorders such as depression.

  4. Broadening sources of Diginity and Affirmation in Work and Relationship

    PubMed Central

    Byars-Winston, Angela

    2012-01-01

    This article builds on assertions in Richardson’s (2012, this issue) Major Contribution on counseling for work and relationship. In this reaction, I expand on the relevance and potential of the counseling for work and relationship perspective to enrich the field of counseling psychology. My comments focus on three considerations to further extend the cultural relevance of Richardson’s work and relationship perspective: (1) broadening sources of dignity, (2) centering knowledge of marginalized communities, and (3) promoting psychologists’ critical consciousness. Richardson’s perspective holds great promise for being a guiding heuristic to inform counseling psychology research, theory, and practice. PMID:22563131

  5. Comparison of source apportionment of PM2.5 using receptor models in the main hub port city of East Asia: Busan

    NASA Astrophysics Data System (ADS)

    Jeong, Ju-Hee; Shon, Zang-Ho; Kang, Minsung; Song, Sang-Keun; Kim, Yoo-Keun; Park, Jinsoo; Kim, Hyunjae

    2017-01-01

    The contributions of various PM2.5 emission sources to ambient PM2.5 levels during 2013 in the main hub port city (Busan, South Korea) of East Asia was quantified using several receptor modeling techniques. Three receptor models of principal component analysis/absolute principal component score (PCA/APCS), positive matrix factorization (PMF), and chemical mass balance (CMB) were used to apportion the source of PM2.5 obtained from the target city. The results of the receptor models indicated that the secondary formation of PM2.5 was the dominant (45-60%) contributor to PM2.5 levels in the port city of Busan. The PMF and PCA/APCS suggested that ship emission was a non-negligible contributor of PM2.5 (up to about 10%) in the study area, whereas it was a negligible contributor based on CMB. The magnitude of source contribution estimates to PM2.5 levels differed significantly among these three models due to their limitations (e.g., PM2.5 emission source profiles and restrictions of the models). Potential source contribution function and concentration-weighted trajectory analyses indicated that long-range transport from sources in the eastern China and Yellow Sea contributed significantly to the level of PM2.5 in Busan.

  6. RECEPTOR MODEL DEVELOPMENT AND APPLICATION

    EPA Science Inventory

    Source apportionment (receptor) models are mathematical procedures for identifying and quantifying the sources of ambient air pollutants and their effects at a site (the receptor), primarily on the basis of species concentration measurements at the receptor, and generally without...

  7. Evaluation for relationship among source parameters of underground nuclear tests in Northern Korean Peninsula

    NASA Astrophysics Data System (ADS)

    Kim, G.; Che, I. Y.

    2017-12-01

    We evaluated relationship among source parameters of underground nuclear tests in northern Korean Peninsula using regional seismic data. Dense global and regional seismic networks are incorporated to measure locations and origin times precisely. Location analyses show that distance among the locations is tiny on a regional scale. The tiny location-differences validate a linear model assumption. We estimated source spectral ratios by excluding path effects based spectral ratios of the observed seismograms. We estimated empirical relationship among depth of burials and yields based on theoretical source models.

  8. Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists.

    PubMed

    Hartz, Richard A; Ahuja, Vijay T; Arvanitis, Argyrios G; Rafalski, Maria; Yue, Eddy W; Denhart, Derek J; Schmitz, William D; Ditta, Jonathan L; Deskus, Jeffrey A; Brenner, Allison B; Hobbs, Frank W; Payne, Joseph; Lelas, Snjezana; Li, Yu-Wen; Molski, Thaddeus F; Mattson, Gail K; Peng, Yong; Wong, Harvey; Grace, James E; Lentz, Kimberley A; Qian-Cutrone, Jingfang; Zhuo, Xiaoliang; Shu, Yue-Zhong; Lodge, Nicholas J; Zaczek, Robert; Combs, Andrew P; Olson, Richard E; Bronson, Joanne J; Mattson, Ronald J; Macor, John E

    2009-07-23

    Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.

  9. Solid-phase synthesis and structure-activity relationships of novel biarylethers as melanin-concentrating hormone receptor-1 antagonists.

    PubMed

    Ma, Vu; Bannon, Anthony W; Baumgartner, Jamie; Hale, Clarence; Hsieh, Faye; Hulme, Christopher; Rorrer, Kirk; Salon, John; van Staden, Carlo; Tempest, Paul

    2006-10-01

    Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic neuropeptide. The action of MCH on feeding is thought to involve the activation of its respective G protein-coupled receptor MCH-R1. Consequently, antagonists that block MCH regulated MCH-R1 activity may provide a viable approach to the treatment of diet-induced obesity. This communication reports the discovery of a novel MCH-R1 receptor antagonist, the biarylether 7, identified through high throughput screening. The solid-phase synthesis and structure-activity relationship of related analogs is described.

  10. Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders

    PubMed Central

    Leopoldo, Marcello; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto; Hedlund, Peter B.

    2010-01-01

    Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented. PMID:20923682

  11. A Review of Advancements in Particulate Matter Sampling and Analysis and its Application to Identifying Source Impacts at Receptor Locations

    EPA Science Inventory

    Time-integrated (typically 24-hr) filter-based methods (historical methods) form the underpinning of our understanding of the fate, impact of source emissions at receptor locations (source impacts), and potential health and welfare effects of particulate matter (PM) in air. Over...

  12. Constrained positive matrix factorization: Elemental ratios, spatial distinction, and chemical transport model source contributions

    NASA Astrophysics Data System (ADS)

    Sturtz, Timothy M.

    Source apportionment models attempt to untangle the relationship between pollution sources and the impacts at downwind receptors. Two frameworks of source apportionment models exist: source-oriented and receptor-oriented. Source based apportionment models use presumed emissions and atmospheric processes to estimate the downwind source contributions. Conversely, receptor based models leverage speciated concentration data from downwind receptors and apply statistical methods to predict source contributions. Integration of both source-oriented and receptor-oriented models could lead to a better understanding of the implications sources have on the environment and society. The research presented here investigated three different types of constraints applied to the Positive Matrix Factorization (PMF) receptor model within the framework of the Multilinear Engine (ME-2): element ratio constraints, spatial separation constraints, and chemical transport model (CTM) source attribution constraints. PM10-2.5 mass and trace element concentrations were measured in Winston-Salem, Chicago, and St. Paul at up to 60 sites per city during two different seasons in 2010. PMF was used to explore the underlying sources of variability. Information on previously reported PM10-2.5 tire and brake wear profiles were used to constrain these features in PMF by prior specification of selected species ratios. We also modified PMF to allow for combining the measurements from all three cities into a single model while preserving city-specific soil features. Relatively minor differences were observed between model predictions with and without the prior ratio constraints, increasing confidence in our ability to identify separate brake wear and tire wear features. Using separate data, source contributions to total fine particle carbon predicted by a CTM were incorporated into the PMF receptor model to form a receptor-oriented hybrid model. The level of influence of the CTM versus traditional PMF was

  13. Insight into illness and its relationship to illness severity, cognition and estimated antipsychotic dopamine receptor occupancy in schizophrenia: An antipsychotic dose reduction study.

    PubMed

    Gerretsen, Philip; Takeuchi, Hiroyoshi; Ozzoude, Miracle; Graff-Guerrero, Ariel; Uchida, Hiroyuki

    2017-05-01

    Little is known about the influence of D 2 receptor occupancy on impaired insight into illness (III)-a core feature of schizophrenia. III is associated with illness severity and cognitive dysfunction. Comparably, supratherapeutic D 2 receptor occupancy can impair cognition. However, it is unclear how illness severity, cognition, and D 2 receptor occupancy interact to influence III in schizophrenia. The aim of this study was to explore the influence of antipsychotic dose reduction on the relationships of illness severity and cognition to III. III was assessed at baseline and 28 weeks post-antipsychotic dose reduction in 16 participants with schizophrenia and plasma antipsychotic concentrations. III was assessed primarily with the Schedule for the Assessment of Insight-Japanese version, and secondarily with the Positive and Negative Syndrome Scale item G12. Correlation and regression analyses were performed to explore III's relationship to illness severity, cognition, and estimated D 2 receptor occupancy (Est.D 2 ). Cognition and Est.D 2 predicted III at baseline. At 28 weeks post-reduction, illness severity and Est.D 2 predicted III. Our findings suggest a complex relationship may exist among III, illness severity, cognition and Est.D 2 . At higher D 2 receptor occupancies, III is influenced by cognitive dysfunction, whereas, at lower occupancies, illness severity has a stronger effect on III. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  14. Relationships between muscular strength and the level of energy sources in the muscle.

    PubMed

    Wit, A; Juskiak, R; Wit, B; Zieliński, J R

    1978-01-01

    Relationships between muscular strength and the level of energy sources in the muscle. Acta Physiol. Pol., 1978, 29 (2): 139--151. An attempt was made to establish a relationship between the post-excercise changes in the level of anaerobic energy sources and changes in the muscular strength. The gastrocnemius muscle of Wistar rats was examined. The muscle strength was measured by the resistance tensometry. In muscle specimens ATP, CP and glycogen contents were determined. It was demonstrated that changes in the post-excersise muscle response to electric stimulus have a phasic character resembling the overcompensation curve. The percent changes in the content of anaerobic energy sources in the muscle after contractions varying in duration suggests also overcompensation the muscle content of these substances. The parallelity between the time of appearance of peak overcompensation phase in the muscle strength and in the post-exercise level of musclar ATP, CP and glycogen contents suggest a casual relationship between these changes.

  15. Anatomical relationships between serotonin 5-HT2A and dopamine D2 receptors in living human brain.

    PubMed

    Ishii, Tatsuya; Kimura, Yasuyuki; Ichise, Masanori; Takahata, Keisuke; Kitamura, Soichiro; Moriguchi, Sho; Kubota, Manabu; Zhang, Ming-Rong; Yamada, Makiko; Higuchi, Makoto; Okubo, Yoshinori; Suhara, Tetsuya

    2017-01-01

    Seven healthy volunteers underwent PET scans with [18F]altanserin and [11C]FLB 457 for 5-HT2A and D2 receptors, respectively. As a measure of receptor density, a binding potential (BP) was calculated from PET data for 76 cerebral cortical regions. A correlation matrix was calculated between the binding potentials of [18F]altanserin and [11C]FLB 457 for those regions. The regional relationships were investigated using a bicluster analysis of the correlation matrix with an iterative signature algorithm. We identified two clusters of regions. The first cluster identified a distinct profile of correlation coefficients between 5-HT2A and D2 receptors, with the former in regions related to sensorimotor integration (supplementary motor area, superior parietal gyrus, and paracentral lobule) and the latter in most cortical regions. The second cluster identified another distinct profile of correlation coefficients between 5-HT2A receptors in the bilateral hippocampi and D2 receptors in most cortical regions. The observation of two distinct clusters in the correlation matrix suggests regional interactions between 5-HT2A and D2 receptors in sensorimotor integration and hippocampal function. A bicluster analysis of the correlation matrix of these neuroreceptors may be beneficial in understanding molecular networks in the human brain.

  16. The Relationship between School Collective Reflective Practice and Teacher Physiological Efficacy Sources

    ERIC Educational Resources Information Center

    Kennedy, Sheryl Y.; Smith, Julia B.

    2013-01-01

    This study used Hierarchical Linear Modeling to analyze the relationship between school organizational behaviors and practices (at the school level) on teachers' reports of internal and external physiological sources of efficacy. Six hundred sixty-one teachers from 42 schools in the United States were surveyed to measure both individual sources of…

  17. Atmospheric mercury measurements at a suburban site in the Mid-Atlantic United States: Inter-annual, seasonal and diurnal variations and source-receptor relationships

    NASA Astrophysics Data System (ADS)

    Ren, Xinrong; Luke, Winston T.; Kelley, Paul; Cohen, Mark D.; Artz, Richard; Olson, Mark L.; Schmeltz, David; Puchalski, Melissa; Goldberg, Daniel L.; Ring, Allison; Mazzuca, Gina M.; Cummings, Kristin A.; Wojdan, Lisa; Preaux, Sandra; Stehr, Jeff W.

    2016-12-01

    Different atmospheric mercury forms have been measured at a suburban site in Beltsville, Maryland in the Mid-Atlantic United States since 2007 to investigate their inter-annual, seasonal and diurnal variabilities. Average concentrations and standard deviations of hourly measurements from 2007 to 2015 were 1.41 ± 0.23 ng m-3 for gaseous elemental mercury (GEM), 4.6 ± 33.7 pg m-3 for gaseous oxidized mercury (GOM), and 8.6 ± 56.8 pg m-3 for particulate-bound mercury (PBM). Observations show that on average, the rates of decrease were 0.020 ± 0.007 ng m-3 yr-1 (or 1.3 ± 0.5% yr-1, statistically significant, p-value < 0.01) for GEM, 0.54 ± 0.19 pg m-3 yr-1 (or 7.3 ± 2.6% yr-1, statistically significant, p-value < 0.01) for GOM, and 0.15 ± 0.35 pg m-3 yr-1 (or 1.6 ± 3.8% yr-1, statistically insignificant, p-value > 0.01) for PBM over this nine-year period. In addition, the collocated annual mercury wet deposition decreased at a rate of 0.51 ± 0.24 μg m-2 yr-2 (or 4.2 ± 1.9% yr-1, statistically insignificant, p-value > 0.01). Diurnal variation of GEM shows a slight peak in the morning, likely due to the shallow boundary layer. Seasonal variation of GEM shows lower levels in fall. Both diurnal variations of GOM and PBM show peaks in the afternoon likely due to the photochemical production of reactive mercury from the oxidation of GEM and the influence of boundary layer processes. Seasonally, GOM measurements show high levels in spring and constant low levels in the other three seasons, while PBM measurements exhibit higher levels from late fall to early spring and lower levels from late spring to fall. These measurement data were analyzed using the HYSPLIT back trajectory model in order to examine possible source-receptor relationships at this suburban site. Trajectory frequency analysis shows that high GEM/GOM/PBM events were generally associated with high frequencies of the trajectories passing through areas with high mercury emissions, while low GEM

  18. The First Structure–Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs

    PubMed Central

    2016-01-01

    Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand–receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure–activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3. PMID:25587888

  19. Receptor model comparisons and wind direction analyses of volatile organic compounds and submicrometer particles in an arid, binational, urban air shed.

    PubMed

    Mukerjee, Shaibal; Norris, Gary A; Smith, Luther A; Noble, Christopher A; Neas, Lucas M; Ozkaynak, A Halûk; Gonzales, Melissa

    2004-04-15

    The relationship between continuous measurements of volatile organic compounds sources and particle number was evaluated at a Photochemical Assessment Monitoring Station Network (PAMS) site located near the U.S.-Mexico Border in central El Paso, TX. Sources of volatile organic compounds (VOCs) were investigated using the multivariate receptor model UNMIX and the effective variance least squares receptor model known as Chemical Mass Balance (CMB, Version 8.0). As expected from PAMS measurements, overall findings from data screening as well as both receptor models confirmed that mobile sources were the major source of VOCs. Comparison of hourly source contribution estimates (SCEs) from the two receptor models revealed significant differences in motor vehicle exhaust and evaporative gasoline contributions. However, the motor vehicle exhaust contributions were highly correlated with each other. Motor vehicle exhaust was also correlated with the ultrafine and accumulation mode particle count, which suggests that motor vehicle exhaust is a source of these particles at the measurement site. Wind sector analyses were performed using the SCE and pollutant data to assess source location of VOCs, particle count, and criteria pollutants. Results from this study have application to source apportionment studies and mobile source emission control strategies that are ongoing in this air shed.

  20. ATMOSPHERIC AEROSOL SOURCE-RECEPTOR RELATIONSHIPS: THE ROLE OF COAL-FIRED POWER PLANTS

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Allen L. Robinson; Spyros N. Pandis; Cliff I. Davidson

    2004-04-01

    This report describes the technical progress made on the Pittsburgh Air Quality Study (PAQS) during the period of September 2003 through February 2004. Significant progress was made this project period on the analysis of ambient data, source apportionment, and deterministic modeling activities. Results highlighted in this report include chemical fractionation of the organic fraction to quantify the ratio of organic mass to organic carbon (OM/OC). The average OM/OC ratio for the 31 samples analyzed so far is 1.89, ranging between 1.62 and 2.53, which is consistent with expectations for an atmospherically processed regional aerosol. Analysis of the single particle datamore » reveals that a on a particles in Pittsburgh consist of complex mixture of primary and secondary components. Approximately 79% of all particles measured with the instrument containing some form of carbon, with Carbonaceous Ammonium Nitrate (54.43%) being the dominant particle class. PMCAMx predictions were compared with data from more than 50 sites of the STN network located throughout the Eastern United States for the July 2001 period. OC and sulfate concentrations predicted by PMCAMx are within {+-}30% of the observed concentration at most of these sites. Spherical Aluminum Silicate particle concentrations (SAS) were used to estimate the contribution of primary coal emissions to fine particle levels at the central monitoring site. Primary emissions from coal combustion contribute on average 0.44 {+-} 0.3 {micro}g/m{sup 3} to PM{sub 2.5} at the site or 1.4 {+-} 1.3% of the total PM{sub 2.5} mass. Chemical mass balance analysis was performed to apportion the primary organic aerosol. About 70% of the primary OC emissions are from vehicular sources, with the gasoline contribution being on average three times greater than the diesel emissions in the summer.« less

  1. Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer

    PubMed Central

    Dai, Donghai; Meng, Xiangbing; Thiel, Kristina W.; Leslie, Kimberly K.; Yang, Shujie

    2016-01-01

    Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated disease. Response to progestin therapy positively correlates with hormone receptor expression, in particular progesterone receptor (PR). However, many advanced tumors lose PR expression. We recently reported that the efficacy of progestin therapy can be significantly enhanced by combining progestin with epigenetic modulators, which we term “molecularly enhanced progestin therapy.” What remained unclear was the mechanism of action and if estrogen receptor α (ERα), the principle inducer of PR, is necessary to restore functional expression of PR via molecularly enhanced progestin therapy. Therefore, we modeled advanced endometrial tumors that have lost both ERα and PR expression by generating ERα-null endometrial cancer cell lines. CRISPR-Cas9 technology was used to delete ERα at the genomic level. Our data demonstrate that treatment with a histone deacetylase inhibitor (HDACi) was sufficient to restore functional PR expression, even in cells devoid of ERα. Our studies also revealed that HDACi treatment results in marked downregulation of the oncogene Myc. We established that PR is a negative transcriptional regulator of Myc in endometrial cancer in the presence or absence of ERα, which is in contrast to studies in breast cancer cells. First, estrogen stimulation augmented PR expression and decreased Myc in endometrial cancer cell lines. Second, progesterone increased PR activity yet blunted Myc mRNA and protein expression. Finally, overexpression of PR by adenoviral transduction in ERα-null endometrial cancer cells significantly decreased expression of Myc and Myc-regulated genes. Analysis of the Cancer Genome Atlas (TCGA) database of endometrial tumors identified an inverse correlation between PR and Myc mRNA levels, with a corresponding inverse correlation between PR and Myc downstream transcriptional targets SRD5A1, CDK2 and CCNB1. Together, these data reveal a

  2. Source apportionments of PM2.5 organic carbon using molecular marker Positive Matrix Factorization and comparison of results from different receptor models

    NASA Astrophysics Data System (ADS)

    Heo, Jongbae; Dulger, Muaz; Olson, Michael R.; McGinnis, Jerome E.; Shelton, Brandon R.; Matsunaga, Aiko; Sioutas, Constantinos; Schauer, James J.

    2013-07-01

    Four hundred fine particulate matter (PM2.5) samples collected over a 1-year period at two sites in the Los Angeles Basin were analyzed for organic carbon (OC), elemental carbon (EC), water soluble organic carbon (WSOC) and organic molecular markers. The results were used in a Positive Matrix Factorization (PMF) receptor model to obtain daily, monthly and annual average source contributions to PM2.5 OC. Results of the PMF model showed similar source categories with comparable year-long contributions to PM2.5 OC across the sites. Five source categories providing reasonably stable profiles were identified: mobile, wood smoke, primary biogenic, and two types of secondary organic carbon (SOC) (i.e., anthropogenic and biogenic emissions). Total primary emission factors and total SOC factors contributed approximately 60% and 40%, respectively, to the annual-average OC concentrations. Primary sources showed strong seasonal patterns with high winter peaks and low summer peaks, while SOC showed a reverse pattern with highs in the spring and summer in the region. Interestingly, smoke from forest fires which occurred episodically in California during the summer and fall of 2009 was identified and combined with the primary biogenic source as one distinct factor to the OC budget. The PMF resolved factors were further investigated and compared to a chemical mass balance (CMB) model and a second multi-variant receptor model (UNMIX) using molecular markers considered in the PMF. Good agreement between the source contribution from mobile sources and biomass burning for three models were obtained, providing additional weight of evidence that these source apportionment techniques are sufficiently accurate for policy development. However, the CMB model did not quantify primary biogenic emissions, which were included in other sources with the SOC. Both multivariate receptor models, the PMF and the UNMIX, were unable to separate source contributions from diesel and gasoline engines.

  3. Source-to-exposure assessment with the Pangea multi-scale framework - case study in Australia.

    PubMed

    Wannaz, Cedric; Fantke, Peter; Lane, Joe; Jolliet, Olivier

    2018-01-24

    Effective planning of airshed pollution mitigation is often constrained by a lack of integrative analysis able to relate the relevant emitters to the receptor populations at risk. Both emitter and receptor perspectives are therefore needed to consistently inform emission and exposure reduction measures. This paper aims to extend the Pangea spatial multi-scale multimedia framework to evaluate source-to-receptor relationships of industrial sources of organic pollutants in Australia. Pangea solves a large compartmental system in parallel by block to determine arrays of masses at steady-state for 100 000+ compartments and 4000+ emission scenarios, and further computes population exposure by inhalation and ingestion. From an emitter perspective, radial spatial distributions of population intakes show high spatial variation in intake fractions from 0.68 to 33 ppm for benzene, and from 0.006 to 9.5 ppm for formaldehyde, contrasting urban, rural, desert, and sea source locations. Extending analyses to the receptor perspective, population exposures from the combined emissions of 4101 Australian point sources are more extended for benzene that travels over longer distances, versus formaldehyde that has a more local impact. Decomposing exposure per industrial sector shows petroleum and steel industry as the highest contributing industrial sectors for benzene, whereas the electricity sector and petroleum refining contribute most to formaldehyde exposures. The source apportionment identifies the main sources contributing to exposure at five locations. Overall, this paper demonstrates high interest in addressing exposures from both an emitter perspective well-suited to inform product oriented approaches such as LCA, and from a receptor perspective for health risk mitigation.

  4. Determining the behavioural dose-response relationship of marine mammals to air gun noise and source proximity.

    PubMed

    Dunlop, Rebecca A; Noad, Michael J; McCauley, Robert D; Scott-Hayward, Lindsay; Kniest, Eric; Slade, Robert; Paton, David; Cato, Douglas H

    2017-08-15

    The effect of various anthropogenic sources of noise (e.g. sonar, seismic surveys) on the behaviour of marine mammals is sometimes quantified as a dose-response relationship, where the probability of an animal behaviourally 'responding' (e.g. avoiding the source) increases with 'dose' (or received level of noise). To do this, however, requires a definition of a 'significant' response (avoidance), which can be difficult to quantify. There is also the potential that the animal 'avoids' not only the source of noise but also the vessel operating the source, complicating the relationship. The proximity of the source is an important variable to consider in the response, yet difficult to account for given that received level and proximity are highly correlated. This study used the behavioural response of humpback whales to noise from two different air gun arrays (20 and 140 cubic inch air gun array) to determine whether a dose-response relationship existed. To do this, a measure of avoidance of the source was developed, and the magnitude (rather than probability) of this response was tested against dose. The proximity to the source, and the vessel itself, was included within the one-analysis model. Humpback whales were more likely to avoid the air gun arrays (but not the controls) within 3 km of the source at levels over 140 re. 1 µPa 2  s -1 , meaning that both the proximity and the received level were important factors and the relationship between dose (received level) and response is not a simple one. © 2017. Published by The Company of Biologists Ltd.

  5. Cloning and sequence analysis of the human brain beta-adrenergic receptor. Evolutionary relationship to rodent and avian beta-receptors and porcine muscarinic receptors.

    PubMed

    Chung, F Z; Lentes, K U; Gocayne, J; Fitzgerald, M; Robinson, D; Kerlavage, A R; Fraser, C M; Venter, J C

    1987-01-26

    Two cDNA clones, lambda-CLFV-108 and lambda-CLFV-119, encoding for the beta-adrenergic receptor, have been isolated from a human brain stem cDNA library. One human genomic clone, LCV-517 (20 kb), was characterized by restriction mapping and partial sequencing. The human brain beta-receptor consists of 413 amino acids with a calculated Mr of 46480. The gene contains three potential glucocorticoid receptor-binding sites. The beta-receptor expressed in human brain was homology with rodent (88%) and avian (52%) beta-receptors and with porcine muscarinic cholinergic receptors (31%), supporting our proposal [(1984) Proc. Natl. Acad. Sci. USA 81, 272 276] that adrenergic and muscarinic cholinergic receptors are structurally related. This represents the first cloning of a neurotransmitter receptor gene from human brain.

  6. A Bayesian Multivariate Receptor Model for Estimating Source Contributions to Particulate Matter Pollution using National Databases.

    PubMed

    Hackstadt, Amber J; Peng, Roger D

    2014-11-01

    Time series studies have suggested that air pollution can negatively impact health. These studies have typically focused on the total mass of fine particulate matter air pollution or the individual chemical constituents that contribute to it, and not source-specific contributions to air pollution. Source-specific contribution estimates are useful from a regulatory standpoint by allowing regulators to focus limited resources on reducing emissions from sources that are major contributors to air pollution and are also desired when estimating source-specific health effects. However, researchers often lack direct observations of the emissions at the source level. We propose a Bayesian multivariate receptor model to infer information about source contributions from ambient air pollution measurements. The proposed model incorporates information from national databases containing data on both the composition of source emissions and the amount of emissions from known sources of air pollution. The proposed model is used to perform source apportionment analyses for two distinct locations in the United States (Boston, Massachusetts and Phoenix, Arizona). Our results mirror previous source apportionment analyses that did not utilize the information from national databases and provide additional information about uncertainty that is relevant to the estimation of health effects.

  7. Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists.

    PubMed

    Morin, Matthew D; Wang, Ying; Jones, Brian T; Su, Lijing; Surakattula, Murali M R P; Berger, Michael; Huang, Hua; Beutler, Elliot K; Zhang, Hong; Beutler, Bruce; Boger, Dale L

    2016-05-26

    Herein, we report studies leading to the discovery of the neoseptins and a comprehensive examination of the structure-activity relationships (SARs) of this new class of small-molecule mouse Toll-like receptor 4 (mTLR4) agonists. The compounds in this class, which emerged from screening an α-helix mimetic library, stimulate the immune response, act by a well-defined mechanism (mouse TLR4 agonist), are easy to produce and structurally manipulate, exhibit exquisite SARs, are nontoxic, and elicit improved and qualitatively different responses compared to lipopolysaccharide, even though they share the same receptor.

  8. Bovine gallbladder muscularis: Source of a myogenic receptor for cholecystokinin

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Schjoldager, B.; Shaw, M.J.; Powers, S.P.

    1988-03-01

    Despite being a classic target for the gastrointestinal peptide hormone, cholecystokinin (CCK), the gallbladder CCK receptor is not well characterized. Pharmacological studies of small species suggest that CCK action can be mediated by direct myogenic or by both myogenic and neurogenic receptors. To prepare for the biochemical characterization of a gallbladder CCK receptor and to define the subtype of the receptor being studied. The authors have performed autoradiographic localization and pharmacological characterization of CCK receptors on bovine gallbladder. Autoradiography demonstrated high-affinity specific CCK-binding sites only on the muscularis. CCK-8 stimulated tonic contraction of longitudinal strips of gallbladder muscularis in amore » concentration-dependent manner. Antagonism at the cholinergic receptor with 1{mu}M atropine or axonal transmission with 1{mu}M tetrodotoxin did not modify CCK-induced contraction, supporting a direct myogenic effect of this hormone. Optimal electrical field stimulation to elicit a neuronal response resulted in muscle strip relaxation, which was abolished with adrenergic blockade. Although acetylcholine administration stimulated contraction, electrical field stimulation did not, even in the presence of phentolamine, propranolol, and/or CCK. Thus, in bovine gallbladder muscularis, there is evidence for a functional CCK receptor only on smooth muscle cells. Demonstration of a single, high-affinity specific CCK-binding site on an enriched plasma membrane preparation of bovine gallbladder muscularis is consistent with this representing a myogenic CCK receptor.« less

  9. Determining the contribution of long-range transport, regional and local source areas, to PM10 mass loading in Hessen, Germany using a novel multi-receptor based statistical approach

    NASA Astrophysics Data System (ADS)

    Garg, Saryu; Sinha, Baerbel

    2017-10-01

    This study uses two newly developed statistical source apportionment models, MuSAM and MuReSAM, to perform quantitative statistical source apportionment of PM10 at multiple receptor sites in South Hessen. MuSAM uses multi-site back trajectory data to quantify the contribution of long-range transport, while MuReSAM uses wind speed and direction as proxy for regional transport and quantifies the contribution of regional source areas. On average, between 7.8 and 9.1 μg/m3 of PM10 (∼50%) at receptor sites in South Hessen is contributed by long-range transport. The dominant source regions are Eastern, South Eastern, and Southern Europe. 32% of the PM10 at receptor sites in South Hessen is contributed by regional source areas (2.8-9.41 μg/m3). This fraction varies from <20% at remote sites to >40% for urban stations. Sources located within a 2 km radius around the receptor site are responsible for 7%-20% of the total PM10 mass (0.7-4.4 μg/m3). The perturbation study of the traffic flow due to the closing and reopening of the Schiersteiner Brücke revealed that the contribution of the bridge to PM10 mass loadings at two nearby receptor sites increased by approximately 120% after it reopened and became a bottleneck, although in absolute terms, the increase is small.

  10. Probing receptor structure/function with chimeric G-protein-coupled receptors.

    PubMed

    Yin, Dezhong; Gavi, Shai; Wang, Hsien-yu; Malbon, Craig C

    2004-06-01

    Owing its name to an image borrowed from Greek mythology, a chimera is seen to represent a new entity created as a composite from existing creatures or, in this case, molecules. Making use of various combinations of three basic domains of the receptors (i.e., exofacial, transmembrane, and cytoplasmic segments) that couple agonist binding into activation of effectors through heterotrimeric G-proteins, molecular pharmacology has probed the basic organization, structure/function relationships of this superfamily of heptahelical receptors. Chimeric G-protein-coupled receptors obviate the need for a particular agonist ligand when the ligand is resistant to purification or, in the case of orphan receptors, is not known. Chimeric receptors created from distant members of the heptahelical receptors enable new strategies in understanding how these receptors transduce agonist binding into receptor activation and may be able to offer insights into the evolution of G-protein-coupled receptors from yeast to humans.

  11. A COMPARISON OF THE UCD/CIT AIR QUALITY MODEL AND THE CMB SOURCE-RECEPTOR MODEL FOR PRIMARY AIRBORNE PARTICULATE MATTER. (R831082)

    EPA Science Inventory

    Source contributions to primary airborne particulate matter calculated using the source-oriented UCD/CIT air quality model and the receptor-oriented chemical mass balance (CMB) model are compared for two air quality episodes in different parts of California. The first episode ...

  12. Estrogen-related receptor gamma disruption of source water and drinking water treatment processes extracts.

    PubMed

    Li, Na; Jiang, Weiwei; Rao, Kaifeng; Ma, Mei; Wang, Zijian; Kumaran, Satyanarayanan Senthik

    2011-01-01

    Environmental chemicals in drinking water can impact human health through nuclear receptors. Additionally, estrogen-related receptors (ERRs) are vulnerable to endocrine-disrupting effects. To date, however, ERR disruption of drinking water potency has not been reported. We used ERRgamma two-hybrid yeast assay to screen ERRgamma disrupting activities in a drinking water treatment plant (DWTP) located in north China and in source water from a reservoir, focusing on agonistic, antagonistic, and inverse agonistic activity to 4-hydroxytamoxifen (4-OHT). Water treatment processes in the DWTP consisted of pre-chlorination, coagulation, coal and sand filtration, activated carbon filtration, and secondary chlorination processes. Samples were extracted by solid phase extraction. Results showed that ERRgamma antagonistic activities were found in all sample extracts, but agonistic and inverse agonistic activity to 4-OHT was not found. When calibrated with the toxic equivalent of 4-OHT, antagonistic effluent effects ranged from 3.4 to 33.1 microg/L. In the treatment processes, secondary chlorination was effective in removing ERRgamma antagonists, but the coagulation process led to significantly increased ERRgamma antagonistic activity. The drinking water treatment processes removed 73.5% of ERRgamma antagonists. To our knowledge, the occurrence of ERRgamma disruption activities on source and drinking water in vitro had not been reported previously. It is vital, therefore, to increase our understanding of ERRy disrupting activities in drinking water.

  13. Relationship between mass-flux reduction and source-zone mass removal: analysis of field data.

    PubMed

    Difilippo, Erica L; Brusseau, Mark L

    2008-05-26

    The magnitude of contaminant mass-flux reduction associated with a specific amount of contaminant mass removed is a key consideration for evaluating the effectiveness of a source-zone remediation effort. Thus, there is great interest in characterizing, estimating, and predicting relationships between mass-flux reduction and mass removal. Published data collected for several field studies were examined to evaluate relationships between mass-flux reduction and source-zone mass removal. The studies analyzed herein represent a variety of source-zone architectures, immiscible-liquid compositions, and implemented remediation technologies. There are two general approaches to characterizing the mass-flux-reduction/mass-removal relationship, end-point analysis and time-continuous analysis. End-point analysis, based on comparing masses and mass fluxes measured before and after a source-zone remediation effort, was conducted for 21 remediation projects. Mass removals were greater than 60% for all but three of the studies. Mass-flux reductions ranging from slightly less than to slightly greater than one-to-one were observed for the majority of the sites. However, these single-snapshot characterizations are limited in that the antecedent behavior is indeterminate. Time-continuous analysis, based on continuous monitoring of mass removal and mass flux, was performed for two sites, both for which data were obtained under water-flushing conditions. The reductions in mass flux were significantly different for the two sites (90% vs. approximately 8%) for similar mass removals ( approximately 40%). These results illustrate the dependence of the mass-flux-reduction/mass-removal relationship on source-zone architecture and associated mass-transfer processes. Minimal mass-flux reduction was observed for a system wherein mass removal was relatively efficient (ideal mass-transfer and displacement). Conversely, a significant degree of mass-flux reduction was observed for a site wherein mass

  14. Examining the Relationships among Item Recognition, Source Recognition, and Recall from an Individual Differences Perspective

    ERIC Educational Resources Information Center

    Unsworth, Nash; Brewer, Gene A.

    2009-01-01

    The authors of the current study examined the relationships among item-recognition, source-recognition, free recall, and other memory and cognitive ability tasks via an individual differences analysis. Two independent sources of variance contributed to item-recognition and source-recognition performance, and these two constructs related…

  15. SOURCE APPORTIONMENT OF EXPOSURES TO VOLATILE ORGANIC COMPOUNDS: II. APPLICATION OF RECEPTOR MODELS TO TEAM STUDY DATA. (R826788)

    EPA Science Inventory

    Four receptor-oriented source apportionment models were applied to personal exposure measurements for toxic volatile organic compounds (VOCs). The measurements are from the total exposure assessment methodology studies conducted from 1980 to 1984 in New Jersey (NJ) and Califor...

  16. Influence of music on steroid hormones and the relationship between receptor polymorphisms and musical ability: a pilot study.

    PubMed

    Fukui, Hajime; Toyoshima, Kumiko

    2013-01-01

    Studies have shown that music confers plasticity to the brain. In a preliminary pilot study, we examined the effect of music listening on steroid hormones and the relationship between steroid hormone receptor polymorphisms and musical ability. Twenty-one subjects (10 males and 11 females) were recruited and divided into musically talented and control groups. The subjects selected (1) music they preferred (chill-inducing music) and (2) music they did not like. Before and after the experiments, saliva was collected to measure the levels of steroid hormones such as testosterone, estradiol, and cortisol. DNA was also isolated from the saliva samples to determine the androgen receptor (AR) and arginine vasopressin receptor 1A genotypes. Advanced Measures of Music Audiation (AMMA) was used to determine the musical ability of the subjects. With both types of music, the cortisol levels decreased significantly in both sexes. The testosterone (T) levels declined in males when they listened to both types of music. In females, the T levels increased in those listening to chill-inducing music but declined when they listened to music they disliked. However, these differences were not significant. The 17-beta estradiol levels increased in males with both types of music, whereas the levels increased with chill-inducing music but declined with disliked music in females. The AMMA scores were higher for the short repeat length-type AR than for the long repeat length-type. Comparisons of AR polymorphisms and T levels before the experiments showed that the T levels were within the low range in the short repeat length-type group and there was a positive relationship with the repeat length, although it was not significant. This is the first study conducted in humans to analyze the relationships between the AR gene, T levels, and musical ability.

  17. Influence of music on steroid hormones and the relationship between receptor polymorphisms and musical ability: a pilot study

    PubMed Central

    Fukui, Hajime; Toyoshima, Kumiko

    2013-01-01

    Studies have shown that music confers plasticity to the brain. In a preliminary pilot study, we examined the effect of music listening on steroid hormones and the relationship between steroid hormone receptor polymorphisms and musical ability. Twenty-one subjects (10 males and 11 females) were recruited and divided into musically talented and control groups. The subjects selected (1) music they preferred (chill-inducing music) and (2) music they did not like. Before and after the experiments, saliva was collected to measure the levels of steroid hormones such as testosterone, estradiol, and cortisol. DNA was also isolated from the saliva samples to determine the androgen receptor (AR) and arginine vasopressin receptor 1A genotypes. Advanced Measures of Music Audiation (AMMA) was used to determine the musical ability of the subjects. With both types of music, the cortisol levels decreased significantly in both sexes. The testosterone (T) levels declined in males when they listened to both types of music. In females, the T levels increased in those listening to chill-inducing music but declined when they listened to music they disliked. However, these differences were not significant. The 17-beta estradiol levels increased in males with both types of music, whereas the levels increased with chill-inducing music but declined with disliked music in females. The AMMA scores were higher for the short repeat length-type AR than for the long repeat length-type. Comparisons of AR polymorphisms and T levels before the experiments showed that the T levels were within the low range in the short repeat length-type group and there was a positive relationship with the repeat length, although it was not significant. This is the first study conducted in humans to analyze the relationships between the AR gene, T levels, and musical ability. PMID:24348454

  18. Rational Quantitative Structure-Activity Relationship (RQSAR) Screen for PXR and CAR Isoform-Specific Nuclear Receptor Ligands

    PubMed Central

    Dring, Ann M.; Anderson, Linnea E.; Qamar, Saima; Stoner, Matthew A.

    2010-01-01

    Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related orphan nuclear receptor proteins that share several ligands and target overlapping sets of genes involved in homeostasis and all phases of drug metabolism. CAR and PXR are involved in the development of certain diseases, including diabetes, metabolic syndrome and obesity. Ligand screens for these receptors so far have typically focused on steroid hormone analogs with pharmacophore-based approaches, only to find relatively few new hits. Multiple CAR isoforms have been detected in human liver, with the most abundant being the constitutively active reference, CAR1, and the ligand-dependent isoform CAR3. It has been assumed that any compound that binds CAR1 should also activate CAR3, and so CAR3 can be used as a ligand-activated surrogate for CAR1 studies. The possibility of CAR3-specific ligands has not, so far, been addressed. To investigate the differences between CAR1, CAR3 and PXR, and to look for more CAR ligands that may be of use in quantitative structure-activity relationship (QSAR) studies, we performed a luciferase transactivation assay screen of 60 mostly non-steroid compounds. Known active compounds with different core chemistries were chosen as starting points and structural variants were rationally selected for screening. Distinct differences in agonist versus inverse agonist/antagonist effects were seen in 49 compounds that had some ligand effect on at least one receptor and 18 that had effects on all three receptors; eight were CAR1 ligands only, three were CAR3 only ligands and four affected PXR only. This work provides evidence for new CAR ligands, some of which have CAR3-specific effects, and provides observational data on CAR and PXR ligands with which to inform in silico strategies. Compounds that demonstrated unique activity on any one receptor are potentially valuable diagnostic tools for the investigation of in vivo molecular targets. PMID:20869355

  19. Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression.

    PubMed

    Toyota, Yosuke; Nomura, Sayaka; Makishima, Makoto; Hashimoto, Yuichi; Ishikawa, Minoru

    2017-06-15

    Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated transrepression. Thus, transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC 50 : 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Atmospheric aerosol source identification and estimates of source contributions to air pollution in Dundee, UK

    NASA Astrophysics Data System (ADS)

    Qin, Y.; Oduyemi, K.

    Anthropogenic aerosol (PM 10) emission sources sampled at an air quality monitoring station in Dundee have been analysed. However, the information on local natural aerosol emission sources was unavailable. A method that combines receptor model and atmospheric dispersion model was used to identify aerosol sources and estimate source contributions to air pollution. The receptor model identified five sources. These are aged marine aerosol source with some chlorine replaced by sulphate, secondary aerosol source of ammonium sulphate, secondary aerosol source of ammonium nitrate, soil and construction dust source, and incinerator and fuel oil burning emission source. For the vehicle emission source, which has been comprehensively described in the atmospheric emission inventory but cannot be identified by the receptor model, an atmospheric dispersion model was used to estimate its contributions. In Dundee, a significant percentage, 67.5%, of the aerosol mass sampled at the study station could be attributed to the six sources named above.

  1. The Solar Wind Source Cycle: Relationship to Dynamo Behavior

    NASA Astrophysics Data System (ADS)

    Luhmann, J. G.; Li, Y.; Lee, C. O.; Jian, L. K.; Petrie, G. J. D.; Arge, C. N.

    2017-12-01

    Solar cycle trends of interest include the evolving properties of the solar wind, the heliospheric medium through which the Sun's plasmas and fields interact with Earth and the planets -including the evolution of CME/ICMEs enroute. Solar wind sources include the coronal holes-the open field regions that constantly evolve with solar magnetic fields as the cycle progresses, and the streamers between them. The recent cycle has been notably important in demonstrating that not all solar cycles are alike when it comes to contributions from these sources, including in the case of ecliptic solar wind. In particular, it has modified our appreciation of the low latitude coronal hole and streamer sources because of their relative prevalence. One way to understand the basic relationship between these source differences and what is happening inside the Sun and on its surface is to use observation-based models like the PFSS model to evaluate the evolution of the coronal field geometry. Although the accuracy of these models is compromised around solar maximum by lack of global surface field information and the sometimes non-potential evolution of the field related to more frequent and widespread emergence of active regions, they still approximate the character of the coronal field state. We use these models to compare the inferred recent cycle coronal holes and streamer belt sources of solar wind with past cycle counterparts. The results illustrate how (still) hemispherically asymmetric weak polar fields maintain a complex mix of low-to-mid latitude solar wind sources throughout the latest cycle, with a related marked asymmetry in the hemispheric distribution of the ecliptic wind sources. This is likely to be repeated until the polar field strength significantly increases relative to the fields at low latitudes, and the latter symmetrize.

  2. Using Chou's general PseAAC to analyze the evolutionary relationship of receptor associated proteins (RAP) with various folding patterns of protein domains.

    PubMed

    Muthu Krishnan, S

    2018-05-14

    The receptor-associated protein (RAP) is an inhibitor of endocytic receptors that belong to the lipoprotein receptor gene family. In this study, a computational approach was tried to find the evolutionarily related fold of the RAP proteins. Through the structural and sequence-based analysis, found various protein folds that are very close to the RAP folds. Remote homolog datasets were used potentially to develop a different support vector machine (SVM) methods to recognize the homologous RAP fold. This study helps in understanding the relationship of RAP homologs folds based on the structure, function and evolutionary history. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. A receptor-grounded approach to teaching nonsteroidal antiinflammatory drug chemistry and structure-activity relationships.

    PubMed

    Roche, Victoria F

    2009-12-17

    To describe a receptor-based approach to promote learning about nonsteroidal anti-inflammatory drug (NSAID) chemistry, structure-activity relationships, and therapeutic decision-making. Three lessons on cyclooxygenase (COX) and NSAID chemistry, and NSAID therapeutic utility, were developed using text-based resources and primary medicinal chemistry and pharmacy practice literature. Learning tools were developed to assist students in content mastery. Student learning was evaluated via performance on quizzes and examinations that measured understanding of COX and NSAID chemistry, and the application of that knowledge to therapeutic problem solving. Student performance on NSAID-focused quizzes and examinations documented the success of this approach.

  4. A modified receptor model for source apportionment of heavy metal pollution in soil.

    PubMed

    Huang, Ying; Deng, Meihua; Wu, Shaofu; Japenga, Jan; Li, Tingqiang; Yang, Xiaoe; He, Zhenli

    2018-07-15

    Source apportionment is a crucial step toward reduction of heavy metal pollution in soil. Existing methods are generally based on receptor models. However, overestimation or underestimation occurs when they are applied to heavy metal source apportionment in soil. Therefore, a modified model (PCA-MLRD) was developed, which is based on principal component analysis (PCA) and multiple linear regression with distance (MLRD). This model was applied to a case study conducted in a peri-urban area in southeast China where soils were contaminated by arsenic (As), cadmium (Cd), mercury (Hg) and lead (Pb). Compared with existing models, PCA-MLRD is able to identify specific sources and quantify the extent of influence for each emission. The zinc (Zn)-Pb mine was identified as the most important anthropogenic emission, which affected approximately half area for Pb and As accumulation, and approximately one third for Cd. Overall, the influence extent of the anthropogenic emissions decreased in the order of mine (3 km) > dyeing mill (2 km) ≈ industrial hub (2 km) > fluorescent factory (1.5 km) > road (0.5 km). Although algorithm still needs to improved, the PCA-MLRD model has the potential to become a useful tool for heavy metal source apportionment in soil. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Structure-activity relationships of seco-prezizaane terpenoids in gamma-aminobutyric acid receptors of houseflies and rats.

    PubMed

    Kuriyama, Tadahiko; Schmidt, Thomas J; Okuyama, Emi; Ozoe, Yoshihisa

    2002-06-01

    Thirteen seco-prezizaane terpenoids isolated from star anise species (Illcium floridanum, Illcium parviflorum, and Illcium verum) were investigated for their ability to inhibit the specific binding of [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist of gamma-aminobutyric acid (GABA) receptors, to housefly-head and rat-brain membranes. Veranisatin A was found to be the most potent inhibitor in both membranes, with an IC(50)(fly) of 78.5 nM and an IC(50)(rat) of 271 nM, followed by anisatin (IC(50)(fly)=123 nM; IC(50)(rat)=282 nM). Six of the other 11 tested compounds were effective only in housefly-head membranes. Pseudoanisatin proved to display a high (>26-fold) selectivity for housefly versus rat GABA receptors (IC(50)(fly)=376 nM; IC(50)(rat) >10,000 nM). Although pseudoanisatin does not structurally resemble EBOB, Scatchard plots indicated that the two compounds bind to the same site in housefly receptors. Anisatin and pseudoanisatin exhibited moderate insecticidal activity against German cockroaches. Comparative molecular field analysis (CoMFA), a method of three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, demonstrated that seco-prezizaane terpenoids can bind to the same site as do picrotoxane terpenoids such as picrotoxinin and picrodendrins, and the CoMFA maps allowed us to identify the parts of the molecules essential to high activity in housefly GABA receptors.

  6. Source Apportionment of Atmospheric Particles by Electron Probe X-Ray Microanalysis and Receptor Models.

    NASA Astrophysics Data System (ADS)

    van Borm, Werner August

    abundance and particle composition. Alternatively, the bulk analysis of filters (total, fine and coarse mode) using Particle Induced X -Ray Emission (PIXE) and the application of a receptor modeling approach provided for complementary information on a macroscopical level. A computer program was developed incorporating an absolute factor analysis based receptor modeling procedure. Source profiles and contributions are described by elemental concentrations and an atmospheric mass balance is put forward. The latter method was applied in a two year study of the Antwerp urban aerosol and for the swiss aerosol, revealing a number of previously known and unknown sources. Both methods were successfully combined to increase the source resolution.

  7. MULTIVARIATE RECEPTOR MODELS AND MODEL UNCERTAINTY. (R825173)

    EPA Science Inventory

    Abstract

    Estimation of the number of major pollution sources, the source composition profiles, and the source contributions are the main interests in multivariate receptor modeling. Due to lack of identifiability of the receptor model, however, the estimation cannot be...

  8. Operational source receptor calculations for large agglomerations

    NASA Astrophysics Data System (ADS)

    Gauss, Michael; Shamsudheen, Semeena V.; Valdebenito, Alvaro; Pommier, Matthieu; Schulz, Michael

    2016-04-01

    For Air quality policy an important question is how much of the air pollution within an urbanized region can be attributed to local sources and how much of it is imported through long-range transport. This is critical information for a correct assessment of the effectiveness of potential emission measures. The ratio between indigenous and long-range transported air pollution for a given region depends on its geographic location, the size of its area, the strength and spatial distribution of emission sources, the time of the year, but also - very strongly - on the current meteorological conditions, which change from day to day and thus make it important to provide such calculations in near-real-time to support short-term legislation. Similarly, long-term analysis over longer periods (e.g. one year), or of specific air quality episodes in the past, can help to scientifically underpin multi-regional agreements and long-term legislation. Within the European MACC projects (Monitoring Atmospheric Composition and Climate) and the transition to the operational CAMS service (Copernicus Atmosphere Monitoring Service) the computationally efficient EMEP MSC-W air quality model has been applied with detailed emission data, comprehensive calculations of chemistry and microphysics, driven by high quality meteorological forecast data (up to 96-hour forecasts), to provide source-receptor calculations on a regular basis in forecast mode. In its current state, the product allows the user to choose among different regions and regulatory pollutants (e.g. ozone and PM) to assess the effectiveness of fictive emission reductions in air pollutant emissions that are implemented immediately, either within the agglomeration or outside. The effects are visualized as bar charts, showing resulting changes in air pollution levels within the agglomeration as a function of time (hourly resolution, 0 to 4 days into the future). The bar charts not only allow assessing the effects of emission

  9. A Receptor-Grounded Approach to Teaching Nonsteroidal Antiinflammatory Drug Chemistry and Structure-Activity Relationships

    PubMed Central

    2009-01-01

    Objective To describe a receptor-based approach to promote learning about nonsteroidal anti-inflammatory drug (NSAID) chemistry, structure-activity relationships, and therapeutic decision-making. Design Three lessons on cyclooxygenase (COX) and NSAID chemistry, and NSAID therapeutic utility, were developed using text-based resources and primary medicinal chemistry and pharmacy practice literature. Learning tools were developed to assist students in content mastery. Assessment Student learning was evaluated via performance on quizzes and examinations that measured understanding of COX and NSAID chemistry, and the application of that knowledge to therapeutic problem solving. Conclusion Student performance on NSAID-focused quizzes and examinations documented the success of this approach. PMID:20221336

  10. [Studies on the structure-activity relationship of retinoids--Hansch analysis and 3D-OSAR studies on specific ligands of retinoid x receptor].

    PubMed

    Huang, N; Chu, F; Guo, Z

    1998-06-01

    Retinoids (Vitamin A, its metabolites and synthetic analogues) play important roles in a variety of biological processes, including cellular differentiation, proliferation and apoptosis. The many diverse actions of retinoids attribute to the ability of regulating transcription of different target genes through activation of multiple retinoid nuclear receptors (RAR of RXR). So, retinoids with selective binding ability to specific receptor may not only have improved therapeutic indices, but may also be invaluable for elucidating the molecular mechanism of retinoidal transcriptional activation. Based on the two dimensional and three dimensional quantitative structure-activity relationships of specific ligands of RXR, we carried out mimesis of environment of ligands interacting with their receptor and, to some extent, mapping the topological and physico-chemical characteristics of receptor. The knowledge of the QSAR study will offer detailed molecular information for design, synthesis and biological evaluation in drug research and development.

  11. Computer-aided structure-affinity relationships in a set of piperazine and 3,8-diazabicyclo[3.2.1]octane derivatives binding to the μ-opioid receptor

    NASA Astrophysics Data System (ADS)

    Barlocco, Daniela; Cignarella, Giorgio; Greco, Giovanni; Novellino, Ettore

    1993-10-01

    Molecular modeling studies were carried out on a set of piperazine and 3,8-diazabicyclo[3.2.1]octane derivatives with the aim to highlight the main factors modulating their affinity for the μ-opioid receptor. Structure-affinity relationships were developed with the aid of molecular mechanics and semiempirical quantum-mechanics methods. According to our proposed pharmacodynamic model, the binding to the μ-receptor is promoted by the following physico-chemical features: the presence of hydrocarbon fragments on the nitrogen ring frame capable of interacting with one of two hypothesized hydrophobic receptor pockets; a `correct' orientation of an N-propionyl side chain so as to avoid a sterically hindered region of the receptor; the possibility of accepting a hydrogen bond from a receptor site complementary to the morphine phenol oxygen.

  12. The Relationship between Agriculture Knowledge Bases for Teaching and Sources of Knowledge

    ERIC Educational Resources Information Center

    Rice, Amber H.; Kitchel, Tracy

    2015-01-01

    The purpose of this study was to describe the agriculture knowledge bases for teaching of agriculture teachers and to see if a relationship existed between years of teaching experience, sources of knowledge, and development of pedagogical content knowledge (PCK), using quantitative methods. A model of PCK from mathematics was utilized as a…

  13. Source apportionment for fine particulate matter in a Chinese city using an improved gas-constrained method and comparison with multiple receptor models.

    PubMed

    Shi, Guoliang; Liu, Jiayuan; Wang, Haiting; Tian, Yingze; Wen, Jie; Shi, Xurong; Feng, Yinchang; Ivey, Cesunica E; Russell, Armistead G

    2018-02-01

    PM 2.5 is one of the most studied atmospheric pollutants due to its adverse impacts on human health and welfare and the environment. An improved model (the chemical mass balance gas constraint-Iteration: CMBGC-Iteration) is proposed and applied to identify source categories and estimate source contributions of PM 2.5. The CMBGC-Iteration model uses the ratio of gases to PM as constraints and considers the uncertainties of source profiles and receptor datasets, which is crucial information for source apportionment. To apply this model, samples of PM 2.5 were collected at Tianjin, a megacity in northern China. The ambient PM 2.5 dataset, source information, and gas-to-particle ratios (such as SO 2 /PM 2.5 , CO/PM 2.5 , and NOx/PM 2.5 ratios) were introduced into the CMBGC-Iteration to identify the potential sources and their contributions. Six source categories were identified by this model and the order based on their contributions to PM 2.5 was as follows: secondary sources (30%), crustal dust (25%), vehicle exhaust (16%), coal combustion (13%), SOC (7.6%), and cement dust (0.40%). In addition, the same dataset was also calculated by other receptor models (CMB, CMB-Iteration, CMB-GC, PMF, WALSPMF, and NCAPCA), and the results obtained were compared. Ensemble-average source impacts were calculated based on the seven source apportionment results: contributions of secondary sources (28%), crustal dust (20%), coal combustion (18%), vehicle exhaust (17%), SOC (11%), and cement dust (1.3%). The similar results of CMBGC-Iteration and ensemble method indicated that CMBGC-Iteration can produce relatively appropriate results. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Neutrophil formyl-peptide receptors. Relationship to peptide-induced responses and emphysema.

    PubMed

    Stockley, R A; Grant, R A; Llewellyn-Jones, C G; Hill, S L; Burnett, D

    1994-02-01

    A reproducible assay was established to assess the number of formyl-peptide receptors expressed on the surface of human polymorphonuclear leukocytes (PMN). Using this assay the number of receptors was shown to demonstrate wide within- and between-subject variability. However, the receptor numbers were related to the chemotactic response (r = 0.572) and degranulation response (r = 0.512) to the peptide formyl-methionyl-leucyl-phenylalanine. Subsequent studies showed increased receptor numbers on PMN from patients with emphysema (median, 459 x 10(3)/cell; range, 207 to 1,080) as compared with age-matched control subjects (median, 288; range, 168 to 519; p < 0.02), which may explain the increased chemotactic response of the PMN to formyl peptides. This difference was not observed in patients with bronchiectasis, suggesting that the increased receptor number is a feature of emphysema. Furthermore, the increase was largely a feature of smokers with emphysema (median, 463; range, 362 to 1,080), whereas age-matched smokers without emphysema had lower numbers of receptors (p < 0.001; median, 332; range, 243 to 411). This observation suggests a mechanism that may explain the susceptibility of some smokers to the development of emphysema.

  15. Quantitative structure-activity relationship and molecular docking of artemisinin derivatives to vascular endothelial growth factor receptor 1.

    PubMed

    Saeed, Mohamed E M; Kadioglu, Onat; Seo, Ean-Jeong; Greten, Henry Johannes; Brenk, Ruth; Efferth, Thomas

    2015-04-01

    The antimalarial drug artemisinin has been shown to exert anticancer activity through anti-angiogenic effects. For further drug development, it may be useful to have derivatives with improved anti-angiogenic properties. We performed molecular docking of 52 artemisinin derivatives to vascular endothelial growth factor receptors (VEGFR1, VEGFR2), and VEGFA ligand using Autodock4 and AutodockTools-1.5.7.rc1 using the Lamarckian genetic algorithm. Quantitative structure-activity relationship (QSAR) analyses of the compounds prepared by Corina Molecular Networks were performed using the Molecular Operating Environment MOE 2012.10. A statistically significant inverse relationship was obtained between in silico binding energies to VEGFR1 and anti-angiogenic activity in vivo of a test-set of artemisinin derivatives (R=-0.843; p=0.035). This served as a control experiment to validate molecular docking predicting anti-angiogenc effects. Furthermore, 52 artemisinin derivatives were docked to VEGFR1 and in selected examples also to VEGFR2 and VEGFA. Higher binding affinities were calculated for receptors than for the ligand. The best binding affinities to VEGFR1 were found for an artemisinin dimer, 10-dihydroartemisinyl-2-propylpentanoate, and dihydroartemisinin α-hemisuccinate sodium salt. QSAR analyses revealed significant relationships between VEGFR1 binding energies and defined molecular descriptors of 35 artemisinins assigned to the training set (R=0.0848, p<0.0001) and 17 derivatives assigned to the test set (R=0.761, p<0.001). Molecular docking and QSAR calculations can be used to identify novel artemisinin derivatives with anti-angiogenic effects. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  16. Differential relationships between D1 and D2 dopamine receptor expression in the medial preoptic nucleus and sexually-motivated song in male European starlings (Sturnus vulgaris)

    PubMed Central

    DeVries, M. S.; Cordes, M.A.; Stevenson, S.A.; Riters, L.V.

    2015-01-01

    Converging data in songbirds support a central role for the medial preoptic nucleus (POM) in motivational aspects of vocal production. Recent data suggest that dopamine in the POM plays a complex modulatory role in the production of sexually-motivated song and that an optimal level of dopamine D1 receptor stimulation is required to facilitate singing behavior. To further explore this possibility, we used quantitative real time PCR to examine relationships between mRNA expression of D1 as well as D2 receptors in the POM (and also the lateral septum and Area X) and sexually-motivated singing behavior in male European starlings. Results showed that both males with the highest and lowest D1 expression in the POM sang significantly less than males with intermediate levels of expression. Furthermore, singing behavior rose linearly in association with increasing levels of D1 expression in POM but dropped abruptly, such that individuals with D1 expression values higher than the mean sang very little. Analysis of birds with low and intermediate levels of D1 expression in POM revealed strong positive correlations between D1 expression and song but negative relationships between D2 receptor expression and song. These findings support prior work suggesting an optimal level of POM D1 receptor stimulation best facilitates sexually-motivated singing behavior. Results also suggest that D2 receptors may work in opposition to D1 receptors in POM to modify vocal production. PMID:26079111

  17. The Relationship between Finnish Student Teachers' Practical Theories, Sources, and Teacher Education

    ERIC Educational Resources Information Center

    Pitkäniemi, Harri; Karlsson, Liisa; Stenberg, Katariina

    2014-01-01

    The purpose of this research is two-fold: 1) to describe what kind of practical theories student teachers have in the Finnish class teacher education context and 2) to analyse their differences and similarities at the initial and final phase of teacher education. We further analyse the relationship between the practical theories and their sources.…

  18. The relationship between somatostatin, epidermal growth factor, and steroid hormone receptors in breast cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Reubi, J.C.; Torhorst, J.

    1989-09-15

    The somatostatin (SS) and the epidermal growth factor (EGF) receptor content have been established in 36 primary breast cancers by receptor autoradiography on adjacent tissue sections. Iodine 125 (125I)-EGF was used as radioligand for EGF receptor visualization whereas an iodinated SS-28 analogue or an octapeptide SS analogue were used to measure SS receptors. Six of 36 tumors contained SS receptors, whereas ten of the 36 tumors were shown to contain EGF receptors. None of the tumor samples containing SS receptors were simultaneously EGF receptor positive. In contrast, all SS receptor-positive tumors simultaneously contained steroid receptors. The positive correlation between SSmore » receptors and steroid receptors as well as the negative correlation between SS receptors and EGF receptors therefore suggest that the small percentage of SS receptor-positive breast tumors are a group of differentiated breast tumors with a good prognosis. In these cases, combined hormonetherapy including SS analogs may be of potential interest.« less

  19. In-time source tracking of watershed loads of Taihu Lake Basin, China based on spatial relationship modeling.

    PubMed

    Wang, Ce; Bi, Jun; Zhang, Xu-Xiang; Fang, Qiang; Qi, Yi

    2018-05-25

    Influent river carrying cumulative watershed load plays a significant role in promoting nuisance algal bloom in river-fed lake. It is most relevant to discern in-stream water quality exceedance and evaluate the spatial relationship between risk location and potential pollution sources. However, no comprehensive studies of source tracking in watershed based on management grid have been conducted for refined water quality management, particularly for plain terrain with complex river network. In this study, field investigations were implemented during 2014 in Taige Canal watershed of Taihu Lake Basin. A Geographical Information System (GIS)-based spatial relationship model was established to characterize the spatial relationships of "point (point-source location and monitoring site)-line (river segment)-plane (catchment)." As a practical exemplification, in-time source tracking was triggered on April 15, 2015 at Huangnianqiao station, where TN and TP concentration violated the water quality standard (TN 4.0 mg/L, TP 0.15 mg/L). Of the target grid cells, 53 and 46 were identified as crucial areas having high pollution intensity for TN and TP pollution, respectively. The estimated non-point source load in each grid cell could be apportioned into different source types based on spatial pollution-related entity objects. We found that the non-point source load derived from rural sewage and livestock and poultry breeding accounted for more than 80% of total TN or TP load than another source type of crop farming. The approach in this study would be of great benefit to local authorities for identifying the serious polluted regions and efficiently making environmental policies to reduce watershed load.

  20. Imidazole derivatives as angiotensin II AT1 receptor blockers: Benchmarks, drug-like calculations and quantitative structure-activity relationships modeling

    NASA Astrophysics Data System (ADS)

    Alloui, Mebarka; Belaidi, Salah; Othmani, Hasna; Jaidane, Nejm-Eddine; Hochlaf, Majdi

    2018-03-01

    We performed benchmark studies on the molecular geometry, electron properties and vibrational analysis of imidazole using semi-empirical, density functional theory and post Hartree-Fock methods. These studies validated the use of AM1 for the treatment of larger systems. Then, we treated the structural, physical and chemical relationships for a series of imidazole derivatives acting as angiotensin II AT1 receptor blockers using AM1. QSAR studies were done for these imidazole derivatives using a combination of various physicochemical descriptors. A multiple linear regression procedure was used to design the relationships between molecular descriptor and the activity of imidazole derivatives. Results validate the derived QSAR model.

  1. GABA(B) receptors, schizophrenia and sleep dysfunction: a review of the relationship and its potential clinical and therapeutic implications.

    PubMed

    Kantrowitz, Joshua; Citrome, Leslie; Javitt, Daniel

    2009-08-01

    Evidence for an intrinsic relationship between sleep, cognition and the symptomatic manifestations of schizophrenia is accumulating. This review presents evidence for the possible utility of GABA(B) receptor agonists for the treatment of subjective and objective sleep abnormalities related to schizophrenia. At the phenotypic level, sleep disturbance occurs in 16-30% of patients with schizophrenia and is related to reduced quality of life and poor coping skills. On the neurophysiological level, studies suggest that sleep deficits reflect a core component of schizophrenia. Specifically, slow-wave sleep deficits, which are inversely correlated with cognition scores, are seen. Moreover, sleep plays an increasingly well documented role in memory consolidation in schizophrenia. Correlations of slow-wave sleep deficits with impaired reaction time and declarative memory have also been reported. Thus, both behavioural insomnia and sleep architecture are critical therapeutic targets in patients with schizophrenia. However, long-term treatment with antipsychotics often results in residual sleep dysfunction and does not improve slow-wave sleep, and adjunctive GABA(A) receptor modulators, such as benzodiazepines and zolpidem, can impair sleep architecture and cognition in schizophrenia. GABA(B) receptor agonists have therapeutic potential in schizophrenia. These agents have minimal effect on rapid eye movement sleep while increasing slow-wave sleep. Preclinical associations with increased expression of genes related to slow-wave sleep production and circadian rhythm function have also been reported. GABA(B) receptor deficits result in a sustained hyperdopaminergic state and can be reversed by a GABA(B) receptor agonist. Genetic, postmortem and electrophysiological studies also associate GABA(B) receptors with schizophrenia. While studies thus far have not shown significant effects, prior focus on the use of GABA(B) receptor agonists has been on the positive symptoms of

  2. Multi-Decadal Variation of Aerosols: Sources, Transport, and Climate Effects

    NASA Technical Reports Server (NTRS)

    Chin, Mian; Diehl, Thomas; Bian, Huisheng; Streets, David

    2008-01-01

    We present a global model study of multi-decadal changes of atmospheric aerosols and their climate effects using a global chemistry transport model along with the near-term to longterm data records. We focus on a 27-year time period of satellite era from 1980 to 2006, during which a suite of aerosol data from satellite observations, ground-based measurements, and intensive field experiments have become available. We will use the Goddard Chemistry Aerosol Radiation and Transport (GOCART) model, which involves a time-varying, comprehensive global emission dataset that we put together in our previous investigations and will be improved/extended in this project. This global emission dataset includes emissions of aerosols and their precursors from fuel combustion, biomass burning, volcanic eruptions, and other sources from 1980 to the present. Using the model and satellite data, we will analyze (1) the long-term global and regional aerosol trends and their relationship to the changes of aerosol and precursor emissions from anthropogenic and natural sources, (2) the intercontinental source-receptor relationships controlled by emission, transport pathway, and climate variability.

  3. Relationship between variant forms of estrogen receptor RNA and an apoptosis-related RNA, TRPM-2, with survival in patients with breast cancer.

    PubMed

    Rennie, P S; Mawji, N R; Coldman, A J; Godolphin, W; Jones, E C; Vielkind, J R; Bruchovsky, N

    1993-12-15

    Although smaller variant forms of estrogen receptor (ER) messenger RNA (mRNA) have been detected in breast tumors, neither their prevalence nor their prognostic significance have been evaluated. Similarly, TRPM-2 mRNA, the product of a gene induced principally during the onset of apoptosis, is present in mouse and human breast cancer cell lines, but whether it also occurs in primary breast tumors and is related to disease outcome is unknown. The relative expression and transcript size of ER mRNA and TRPM-2 mRNA in 126 primary breast tumors were measured by Northern analysis and compared with tumor grade, hormone receptor status, extent of tumor necrosis, and survival. In ER-positive tumors, 64% of the tumors had only the normal 6.5 kb ER mRNA, an additional 9% had the normal plus smaller ER mRNA, and 2% had variant forms. Only 8% of ER-negative tumors had ER mRNA transcripts. There were significant relationships between the occurrence of ER mRNA and low tumor grade, ER-positive receptor status, and better survival. In contrast, TRPM-2 mRNA was found in only 17% of breast tumors, none of which could be grouped with respect to grade, hormone receptor status, or survival. The presence of smaller variant forms of ER mRNA either alone or in association with the normal ER transcript is not indicative of an unfavorable prognosis, whereas TRPM-2 mRNA occurs in many primary breast tumors, but has no apparent relationship to survival.

  4. Sources of computer self-efficacy: The relationship to outcome expectations, computer anxiety, and intention to use computers

    NASA Astrophysics Data System (ADS)

    Antoine, Marilyn V.

    2011-12-01

    The purpose of this research was to extend earlier research on sources of selfefficacy (Lent, Lopez, & Biechke, 1991; Usher & Pajares, 2009) to the information technology domain. The principal investigator examined how Bandura's (1977) sources of self-efficacy information---mastery experience, vicarious experience, verbal persuasion, and physiological states---shape computer self-efficacy beliefs and influence the decision to use or not use computers. The study took place at a mid-sized Historically Black College or University in the South. A convenience sample of 105 undergraduates was drawn from students enrolled in multiple sections of two introductory computer courses. There were 67 females and 38 males. This research was a correlational study of the following variables: sources of computer self-efficacy, general computer self-efficacy, outcome expectations, computer anxiety, and intention to use computers. The principal investigator administered a survey questionnaire containing 52 Likert items to measure the major study variables. Additionally, the survey instrument collected demographic variables such as gender, age, race, intended major, classification, technology use, technology adoption category, and whether the student owns a computer. The results reveal the following: (1) Mastery experience and verbal persuasion had statistically significant relationships to general computer self-efficacy, while vicarious experience and physiological states had non-significant relationships. Mastery experience had the strongest correlation to general computer self-efficacy. (2) All of the sources of computer self-efficacy had statistically significant relationships to personal outcome expectations. Vicarious experience had the strongest correlation to personal outcome expectations. (3) All of the sources of self-efficacy had statistically significant relationships to performance outcome expectations. Vicarious experience had the strongest correlation to performance

  5. Water quality assessment and apportionment of pollution sources using APCS-MLR and PMF receptor modeling techniques in three major rivers of South Florida.

    PubMed

    Haji Gholizadeh, Mohammad; Melesse, Assefa M; Reddi, Lakshmi

    2016-10-01

    In this study, principal component analysis (PCA), factor analysis (FA), and the absolute principal component score-multiple linear regression (APCS-MLR) receptor modeling technique were used to assess the water quality and identify and quantify the potential pollution sources affecting the water quality of three major rivers of South Florida. For this purpose, 15years (2000-2014) dataset of 12 water quality variables covering 16 monitoring stations, and approximately 35,000 observations was used. The PCA/FA method identified five and four potential pollution sources in wet and dry seasons, respectively, and the effective mechanisms, rules and causes were explained. The APCS-MLR apportioned their contributions to each water quality variable. Results showed that the point source pollution discharges from anthropogenic factors due to the discharge of agriculture waste and domestic and industrial wastewater were the major sources of river water contamination. Also, the studied variables were categorized into three groups of nutrients (total kjeldahl nitrogen, total phosphorus, total phosphate, and ammonia-N), water murkiness conducive parameters (total suspended solids, turbidity, and chlorophyll-a), and salt ions (magnesium, chloride, and sodium), and average contributions of different potential pollution sources to these categories were considered separately. The data matrix was also subjected to PMF receptor model using the EPA PMF-5.0 program and the two-way model described was performed for the PMF analyses. Comparison of the obtained results of PMF and APCS-MLR models showed that there were some significant differences in estimated contribution for each potential pollution source, especially in the wet season. Eventually, it was concluded that the APCS-MLR receptor modeling approach appears to be more physically plausible for the current study. It is believed that the results of apportionment could be very useful to the local authorities for the control and

  6. Probing ligand recognition of the opioid pan antagonist AT-076 at nociceptin, kappa, mu, and delta opioid receptors through structure-activity relationships.

    PubMed

    Journigan, V Blair; Polgar, Willma E; Tuan, Edward W; Lu, James; Daga, Pankaj R; Zaveri, Nurulain T

    2017-10-16

    Few opioid ligands binding to the three classic opioid receptor subtypes, mu, kappa and delta, have high affinity at the fourth opioid receptor, the nociceptin/orphanin FQ receptor (NOP). We recently reported the discovery of AT-076 (1), (R)-7-hydroxy-N-((S)-1-(4-(3-hydroxyphenyl)piperidin-1-yl)-3-methylbutan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, a pan antagonist with nanomolar affinity for all four subtypes. Since AT-076 binds with high affinity at all four subtypes, we conducted a structure-activity relationship (SAR) study to probe ligand recognition features important for pan opioid receptor activity, using chemical modifications of key pharmacophoric groups. SAR analysis of the resulting analogs suggests that for the NOP receptor, the entire AT-076 scaffold is crucial for high binding affinity, but the binding mode is likely different from that of NOP antagonists C-24 and SB-612111 bound in the NOP crystal structure. On the other hand, modifications of the 3-hydroxyphenyl pharmacophore, but not the 7-hydroxy Tic pharmacophore, are better tolerated at kappa and mu receptors and yield very high affinity multifunctional (e.g. 12) or highly selective (e.g. 16) kappa ligands. With the availability of the opioid receptor crystal structures, our SAR analysis of the common chemotype of AT-076 suggests rational approaches to modulate binding selectivity, enabling the design of multifunctional or selective opioid ligands from such scaffolds.

  7. Analysis of ecosystem controls on soil carbon source-sink relationships in the northwest Great Plains

    USGS Publications Warehouse

    Tan, Z.; Liu, S.; Johnston, C.A.; Liu, J.; Tieszen, L.L.

    2006-01-01

    Our ability to forecast the role of ecosystem processes in mitigating global greenhouse effects relies on understanding the driving forces on terrestrial C dynamics. This study evaluated the controls on soil organic C (SOC) changes from 1973 to 2000 in the northwest Great Plains. SOC source-sink relationships were quantified using the General Ensemble Biogeochemical Modeling System (GEMS) based on 40 randomly located 10 × 10 km2 sample blocks. These sample blocks were aggregated into cropland, grassland, and forestland groups based on land cover composition within each sample block. Canonical correlation analysis indicated that SOC source-sink relationship from 1973 to 2000 was significantly related to the land cover type while the change rates mainly depended on the baseline SOC level and annual precipitation. Of all selected driving factors, the baseline SOC and nitrogen levels controlled the SOC change rates for the forestland and cropland groups, while annual precipitation determined the C source-sink relationship for the grassland group in which noticeable SOC sink strength was attributed to the conversion from cropped area to grass cover. Canonical correlation analysis also showed that grassland ecosystems are more complicated than others in the ecoregion, which may be difficult to identify on a field scale. Current model simulations need further adjustments to the model input variables for the grass cover-dominated ecosystems in the ecoregion.

  8. Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists.

    PubMed

    Vilums, Maris; Zweemer, Annelien J M; Yu, Zhiyi; de Vries, Henk; Hillger, Julia M; Wapenaar, Hannah; Bollen, Ilse A E; Barmare, Farhana; Gross, Raymond; Clemens, Jeremy; Krenitsky, Paul; Brussee, Johannes; Stamos, Dean; Saunders, John; Heitman, Laura H; Ijzerman, Adriaan P

    2013-10-10

    Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.

  9. An inter-comparison of PM10 source apportionment using PCA and PMF receptor models in three European sites.

    PubMed

    Cesari, Daniela; Amato, F; Pandolfi, M; Alastuey, A; Querol, X; Contini, D

    2016-08-01

    Source apportionment of aerosol is an important approach to investigate aerosol formation and transformation processes as well as to assess appropriate mitigation strategies and to investigate causes of non-compliance with air quality standards (Directive 2008/50/CE). Receptor models (RMs) based on chemical composition of aerosol measured at specific sites are a useful, and widely used, tool to perform source apportionment. However, an analysis of available studies in the scientific literature reveals heterogeneities in the approaches used, in terms of "working variables" such as the number of samples in the dataset and the number of chemical species used as well as in the modeling tools used. In this work, an inter-comparison of PM10 source apportionment results obtained at three European measurement sites is presented, using two receptor models: principal component analysis coupled with multi-linear regression analysis (PCA-MLRA) and positive matrix factorization (PMF). The inter-comparison focuses on source identification, quantification of source contribution to PM10, robustness of the results, and how these are influenced by the number of chemical species available in the datasets. Results show very similar component/factor profiles identified by PCA and PMF, with some discrepancies in the number of factors. The PMF model appears to be more suitable to separate secondary sulfate and secondary nitrate with respect to PCA at least in the datasets analyzed. Further, some difficulties have been observed with PCA in separating industrial and heavy oil combustion contributions. Commonly at all sites, the crustal contributions found with PCA were larger than those found with PMF, and the secondary inorganic aerosol contributions found by PCA were lower than those found by PMF. Site-dependent differences were also observed for traffic and marine contributions. The inter-comparison of source apportionment performed on complete datasets (using the full range of

  10. Regulation Effects of Water and Nitrogen on the Source-Sink Relationship in Potato during the Tuber Bulking Stage

    PubMed Central

    Li, Wenting; Xiong, Binglin; Wang, Shiwen; Deng, Xiping; Yin, Lina; Li, Hongbing

    2016-01-01

    The source-sink relationship determines crop yield, and it is largely regulated by water and nutrients in agricultural production. This has been widely investigated in cereals, but fewer studies have been conducted in root and tuber crops such as potato (Solanum tuberosum L.). The objective of this study was to investigate the source-sink relationship in potato and the regulation of water and nitrogen on the source-sink relationship during the tuber bulking stage. A pot experiment using virus-free plantlets of the Atlantic potato cultivar was conducted, using three water levels (50%, 70% and 90% of field capacity) and three nitrogen levels (0, 0.2, 0.4 g N∙kg−1 soil). The results showed that, under all water and nitrogen levels, plant source capacity were small at the end of the experiment, since photosynthetic activity in leaves were low and non-structural reserves in underground stems were completely remobilized. While at this time, there were very big differences in maximum and minimum tuber number and tuber weight, indicating that the sink tuber still had a large potential capacity to take in assimilates. These results suggest that the source-supplied assimilates were not sufficient enough to meet the demands of sink growth. Thus, we concluded that, unlike cereals, potato yield is more likely to be source-limited than sink-limited during the tuber bulking stage. Water and nitrogen are two key factors in potato production management. Our results showed that water level, nitrogen level and the interaction between water and nitrogen influence potato yield mainly through affecting source capacity via the net photosynthetic rate, total leaf area and leaf life span. Well-watered, sufficient nitrogen and well-watered combined with sufficient nitrogen increased yield mainly by enhancing the source capacity. Therefore, this suggests that increasing source capacity is more crucial to improve potato yield. PMID:26752657

  11. Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28.

    PubMed

    Hulshof, Janneke W; Casarosa, Paola; Menge, Wiro M P B; Kuusisto, Leena M S; van der Goot, Henk; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

    2005-10-06

    US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signals in a constitutively active manner. Recently, we identified 1 [5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylpentanenitrile] as the first reported nonpeptidergic inverse agonist for a viral-encoded chemokine receptor. Interestingly, this compound is able to partially inhibit the viral entry of HIV-1. In this study we describe the synthesis of 1 and several of its analogues and unique structure-activity relationships for this first class of small-molecule ligands for the chemokine receptor US28. Moreover, the compounds have been pharmacologically characterized as inverse agonists on US28. By modification of lead structure 1, it is shown that a 4-phenylpiperidine moiety is essential for affinity and activity. Other structural features of 1 are shown to be of less importance. These compounds define the first SAR of ligands on a viral GPCR (US28) and may therefore serve as important tools to investigate the significance of US28-mediated constitutive activity during viral infection.

  12. Characterization of VOC sources in an urban area based on PTR-MS measurements and receptor modelling.

    PubMed

    Stojić, A; Stojić, S Stanišić; Šoštarić, A; Ilić, L; Mijić, Z; Rajšić, S

    2015-09-01

    In this study, the concentrations of volatile organic compounds were measured by the use of proton transfer reaction mass spectrometry, together with NO x , NO, NO2, SO2, CO and PM10 and meteorological parameters in an urban area of Belgrade during winter 2014. The multivariate receptor model US EPA Unmix was applied to the obtained dataset resolving six source profiles, which can be attributed to traffic-related emissions, gasoline evaporation/oil refineries, petrochemical industry/biogenic emissions, aged plumes, solid-fuel burning and local laboratories. Besides the vehicle exhaust, accounting for 27.6 % of the total mixing ratios, industrial emissions, which are present in three out of six resolved profiles, exert a significant impact on air quality in the urban area. The major contribution of regional and long-range transport was determined for source profiles associated with petrochemical industry/biogenic emissions (40 %) and gasoline evaporation/oil refineries (29 %) using trajectory sector analysis. The concentration-weighted trajectory model was applied with the aim of resolving the spatial distribution of potential distant sources, and the results indicated that emission sources from neighbouring countries, as well as from Slovakia, Greece, Poland and Scandinavian countries, significantly contribute to the observed concentrations.

  13. Glutamate receptors as seen by light: Spectroscopic studies of structure-function relationships

    PubMed Central

    Mankiewicz, Kimberly A.; Jayaraman, Vasanthi

    2010-01-01

    Ionotropic glutamate receptors are major excitatory receptors in the central nervous system and also have far reaching influence in other areas of the body. Their modular nature has allowed for the isolation of the ligand binding domain and subsequent structural studies using a variety of spectroscopic techniques. This review will discuss the role of specific ligand:protein interactions in mediating activation in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptors as established by various spectroscopic investigations of the GluR2 and GluR4 subunits of this receptor. Specifically, this review will provide an introduction of the insight gained from X-ray crystallography and nuclear magnetic resonance (NMR) investigations and then go on to focus on studies utilizing vibrational spectroscopy and fluorescence resonance energy transfer (FRET) to study the behavior of the isolated ligand binding domain in solution and discuss the importance of specific ligand:protein interactions in the mechanism of receptor activation. PMID:17934637

  14. GPR-4 Is a Predicted G-Protein-Coupled Receptor Required for Carbon Source-Dependent Asexual Growth and Development in Neurospora crassa

    PubMed Central

    Li, Liande; Borkovich, Katherine A.

    2006-01-01

    The filamentous fungus Neurospora crassa is able to utilize a wide variety of carbon sources. Here, we examine the involvement of a predicted G-protein-coupled receptor (GPCR), GPR-4, during growth and development in the presence of different carbon sources in N. crassa. Δgpr-4 mutants have reduced mass accumulation compared to the wild type when cultured on high levels of glycerol, mannitol, or arabinose. The defect is most severe on glycerol and is cell density dependent. The genetic and physical relationship between GPR-4 and the three N. crassa Gα subunits (GNA-1, GNA-2, and GNA-3) was explored. All three Gα mutants are defective in mass accumulation when cultured on glycerol. However, the phenotypes of Δgna-1 and Δgpr-4 Δgna-1 mutants are identical, introduction of a constitutively activated gna-1 allele suppresses the defects of the Δgpr-4 mutation, and the carboxy terminus of GPR-4 interacts most strongly with GNA-1 in the yeast two-hybrid assay. Although steady-state cyclic AMP (cAMP) levels are normal in Δgpr-4 strains, exogenous cAMP partially remediates the dry mass defects of Δgpr-4 mutants on glycerol medium and Δgpr-4 strains lack the transient increase in cAMP levels observed in the wild type after addition of glucose to glycerol-grown liquid cultures. Our results support the hypothesis that GPR-4 is coupled to GNA-1 in a cAMP signaling pathway that regulates the response to carbon source in N. crassa. GPR-4-related GPCRs are present in the genomes of several filamentous ascomycete fungal pathogens, raising the possibility that a similar pathway regulates carbon sensing in these organisms. PMID:16896213

  15. Impact of source collinearity in simulated PM 2.5 data on the PMF receptor model solution

    NASA Astrophysics Data System (ADS)

    Habre, Rima; Coull, Brent; Koutrakis, Petros

    2011-12-01

    Positive Matrix Factorization (PMF) is a factor analytic model used to identify particle sources and to estimate their contributions to PM 2.5 concentrations observed at receptor sites. Collinearity in source contributions due to meteorological conditions introduces uncertainty in the PMF solution. We simulated datasets of speciated PM 2.5 concentrations associated with three ambient particle sources: "Motor Vehicle" (MV), "Sodium Chloride" (NaCl), and "Sulfur" (S), and we varied the correlation structure between their mass contributions to simulate collinearity. We analyzed the datasets in PMF using the ME-2 multilinear engine. The Pearson correlation coefficients between the simulated and PMF-predicted source contributions and profiles are denoted by " G correlation" and " F correlation", respectively. In sensitivity analyses, we examined how the means or variances of the source contributions affected the stability of the PMF solution with collinearity. The % errors in predicting the average source contributions were 23, 80 and 23% for MV, NaCl, and S, respectively. On average, the NaCl contribution was overestimated, while MV and S contributions were underestimated. The ability of PMF to predict the contributions and profiles of the three sources deteriorated significantly as collinearity in their contributions increased. When the mean of NaCl or variance of NaCl and MV source contributions was increased, the deterioration in G correlation with increasing collinearity became less significant, and the ability of PMF to predict the NaCl and MV loading profiles improved. When the three factor profiles were simulated to share more elements, the decrease in G and F correlations became non-significant. Our findings agree with previous simulation studies reporting that correlated sources are predicted with higher error and bias. Consequently, the power to detect significant concentration-response estimates in health effect analyses weakens.

  16. Structure-activity relationships for serotonin transporter and dopamine receptor selectivity.

    PubMed

    Agatonovic-Kustrin, Snezana; Davies, Paul; Turner, Joseph V

    2009-05-01

    Antipsychotic medications have a diverse pharmacology with affinity for serotonergic, dopaminergic, adrenergic, histaminergic and cholinergic receptors. Their clinical use now also includes the treatment of mood disorders, thought to be mediated by serotonergic receptor activity. The aim of our study was to characterise the molecular properties of antipsychotic agents, and to develop a model that would indicate molecular specificity for the dopamine (D(2)) receptor and the serotonin (5-HT) transporter. Back-propagation artificial neural networks (ANNs) were trained on a dataset of 47 ligands categorically assigned antidepressant or antipsychotic utility. The structure of each compound was encoded with 63 calculated molecular descriptors. ANN parameters including hidden neurons and input descriptors were optimised based on sensitivity analyses, with optimum models containing between four and 14 descriptors. Predicted binding preferences were in excellent agreement with clinical antipsychotic or antidepressant utility. Validated models were further tested by use of an external prediction set of five drugs with unknown mechanism of action. The SAR models developed revealed the importance of simple molecular characteristics for differential binding to the D(2) receptor and the 5-HT transporter. These included molecular size and shape, solubility parameters, hydrogen donating potential, electrostatic parameters, stereochemistry and presence of nitrogen. The developed models and techniques employed are expected to be useful in the rational design of future therapeutic agents.

  17. The relationship between sources and functions of social support and dimensions of child- and parent-related stress.

    PubMed

    Guralnick, M J; Hammond, M A; Neville, B; Connor, R T

    2008-12-01

    In this longitudinal study, we examined the relationship between the sources and functions of social support and dimensions of child- and parent-related stress for mothers of young children with mild developmental delays. Sixty-three mothers completed assessments of stress and support at two time points. Multiple regression analyses revealed that parenting support during the early childhood period (i.e. advice on problems specific to their child and assistance with child care responsibilities), irrespective of source, consistently predicted most dimensions of parent stress assessed during the early elementary years and contributed unique variance. General support (i.e. primarily emotional support and validation) from various sources had other, less widespread effects on parental stress. The multidimensional perspective of the construct of social support that emerged suggested mechanisms mediating the relationship between support and stress and provided a framework for intervention.

  18. Relationships between chemical structure and affinity for acetylcholine receptors

    PubMed Central

    Abramson, F. B.; Barlow, R. B.; Mustafa, M. G.; Stephenson, R. P.

    1969-01-01

    1. Series of analogues of acetylcholine have been prepared in which the acetyl group was replaced by phenylacetyl, cyclohexylacetyl, diphenylacetyl, dicyclohexylacetyl, (±)-phenylcyclohexylacetyl, benziloyl and (±)-phenylcyclohexylhydroxyacetyl groups and the trimethylammonium group was replaced by Me2EtN+, MeEt2N+, Et3N+, [Formula: see text] Further series were prepared in which the acetoxyethyl group was replaced by ethoxyethyl, phenylethoxyethyl, cyclohexylethoxyethyl, diphenylethoxyethyl, and dicyclohexylethoxyethyl groups, and by n-pentyl, 5-phenylpentyl, 5-cyclohexylpentyl and 5:5-diphenylpentyl groups. 2. The ethoxyethyl and n-pentyl series contain some compounds which are agonists or partial agonists when tested on the isolated guinea-pig ileum, but all the other compounds are antagonists. 3. The affinity of the compounds for the postganglionic (“muscarinesensitive”) acetylcholine receptors has been measured in conditions in which the antagonists have been shown to be acting competitively. There were considerable differences between their affinities, the most active (log K, 9·8) having one million times the affinity of the least active (log K, 3·7). 4. The changes in affinity as the onium group was modified were not entirely independent of changes in the rest of the molecule. Increasing the size of the onium group, as judged from conductivity measurements on simpler onium salts, increased affinity in the series containing one large group (phenyl or cyclohexyl) but, in the series with two large groups, affinity declined when the size was increased beyond -+NMeEt2. 5. In general, the effects of changes in the rest of the molecule on affinity were bigger than the effects of changes in the onium group and there were bigger interactions. Affinity was increased to a greater extent by introducing one phenyl and one cyclohexyl group together than by introducing either two phenyl or two cyclohexyl groups; the increment was greater than the separate

  19. Investigating the Relationship between Students' Science Knowledge and Their Reported Sources of Information

    NASA Astrophysics Data System (ADS)

    Buxner, S.; Romine, J.; Impey, C.; Nieberding, M.

    2015-11-01

    Building on a 25 year study of undergraduate students' science literacy, we have been investigating where students report getting information about science. In this study, we investigated the relationship between students' basic science knowledge, responses about studying something scientifically, and where they report gaining information about science. Data for this study was collected through an online survey of astronomy courses during 2014. Responses were collected from a total of 400 students through online surveys. Most survey respondents were non-science majors in the first two years of college who had taken 3 or fewer college science courses. Our results show a relationship between students who report online searches and Wikipedia as reliable sources of information and lower science literacy scores, although there was no relationship between science knowledge and where students report getting information about science. Our results suggest that information literacy is an important component to overall science literacy.

  20. Brain-behavior relationships in source memory: Effects of age and memory ability.

    PubMed

    Meusel, Liesel-Ann; Grady, Cheryl L; Ebert, Patricia E; Anderson, Nicole D

    2017-06-01

    There is considerable evidence for age-related decrements in source memory retrieval, but the literature on the neural correlates of these impairments is mixed. In this study, we used functional magnetic resonance imaging to examine source memory retrieval-related brain activity, and the monotonic relationship between retrieval-related brain activity and source memory accuracy, as a function of both healthy aging (younger vs older) and memory ability within the older adult group (Hi-Old vs Lo-Old). Participants studied lists of word pairs, half visually, half aurally; these were re-presented visually in a scanned test phase and participants indicated if the pair was 'seen' or 'heard' in the study phase. The Lo-Old, but not the Hi-Old, showed source memory performance decrements compared to the Young. During retrieval of source memories, younger and older adults engaged lateral and medial prefrontal cortex (PFC) and medial posterior parietal (and occipital) cortices. The groups differed in how brain activity related to source memory accuracy in dorsal anterior cingulate cortex, precuneus/cuneus, and the inferior parietal cortex; in each of these areas, greater activity was associated with poorer accuracy in the Young, but with higher accuracy in the Hi-Old (anterior cingulate and precuneus/cuneus) and Lo-Old (inferior parietal lobe). Follow-up pairwise group interaction analyses revealed that greater activity in right parahippocampal gyrus was associated with better source memory in the Hi-Old, but not in the Lo-Old. We conclude that older adults recruit additional brain regions to compensate for age-related decline in source memory, but the specific regions involved differ depending on their episodic memory ability. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. SIZE DISTRIBUTION AND DIURNAL CHARACTERISTICS OF PARTICLE-BOUND METALS IN SOURCE AND RECEPTOR SITES OF THE LOS ANGELES BASIN. (R827352C006)

    EPA Science Inventory

    Measurement of daily size-fractionated ambient PM10 mass, metals, inorganic ions (nitrate and sulfate) and elemental and organic carbon were conducted at source (Downey) and receptor (Riverside) sites within the Los Angeles Basin. In addition to 24-h concentration m...

  2. Evolving Relationship Structures in Multi-sourcing Arrangements: The Case of Mission Critical Outsourcing

    NASA Astrophysics Data System (ADS)

    Heitlager, Ilja; Helms, Remko; Brinkkemper, Sjaak

    Information Technology Outsourcing practice and research mainly considers the outsourcing phenomenon as a generic fulfilment of the IT function by external parties. Inspired by the logic of commodity, core competencies and economies of scale; assets, existing departments and IT functions are transferred to external parties. Although the generic approach might work for desktop outsourcing, where standardisation is the dominant factor, it does not work for the management of mission critical applications. Managing mission critical applications requires a different approach where building relationships is critical. The relationships involve inter and intra organisational parties in a multi-sourcing arrangement, called an IT service chain, consisting of multiple (specialist) parties that have to collaborate closely to deliver high quality services.

  3. Identification and elucidation of anthropogenic source contribution in PM10 pollutant: Insight gain from dispersion and receptor models.

    PubMed

    Roy, Debananda; Singh, Gurdeep; Yadav, Pankaj

    2016-10-01

    Source apportionment study of PM 10 (Particulate Matter) in a critically polluted area of Jharia coalfield, India has been carried out using Dispersion model, Principle Component Analysis (PCA) and Chemical Mass Balance (CMB) techniques. Dispersion model Atmospheric Dispersion Model (AERMOD) was introduced to simplify the complexity of sources in Jharia coalfield. PCA and CMB analysis indicates that monitoring stations near the mining area were mainly affected by the emission from open coal mining and its associated activities such as coal transportation, loading and unloading of coal. Mine fire emission also contributed a considerable amount of particulate matters in monitoring stations. Locations in the city area were mostly affected by vehicular, Liquid Petroleum Gas (LPG) & Diesel Generator (DG) set emissions, residential, and commercial activities. The experimental data sampling and their analysis could aid understanding how dispersion based model technique along with receptor model based concept can be strategically used for quantitative analysis of Natural and Anthropogenic sources of PM 10 . Copyright © 2016. Published by Elsevier B.V.

  4. Historical evolution of sources identification by means of Receptor Modeling in the Metropolitan Area of São Paulo, Brazil.

    NASA Astrophysics Data System (ADS)

    Miranda, R. M.; Andrade, M. D. F.; Marien, Y., Sr.

    2017-12-01

    The atmospheric aerosols sources have been identified in Sao Paulo since the 80´s with the use of receptor models. The Metropolitan Area of São Paulo (MASP) is a megacity with a population of 21 million, corresponding to more than 11% of the total population of Brazil. The first results for the identification of sources of particles were obtained with the application of Absolute Principal Component Analysis, Factor Analysis and Chemical Mass Balance. More recently the Positive Matrix Factorization has been used in combination with the other receptor models. With the improvement of the aerosol composition analytical determination (more elements and better resolution) the source identification has became more accurate. But, in spite of that, the main sources are the same for fine particles: vehicular emission, secondary formation and biomass burning. The large amount of biofuels used in the MASP makes this region an important example of the atmospheric chemistry of fossil fuel and biofuel emissions. The 7 million vehicles can run on gasohol, ethanol (95% ethanol + 5% gasoline) and biodiesel (mostly for trucks and buses). We have considered the Black Carbon as the tracer for diesel engines and biomass burning, being this last source associated not only with burning of sugar cane plantation and forest fires, but also with wood and charcoal used in restaurant and domestic cooking and residues burning. The responsibility of the vehicular emission to the fine particles has been maintained in approximately 50% of the mass. The soil resuspension was associated with 8% of the fine particles origin. We are presenting the data obtained from experiments performed from 1983 to 2014, not continuously and mainly performed in the winter time. It is a long period of data that is going to be considered. The previous results obtained with the application of PCA were compared to that obtained with PMF applied to the historical data collected at MASP, showing the evolution of the

  5. Relationship stigma and relationship outcomes in interracial and same-sex relationships: Examination of sources and buffers.

    PubMed

    Rosenthal, Lisa; Starks, Tyrel J

    2015-12-01

    Interracial and same-sex romantic relationships are more common and socially accepted in the United States than ever before; yet, stigmatization of these relationships persists, with consequences for relationship dynamics. We conducted an online survey study with adults living in the United States in interracial and same-sex relationships to examine associations of relationship stigma from family, friends, and public with several relationship outcomes (i.e., investment, satisfaction, intimate partner aggression victimization and perpetration, commitment, intimacy, trust, passion, love, sexual communication, and sexual satisfaction), as well as the potential buffering roles of egalitarianism and dyadic coping. Regression analyses with 480 participants support that above and beyond individually experienced discrimination and other well-known predictors of relationship outcomes, relationship stigma from friends in particular was associated with lower relationship commitment, trust, love, and sexual communication, as well as greater odds of intimate partner aggression victimization. Egalitarianism and dyadic coping moderated some of the associations of relationship stigma from family, friends, and public with relationship outcomes, supporting their potential roles as buffers. These findings suggest many avenues for future research and implications for clinicians working with interracial and same-sex couples, individuals in those couples, and their families. Given increasing prevalence of interracial and same-sex relationships and marriages, more work should continue to explore these couples' experiences and how best to support them. (c) 2015 APA, all rights reserved).

  6. Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor.

    PubMed

    Abdi, Muna H; Beswick, Paul J; Billinton, Andy; Chambers, Laura J; Charlton, Andrew; Collins, Sue D; Collis, Katharine L; Dean, David K; Fonfria, Elena; Gleave, Robert J; Lejeune, Clarisse L; Livermore, David G; Medhurst, Stephen J; Michel, Anton D; Moses, Andrew P; Page, Lee; Patel, Sadhana; Roman, Shilina A; Senger, Stefan; Slingsby, Brian; Steadman, Jon G A; Stevens, Alexander J; Walter, Daryl S

    2010-09-01

    A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies. Copyright 2010 Elsevier Ltd. All rights reserved.

  7. Roles of Oestrogen Receptors α and β in Behavioural Neuroendocrinology: Beyond Yin/Yang

    PubMed Central

    Rissman, E. F.

    2009-01-01

    Oestrogen receptor β (ERβ) was discovered more than 10 years ago. It is widely distributed in the brain. In some areas, such as the entorhinal cortex, it is present as the only ER, whereas in other regions, such as the bed nucleus of the stria terminalis and preoptic area, it can be found co-expressed with ERα, often within the same neurones. These ERs share ligands, and there are several complex relationships between the two receptors. Initially, the relationship between them was labelled as ‘yin/yang’, meaning that the actions of each complemented those of the other, but now, years later, other relationships have been described. Based on evidence from neuroendocrine and behavioural studies, three types of interactions between the two oestrogen receptors are described in this review. The first relationship is antagonistic; this is evident from studies on the role of oestrogen in spatial learning. When oestradiol is given in a high, chronic dose, spatial learning is impaired. This action of oestradiol requires ERα, and when ERβ is not functional, lower doses of oestradiol have this negative effect on behaviour. The second relationship between the two receptors is one that is synergistic, and this is illustrated in the combined effects of the two receptors on the production of the neuropeptide oxytocin and its receptor. The third relationship is sequential; separate actions of the two receptors are postulated in activation and organisation of sexually dimorphic reproductive behaviours. Future studies on all of these topics will inform us about how ER selective ligands might affect oestrogen functions at the organismal level. PMID:18601711

  8. A Regional Assessment of Marine Vessel PM2.5 Impacts in the U.S. Pacific Northwest Using a Receptor Based Source Apportionment Method

    EPA Science Inventory

    This work reports the results of a regional receptor-based source apportionment analysis using the Positive Matrix Factorization (PMF) model on chemically speciated PM2.5 data from 36 urban and rural monitoring sites within the U.S. Pacific Northwest. The approach taken is to mo...

  9. Bayesian probabilistic approach for inverse source determination from limited and noisy chemical or biological sensor concentration measurements

    NASA Astrophysics Data System (ADS)

    Yee, Eugene

    2007-04-01

    Although a great deal of research effort has been focused on the forward prediction of the dispersion of contaminants (e.g., chemical and biological warfare agents) released into the turbulent atmosphere, much less work has been directed toward the inverse prediction of agent source location and strength from the measured concentration, even though the importance of this problem for a number of practical applications is obvious. In general, the inverse problem of source reconstruction is ill-posed and unsolvable without additional information. It is demonstrated that a Bayesian probabilistic inferential framework provides a natural and logically consistent method for source reconstruction from a limited number of noisy concentration data. In particular, the Bayesian approach permits one to incorporate prior knowledge about the source as well as additional information regarding both model and data errors. The latter enables a rigorous determination of the uncertainty in the inference of the source parameters (e.g., spatial location, emission rate, release time, etc.), hence extending the potential of the methodology as a tool for quantitative source reconstruction. A model (or, source-receptor relationship) that relates the source distribution to the concentration data measured by a number of sensors is formulated, and Bayesian probability theory is used to derive the posterior probability density function of the source parameters. A computationally efficient methodology for determination of the likelihood function for the problem, based on an adjoint representation of the source-receptor relationship, is described. Furthermore, we describe the application of efficient stochastic algorithms based on Markov chain Monte Carlo (MCMC) for sampling from the posterior distribution of the source parameters, the latter of which is required to undertake the Bayesian computation. The Bayesian inferential methodology for source reconstruction is validated against real

  10. Two Model-Based Methods for Policy Analyses of Fine Particulate Matter Control in China: Source Apportionment and Source Sensitivity

    NASA Astrophysics Data System (ADS)

    Li, X.; Zhang, Y.; Zheng, B.; Zhang, Q.; He, K.

    2013-12-01

    Anthropogenic emissions have been controlled in recent years in China to mitigate fine particulate matter (PM2.5) pollution. Recent studies show that sulfate dioxide (SO2)-only control cannot reduce total PM2.5 levels efficiently. Other species such as nitrogen oxide, ammonia, black carbon, and organic carbon may be equally important during particular seasons. Furthermore, each species is emitted from several anthropogenic sectors (e.g., industry, power plant, transportation, residential and agriculture). On the other hand, contribution of one emission sector to PM2.5 represents contributions of all species in this sector. In this work, two model-based methods are used to identify the most influential emission sectors and areas to PM2.5. The first method is the source apportionment (SA) based on the Particulate Source Apportionment Technology (PSAT) available in the Comprehensive Air Quality Model with extensions (CAMx) driven by meteorological predictions of the Weather Research and Forecast (WRF) model. The second method is the source sensitivity (SS) based on an adjoint integration technique (AIT) available in the GEOS-Chem model. The SA method attributes simulated PM2.5 concentrations to each emission group, while the SS method calculates their sensitivity to each emission group, accounting for the non-linear relationship between PM2.5 and its precursors. Despite their differences, the complementary nature of the two methods enables a complete analysis of source-receptor relationships to support emission control policies. Our objectives are to quantify the contributions of each emission group/area to PM2.5 in the receptor areas and to intercompare results from the two methods to gain a comprehensive understanding of the role of emission sources in PM2.5 formation. The results will be compared in terms of the magnitudes and rankings of SS or SA of emitted species and emission groups/areas. GEOS-Chem with AIT is applied over East Asia at a horizontal grid

  11. Colored dissolved organic matter in shallow estuaries: relationships between carbon sources and light attenuation

    NASA Astrophysics Data System (ADS)

    Oestreich, W. K.; Ganju, N. K.; Pohlman, J. W.; Suttles, S. E.

    2016-02-01

    Light availability is of primary importance to the ecological function of shallow estuaries. For example, benthic primary production by submerged aquatic vegetation is contingent upon light penetration to the seabed. A major component that attenuates light in estuaries is colored dissolved organic matter (CDOM). CDOM is often measured via a proxy, fluorescing dissolved organic matter (fDOM), due to the ease of in situ fDOM sensor measurements. Fluorescence must be converted to CDOM absorbance for use in light attenuation calculations. However, this CDOM-fDOM relationship varies among and within estuaries. We quantified the variability in this relationship within three estuaries along the mid-Atlantic margin of the eastern United States: West Falmouth Harbor (MA), Barnegat Bay (NJ), and Chincoteague Bay (MD/VA). Land use surrounding these estuaries ranges from urban to developed, with varying sources of nutrients and organic matter. Measurements of fDOM (excitation and emission wavelengths of 365 nm (±5 nm) and 460 nm (±40 nm), respectively) and CDOM absorbance were taken along a terrestrial-to-marine gradient in all three estuaries. The ratio of the absorption coefficient at 340 nm (m-1) to fDOM (QSU) was higher in West Falmouth Harbor (1.22) than in Barnegat Bay (0.22) and Chincoteague Bay (0.17). The CDOM : fDOM absorption ratio was variable between sites within West Falmouth Harbor and Barnegat Bay, but consistent between sites within Chincoteague Bay. Stable carbon isotope analysis for constraining the source of dissolved organic matter (DOM) in West Falmouth Harbor and Barnegat Bay yielded δ13C values ranging from -19.7 to -26.1 ‰ and -20.8 to -26.7 ‰, respectively. Concentration and stable carbon isotope mixing models of DOC (dissolved organic carbon) indicate a contribution of 13C-enriched DOC in the estuaries. The most likely source of 13C-enriched DOC for the systems we investigated is Spartina cordgrass. Comparison of DOC source to CDOM : f

  12. Source apportionment of ambient non-methane hydrocarbons in Hong Kong: application of a principal component analysis/absolute principal component scores (PCA/APCS) receptor model.

    PubMed

    Guo, H; Wang, T; Louie, P K K

    2004-06-01

    Receptor-oriented source apportionment models are often used to identify sources of ambient air pollutants and to estimate source contributions to air pollutant concentrations. In this study, a PCA/APCS model was applied to the data on non-methane hydrocarbons (NMHCs) measured from January to December 2001 at two sampling sites: Tsuen Wan (TW) and Central & Western (CW) Toxic Air Pollutants Monitoring Stations in Hong Kong. This multivariate method enables the identification of major air pollution sources along with the quantitative apportionment of each source to pollutant species. The PCA analysis identified four major pollution sources at TW site and five major sources at CW site. The extracted pollution sources included vehicular internal engine combustion with unburned fuel emissions, use of solvent particularly paints, liquefied petroleum gas (LPG) or natural gas leakage, and industrial, commercial and domestic sources such as solvents, decoration, fuel combustion, chemical factories and power plants. The results of APCS receptor model indicated that 39% and 48% of the total NMHCs mass concentrations measured at CW and TW were originated from vehicle emissions, respectively. 32% and 36.4% of the total NMHCs were emitted from the use of solvent and 11% and 19.4% were apportioned to the LPG or natural gas leakage, respectively. 5.2% and 9% of the total NMHCs mass concentrations were attributed to other industrial, commercial and domestic sources, respectively. It was also found that vehicle emissions and LPG or natural gas leakage were the main sources of C(3)-C(5) alkanes and C(3)-C(5) alkenes while aromatics were predominantly released from paints. Comparison of source contributions to ambient NMHCs at the two sites indicated that the contribution of LPG or natural gas at CW site was almost twice that at TW site. High correlation coefficients (R(2) > 0.8) between the measured and predicted values suggested that the PCA/APCS model was applicable for estimation

  13. A comparison between exposure-response relationships for wind turbine annoyance and annoyance due to other noise sources.

    PubMed

    Janssen, Sabine A; Vos, Henk; Eisses, Arno R; Pedersen, Eja

    2011-12-01

    Surveys have shown that noise from wind turbines is perceived as annoying by a proportion of residents living in their vicinity, apparently at much lower noise levels than those inducing annoyance due to other environmental sources. The aim of the present study was to derive the exposure-response relationship between wind turbine noise exposure in L(den) and the expected percentage annoyed residents and to compare it to previously established relationships for industrial noise and transportation noise. In addition, the influence of several individual and situational factors was assessed. On the basis of available data from two surveys in Sweden (N=341, N=754) and one survey in the Netherlands (N=725), a relationship was derived for annoyance indoors and for annoyance outdoors at the dwelling. In comparison to other sources of environmental noise, annoyance due to wind turbine noise was found at relatively low noise exposure levels. Furthermore, annoyance was lower among residents who received economical benefit from wind turbines and higher among residents for whom the wind turbine was visible from the dwelling. Age and noise sensitivity had similar effects on annoyance to those found in research on annoyance by other sources. © 2011 Acoustical Society of America

  14. Molecular identification of organic compounds in atmospheric complex mixtures and relationship to atmospheric chemistry and sources.

    PubMed

    Mazurek, Monica A

    2002-12-01

    This article describes a chemical characterization approach for complex organic compound mixtures associated with fine atmospheric particles of diameters less than 2.5 m (PM2.5). It relates molecular- and bulk-level chemical characteristics of the complex mixture to atmospheric chemistry and to emission sources. Overall, the analytical approach describes the organic complex mixtures in terms of a chemical mass balance (CMB). Here, the complex mixture is related to a bulk elemental measurement (total carbon) and is broken down systematically into functional groups and molecular compositions. The CMB and molecular-level information can be used to understand the sources of the atmospheric fine particles through conversion of chromatographic data and by incorporation into receptor-based CMB models. Once described and quantified within a mass balance framework, the chemical profiles for aerosol organic matter can be applied to existing air quality issues. Examples include understanding health effects of PM2.5 and defining and controlling key sources of anthropogenic fine particles. Overall, the organic aerosol compositional data provide chemical information needed for effective PM2.5 management.

  15. Analyzing the relationships between reflection source DPOAEs and SFOAEs using a computational model

    NASA Astrophysics Data System (ADS)

    Wen, Haiqi; Bowling, Thomas; Meaud, Julien

    2018-05-01

    Distortion product otoacoustic emissions (DPOAEs) are sounds generated by the cochlea in response to a stimulus that consists of two primary tones. DPOAEs consist of a mixture of emissions arising from two different mechanisms: nonlinear distortion and coherent reflection. Stimulus Frequency Otoacoustic Emissions (SFOAEs) are sounds generated by the cochlea in response to a pure tone; SFOAEs are commonly hypothesized to be generated due to coherent reflection. Nonlinearity of the outer hair cells (OHCs) provides nonlinear amplification to the traveling wave while reflections occur due to pre-existing micromechanical impedance perturbations. In this work, DPOAEs are obtained from a time domain computational model coupling a lumped parameter middle ear model with a multiphysics mechanical-electrical-acoustical model of cochlea. Cochlear roughness is intro-duced by perturbing the value of the OHC electromechanical coupling coefficient to account for the putative inhomogeneities inside the cochlea. The DPOAEs emitted in the ear canal are decomposed into distortion source and reflection source components. The reflection source component of DPOAEs is compared to SFOAEs obtained using a frequency-domain implementation of the model, to help us understand how distortion source and reflection source contributes to total DPOAEs. Moreover, the group delays of reflection sources OAEs are compared to group delays in the basilar membrane velocity to clarify the relationship between basilar membrane and OAE group delays.

  16. PM2.5 Source Apportionment: Reconciling Receptor Models for U.S. Nonurban and Urban Long-Term Networks.

    PubMed

    Chen, L-W Antony; Watson, John G; Chow, Judith C; DuBois, Dave W; Herschberger, Lisa

    2011-11-01

    Chemical mass balance (CMB) and trajectory receptor models were applied to speciated particulate matter with aerodynamic diameter ≤2.5 μm (PM 2.5 ) measurements from Speciation Trends Network (STN; part of the Chemical Speciation Network [CSN]) and Interagency Monitoring of Protected Visual Environments (IMPROVE) monitoring network across the state of Minnesota as part of the Minnesota PM 2.5 Source Apportionment Study (MPSAS). CMB equations were solved by the Unmix, positive matrix factorization (PMF), and effective variance (EV) methods, giving collective source contribution and uncertainty estimates. Geological source profiles developed from local dust materials were either incorporated into the EV-CMB model or used to verify factors derived from Unmix and PMF. Common sources include soil dust, calcium (Ca)-rich dust, diesel and gasoline vehicle exhausts, biomass burning, secondary sulfate, and secondary nitrate. Secondary sulfate and nitrate aerosols dominate PM 2.5 mass (50-69%). Mobile sources outweigh area sources at urban sites, and vice versa at rural sites due to traffic emissions. Gasoline and diesel contributions can be separated using data from the STN, despite significant uncertainties. Major differences between MPSAS and earlier studies on similar environments appear to be the type and magnitude of stationary sources, but these sources are generally minor (<7%) in this and other studies. Ensemble back-trajectory analysis shows that the lower Midwestern states are the predominant source region for secondary ammoniated sulfate in Minnesota. It also suggests substantial contributions of biomass burning and soil dust from out-of-state on occasions, although a quantitative separation of local and regional contributions was not achieved in the current study. Supplemental materials are available for this article. Go to the publisher's online edition of the Journal of the Air & Waste Management Association for a summary of input data, Unmix and PMF factor

  17. Analysis of Ethylene Receptors: Ethylene-Binding Assays.

    PubMed

    Binder, Brad M; Schaller, G Eric

    2017-01-01

    Plant ethylene receptors bind ethylene with high affinity. Most of the characterization of ethylene binding to the receptors has been carried out using a radioligand-binding assay on functional receptors expressed in yeast. In this chapter, we describe methods for expressing ethylene receptors in yeast and conducting ethylene-binding assays on intact yeast and yeast membranes. The ethylene-binding assays can be modified to analyze ethylene binding to intact plants and other organisms as well as membranes isolated from any biological source.

  18. An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors

    PubMed Central

    Feng, Wei; Zheng, Jing; Dong, Yao; Li, Xueshu; Lehmler, Hans-Joachim; Pessah, Isaac N.

    2017-01-01

    Nondioxin-like polychlorinated biphenyls (NDL PCBs) activate ryanodine-sensitive Ca2+ channels (RyRs) and this activation has been associated with neurotoxicity in exposed animals. RyR-active congeners follow a distinct structure–activity relationship and a quantitative structure–activity relationship (QSAR) predicts that a large number of PCBs likely activate the receptor, which requires validation. Additionally, previous structural based conclusions have been established using receptor ligand binding assays but the impact of varying PCB structures on ion channel gating behavior is not understood. We used [3H]Ryanodine ([3H]Ry) binding to assess the RyR-activity of 14 previously untested PCB congeners evaluating the predictability of the QSAR. Congeners determined to display widely varying potency were then assayed with single channel voltage clamp analysis to assess direct influences on channel gating kinetics. The RyR-activity of individual PCBs assessed in in vitro assays followed the general pattern predicted by the QSAR but binding and lipid bilayer experiments demonstrated higher potency than predicted. Of the 49 congeners tested to date, tetra-ortho PCB 202 was found to be the most potent RyR-active congener increasing channel open probability at 200 pM. Shifting meta-substitutions to the para-position resulted in a > 100-fold reduction in potency as seen with PCB 197. Non-ortho PCB 11 was found to lack activity at the receptor supporting a minimum mono-ortho substitution for PCB RyR activity. These findings expand and support previous SAR assessments; where out of the 49 congeners tested to date 42 activate the receptor demonstrating that the RyR is a sensitive and common target of PCBs. PMID:27655348

  19. α7 nicotinic ACh receptors as a ligand-gated source of Ca(2+) ions: the search for a Ca(2+) optimum.

    PubMed

    Uteshev, Victor V

    2012-01-01

    The spatiotemporal distribution of cytosolic Ca(2+) ions is a key determinant of neuronal behavior and survival. Distinct sources of Ca(2+) ions including ligand- and voltage-gated Ca(2+) channels contribute to intracellular Ca(2+) homeostasis. Many normal physiological and therapeutic neuronal functions are Ca(2+)-dependent, however an excess of cytosolic Ca(2+) or a lack of the appropriate balance between Ca(2+) entry and clearance may destroy cellular integrity and cause cellular death. Therefore, the existence of optimal spatiotemporal patterns of cytosolic Ca(2+) elevations and thus, optimal activation of ligand- and voltage-gated Ca(2+) ion channels are postulated to benefit neuronal function and survival. Alpha7 nicotinic -acetylcholine receptors (nAChRs) are highly permeable to Ca(2+) ions and play an important role in modulation of neurotransmitter release, gene expression and neuroprotection in a variety of neuronal and non-neuronal cells. In this review, the focus is placed on α7 nAChR-mediated currents and Ca(2+) influx and how this source of Ca(2+) entry compares to NMDA receptors in supporting cytosolic Ca(2+) homeostasis, neuronal function and survival.

  20. Relationship between serum response factor and androgen receptor in prostate cancer.

    PubMed

    Prencipe, Maria; O'Neill, Amanda; O'Hurley, Gillian; Nguyen, Lan K; Fabre, Aurelie; Bjartell, Anders; Gallagher, William M; Morrissey, Colm; Kay, Elaine W; Watson, R William

    2015-11-01

    Serum response factor (SRF) is an important transcription factor in castrate-resistant prostate cancer (CRPC). Since CRPC is associated with androgen receptor (AR) hypersensitivity, we investigated the relationship between SRF and AR. Transcriptional activity was assessed by luciferase assay. Cell proliferation was measured by MTT and flow cytometry. Protein expression in patients was assessed by immunohistochemistry. To investigate AR involvement in SRF response to androgen, AR expression was down-regulated using siRNA. This resulted in the abrogation of SRF induction post-DHT. Moreover, DHT stimulation failed to induce SRF transcriptional activity in AR-negative PC346 DCC cells, which was only restored following AR over-expression. Next, SRF expression was down-regulated by siRNA, resulting in AR increased transcriptional activity in castrate-resistant LNCaP Abl cells but not in the parental LNCaP. This negative feedback loop in the resistant cells was confirmed by immunohistochemistry which showed a negative correlation between AR and SRF expression in CRPC bone metastases and a positive correlation in androgen-naïve prostatectomies. Cell proliferation was next assessed following SRF inhibition, demonstrating that SRF inhibition is more effective than AR inhibition in castrate-resistant cells. Our data support SRF as a promising therapeutic target in combination with current treatments. © 2015 Wiley Periodicals, Inc.

  1. Evolution of melanocortin receptors in cartilaginous fish: melanocortin receptors and the stress axis in elasmobranches.

    PubMed

    Liang, Liang; Reinick, Christina; Angleson, Joseph K; Dores, Robert M

    2013-01-15

    There is general agreement that the presence of five melanocortin receptor genes in tetrapods is the result of two genome duplications that occurred prior to the emergence of the gnathostomes, and at least one local gene duplication that occurred early in the radiation of the ancestral gnathostomes. Hence, it is assumed that representatives from the extant classes of gnathostomes (i.e., Chondrichthyes, Actinopterygii, Sarcopterygii) should also have five paralogous melanocortin genes. Current studies on cartilaginous fishes indicate that while there is evidence for five paralogous melanocortin receptor genes in this class, to date all five paralogs have not been detected in the genome of a single species. This mini-review will discuss the ligand selectivity properties of the melanocortin-3 receptor of the elephant shark (subclass Holocephali) and the ligand selectivity properties of the melanocortin-3 receptor, melanocortin-4 receptor, and the melanocortin-5 receptor of the dogfish (subclass Elasmobranchii). The potential relationship of these melanocortin receptors to the hypothalamus/pituitary/interrenal axis will be discussed. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Relationship of source and sink in determining kernel composition of maize

    PubMed Central

    Seebauer, Juliann R.; Singletary, George W.; Krumpelman, Paulette M.; Ruffo, Matías L.; Below, Frederick E.

    2010-01-01

    The relative role of the maternal source and the filial sink in controlling the composition of maize (Zea mays L.) kernels is unclear and may be influenced by the genotype and the N supply. The objective of this study was to determine the influence of assimilate supply from the vegetative source and utilization of assimilates by the grain sink on the final composition of maize kernels. Intermated B73×Mo17 recombinant inbred lines (IBM RILs) which displayed contrasting concentrations of endosperm starch were grown in the field with deficient or sufficient N, and the source supply altered by ear truncation (45% reduction) at 15 d after pollination (DAP). The assimilate supply into the kernels was determined at 19 DAP using the agar trap technique, and the final kernel composition was measured. The influence of N supply and kernel ear position on final kernel composition was also determined for a commercial hybrid. Concentrations of kernel protein and starch could be altered by genotype or the N supply, but remained fairly constant along the length of the ear. Ear truncation also produced a range of variation in endosperm starch and protein concentrations. The C/N ratio of the assimilate supply at 19 DAP was directly related to the final kernel composition, with an inverse relationship between the concentrations of starch and protein in the mature endosperm. The accumulation of kernel starch and protein in maize is uniform along the ear, yet adaptable within genotypic limits, suggesting that kernel composition is source limited in maize. PMID:19917600

  3. 3D-QSAR comparative molecular field analysis on opioid receptor antagonists: pooling data from different studies.

    PubMed

    Peng, Youyi; Keenan, Susan M; Zhang, Qiang; Kholodovych, Vladyslav; Welsh, William J

    2005-03-10

    Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were constructed using comparative molecular field analysis (CoMFA) on a series of opioid receptor antagonists. To obtain statistically significant and robust CoMFA models, a sizable data set of naltrindole and naltrexone analogues was assembled by pooling biological and structural data from independent studies. A process of "leave one data set out", similar to the traditional "leave one out" cross-validation procedure employed in partial least squares (PLS) analysis, was utilized to study the feasibility of pooling data in the present case. These studies indicate that our approach yields statistically significant and highly predictive CoMFA models from the pooled data set of delta, mu, and kappa opioid receptor antagonists. All models showed excellent internal predictability and self-consistency: q(2) = 0.69/r(2) = 0.91 (delta), q(2) = 0.67/r(2) = 0.92 (mu), and q(2) = 0.60/r(2) = 0.96 (kappa). The CoMFA models were further validated using two separate test sets: one test set was selected randomly from the pooled data set, while the other test set was retrieved from other published sources. The overall excellent agreement between CoMFA-predicted and experimental binding affinities for a structurally diverse array of ligands across all three opioid receptor subtypes gives testimony to the superb predictive power of these models. CoMFA field analysis demonstrated that the variations in binding affinity of opioid antagonists are dominated by steric rather than electrostatic interactions with the three opioid receptor binding sites. The CoMFA steric-electrostatic contour maps corresponding to the delta, mu, and kappa opioid receptor subtypes reflected the characteristic similarities and differences in the familiar "message-address" concept of opioid receptor ligands. Structural modifications to increase selectivity for the delta over mu and kappa opioid receptors have been predicted on the

  4. Colored dissolved organic matter in shallow estuaries: relationships between carbon sources and light attenuation

    USGS Publications Warehouse

    Oestreich, W.K.; Ganju, Neil K.; Pohlman, John; Suttles, Steven E.

    2016-01-01

    Light availability is of primary importance to the ecological function of shallow estuaries. For example, benthic primary production by submerged aquatic vegetation is contingent upon light penetration to the seabed. A major component that attenuates light in estuaries is colored dissolved organic matter (CDOM). CDOM is often measured via a proxy, fluorescing dissolved organic matter (fDOM), due to the ease of in situ fDOM sensor measurements. Fluorescence must be converted to CDOM absorbance for use in light attenuation calculations. However, this CDOM–fDOM relationship varies among and within estuaries. We quantified the variability in this relationship within three estuaries along the mid-Atlantic margin of the eastern United States: West Falmouth Harbor (MA), Barnegat Bay (NJ), and Chincoteague Bay (MD/VA). Land use surrounding these estuaries ranges from urban to developed, with varying sources of nutrients and organic matter. Measurements of fDOM (excitation and emission wavelengths of 365 nm (±5 nm) and 460 nm (±40 nm), respectively) and CDOM absorbance were taken along a terrestrial-to-marine gradient in all three estuaries. The ratio of the absorption coefficient at 340 nm (m−1) to fDOM (QSU) was higher in West Falmouth Harbor (1.22) than in Barnegat Bay (0.22) and Chincoteague Bay (0.17). The CDOM : fDOM absorption ratio was variable between sites within West Falmouth Harbor and Barnegat Bay, but consistent between sites within Chincoteague Bay. Stable carbon isotope analysis for constraining the source of dissolved organic matter (DOM) in West Falmouth Harbor and Barnegat Bay yielded δ13C values ranging from −19.7 to −26.1 ‰ and −20.8 to −26.7 ‰, respectively. Concentration and stable carbon isotope mixing models of DOC (dissolved organic carbon) indicate a contribution of 13C-enriched DOC in the estuaries. The most likely source of 13C-enriched DOC for the systems we investigated is Spartina cordgrass. Comparison of

  5. Application of receptor models on water quality data in source apportionment in Kuantan River Basin

    PubMed Central

    2012-01-01

    Recent techniques in the management of surface river water have been expanding the demand on the method that can provide more representative of multivariate data set. A proper technique of the architecture of artificial neural network (ANN) model and multiple linear regression (MLR) provides an advance tool for surface water modeling and forecasting. The development of receptor model was applied in order to determine the major sources of pollutants at Kuantan River Basin, Malaysia. Thirteen water quality parameters were used in principal component analysis (PCA) and new variables of fertilizer waste, surface runoff, anthropogenic input, chemical and mineral changes and erosion are successfully developed for modeling purposes. Two models were compared in terms of efficiency and goodness-of-fit for water quality index (WQI) prediction. The results show that APCS-ANN model gives better performance with high R2 value (0.9680) and small root mean square error (RMSE) value (2.6409) compared to APCS-MLR model. Meanwhile from the sensitivity analysis, fertilizer waste acts as the dominant pollutant contributor (59.82%) to the basin studied followed by anthropogenic input (22.48%), surface runoff (13.42%), erosion (2.33%) and lastly chemical and mineral changes (1.95%). Thus, this study concluded that receptor modeling of APCS-ANN can be used to solve various constraints in environmental problem that exist between water distribution variables toward appropriate water quality management. PMID:23369363

  6. Structure-function relationships of curaremimetic neurotoxin loop 2 and of a structurally similar segment of rabies virus glycoprotein in their interaction with the nicotinic acetylcholine receptor

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lentz, T.L.

    1991-11-12

    Peptides corresponding to portions of curaremimetic neurotoxin loop 2 and to a structurally similar segment of rabies virus glycoprotein were synthetically modified in order to gain information on structure-function relationships of neurotoxin loop 2 interactions with the acetylcholine receptor. Binding of synthetic peptides to the acetylcholine receptor of Torpedo electric organ membranes was assessed by measuring their ability to inhibit the binding of {sup 125}I-{alpha}-bungarotoxin to the receptor. The peptides showing the highest affinity for the receptor were a peptide corresponding to the sequence of loop 2 (residues 25-44) of Ophiophagus hannah (king cobra) toxin b and the structurally similarmore » segment of CVS rabies virus glycoprotein. These affinities were comparable to those of d-tubocurarine and suberyldicholine. These results demonstrate the importance of loop 2 in the neurotoxin interaction with the receptor. N- and C-terminal deletions of the loop 2 peptides and substitution of residues invariant or highly conserved among neurotoxins were performed in order to determine the role of individual residues in binding. Residues 25-40 are the most crucial in the interaction with the acetylcholine receptor. Since this region of the glycoprotein contains residues corresponding to all of the functionally invariant neurotoxin residues, it may interact with the acetylcholine receptor through a mechanism similar to that of the neurotoxins.« less

  7. Dissecting Impulsivity and its Relationships to Drug Addictions

    PubMed Central

    Ashenhurst, James R.; Cervantes, M. Catalina; James, Alexander S.; Groman, Stephanie M.; Pennington, Zachary T.

    2015-01-01

    Addictions are often characterized as forms of impulsive behavior. That said, it is often noted that impulsivity is a multidimensional construct, spanning several psychological domains. This review describes the relationship between varieties of impulsivity and addiction-related behaviors, the nature of the causal relationship between the two and the underlying neurobiological mechanisms that promote impulsive behaviors. We conclude that the available data strongly supports the notion that impulsivity is both a risk factor for, and a consequence of, drug and alcohol consumption. While the evidence indicating that subtypes of impulsive behavior are uniquely informative – either biologically or with respect to their relationships to addictions – is convincing, multiple lines of study link “distinct” subtypes of impulsivity to low dopamine D2 receptor function and perturbed serotonergic transmission, revealing shared mechanisms between the subtypes. Therefore, a common biological framework involving monoaminergic transmitters in key frontostriatal circuits may link multiple forms of impulsivity to drug self-administration and addiction-related behaviors. Further dissection of these relationships is needed before the next phase of genetic and genomic discovery will be able to reveal the biological sources of the vulnerability for addiction indexed by impulsivity. PMID:24654857

  8. Spatial relationships between lead sources and children's blood lead levels in the urban center of Indianapolis (USA).

    PubMed

    Morrison, Deborah; Lin, Qing; Wiehe, Sarah; Liu, Gilbert; Rosenman, Marc; Fuller, Trevor; Wang, Jane; Filippelli, Gabriel

    2013-04-01

    Urban children remain disproportionately at risk of having higher blood lead levels than their suburban counterparts. The Westside Cooperative Organization (WESCO), located in Marion County, Indianapolis, Indiana, has a history of children with high blood lead levels as well as high soil lead (Pb) values. This study aims at determining the spatial relationship between soil Pb sources and children's blood lead levels. Soils have been identified as a source of chronic Pb exposure to children, but the spatial scale of the source-recipient relationship is not well characterized. Neighborhood-wide analysis of soil Pb distribution along with a furnace filter technique for sampling interior Pb accumulation for selected homes (n = 7) in the WESCO community was performed. Blood lead levels for children aged 0-5 years during the period 1999-2008 were collected. The study population's mean blood lead levels were higher than national averages across all ages, race, and gender. Non-Hispanic blacks and those individuals in the Wishard advantage program had the highest proportion of elevated blood lead levels. The results show that while there is not a direct relationship between soil Pb and children's blood lead levels at a spatial scale of ~100 m, resuspension of locally sourced soil is occurring based on the interior Pb accumulation. County-wide, the largest predictor of elevated blood lead levels is the location within the urban core. Variation in soil Pb and blood lead levels on the community level is high and not predicted by housing stock age or income. Race is a strong predictor for blood lead levels in the WESCO community.

  9. Structure-activity relationships and mechanism of action of Eph-ephrin antagonists: interaction of cholanic acid with the EphA2 receptor

    PubMed Central

    Tognolini, Massimiliano; Incerti, Matteo; Mohamed, Iftiin Hassan; Giorgio, Carmine; Russo, Simonetta; Bruni, Renato; Lelli, Barbara; Bracci, Luisa; Noberini, Roberta; Pasquale, Elena B.; Barocelli, Elisabetta; Vicini, Paola; Mor, Marco

    2012-01-01

    The Eph–ephrin system, including the EphA2 receptor and the ephrin-A1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3α,5β)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist able to inhibit EphA2 receptor activation and therefore potentially useful as a novel EphA2 receptor targeting agent. Here, we explore the structure-activity relationships of a focused set of lithocholic acid derivatives, based on molecular modelling investigation and displacement binding assays. Our exploration shows that while the 3-α-hydroxyl group of lithocholic acid has a negligible role in the recognition of the EphA2 receptor, its carboxylate group is critical for disrupting the binding of ephrin-A1 to the EphA2. As a result of our investigation, we identified (5β)-cholan-24-oic acid (cholanic acid) as a novel compound that competitively inhibits EphA2-ephrin-A1 interaction with higher potency than lithocholic acid. Surface plasmon resonance analysis indicates that cholanic acid binds specifically and reversibly to the ligand-binding domain of EphA2, with a steady-state dissociation constant (KD) in the low micromolar range. Furthermore, cholanic acid blocks the phosphorylation of EphA2 and cell retraction and rounding in PC3 prostate cancer cells, two effects that depend on EphA2 activation by the ephrin-A1 ligand. These findings suggest that cholanic acid can be used as a template structure to design effective EphA2 antagonists, with potential impact in the elucidation of the role played by this receptor in pathological conditions. PMID:22529030

  10. An Extended Structure-Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors.

    PubMed

    Holland, Erika B; Feng, Wei; Zheng, Jing; Dong, Yao; Li, Xueshu; Lehmler, Hans-Joachim; Pessah, Isaac N

    2017-01-01

    Nondioxin-like polychlorinated biphenyls (NDL PCBs) activate ryanodine-sensitive Ca 2+  channels (RyRs) and this activation has been associated with neurotoxicity in exposed animals. RyR-active congeners follow a distinct structure-activity relationship and a quantitative structure-activity relationship (QSAR) predicts that a large number of PCBs likely activate the receptor, which requires validation. Additionally, previous structural based conclusions have been established using receptor ligand binding assays but the impact of varying PCB structures on ion channel gating behavior is not understood. We used [ 3 H]Ryanodine ([ 3 H]Ry) binding to assess the RyR-activity of 14 previously untested PCB congeners evaluating the predictability of the QSAR. Congeners determined to display widely varying potency were then assayed with single channel voltage clamp analysis to assess direct influences on channel gating kinetics. The RyR-activity of individual PCBs assessed in in vitro assays followed the general pattern predicted by the QSAR but binding and lipid bilayer experiments demonstrated higher potency than predicted. Of the 49 congeners tested to date, tetra-ortho PCB 202 was found to be the most potent RyR-active congener increasing channel open probability at 200 pM. Shifting meta-substitutions to the para-position resulted in a > 100-fold reduction in potency as seen with PCB 197. Non-ortho PCB 11 was found to lack activity at the receptor supporting a minimum mono-ortho substitution for PCB RyR activity. These findings expand and support previous SAR assessments; where out of the 49 congeners tested to date 42 activate the receptor demonstrating that the RyR is a sensitive and common target of PCBs. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. T cell costimulation by chemokine receptors.

    PubMed

    Molon, Barbara; Gri, Giorgia; Bettella, Monica; Gómez-Moutón, Concepción; Lanzavecchia, Antonio; Martínez-A, Carlos; Mañes, Santos; Viola, Antonella

    2005-05-01

    Signals mediated by chemokine receptors may compete with T cell receptor stop signals and determine the duration of T cell-antigen-presenting cell interactions. Here we show that during T cell stimulation by antigen-presenting cells, T cell chemokine receptors coupled to G(q) and/or G(11) protein were recruited to the immunological synapse by a G(i)-independent mechanism. When chemokine receptors were sequestered at the immunological synapse, T cells became insensitive to chemotactic gradients, formed more stable conjugates and finally responded with enhanced proliferation and cytokine production. We suggest that chemokine receptor trapping at the immunological synapse enhances T cell activation by improving T cell-antigen-presenting cell attraction and impeding the 'distraction' of successfully engaged T cells by other chemokine sources.

  12. T3 receptors in human pituitary tumors.

    PubMed

    Machiavelli, Gloria A; Pauni, Micaela; Heredia Sereno, Gastón M; Szijan, Irene; Basso, Armando; Burdman, José A

    2009-11-01

    The purpose of this work was to investigate the synthesis of T3 receptors in human tumors of the anterior pituitary gland, its relationship with the hormone synthesized and/or secreted by the tumor and the post-surgical evolution of the patient. Patients were evaluated clinically and by magnetic nuclear resonance to classify the adenoma according to their size. Hormonal concentrations in sera were determined by radioimmunoassay. Immunohistochemistry of the pituitary hormones was performed in the tumors. Tumors were obtained at surgery and immediately frozen in ice, transported to the laboratory and stored at -70 degrees C. Reverse transcription was performed with purified RNA from the tumors. Out of 33 pituitary tumors, 29 had RNA for T3 receptors synthesis (88%). They were present in different histological specimens, the tumors were grades 1-4 according to their size, and there was no relationship between the size of the tumor and the presence of T3 receptor RNAs. The post-surgical evolution of the patient was mostly dependent on the size and not on the presence of T3 receptors. The presence of thyroid hormone receptors in pituitary tumors is in line with two important characteristics of these tumors: they are histologically benign and well differentiated.

  13. N-glycosylation of the β2 adrenergic receptor regulates receptor function by modulating dimerization.

    PubMed

    Li, Xiaona; Zhou, Mang; Huang, Wei; Yang, Huaiyu

    2017-07-01

    N-glycosylation is a common post-translational modification of G-protein-coupled receptors (GPCRs). However, it remains unknown how N-glycosylation affects GPCR signaling. β 2 adrenergic receptor (β 2 AR) has three N-glycosylation sites: Asn6, Asn15 at the N-terminus, and Asn187 at the second extracellular loop (ECL2). Here, we show that deletion of the N-glycan did not affect receptor expression and ligand binding. Deletion of the N-glycan at the N-terminus rather than Asn187 showed decreased effects on isoproterenol-promoted G-protein-dependent signaling, β-arrestin2 recruitment, and receptor internalization. Both N6Q and N15Q showed decreased receptor dimerization, while N187Q did not influence receptor dimerization. As decreased β 2 AR homodimer accompanied with reduced efficiency for receptor function, we proposed that the N-glycosylation of β 2 AR regulated receptor function by influencing receptor dimerization. To verify this hypothesis, we further paid attention to the residues at the dimerization interface. Studies of Lys60 and Glu338, two residues at the receptor dimerization interface, exhibited that the K60A/E338A showed decreased β 2 AR dimerization and its effects on receptor signaling were similar to N6Q and N15Q, which further supported the importance of receptor dimerization for receptor function. This work provides new insights into the relationship among glycosylation, dimerization, and function of GPCRs. Peptide-N-glycosidase F (PNGase F, EC 3.2.2.11); endo-β-N-acetylglucosaminidase A (Endo-A, EC 3.2.1.96). © 2017 Federation of European Biochemical Societies.

  14. Source apportionment of soil heavy metals using robust absolute principal component scores-robust geographically weighted regression (RAPCS-RGWR) receptor model.

    PubMed

    Qu, Mingkai; Wang, Yan; Huang, Biao; Zhao, Yongcun

    2018-06-01

    The traditional source apportionment models, such as absolute principal component scores-multiple linear regression (APCS-MLR), are usually susceptible to outliers, which may be widely present in the regional geochemical dataset. Furthermore, the models are merely built on variable space instead of geographical space and thus cannot effectively capture the local spatial characteristics of each source contributions. To overcome the limitations, a new receptor model, robust absolute principal component scores-robust geographically weighted regression (RAPCS-RGWR), was proposed based on the traditional APCS-MLR model. Then, the new method was applied to the source apportionment of soil metal elements in a region of Wuhan City, China as a case study. Evaluations revealed that: (i) RAPCS-RGWR model had better performance than APCS-MLR model in the identification of the major sources of soil metal elements, and (ii) source contributions estimated by RAPCS-RGWR model were more close to the true soil metal concentrations than that estimated by APCS-MLR model. It is shown that the proposed RAPCS-RGWR model is a more effective source apportionment method than APCS-MLR (i.e., non-robust and global model) in dealing with the regional geochemical dataset. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors.

    PubMed

    Carter, Olivia L; Burr, David C; Pettigrew, John D; Wallis, Guy M; Hasler, Felix; Vollenweider, Franz X

    2005-10-01

    Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight healthy human volunteers were tested on a multiple-object tracking task and spatial working memory task under the four conditions: placebo, psilocybin (215 microg/kg), ketanserin (50 mg), and psilocybin and ketanserin. Psilocybin significantly reduced attentional tracking ability, but had no significant effect on spatial working memory, suggesting a functional dissociation between the two tasks. Pretreatment with ketanserin did not attenuate the effect of psilocybin on attentional performance, suggesting a primary involvement of the 5-HT1A receptor in the observed deficit. Based on physiological and pharmacological data, we speculate that this impaired attentional performance may reflect a reduced ability to suppress or ignore distracting stimuli rather than reduced attentional capacity. The clinical relevance of these results is also discussed.

  16. Structure-activity relationships of seco-prezizaane and picrotoxane/picrodendrane terpenoids by Quasar receptor-surface modeling.

    PubMed

    Schmidt, Thomas J; Gurrath, Marion; Ozoe, Yoshihisa

    2004-08-01

    The seco-prezizaane-type sesquiterpenes pseudoanisatin and parviflorolide from Illicium are noncompetitive antagonists at housefly (Musca domestica) gamma-aminobutyric acid (GABA) receptors. They show selectivity toward the insect receptor and thus represent new leads toward selective insecticides. Based on the binding data for 13 seco-prezizaane terpenoids and 17 picrotoxane and picrodendrane-type terpenoids to housefly and rat GABA receptors, a QSAR study was conducted by quasi-atomistic receptor-surface modeling (Quasar). The resulting models provide insight into the structural basis of selectivity and properties of the binding sites at GABA receptor-coupled chloride channels of insects and mammals.

  17. The innovative concept of three-dimensional hybrid receptor modeling

    NASA Astrophysics Data System (ADS)

    Stojić, A.; Stanišić Stojić, S.

    2017-09-01

    The aim of this study was to improve the current understanding of air pollution transport processes at regional and long-range scale. For this purpose, three-dimensional (3D) potential source contribution function and concentration weighted trajectory models, as well as new hybrid receptor model, concentration weighted boundary layer (CWBL), which uses a two-dimensional grid and a planetary boundary layer height as a frame of reference, are presented. The refined approach to hybrid receptor modeling has two advantages. At first, it considers whether each trajectory endpoint meets the inclusion criteria based on planetary boundary layer height, which is expected to provide a more realistic representation of the spatial distribution of emission sources and pollutant transport pathways. Secondly, it includes pollutant time series preprocessing to make hybrid receptor models more applicable for suburban and urban locations. The 3D hybrid receptor models presented herein are designed to identify altitude distribution of potential sources, whereas CWBL can be used for analyzing the vertical distribution of pollutant concentrations along the transport pathway.

  18. The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery

    PubMed Central

    Salon, John A.; Lodowski, David T.

    2011-01-01

    Crucial as molecular sensors for many vital physiological processes, seven-transmembrane domain G protein-coupled receptors (GPCRs) comprise the largest family of proteins targeted by drug discovery. Together with structures of the prototypical GPCR rhodopsin, solved structures of other liganded GPCRs promise to provide insights into the structural basis of the superfamily's biochemical functions and assist in the development of new therapeutic modalities and drugs. One of the greatest technical and theoretical challenges to elucidating and exploiting structure-function relationships in these systems is the emerging concept of GPCR conformational flexibility and its cause-effect relationship for receptor-receptor and receptor-effector interactions. Such conformational changes can be subtle and triggered by relatively small binding energy effects, leading to full or partial efficacy in the activation or inactivation of the receptor system at large. Pharmacological dogma generally dictates that these changes manifest themselves through kinetic modulation of the receptor's G protein partners. Atomic resolution information derived from increasingly available receptor structures provides an entrée to the understanding of these events and practically applying it to drug design. Supported by structure-activity relationship information arising from empirical screening, a unified structural model of GPCR activation/inactivation promises to both accelerate drug discovery in this field and improve our fundamental understanding of structure-based drug design in general. This review discusses fundamental problems that persist in drug design and GPCR structural determination. PMID:21969326

  19. Functional efficacy of adenosine A2A receptor agonists is positively correlated to their receptor residence time

    PubMed Central

    Guo, Dong; Mulder-Krieger, Thea; IJzerman, Adriaan P; Heitman, Laura H

    2012-01-01

    BACKGROUND AND PURPOSE The adenosine A2A receptor belongs to the superfamily of GPCRs and is a promising therapeutic target. Traditionally, the discovery of novel agents for the A2A receptor has been guided by their affinity for the receptor. This parameter is determined under equilibrium conditions, largely ignoring the kinetic aspects of the ligand-receptor interaction. The aim of this study was to assess the binding kinetics of A2A receptor agonists and explore a possible relationship with their functional efficacy. EXPERIMENTAL APPROACH We set up, validated and optimized a kinetic radioligand binding assay (a so-called competition association assay) at the A2A receptor from which the binding kinetics of unlabelled ligands were determined. Subsequently, functional efficacies of A2A receptor agonists were determined in two different assays: a novel label-free impedance-based assay and a more traditional cAMP determination. KEY RESULTS A simplified competition association assay yielded an accurate determination of the association and dissociation rates of unlabelled A2A receptor ligands at their receptor. A correlation was observed between the receptor residence time of A2A receptor agonists and their intrinsic efficacies in both functional assays. The affinity of A2A receptor agonists was not correlated to their functional efficacy. CONCLUSIONS AND IMPLICATIONS This study indicates that the molecular basis of different agonist efficacies at the A2A receptor lies within their different residence times at this receptor. PMID:22324512

  20. Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor.

    PubMed

    Laudet, V

    1997-12-01

    From a database containing the published nuclear hormone receptor (NR) sequences I constructed an alignment of the C, D and E domains of these molecules. Using this alignment, I have performed tree reconstruction using both distance matrix and parsimony analysis. The robustness of each branch was estimated using bootstrap resampling methods. The trees constructed by these two methods gave congruent topologies. From these analyses I defined six NR subfamilies: (i) a large one clustering thyroid hormone receptors (TRs), retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (PPARs), vitamin D receptors (VDRs) and ecdysone receptors (EcRs) as well as numerous orphan receptors such as RORs or Rev-erbs; (ii) one containing retinoid X receptors (RXRs) together with COUP, HNF4, tailless, TR2 and TR4 orphan receptors; (iii) one containing steroid receptors; (iv) one containing the NGFIB orphan receptors; (v) one containing FTZ-F1 orphan receptors; and finally (vi) one containing to date only one gene, the GCNF1 orphan receptor. The relationships between the six subfamilies are not known except for subfamilies I and IV which appear to be related. Interestingly, most of the liganded receptors appear to be derived when compared with orphan receptors. This suggests that the ligand-binding ability of NRs has been gained by orphan receptors during the course of evolution to give rise to the presently known receptors. The distribution into six subfamilies correlates with the known abilities of the various NRs to bind to DNA as homo- or heterodimers. For example, receptors heterodimerizing efficiently with RXR belong to the first or the fourth subfamilies. I suggest that the ability to heterodimerize evolved once, just before the separation of subfamilies I and IV and that the first NR was able to bind to DNA as a homodimer. From the study of NR sequences existing in vertebrates, arthropods and nematodes, I define two major steps of NR diversification: one

  1. The endocrinology of taste receptors

    PubMed Central

    Santa-Cruz Calvo, Sara; Egan, Josephine M.

    2016-01-01

    Levels of obesity have reached epidemic proportions on a global scale, which has led to considerable increases in health problems and increased risk of several diseases, including cardiovascular and pulmonary diseases, cancer and diabetes mellitus. People with obesity consume more food than is needed to maintain an ideal body weight, despite the discrimination that accompanies being overweight and the wealth of available information that overconsumption is detrimental to health. The relationship between energy expenditure and energy intake throughout an individual’s lifetime is far more complicated than previously thought. An improved comprehension of the relationships between taste, palatability, taste receptors and hedonic responses to food might lead to increased understanding of the biological underpinnings of energy acquisition, as well as why humans sometimes eat more than is needed and more than we know is healthy. This Review discusses the role of taste receptors in the tongue, gut, pancreas and brain and their hormonal involvement in taste perception, as well as the relationship between taste perception, overeating and the development of obesity. PMID:25707779

  2. The endocrinology of taste receptors.

    PubMed

    Calvo, Sara Santa-Cruz; Egan, Josephine M

    2015-04-01

    Levels of obesity have reached epidemic proportions on a global scale, which has led to considerable increases in health problems and increased risk of several diseases, including cardiovascular and pulmonary diseases, cancer and diabetes mellitus. People with obesity consume more food than is needed to maintain an ideal body weight, despite the discrimination that accompanies being overweight and the wealth of available information that overconsumption is detrimental to health. The relationship between energy expenditure and energy intake throughout an individual's lifetime is far more complicated than previously thought. An improved comprehension of the relationships between taste, palatability, taste receptors and hedonic responses to food might lead to increased understanding of the biological underpinnings of energy acquisition, as well as why humans sometimes eat more than is needed and more than we know is healthy. This Review discusses the role of taste receptors in the tongue, gut, pancreas and brain and their hormonal involvement in taste perception, as well as the relationship between taste perception, overeating and the development of obesity.

  3. Structure-Activity Relationships of Constrained Phenylethylamine Ligands for the Serotonin 5-HT2 Receptors

    PubMed Central

    Isberg, Vignir; Paine, James; Leth-Petersen, Sebastian; Kristensen, Jesper L.; Gloriam, David E.

    2013-01-01

    Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9–11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9–11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9–11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands. PMID:24244317

  4. Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors.

    PubMed

    Isberg, Vignir; Paine, James; Leth-Petersen, Sebastian; Kristensen, Jesper L; Gloriam, David E

    2013-01-01

    Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.

  5. Identification of Thyroid Receptor Ant/Agonists in Water Sources Using Mass Balance Analysis and Monte Carlo Simulation

    PubMed Central

    Shi, Wei; Wei, Si; Hu, Xin-xin; Hu, Guan-jiu; Chen, Cu-lan; Wang, Xin-ru; Giesy, John P.; Yu, Hong-xia

    2013-01-01

    Some synthetic chemicals, which have been shown to disrupt thyroid hormone (TH) function, have been detected in surface waters and people have the potential to be exposed through water-drinking. Here, the presence of thyroid-active chemicals and their toxic potential in drinking water sources in Yangtze River Delta were investigated by use of instrumental analysis combined with cell-based reporter gene assay. A novel approach was developed to use Monte Carlo simulation, for evaluation of the potential risks of measured concentrations of TH agonists and antagonists and to determine the major contributors to observed thyroid receptor (TR) antagonist potency. None of the extracts exhibited TR agonist potency, while 12 of 14 water samples exhibited TR antagonistic potency. The most probable observed antagonist equivalents ranged from 1.4 to 5.6 µg di-n-butyl phthalate (DNBP)/L, which posed potential risk in water sources. Based on Monte Carlo simulation related mass balance analysis, DNBP accounted for 64.4% for the entire observed antagonist toxic unit in water sources, while diisobutyl phthalate (DIBP), di-n-octyl phthalate (DNOP) and di-2-ethylhexyl phthalate (DEHP) also contributed. The most probable observed equivalent and most probable relative potency (REP) derived from Monte Carlo simulation is useful for potency comparison and responsible chemicals screening. PMID:24204563

  6. Structure/function relationships of calcitonin analogues as agonists, antagonists, or inverse agonists in a constitutively activated receptor cell system.

    PubMed

    Pozvek, G; Hilton, J M; Quiza, M; Houssami, S; Sexton, P M

    1997-04-01

    The structure/function relationship of salmon calcitonin (sCT) analogues was investigated in heterologous calcitonin receptor (CTR) expression systems. sCT analogues with progressive amino-terminal truncations intermediate of sCT-(1-32) to sCT-(8-32) were examined for their ability to act as agonists, antagonists, or inverse agonists. Two CTR cell clones, B8-H10 and G12-E12, which express approximately 5 million and 25,000 C1b receptors/cell, respectively, were used for this study. The B8-H10 clone has an approximately 80-fold increase in basal levels of intracellular cAMP due to constitutive activation of the overexpressed receptor. In whole-cell competition binding studies, sCT-(1-32) was more potent than any of its amino-terminally truncated analogues in competition for 125I-sCT binding. In cAMP accumulation studies, sCT-(1-32) and modified analogues sCT-(2-32) and sCT-(3-32) had agonist activities. SDZ-216-710, with an amino-terminal truncation of four amino acids, behaved as a partial agonist/antagonist, whereas amino-terminal truncations of six or seven amino acid residues produced a 16-fold reduction in basal cAMP levels and attenuated the response to the agonist sCT-(1-32) in the constitutively active CTR system. This inverse agonist effect was insensitive to pertussis toxin inhibition. In contrast, the inverse agonist activity of these peptides was not observed in the nonconstitutively active CTR system, in which sCT analogues with amino-terminal truncations of four or more amino acids behaved as neutral competitive antagonists. These results suggest that the inverse agonist activity is mediated by stabilization of the inactive state of the receptor, which does not couple to G protein, and attenuates basal signaling initiated by ligand-independent activation of the effector adenylyl cyclase.

  7. Predicting receptor-ligand pairs through kernel learning

    PubMed Central

    2011-01-01

    Background Regulation of cellular events is, often, initiated via extracellular signaling. Extracellular signaling occurs when a circulating ligand interacts with one or more membrane-bound receptors. Identification of receptor-ligand pairs is thus an important and specific form of PPI prediction. Results Given a set of disparate data sources (expression data, domain content, and phylogenetic profile) we seek to predict new receptor-ligand pairs. We create a combined kernel classifier and assess its performance with respect to the Database of Ligand-Receptor Partners (DLRP) 'golden standard' as well as the method proposed by Gertz et al. Among our findings, we discover that our predictions for the tgfβ family accurately reconstruct over 76% of the supported edges (0.76 recall and 0.67 precision) of the receptor-ligand bipartite graph defined by the DLRP "golden standard". In addition, for the tgfβ family, the combined kernel classifier is able to relatively improve upon the Gertz et al. work by a factor of approximately 1.5 when considering that our method has an F-measure of 0.71 while that of Gertz et al. has a value of 0.48. Conclusions The prediction of receptor-ligand pairings is a difficult and complex task. We have demonstrated that using kernel learning on multiple data sources provides a stronger alternative to the existing method in solving this task. PMID:21834994

  8. Late Cretaceous Turbidite Reservoirs Along the Equatorial West African Margin: An Industry Perspective on Source-to-Sink Relationships

    NASA Astrophysics Data System (ADS)

    Wilson, Jonathan; Kohlmann, Fabian; Nicoll, Graeme

    2017-04-01

    The source-to-sink mindset provides an important framework for the exploration geologist. It enables an integrated understanding of hinterland and basin, and can lead to subsurface risk mitigation, particularly with respect to predicting reservoir location and quality. Despite the numerous benefits associated with source-to-sink analysis, such studies are time-consuming to generate, encompassing a large array of disciplines and data, and are not routinely performed within the hydrocarbon industry. The discovery of several significant hydrocarbon fields along the equatorial West African margin has been followed by a series of expensive failures throughout the last decade associated with reservoir quality/presence. This paper discusses a case study focused on the equatorial West African margin, demonstrating how three well-known but effective approaches can be integrated to reconstruct source-to-sink relationships in an ancient sedimentary system, helping de-risk exploration efforts. The first step is to characterize the hinterland. To do this, detailed information was collected for two separate but interlinked datasets—mineral deposits and hard rock geochronology. Combined, these two datasets allow an understanding of the timing and nature of an areas tectonic evolution to be easily developed. The data can be used alongside stratigraphic data and geodynamic information from a plate tectonic model to reconstruct topography and bathymetry of the earth at different episodes of geological time. Paleo digital elevation models (PDEMs) give a first-order approximation of hinterland topography and therefore allow possible sediment source areas to be identified and potential sediment transport pathways to be visualized by means of the digital reconstruction of paleo-drainage networks and their attendant watersheds. This integrated global dataset of hinterland geochronology provides useful "source" information complemented by "sink" information contained within a detrital

  9. Source Region Identification Using Kernel Smoothing

    EPA Science Inventory

    As described in this paper, Nonparametric Wind Regression is a source-to-receptor source apportionment model that can be used to identify and quantify the impact of possible source regions of pollutants as defined by wind direction sectors. It is described in detail with an exam...

  10. The Moderator Role of Perceived Emotional Intelligence in the Relationship between Sources of Stress and Mental Health in Teachers.

    PubMed

    Pulido-Martos, Manuel; Lopez-Zafra, Esther; Estévez-López, Fernando; Augusto-Landa, José María

    2016-03-03

    This study analyzes the role of Perceived Emotional Intelligence (PEI) on sources of job stress and mental health in 250 elementary school teachers from Jaén (Spain). The aim of the study was two-fold: (1) to analyze the associations between Perceived Emotional Intelligence (PEI), sources of occupational stress and mental health; and (2) to determine whether PEI moderates the relationship between sources of occupational stress and mental health. An initial sample of 250 teachers was assessed Three questionnaires, the Trait Meta-Mood Scale, the Sources of Stress Scale in Teachers and the Medical Outcomes Study 36-item Short Form Health Survey, were used to evaluate PEI, sources of occupational stress and mental health, respectively. Teachers with higher levels of emotional attention reported lower levels of mental health (r = -.30; p < .001), while teachers showing high emotional clarity reported better emotional role (r = .14; p < .05) and social functioning (r = .15; p < .05). Moreover, PEI components moderate the relationship between sources of occupational stress and emotional role. Specifically, each significant interaction (i.e., deficiencies x attention, adaptation x attention, and adaptation x clarity) made a small and unique contribution in the explanation of emotional role (all p < .05, all sr 2 ∼ .02). Finally, our results imply that PEI is an important moderator of teachers´ occupational stressors on mental health.

  11. Fine particulates over South Asia: Review and meta-analysis of PM2.5 source apportionment through receptor model.

    PubMed

    Singh, Nandita; Murari, Vishnu; Kumar, Manish; Barman, S C; Banerjee, Tirthankar

    2017-04-01

    Fine particulates (PM 2.5 ) constitute dominant proportion of airborne particulates and have been often associated with human health disorders, changes in regional climate, hydrological cycle and more recently to food security. Intrinsic properties of particulates are direct function of sources. This initiates the necessity of conducting a comprehensive review on PM 2.5 sources over South Asia which in turn may be valuable to develop strategies for emission control. Particulate source apportionment (SA) through receptor models is one of the existing tool to quantify contribution of particulate sources. Review of 51 SA studies were performed of which 48 (94%) were appeared within a span of 2007-2016. Almost half of SA studies (55%) were found concentrated over few typical urban stations (Delhi, Dhaka, Mumbai, Agra and Lahore). Due to lack of local particulate source profile and emission inventory, positive matrix factorization and principal component analysis (62% of studies) were the primary choices, followed by chemical mass balance (CMB, 18%). Metallic species were most regularly used as source tracers while use of organic molecular markers and gas-to-particle conversion were minimum. Among all the SA sites, vehicular emissions (mean ± sd: 37 ± 20%) emerged as most dominating PM 2.5 source followed by industrial emissions (23 ± 16%), secondary aerosols (22 ± 12%) and natural sources (20 ± 15%). Vehicular emissions (39 ± 24%) also identified as dominating source for highly polluted sites (PM 2.5 >100 μgm -3 , n = 15) while site specific influence of either or in combination of industrial, secondary aerosols and natural sources were recognized. Source specific trends were considerably varied in terms of region and seasonality. Both natural and industrial sources were most influential over Pakistan and Afghanistan while over Indo-Gangetic plain, vehicular, natural and industrial emissions appeared dominant. Influence of vehicular emission was

  12. New Insights into Ligand-Receptor Pairing and Coevolution of Relaxin Family Peptides and Their Receptors in Teleosts

    PubMed Central

    Good, Sara; Yegorov, Sergey; Martijn, Joran; Franck, Jens; Bogerd, Jan

    2012-01-01

    Relaxin-like peptides (RLN/INSL) play diverse roles in reproductive and neuroendocrine processes in placental mammals and are functionally associated with two distinct types of receptors (RXFP) for each respective function. The diversification of RLN/INSL and RXFP gene families in vertebrates was predominantly driven by whole genome duplications (2R and 3R). Teleosts preferentially retained duplicates of genes putatively involved in neuroendocrine regulation, harboring a total of 10-11 receptors and 6 ligand genes, while most mammals have equal numbers of ligands and receptors. To date, the ligand-receptor relationships of teleost Rln/Insl peptides and their receptors have largely remained unexplored. Here, we use selection analyses based on sequence data from 5 teleosts and qPCR expression data from zebrafish to explore possible ligand-receptor pairings in teleosts. We find support for the hypothesis that, with the exception of RLN, which has undergone strong positive selection in mammalian lineages, the ligand and receptor genes shared between mammals and teleosts appear to have similar pairings. On the other hand, the teleost-specific receptors show evidence of subfunctionalization. Overall, this study underscores the complexity of RLN/INSL and RXFP ligand-receptor interactions in teleosts and establishes theoretical background for further experimental work in nonmammals. PMID:23008798

  13. Testing the Mediating Role of Teachers' Self-Efficacy Beliefs in the Relationship between Sources of Efficacy Information and Students Achievement

    ERIC Educational Resources Information Center

    Mohamadi, Fatemeh Shaterian; Asadzadeh, Hassan

    2012-01-01

    The purpose of this study is to test the mediating role of teachers' self-efficacy beliefs in the relationship between sources of efficacy information and students achievement. For achieving this aim, this study suggests two alternative models, tested by Structural equation modeling (SEM) technique. In the first model, sources of efficacy…

  14. Source apportionment of Baltimore aerosol from combined size distribution and chemical composition data

    NASA Astrophysics Data System (ADS)

    Ogulei, David; Hopke, Philip K.; Zhou, Liming; Patrick Pancras, J.; Nair, Narayanan; Ondov, John M.

    Several multivariate data analysis methods have been applied to a combination of particle size and composition measurements made at the Baltimore Supersite. Partial least squares (PLS) was used to investigate the relationship (linearity) between number concentrations and the measured PM2.5 mass concentrations of chemical species. The data were obtained at the Ponca Street site and consisted of six days' measurements: 6, 7, 8, 18, 19 July, and 21 August 2002. The PLS analysis showed that the covariance between the data could be explained by 10 latent variables (LVs), but only the first four of these were sufficient to establish the linear relationship between the two data sets. More LVs could not make the model better. The four LVs were found to better explain the covariance between the large sized particles and the chemical species. A bilinear receptor model, PMF2, was then used to simultaneously analyze the size distribution and chemical composition data sets. The resolved sources were identified using information from number and mass contributions from each source (source profiles) as well as meteorological data. Twelve sources were identified: oil-fired power plant emissions, secondary nitrate I, local gasoline traffic, coal-fired power plant, secondary nitrate II, secondary sulfate, diesel emissions/bus maintenance, Quebec wildfire episode, nucleation, incinerator, airborne soil/road-way dust, and steel plant emissions. Local sources were mostly characterized by bi-modal number distributions. Regional sources were characterized by transport mode particles (0.2- 0.5μm).

  15. Relationship between organic precursors and N-nitrosodimethylamine (NDMA) formation in tropical water sources.

    PubMed

    Qi, Wang; Fang Yee, Lim; Jiangyong, Hu

    2014-12-01

    The presence of organic compounds in water sources is one of the concerns in water treatment. They are potential precursors of disinfection byproducts (DBPs) and thus induce health problems in humans. Among the emerging DBPs, carcinogenic compound N-nitrosodimethylamine (NDMA) has been receiving attention during the last decade. This study examined the characteristics of organic components in various water sources and investigated their relationships with NDMA formation. Experiments were carried out on selected water samples from both natural water and wastewater. Results showed similar NDMA formation kinetics for both water sources. However, more contribution of NDMA precursors was found to be from the wastewater due to its higher organic nitrogen content. NDMA formation potential (NDMAFP) of secondary effluent ranged from 264 to 530 ng/L. A correlation study between organic compound characteristics and NDMAFP indicated that the majority of NDMA precursors came from dissolved organic nitrogen (DON) compound with small molecular weight (smaller than 500 Da), with correlation R(2) = 0.898. Although secondary treatment removed more than 90% of NDMA precursors, the remaining precursors in secondary effluent would still pose a challenge for water quality.

  16. Analysis of polymorphisms of the vitamin D receptor, estrogen receptor, and collagen Ialpha1 genes and their relationship with height in children with bone cancer.

    PubMed

    Ruza, Elena; Sotillo, Elena; Sierrasesúmaga, Luis; Azcona, Cristina; Patiño-García, Ana

    2003-10-01

    The authors' objectives were to compare height at diagnosis of children with bone tumors with that of Spanish reference children; to analyze the frequency of the genotypes for the polymorphisms of the vitamin D receptor (VDR), estrogen receptor (ER), and collagen Ialpha1 (COLIalpha1) genes in patients and in healthy controls; and to test the relationship between the genetic markers and height. Height and weight at diagnosis were measured in 58 osteosarcoma and 36 Ewing sarcoma patients and compared with standards published for Spanish reference children according to sex and age. For the molecular analysis, genetic polymorphisms of the VDR (Fok I, Apa I, and TaqI), ER (Pvu II and XbaI), and COLIalpha1 (Msc I) genes were characterized in 72 osteosarcoma and 53 Ewing sarcomas and in a group of 143 healthy matched children. Osteosarcoma and Ewing sarcoma patients were significantly taller than Spanish reference children. Osteosarcoma patients showed a significantly higher frequency of the Ff genotype for the Fok I polymorphism (VDR gene) than the control group. The odds ratio for this genotype was 1.78, with an increased relative risk of 78% for heterozygous Ff carriers. Among Ewing sarcoma patients, this same genotype was significantly associated with lower height than homozygotes (FF or ff). Children with bone cancer are significantly taller than the reference population, which may be influenced by the genotype for the Fok I polymorphism of the VDR gene.

  17. Design, synthesis and structure-activity relationship of novel quinoxalin-2-carboxamides as 5-HT3 receptor antagonists for the management of depression.

    PubMed

    Mahesh, Radhakrishnan; Devadoss, Thangaraj; Pandey, Dilip Kumar; Bhatt, Shvetank; Yadav, Shushil Kumar

    2010-11-15

    A novel series of quinoxalin-2-carboxamides were designed based on the ligand-based approach, employing a three-point pharmacophore model; it consists of an aromatic residue and a linking carbonyl group and a basic nitrogen. The target new chemical entities were synthesized from the key intermediate, quinoxalin-2-carboxylic acid, by coupling it with various amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The obtained compounds' structures were confirmed by spectral data. The target new chemical entities were evaluated for their 5-HT(3) receptor antagonisms in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methyl-5-HT, which was expressed in the form of pA(2) value. All the synthesized compounds showed antagonism towards 5-HT(3) receptor; based on this result, a structure-activity relationship was derived, which reveals that the aromatic residue in 5-HT(3) receptor antagonists may have hydrophobic interaction with 5-HT(3) receptor. Regardless of their antagonistic potentials, all the synthesized molecules were screened for their anti-depressant potentials by using forced swim test in mice model; interestingly none of the tested compounds affect the locomotion of mice in the tested dose levels. Compounds with significant pA(2) values exhibited good anti-depressant-like activity as compared to the vehicle-treated group. Copyright © 2010 Elsevier Ltd. All rights reserved.

  18. Isotopic Evidence of Nitrate Sources and its Relationship to Algae in the San Joaquin River, California

    NASA Astrophysics Data System (ADS)

    Silva, S. R.; Kendall, C.; Young, M. B.; Stringfellow, W. T.; Borglin, S. E.; Kratzer, C. R.; Dahlgren, R. A.; Schmidt, C.; Rollog, M. E.

    2007-12-01

    Many competing demands have been placed on the San Joaquin River including deep water shipping, use as agricultural and drinking water, transport of agricultural and urban runoff, and recreation. These long-established demands limit the management options and increase the importance of understanding the river dynamics. The relationships among sources of water, nitrate, and algae in the San Joaquin River must be understood before management decisions can be made to optimize aquatic health. Isotopic analyses of water samples collected along the San Joaquin River in 2005-2007 have proven useful in assessing these relationships: sources of nitrate, the productivity of the San Joaquin River, and the relationship between nitrate and algae in the river. The San Joaquin River receives water locally from wetlands and agricultural return flow, and from three relatively large tributaries whose headwaters are in the Sierra Nevada. The lowest nitrate concentrations occur during periods of high flow when the proportion of water from the Sierra Nevada is relatively large, reflecting the effect of dilution from the big tributaries and indicating that a large fraction of the nitrate is of local origin. Nitrogen isotopes of nitrate in the San Joaquin River are relatively high (averaging about 12 per mil), suggesting a significant source from animal waste or sewage and/or the effects of denitrification. The d15N of nitrate varies inversely with concentration, indicating that these high isotopic values are also a local product. The d15N values of nitrate from most of the local tributaries is lower than that in the San Joaquin suggesting that nitrate from these tributaries does not account for a significant fraction of nitrate in the river. The source of the non-tributary nitrate must be either small unmeasured surface inputs or groundwater. To investigate whether groundwater might be a significant source of nitrate to the San Joaquin River, groundwater samples are being collected

  19. Investigation of Relationship between Sources of Self-Efficacy Beliefs of Secondary School Students and Some Variables

    ERIC Educational Resources Information Center

    Arslan, Ali

    2013-01-01

    The purpose of this study was to investigate the relationship between students' opinions about the sources of self-efficacy belief and their gender, academic achievement, the grade level, Socio-Economic Status (SES), and learning style. The study was conducted on 984 secondary school students in the fall semester of the 2011-2012 academic year.…

  20. Source attribution and credibility of health and appearance exercise advertisements: relationship with implicit and explicit attitudes and intentions.

    PubMed

    Berry, Tanya R; Shields, Chris

    2014-02-01

    The relationship of attributed source (commercial or nonprofit) and credibility of exercise advertisements to explicit and implicit exercise-related attitudes and intentions was examined. Male and female participants (N = 227) were randomly assigned to watch health or appearance-related advertisements and then completed an implicit attitudes task and questionnaires. Health advertisements and those attributed to a nonprofit source were rated more credible. Appearance condition participants who attributed the advertisement to a nonprofit source also rated the advertisement as more credible. Participants who rated a commercial advertisement as credible reported higher implicit instrumental attitudes. Implications for exercise promotion are discussed.

  1. Spatial variability of mercury wet deposition in eastern Ohio: summertime meteorological case study analysis of local source influences

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Emily M. White; Gerald J. Keeler; Matthew S. Landis

    2009-07-01

    Extensive exploration of event precipitation data in the Ohio River Valley indicates that coal combustion emissions play an important role in mercury (Hg) wet deposition. During July-September 2006, an intensive study was undertaken to discern the degree of local source influence. Source-receptor relationships were explored by establishing a set of wet deposition sites in and around Steubenville, Ohio. For the three month period of study, volume-weighted mean Hg concentrations observed at the eight sites ranged from 10.2 to 22.3 ng L{sup -1}, but this range increased drastically on an event basis with a maximum concentration of 89.4 ng L{sup -1}more » and a minimum concentration of 4.1 ng L{sup -1}. A subset of events was explored in depth, and the degree of variability in Hg concentrations between sites was linked to the degree of local source enhancement. Samples collected at sites less than 1 km from coal-fired utility stacks (near-field) exhibited up to 72% enhancement in Hg concentrations over regionally representative samples on an event basis. Air mass transport and precipitating cell histories were traced in order to evaluate relationships between local point sources and receptor sites. It was found that the interaction of several dynamic atmospheric parameters combined to favor local Hg concentration enhancement over the more regional contribution. When significant meteorological factors (wind speed at time of maximum rain rate, wind speed 24 h prior to precipitation, mixing height, and observed ceiling) were explored, it was estimated that during summertime precipitation, 42% of Hg concentration in near-field samples could be attributed to the adjacent coal-fired utility source. 28 refs., 3 figs., 2 tabs.« less

  2. Fine particle receptor modeling in the atmosphere of Mexico City.

    PubMed

    Vega, Elizabeth; Lowenthal, Douglas; Ruiz, Hugo; Reyes, Elizabeth; Watson, John G; Chow, Judith C; Viana, Mar; Querol, Xavier; Alastuey, Andrés

    2009-12-01

    Source apportionment analyses were carried out by means of receptor modeling techniques to determine the contribution of major fine particulate matter (PM2.5) sources found at six sites in Mexico City. Thirty-six source profiles were determined within Mexico City to establish the fingerprints of particulate matter sources. Additionally, the profiles under the same source category were averaged using cluster analysis and the fingerprints of 10 sources were included. Before application of the chemical mass balance (CMB), several tests were carried out to determine the best combination of source profiles and species used for the fitting. CMB results showed significant spatial variations in source contributions among the six sites that are influenced by local soil types and land use. On average, 24-hr PM2.5 concentrations were dominated by mobile source emissions (45%), followed by secondary inorganic aerosols (16%) and geological material (17%). Industrial emissions representing oil combustion and incineration contributed less than 5%, and their contribution was higher at the industrial areas of Tlalnepantla (11%) and Xalostoc (8%). Other sources such as cooking, biomass burning, and oil fuel combustion were identified at lower levels. A second receptor model (principal component analysis, [PCA]) was subsequently applied to three of the monitoring sites for comparison purposes. Although differences were obtained between source contributions, results evidence the advantages of the combined use of different receptor modeling techniques for source apportionment, given the complementary nature of their results. Further research is needed in this direction to reach a better agreement between the estimated source contributions to the particulate matter mass.

  3. The Relationship Between the Renin-Angiotensin-Aldosterone System and NMDA Receptor-Mediated Signal and the Prevention of Retinal Ganglion Cell Death.

    PubMed

    Kobayashi, Mamoru; Hirooka, Kazuyuki; Ono, Aoi; Nakano, Yuki; Nishiyama, Akira; Tsujikawa, Akitaka

    2017-03-01

    Excitotoxicity, which is due to glutamate-induced toxic effects on the retinal ganglion cell (RGC), is one of several mechanisms of RGC loss. The renin-angiotensin-aldosterone system (RAAS) has also been implicated in RGC death. Therefore, it is important to determine the exact relationship between the RAAS and N-methyl-d-aspartate (NMDA) receptor-mediated signal in order to prevent RGC death. N-methyl-d-aspartate or aldosterone was injected into the vitreous body. After intravitreal injection of NMDA or aldosterone, animals were treated with spironolactone or memantine. Retinal damage was evaluated by measuring the number of RGCs at 4 weeks after local administration of aldosterone or at 2 weeks after local administration of NMDA. Vitreous humor levels of aldosterone were measured using enzyme immunoassay kits. A significantly decreased number of RGCs were observed after intravitreal injection of NMDA. Although spironolactone did not show any neuroprotective effects, memantine significantly reduced NMDA-induced degeneration in the retina. Furthermore, a significant decrease in the number of RGCs was observed after an intravitreal injection of aldosterone. While memantine did not exhibit any neuroprotective effects, spironolactone caused a significant reduction in the aldosterone-induced degeneration in the retina. There was no change in the aldosterone concentration in the vitreous humor after an NMDA injection. Our findings indirectly show that there is no relationship between the RAAS and NMDA receptor-mediated signal with regard to RGC death.

  4. The anatomy of mammalian sweet taste receptors.

    PubMed

    Chéron, Jean-Baptiste; Golebiowski, Jérôme; Antonczak, Serge; Fiorucci, Sébastien

    2017-02-01

    All sweet-tasting compounds are detected by a single G-protein coupled receptor (GPCR), the heterodimer T1R2-T1R3, for which no experimental structure is available. The sweet taste receptor is a class C GPCR, and the recently published crystallographic structures of metabotropic glutamate receptor (mGluR) 1 and 5 provide a significant step forward for understanding structure-function relationships within this family. In this article, we recapitulate more than 600 single point site-directed mutations and available structural data to obtain a critical alignment of the sweet taste receptor sequences with respect to other class C GPCRs. Using this alignment, a homology 3D-model of the human sweet taste receptor is built and analyzed to dissect out the role of key residues involved in ligand binding and those responsible for receptor activation. Proteins 2017; 85:332-341. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors.

    PubMed Central

    Bacus, S. S.; Chin, D.; Yarden, Y.; Zelnick, C. R.; Stern, D. F.

    1996-01-01

    The neu/erbB-2/HER-2 proto-oncogene is amplified and/or overexpressed in up to 30% of mammary carcinomas and has been variably correlated with poor prognosis. The signaling activity of the encoded receptor tyrosine kinase is regulated by interactions with other type 1 receptors and their ligands. We have used a novel approach, phosphorylation-sensitive anti-Neu antibodies, to quantify signaling by Neu and epidermal growth factor receptor in a panel of frozen sections of mammary carcinoma specimens. We also determined the relationship of Neu, phosphorylated Neu (and epidermal growth factor receptor), and phosphotyrosine to the expression of Neu-related receptors (epidermal growth factor receptor, HER-3, and HER-4) and to prognostic factors (estrogen and progesterone receptor). We found that tyrosine phosphorylation of Neu (and hence signaling activity) is highly variable among mammary carcinomas. Neu and HER-4 were associated with divergent correlates, suggesting that they have profoundly different biological activities. These results have implications for etiology of mammary carcinoma for clinical evaluation of mammary carcinoma patients, and for development of Neu-targeted therapeutic strategies. Images Figure 1 Figure 2 PMID:8579117

  6. A sea lamprey glycoprotein hormone receptor similar with gnathostome thyrotropin hormone receptor.

    PubMed

    Freamat, Mihael; Sower, Stacia A

    2008-10-01

    The specificity of the vertebrate hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid axes is explained by the evolutionary refinement of the specificity of expression and selectivity of interaction between the glycoprotein hormones GpH (FSH, LH, and TSH) and their cognate receptors GpH-R (FSH-R, LH-R, and TSH-R). These two finely tuned signaling pathways evolved by gene duplication and functional divergence from an ancestral GpH/GpH-R pair. Comparative analysis of the protochordate and gnathostome endocrine systems suggests that this process took place prior or concomitantly with the emergence of the gnathostome lineage. Here, we report identification and characterization of a novel glycoprotein hormone receptor (lGpH-R II) in the Agnathan sea lamprey. This 781 residue protein was found approximately 43% identical with mammalian TSH-R and FSH-R representative sequences, and similarly with these two classes of mammalian receptors it is assembled from ten exons. A synthetic ligand containing the lamprey glycoprotein hormone beta-chain tethered upstream of a mammalian alpha-chain activated the lGpH-R II expressed in COS-7 cells but in a lesser extent than lGpH-R I. Molecular phylogenetic analysis of vertebrate GpH-R protein sequences suggests a closer relationship between lGpH-R II and gnathostome thyrotropin receptors. Overall, the presence and characteristics of the lamprey glycoprotein hormone receptors suggest existence of a primitive functionally overlapping glycoprotein hormone/glycoprotein hormone receptor system in this animal.

  7. Characterization of the relationship between ceramic pot filter water production and turbidity in source water.

    PubMed

    Salvinelli, Carlo; Elmore, A Curt; Reidmeyer, Mary R; Drake, K David; Ahmad, Khaldoun I

    2016-11-01

    Ceramic pot filters represent a common and effective household water treatment technology in developing countries, but factors impacting water production rate are not well-known. Turbidity of source water may be principal indicator in characterizing the filter's lifetime in terms of water production capacity. A flow rate study was conducted by creating four controlled scenarios with different turbidities, and influent and effluent water samples were tested for total suspended solids and particle size distribution. A relationship between average flow rate and turbidity was identified with a negative linear trend of 50 mLh -1 /NTU. Also, a positive linear relationship was found between the initial flow rate of the filters and average flow rate calculated over the 23 day life of the experiment. Therefore, it was possible to establish a method to estimate the average flow rate given the initial flow rate and the turbidity in the influent water source, and to back calculate the maximum average turbidity that would need to be maintained in order to achieve a specific average flow rate. However, long-term investigations should be conducted to assess how these relationships change over the expected CPF lifetime. CPFs rejected fine suspended particles (below 75 μm), especially particles with diameters between 0.375 μm and 10 μm. The results confirmed that ceramic pot filters are able to effectively reduce turbidity, but pretreatment of influent water should be performed to avoid premature failure. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. The relationship of plasma decoy receptor 3 and coronary collateral circulation in patients with coronary artery disease.

    PubMed

    Yan, Youyou; Song, Dandan; Liu, Lulu; Meng, Xiuping; Qi, Chao; Wang, Junnan

    2017-11-15

    Previously, decoy receptor 3 (DcR3) was found to be a potential angiogenetic factor, while the relationship of DcR3 with coronary collateral circulation formation has not been investigated. In this study, we aimed to investigate whether plasma decoy receptor 3 levels was associated with CCC formation and evaluate its predictive power for CCC status in patients with coronary artery disease. Among patients who underwent coronary angiography with coronary artery disease and had a stenosis of ≥90% were included in our study. Collateral degree was graded according to Rentrope Cohen classification. Patients with grade 2 or 3 collateral degree were enrolled in good CCC group and patients with grade 0 or 1 collateral degree were enrolled in poor CCC group. Plasma DcR3 level was significantly higher in good CCC group (328.00±230.82 vs 194.84±130.63ng/l, p<0.01) and positively correlated with Rentrope grade (p<0.01). In addition, plasma DcR3 was also positively correlated with VEGF-A. Both ROC (receiver operating characteristic curve) and multinomial logistical regression analysis showed that plasma DcR3 displayed potent predictive power for CCC status. Higher plasma DcR3 level was related to better CCC formation and displayed potent predictive power for CCC status. Copyright © 2017. Published by Elsevier Inc.

  9. The G protein-coupled receptors deorphanization landscape.

    PubMed

    Laschet, Céline; Dupuis, Nadine; Hanson, Julien

    2018-07-01

    G protein-coupled receptors (GPCRs) are usually highlighted as being both the largest family of membrane proteins and the most productive source of drug targets. However, most of the GPCRs are understudied and hence cannot be used immediately for innovative therapeutic strategies. Besides, there are still around 100 orphan receptors, with no described endogenous ligand and no clearly defined function. The race to discover new ligands for these elusive receptors seems to be less intense than before. Here, we present an update of the various strategies employed to assign a function to these receptors and to discover new ligands. We focus on the recent advances in the identification of endogenous ligands with a detailed description of newly deorphanized receptors. Replication being a key parameter in these endeavors, we also discuss the latest controversies about problematic ligand-receptor pairings. In this context, we propose several recommendations in order to strengthen the reporting of new ligand-receptor pairs. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Overview of the Mathematical and Empirical Receptor Models Workshop (Quail Roost II)

    NASA Astrophysics Data System (ADS)

    Stevens, Robert K.; Pace, Thompson G.

    On 14-17 March 1982, the U.S. Environmental Protection Agency sponsored the Mathematical and Empirical Receptor Models Workshop (Quail Roost II) at the Quail Roost Conference Center, Rougemont, NC. Thirty-five scientists were invited to participate. The objective of the workshop was to document and compare results of source apportionment analyses of simulated and real aerosol data sets. The simulated data set was developed by scientists from the National Bureau of Standards. It consisted of elemental mass data generated using a dispersion model that simulated transport of aerosols from a variety of sources to a receptor site. The real data set contained the mass, elemental, and ionic species concentrations of samples obtained in 18 consecutive 12-h sampling periods in Houston, TX. Some participants performed additional analyses of the Houston filters by X-ray powder diffraction, scanning electron microscopy, or light microscopy. Ten groups analyzed these data sets using a variety of modeling procedures. The results of the modeling exercises were evaluated and structured in a manner that permitted model intercomparisons. The major conclusions and recommendations derived from the intercomparisons were: (1) using aerosol elemental composition data, receptor models can resolve major emission sources, but additional analyses (including light microscopy and X-ray diffraction) significantly increase the number of sources that can be resolved; (2) simulated data sets that contain up to 6 dissimilar emission sources need to be generated, so that different receptor models can be adequately compared; (3) source apportionment methods need to be modified to incorporate a means of apportioning such aerosol species as sulfate and nitrate formed from SO 2 and NO, respectively, because current models tend to resolve particles into chemical species rather than to deduce their sources and (4) a source signature library may be required to be compiled for each airshed in order to

  11. Decahydrobenzoquinolin-5-one sigma receptor ligands: Divergent development of both sigma 1 and sigma 2 receptor selective examples.

    PubMed

    McLeod, Michael C; Aubé, Jeffrey; Frankowski, Kevin J

    2016-12-01

    Analogues of the decahydrobenzoquinolin-5-one class of sigma (σ) receptor ligands were used to probe the structure-activity relationship trends for this recently discovered series of σ ligands. In all, 29 representatives were tested for σ and opioid receptor affinity, leading to the identification of compounds possessing improved σ 1 selectivity and, for the first time in this series, examples possessing preferential σ 2 affinity. Several structural features associated with these selectivity trends have been identified. Two analogues of improved selectivity were evaluated in a binding panel of 43 CNS-relevant targets to confirm their sigma receptor preference. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Relationship of neuropeptide FF receptors with pubertal maturation of gilts

    USDA-ARS?s Scientific Manuscript database

    Mechanisms governing the timing of puberty in pigs are poorly understood. A genome-wide association study for age at first estrus in pigs identified candidate genes including NPFFR2, which is a putative receptor for RFamide-related peptides (RFRP). RFRP has been shown to negatively regulate secret...

  13. The Relationship between Sources and Functions of Social Support and Dimensions of Child- and Parent-Related Stress

    ERIC Educational Resources Information Center

    Guralnick, M. J.; Hammond, M. A.; Neville, B.; Connor, R. T.

    2008-01-01

    Background: In this longitudinal study, we examined the relationship between the sources and functions of social support and dimensions of child- and parent-related stress for mothers of young children with mild developmental delays. Methods: Sixty-three mothers completed assessments of stress and support at two time points. Results: Multiple…

  14. Homology Models of Melatonin Receptors: Challenges and Recent Advances

    PubMed Central

    Pala, Daniele; Lodola, Alessio; Bedini, Annalida; Spadoni, Gilberto; Rivara, Silvia

    2013-01-01

    Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore models. The ability of these ligand-receptor complexes to rationalize structure-activity relationships of known series of melatonergic compounds will be commented upon. PMID:23584026

  15. Serotonin and brain function: a tale of two receptors.

    PubMed

    Carhart-Harris, R L; Nutt, D J

    2017-09-01

    Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

  16. Serotonin and brain function: a tale of two receptors

    PubMed Central

    Carhart-Harris, RL; Nutt, DJ

    2017-01-01

    Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes. PMID:28858536

  17. Relationship between strong-motion array parameters and the accuracy of source inversion and physical waves

    USGS Publications Warehouse

    Iida, M.; Miyatake, T.; Shimazaki, K.

    1990-01-01

    We develop general rules for a strong-motion array layout on the basis of our method of applying a prediction analysis to a source inversion scheme. A systematic analysis is done to obtain a relationship between fault-array parameters and the accuracy of a source inversion. Our study of the effects of various physical waves indicates that surface waves at distant stations contribute significantly to the inversion accuracy for the inclined fault plane, whereas only far-field body waves at both small and large distances contribute to the inversion accuracy for the vertical fault, which produces more phase interference. These observations imply the adequacy of the half-space approximation used throughout our present study and suggest rules for actual array designs. -from Authors

  18. Estrogen receptor (ER) and progesterone receptor (PgR) in breast cancer of Indian women

    PubMed Central

    Patil, Amit V; Bhamre, Rahul S; Singhai, Rajeev; Tayade, Mukund B; Patil, Vinayak W

    2011-01-01

    Objective To determine the expressions and relationship between estrogen receptors (ERs) and progesterone receptors (PgRs) in breast cancer in Indian women. Participants Surgically removed breast cancer tissues were collected from Grant Medical College and Sir JJ Group of Hospitals, Mumbai, India, taking (n = 300) cases of infiltrating duct cancer of Indian women after radical mastectomy and lumpectomy; the age- and menopausal-related subgroups satisfied this requirement. Measurements Statistical significance was calculated by the likelihood ratio test; relative risk served to check for significant differences. Relapse-free interval probabilities were calculated according to Kaplan and Meier, with Cox–Mantel test comparing survival functions and P values. Results We observed that only in middle-aged postmenopausal patients bearing pT2 tumors were ER and PgR receptors shown to have a prognostic significance with the lowest tested cutoff value being 5 fmol/mg. Conclusion Immunohistochemistry analysis has been shown to be a prognostic factor for patients with breast cancer; the major aim of determining the ER receptor status is to assess predictive response to hormonal therapy. PMID:24367174

  19. Hormonal receptors and vascular endothelial growth factor in juvenile nasopharyngeal angiofibroma: immunohistochemical and tissue microarray analysis.

    PubMed

    Liu, Zhuofu; Wang, Jingjing; Wang, Huan; Wang, Dehui; Hu, Li; Liu, Quan; Sun, Xicai

    2015-01-01

    This work demonstrated that juvenile nasopharyngeal angiofibromas (JNAs) express high levels of hormone receptors and vascular endothelial growth factor (VEGF) compared with normal nasal mucosa. The interaction between hormone receptors and VEGF may be involved in the initiation and growth of JNA. JNA is a rare benign tumor that occurs almost exclusively in male adolescents. Although generally regarded as a hormone-dependent tumor, this has not been proven in previous studies. The aim of this study was to investigate the role of hormone receptors in JNA and the relationship with clinical characteristics. Standard immunohistochemical microarray analysis was performed on 70 JNA samples and 10 turbinate tissue samples. Specific antibodies for androgen receptor (AR), estrogen receptor-α (ER-α), estrogen receptor-β (ER-β), progesterone receptor (PR), and VEGF were examined, and the relationships of receptor expression with age, tumor stage, and bleeding were evaluated. RESULTS showed that JNA expressed ER-α (92.9%), ER-β (91.4%), AR (65.7%), PR (12.8%), and VEGF (95.7%) at different levels. High level of VEGF was linked to elevated ER-α and ER-β. There was no significant relationship between hormonal receptors and age at diagnosis, tumor stage or bleeding. However, overexpression of ER-α was found to be an indicator of poor prognosis (p = 0.031).

  20. Identification of Complete Repertoire of Apis florea Odorant Receptors Reveals Complex Orthologous Relationships with Apis mellifera

    PubMed Central

    Karpe, Snehal D.; Jain, Rikesh; Brockmann, Axel; Sowdhamini, Ramanathan

    2016-01-01

    Abstract We developed a computational pipeline for homology based identification of the complete repertoire of olfactory receptor (OR) genes in the Asian honey bee species, Apis florea. Apis florea is phylogenetically the most basal honey bee species and also the most distant sister species to the Western honey bee Apis mellifera, for which all OR genes had been identified before. Using our pipeline, we identified 180 OR genes in A. florea, which is very similar to the number of ORs identified in A. mellifera (177 ORs). Many characteristics of the ORs including gene structure, synteny of tandemly repeated ORs and basic phylogenetic clustering are highly conserved. The composite phylogenetic tree of A. florea and A. mellifera ORs could be divided into 21 clades which are in harmony with the existing Hymenopteran tree. However, we found a few nonorthologous OR relationships between both species as well as independent pseudogenization of ORs suggesting separate evolutionary changes. Particularly, a subgroup of the OR gene clade XI, which had been hypothesized to code cuticular hydrocarbon receptors showed a high number of species-specific ORs. RNAseq analysis detected a total number of 145 OR transcripts in male and 162 in female antennae. Most of the OR genes were highly expressed on the female antennae. However, we detected five distinct male-biased OR genes, out of which three genes (AfOr11, AfOr18, AfOr170P) were shown to be male-biased in A. mellifera, too, thus corroborating a behavioral function in sex-pheromone communication. PMID:27540087

  1. Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies.

    PubMed

    Istyastono, Enade P; Nijmeijer, Saskia; Lim, Herman D; van de Stolpe, Andrea; Roumen, Luc; Kooistra, Albert J; Vischer, Henry F; de Esch, Iwan J P; Leurs, Rob; de Graaf, Chris

    2011-12-08

    The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes.

  2. GPR30: A G protein-coupled receptor for estrogen.

    PubMed

    Prossnitz, Eric R; Arterburn, Jeffrey B; Sklar, Larry A

    2007-02-01

    Estrogen is a critical steroid in human physiology exerting its effect both at the transcriptional level as well as at the level of rapid intracellular signaling through second messengers. Many of estrogen's transcriptional effects have long been known to be mediated through classical nuclear steroid receptors but recent studies also demonstrate the existence of a 7-transmembrane G protein-coupled receptor, GPR30 that responds to estrogen with rapid cellular signaling. There is currently controversy over the ability of classical estrogen receptors to recapitulate GPR30-mediated signaling mechanisms and vice versa. This article will summarize recent literature and address the relationship between GPR30 and conventional estrogen receptor signaling.

  3. Are gas exchange responses to resource limitation and defoliation linked to source:sink relationships?

    PubMed

    Pinkard, E A; Eyles, A; O'Grady, A P

    2011-10-01

    Productivity of trees can be affected by limitations in resources such as water and nutrients, and herbivory. However, there is little understanding of their interactive effects on carbon uptake and growth. We hypothesized that: (1) in the absence of defoliation, photosynthetic rate and leaf respiration would be governed by limiting resource(s) and their impact on sink limitation; (2) photosynthetic responses to defoliation would be a consequence of changing source:sink relationships and increased availability of limiting resources; and (3) photosynthesis and leaf respiration would be adjusted in response to limiting resources and defoliation so that growth could be maintained. We tested these hypotheses by examining how leaf photosynthetic processes, respiration, carbohydrate concentrations and growth rates of Eucalyptus globulus were influenced by high or low water and nitrogen (N) availability, and/or defoliation. Photosynthesis of saplings grown with low water was primarily sink limited, whereas photosynthetic responses of saplings grown with low N were suggestive of source limitation. Defoliation resulted in source limitation. Net photosynthetic responses to defoliation were linked to the degree of resource availability, with the largest responses measured in treatments where saplings were ultimately source rather than sink limited. There was good evidence of acclimation to stress, enabling higher rates of C uptake than might otherwise have occurred. © 2011 Blackwell Publishing Ltd.

  4. Structure-function relationship in the binding of snake neurotoxins to the torpedo membrane receptor.

    PubMed

    Chicheportiche, R; Vincent, J P; Kopeyan, C; Schweitz, H; Lazdunski, M

    1975-05-20

    The Cys30-Cus34 bridge present in all long neutotoxins (71-74 amino acids, 5 disulfide bridges), but not in short toxins (60-63 amino acids, 4 disulfide bridges), is exposed at the surface since it can be reduced rapidly and selectively by sodium borohydride. Reduction and alkylation of the Cys30-Cys34 bridge of Naja haje neurotoxin III hardly alter the conformational properties of this model long toxin. Although alkylation by iodoacetic acid of th -SH groups liberated by reduction abolishes the toxicity, alkylation by iodoacetamide or ethylenimine does not affect the curarizing efficacy of the toxin. The Cys30-Cys34 bridge is not very important for the toxic activity of long neurotoxins. Reduction of the Cys30-Cys34 bridge followed by alkylation with radioactive iodoacetamide gave a labeled and active toxin which is a convenient derivative for binding experiments to the toxin receptor in membranes of the Torpedo electric organ. The binding capacity of these membrane is 1200 pmol of toxin/mg of membrane protein. The dissociation constant of the modified toxin-receptor complex at pH 7.4, 20 degrees is 10 minus 8m. Reduction with carbroxamidomethylation of the Cys30-Cys34 bridge decreases the affinity of the native Naja haje toxin only by a factor of 15. Carboxymethylation after reduction prevents binding to the membrane receptor. The binding properties of the derivative obtained by reduction and aminoethylation of Cys30-Cys34 are very similar to those of native neurotoxin III; the affinity is decreased only by a factor of 5. Binding properties to Toredo membrane of long neurotoxins (Naja haje neurotoxin III) and short neurotoxins (Naje haje toxin I and Naja mossambica toxin I) have been compared. Dissociation constants of receptor-long neurotoxin and receptor-short neurotoxin complexes are very similar (5.7 minus 8.2 times 10(-10) M at pH 7.4, 20degrees. However, the kinetics of complex formation and complex dissociation are quite different. Short neurotoxins

  5. Nitrogen and carbon source-sink relationships in trees at the Himalayan treelines compared with lower elevations.

    PubMed

    Li, Mai-He; Xiao, Wen-Fa; Shi, Peili; Wang, San-Gen; Zhong, Yong-De; Liu, Xing-Liang; Wang, Xiao-Dan; Cai, Xiao-Hu; Shi, Zuo-Min

    2008-10-01

    No single hypothesis or theory has been widely accepted for explaining the functional mechanism of global alpine/arctic treeline formation. The present study tested whether the alpine treeline is determined by (1) the needle nitrogen content associated with photosynthesis (carbon gain); (2) a sufficient source-sink ratio of carbon; or (3) a sufficient C-N ratio. Nitrogen does not limit the growth and development of trees studied at the Himalayan treelines. Levels of non-structural carbohydrates (NSC) in trees were species-specific and site-dependent; therefore, the treeline cases studied did not show consistent evidence of source/carbon limitation or sink/growth limitation in treeline trees. However, results of the combined three treelines showed that the treeline trees may suffer from a winter carbon shortage. The source capacity and the sink capacity of a tree influence its tissue NSC concentrations and the carbon balance; therefore, we suggest that the persistence and development of treeline trees in a harsh alpine environment may require a minimum level of the total NSC concentration, a sufficiently high sugar:starch ratio, and a balanced carbon source-sink relationship.

  6. The relationship between dopamine receptor blockade and cognitive performance in schizophrenia: a [11C]-raclopride PET study with aripiprazole.

    PubMed

    Shin, Sangho; Kim, Seoyoung; Seo, Seongho; Lee, Jae Sung; Howes, Oliver D; Kim, Euitae; Kwon, Jun Soo

    2018-04-24

    Aripiprazole's effects on cognitive function in patients with schizophrenia are unclear because of the difficulty in disentangling specific effects on cognitive function from secondary effects due to the improvement in other schizophrenic symptoms. One approach to address this is to use an intermediate biomarker to investigate the relationship between the drug's effect on the brain and change in cognitive function. This study aims to investigate aripiprazole's effect on working memory by determining the correlation between dopamine D2/3 (D2/3) receptor occupancy and working memory of patients with schizophrenia. Seven patients with schizophrenia participated in the study. Serial positron emission tomography (PET) scans with [ 11 C]raclopride were conducted at 2, 26, and 74 h after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [ 11 C]raclopride PET scan. The mean (±SD) D2/3 receptor occupancies were 66.9 ± 6.7% at 2 h, 65.0 ± 8.6% at 26, and 57.7 ± 11.2% at 74 h after administering aripiprazole. Compared with performance on the zero-back condition, performance in memory-loaded conditions (one-, two-, and three-back conditions) was significantly related to D2/3 receptor occupancy by aripiprazole (error rate: ß = -2.236, t = -6.631, df = 53.947, and p = 0.001; reaction time: ß = -9.567, t = -2.808, df = 29.967, and p = 0.009). Although the sample size was relatively small, these results suggest that aripiprazole as a dopamine-partial agonist could improve cognitive function in patients with schizophrenia.

  7. Orexin A/Hypocretin Modulates Leptin Receptor-Mediated Signaling by Allosteric Modulations Mediated by the Ghrelin GHS-R1A Receptor in Hypothalamic Neurons.

    PubMed

    Medrano, Mireia; Aguinaga, David; Reyes-Resina, Irene; Canela, Enric I; Mallol, Josefa; Navarro, Gemma; Franco, Rafael

    2018-06-01

    The hypothalamus is a key integrator of nutrient-seeking signals in the form of hormones and metabolites originated in both the central nervous system and the periphery. The main autocrine and paracrine target of orexinergic-related hormones such as leptin, orexin/hypocretin, and ghrelin are neuropeptide Y neurons located in the arcuate nucleus of the hypothalamus. The aim of this study was to investigate the expression and the molecular and functional relationships between leptin, orexin/hypocretin and ghrelin receptors. Biophysical studies in a heterologous system showed physical interactions between them, with potential formation of heterotrimeric complexes. Functional assays showed robust allosteric interactions particularly different when the three receptors are expressed together. Further biochemical and pharmacological assays provided evidence of heterotrimer functional expression in primary cultures of hypothalamic neurons. These findings constitute evidence of close relationships in the action of the three hormones already starting at the receptor level in hypothalamic cells.

  8. Impact of local and non-local sources of pollution on background US Ozone: synergy of a low-earth orbiting and geostationary sounder constellation

    NASA Astrophysics Data System (ADS)

    Bowman, K. W.; Lee, M.

    2015-12-01

    Dramatic changes in the global distribution of emissions over the last decade have fundamentally altered source-receptor pollution impacts. A new generation of low-earth orbiting (LEO) sounders complimented by geostationary sounders over North America, Europe, and Asia providing a unique opportunity to quantify the current and future trajectory of emissions and their impact on global pollution. We examine the potential of this constellation of air quality sounders to quantify the role of local and non-local sources of pollution on background ozone in the US. Based upon an adjoint sensitivity method, we quantify the role synoptic scale transport of non-US pollution on US background ozone over months representative of different source-receptor relationships. This analysis allows us distinguish emission trajectories from megacities, e.g. Beijing, or regions, e.g., western China, from natural trends on downwind ozone. We subsequently explore how a combination of LEO and GEO observations could help quantify the balance of local emissions against changes in distant sources . These results show how this unprecedented new international ozone observing system can monitor the changing structure of emissions and their impact on global pollution.

  9. Structural and Molecular Modeling Features of P2X Receptors

    PubMed Central

    Alves, Luiz Anastacio; da Silva, João Herminio Martins; Ferreira, Dinarte Neto Moreira; Fidalgo-Neto, Antonio Augusto; Teixeira, Pedro Celso Nogueira; de Souza, Cristina Alves Magalhães; Caffarena, Ernesto Raúl; de Freitas, Mônica Santos

    2014-01-01

    Currently, adenosine 5′-triphosphate (ATP) is recognized as the extracellular messenger that acts through P2 receptors. P2 receptors are divided into two subtypes: P2Y metabotropic receptors and P2X ionotropic receptors, both of which are found in virtually all mammalian cell types studied. Due to the difficulty in studying membrane protein structures by X-ray crystallography or NMR techniques, there is little information about these structures available in the literature. Two structures of the P2X4 receptor in truncated form have been solved by crystallography. Molecular modeling has proven to be an excellent tool for studying ionotropic receptors. Recently, modeling studies carried out on P2X receptors have advanced our knowledge of the P2X receptor structure-function relationships. This review presents a brief history of ion channel structural studies and shows how modeling approaches can be used to address relevant questions about P2X receptors. PMID:24637936

  10. New ligands for melanocortin receptors.

    PubMed

    Kaelin, C B; Candille, S I; Yu, B; Jackson, P; Thompson, D A; Nix, M A; Binkley, J; Millhauser, G L; Barsh, G S

    2008-12-01

    Named originally for their effects on peripheral end organs, the melanocortin system controls a diverse set of physiological processes through a series of five G-protein-coupled receptors and several sets of small peptide ligands. The central melanocortin system plays an essential role in homeostatic regulation of body weight, in which two alternative ligands, alpha-melanocyte-stimulating hormone and agouti-related protein, stimulate and inhibit receptor signaling in several key brain regions that ultimately affect food intake and energy expenditure. Much of what we know about the relationship between central melanocortin signaling and body weight regulation stems from genetic studies. Comparative genomic studies indicate that melanocortin receptors used for controlling pigmentation and body weight regulation existed more than 500 million years ago in primitive vertebrates, but that fine-grained control of melanocortin receptors through neuropeptides and endogenous antagonists developed more recently. Recent studies based on dog coat-color genetics revealed a new class of melanocortin ligands, the beta-defensins, which reveal the potential for cross talk between the melanocortin and the immune systems.

  11. Source Attribution of Tropospheric Ozone using a Global Model

    NASA Astrophysics Data System (ADS)

    Coates, J.; Lupascu, A.; Butler, T. M.; Zhu, S.

    2016-12-01

    Tropospheric ozone is both a short-lived climate forcing pollutant and a radiatively active greenhouse gas. Ozone is not directly emitted into the troposphere but photochemically produced from chemical reactions involving nitrogen oxides (NOx) and volatile organic compounds (VOCs). Emissions of ozone precursors (NOx and VOCs) have both natural and anthropogenic sources and may be transported away from their sources to produce ozone downwind. Also, transport of ozone from the stratosphere into the troposphere also influences tropospheric ozone levels in some regions. Attributing ozone concentrations to the contributions from different sources would indicate the effects of locally emitted or transported precursors on ozone levels in specific regions. This information could be used to inform the emission reduction strategies of ozone precursors by indicating which emission sources could be targeted for effective reductions thus reducing the burden of ozone pollution. We use a "tagging" approach within the CESM global model to attribute ozone levels to their source emissions. We use different tags to quantify the impact from natural (soils, lightning, stratospheric transport) and anthropogenic (aircraft, biomass burning) sources of NOx and VOCs (including methane) on ozone levels. These source sectors of different global regions are assigned based on the global emissions specified by HTAPv2.2. Using these results, we develop a transboundary source-receptor relationship of ozone concentration to its precursor emission regions. Additionally, the transport of ozone precursors from regional anthropogenic sources is analysed to illustrate the extent to which mitigation strategies of regional emissions aid in mitigating global ozone levels.

  12. High throughput mutagenesis for identification of residues regulating human prostacyclin (hIP) receptor expression and function.

    PubMed

    Bill, Anke; Rosethorne, Elizabeth M; Kent, Toby C; Fawcett, Lindsay; Burchell, Lynn; van Diepen, Michiel T; Marelli, Anthony; Batalov, Sergey; Miraglia, Loren; Orth, Anthony P; Renaud, Nicole A; Charlton, Steven J; Gosling, Martin; Gaither, L Alex; Groot-Kormelink, Paul J

    2014-01-01

    The human prostacyclin receptor (hIP receptor) is a seven-transmembrane G protein-coupled receptor (GPCR) that plays a critical role in vascular smooth muscle relaxation and platelet aggregation. hIP receptor dysfunction has been implicated in numerous cardiovascular abnormalities, including myocardial infarction, hypertension, thrombosis and atherosclerosis. Genomic sequencing has discovered several genetic variations in the PTGIR gene coding for hIP receptor, however, its structure-function relationship has not been sufficiently explored. Here we set out to investigate the applicability of high throughput random mutagenesis to study the structure-function relationship of hIP receptor. While chemical mutagenesis was not suitable to generate a mutagenesis library with sufficient coverage, our data demonstrate error-prone PCR (epPCR) mediated mutagenesis as a valuable method for the unbiased screening of residues regulating hIP receptor function and expression. Here we describe the generation and functional characterization of an epPCR derived mutagenesis library compromising >4000 mutants of the hIP receptor. We introduce next generation sequencing as a useful tool to validate the quality of mutagenesis libraries by providing information about the coverage, mutation rate and mutational bias. We identified 18 mutants of the hIP receptor that were expressed at the cell surface, but demonstrated impaired receptor function. A total of 38 non-synonymous mutations were identified within the coding region of the hIP receptor, mapping to 36 distinct residues, including several mutations previously reported to affect the signaling of the hIP receptor. Thus, our data demonstrates epPCR mediated random mutagenesis as a valuable and practical method to study the structure-function relationship of GPCRs.

  13. High Throughput Mutagenesis for Identification of Residues Regulating Human Prostacyclin (hIP) Receptor Expression and Function

    PubMed Central

    Kent, Toby C.; Fawcett, Lindsay; Burchell, Lynn; van Diepen, Michiel T.; Marelli, Anthony; Batalov, Sergey; Miraglia, Loren; Orth, Anthony P.; Renaud, Nicole A.; Charlton, Steven J.; Gosling, Martin; Gaither, L. Alex; Groot-Kormelink, Paul J.

    2014-01-01

    The human prostacyclin receptor (hIP receptor) is a seven-transmembrane G protein-coupled receptor (GPCR) that plays a critical role in vascular smooth muscle relaxation and platelet aggregation. hIP receptor dysfunction has been implicated in numerous cardiovascular abnormalities, including myocardial infarction, hypertension, thrombosis and atherosclerosis. Genomic sequencing has discovered several genetic variations in the PTGIR gene coding for hIP receptor, however, its structure-function relationship has not been sufficiently explored. Here we set out to investigate the applicability of high throughput random mutagenesis to study the structure-function relationship of hIP receptor. While chemical mutagenesis was not suitable to generate a mutagenesis library with sufficient coverage, our data demonstrate error-prone PCR (epPCR) mediated mutagenesis as a valuable method for the unbiased screening of residues regulating hIP receptor function and expression. Here we describe the generation and functional characterization of an epPCR derived mutagenesis library compromising >4000 mutants of the hIP receptor. We introduce next generation sequencing as a useful tool to validate the quality of mutagenesis libraries by providing information about the coverage, mutation rate and mutational bias. We identified 18 mutants of the hIP receptor that were expressed at the cell surface, but demonstrated impaired receptor function. A total of 38 non-synonymous mutations were identified within the coding region of the hIP receptor, mapping to 36 distinct residues, including several mutations previously reported to affect the signaling of the hIP receptor. Thus, our data demonstrates epPCR mediated random mutagenesis as a valuable and practical method to study the structure-function relationship of GPCRs. PMID:24886841

  14. The Entry of Colombian-Sourced Heroin into the US Market: The Relationship between Competition, Price, and Purity

    PubMed Central

    Rosenblum, Daniel; Unick, Jay; Ciccarone, Daniel

    2013-01-01

    There have been large structural changes in the US heroin market over the past 20 years. Colombian-sourced heroin entered the market in the mid-1990s, followed by a large fall in the price per pure gram and the exit of Asian heroin. By the 2000s, Colombian-sourced heroin had become a monopoly on the east coast and Mexican-sourced heroin a monopoly on the west coast with competition between the two in the middle. We estimate the relationship between these changes in competitive market structure on retail-level heroin price and purity. We find that the entry of Colombian-sourced heroin is associated with less competition and a lower price per pure gram of heroin at the national level. However, there is wide variation in changes in market concentration across the US. Controlling for the national fall in the heroin price, more competition in a region or city is associated with a lower price per pure gram. PMID:24211155

  15. Anxiety and beta-adrenergic receptor function in a normal population.

    PubMed

    Kang, Eun-Ho; Yu, Bum-Hee

    2005-06-01

    Many studies have shown a close relationship between anxiety and beta-adrenergic receptor function in patients with anxiety disorders. This study examined the relationship between beta-adrenergic receptor function and anxiety levels in a normal population. Subjects for this study included 36 men and 44 women between the ages of 20 and 40 years whose Body Mass Index (BMI) was between 18 and 26. All of them were healthy subjects who had no previous history of medical or psychiatric illnesses. The authors measured the Spielberger State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), and Chronotropic 25 Dose (CD25) of isoproterenol, previously developed to assess in vivo beta-adrenergic receptor sensitivity. We also examined correlations between log normalized CD25 and mood states. The mean of CD25 was 2.64+/-1.37 mug and the mean of CD25 in men was significantly higher (i.e., lower beta-adrenergic receptor sensitivity) than that of women (3.26+/-1.35 vs. 2.14+/-1.17 microg; t = 3.99, p < 0.001). CD25 showed negative correlations with STAI state anxiety (r = -0.344, p = 0.002), trait anxiety (r = -0.331, p = 0.003), and BDI (r = -0.283, p = 0.011). CD25 was positively correlated with BMI (r = 0.423, p < 0.001) and age (r = 0.271, p = 0.015). In stepwise multiple regression analyses, 34% of the variance in CD25 was accounted for by sex, state anxiety, and BMI. The sensitivity of beta-adrenergic receptors increased as anxiety levels became higher in a normal population. Thus, the relationship between anxiety and beta-adrenergic receptor function in healthy subjects may be different from that of patients with anxiety disorders.

  16. Structure-activity relationship of 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole analogues as 5-HT(6) receptor agonists.

    PubMed

    Mattsson, Cecilia; Svensson, Peder; Boettcher, Henning; Sonesson, Clas

    2013-05-01

    To further investigate the structure-activity relationship (SAR) of the 5-hydroxytryptamine type 6 (5-HT6) receptor agonist 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (EMD386088, 6), a series of 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were synthesized, and in vitro affinity to, and functional activity at 5-HT6 receptors was tested. We focused on substituents made at the indole N(1)-, 2- and 5-positions and these were found to not only influence the affinity at 5-HT6 receptors but also the intrinsic activity leading to antagonists, partial agonists and full agonists. In order for a compound to demonstrate potent 5-HT6 receptor agonist properties, the indole N(1) should be unsubstituted, an alkyl group such as 2-methyl is needed and finally halogen substituents in the indole 5-position (fluoro, chloro or, bromo) were essential requirements. However, the introduction of a benzenesulfonyl group at N(1)-position switched the full agonist 6 to be a 5-HT6 receptor antagonist (30). A few compounds within the 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were also screened for off-targets and generally they displayed low affinity for other 5-HT subtypes and serotonin transporter protein (SERT). Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  17. PM₁₀ and PM₂.₅ sources at an insular location in the western Mediterranean by using source apportionment techniques.

    PubMed

    Pey, Jorge; Alastuey, Andrés; Querol, Xavier

    2013-07-01

    PM₁₀ and PM₂.₅ chemical composition has been determined at a suburban insular site in the Balearic Islands (Spain) during almost one and a half year. As a result, 200 samples with more than 50 chemical parameters analyzed have been obtained. The whole database has been analyzed by two receptor modelling techniques (Principal Component Analysis and Positive Matrix Factorisation) in order to identify the main PM sources. After that, regression analyses with respect to the PM mass concentrations were conducted to quantify the daily contributions of each source. Four common sources were identified by both receptor models: secondary nitrate coupled with vehicular emissions, secondary sulphate influenced by fuel-oil combustion, aged marine aerosols and mineral dust. In addition, PCA isolated harbour emissions and a mixed anthropogenic factor containing industrial emissions; whereas PMF isolated an additional mineral factor interpreted as road dust+harbour emissions, and a vehicular abrasion products factor. The use of both methodologies appeared complementary. Nevertheless, PMF sources by themselves were better differentiated. Besides these receptor models, a specific methodology to quantify African dust was also applied. The combination of these three source apportionment tools allowed the identification of 8 sources, being 4 of them mineral (African, regional, urban and harbour dusts). As a summary, 29% of PM₁₀ was attributed to natural sources (African dust, regional dust and sea spray), whereas the proportion diminished to 11% in PM₂.₅. Furthermore, the secondary sulphate source, which accounted for about 22 and 32% of PM₁₀ and PM₂.₅, is strongly linked to the aged polluted air masses residing over the western Mediterranean in the warm period. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Factors influencing mobile source particulate matter emissions-to-exposure relationships in the Boston urban area.

    PubMed

    Greco, Susan L; Wilson, Andrew M; Hanna, Steven R; Levy, Jonathan I

    2007-11-15

    Benefit-cost and regulatory impact analyses often use atmospheric dispersion models with coarse resolution to estimate the benefits of proposed mobile source emission control regulations. This approach may bias health estimates or miss important intra-urban variability for primary air pollutants. In this study, we estimate primary fine particulate matter (PM2.5) intake fractions (iF; the fraction of a pollutant emitted from a source that is inhaled by the population) for each of 23 398 road segments in the Boston Metro Core area to evaluate the potential for intra-urban variability in the emissions-to-exposure relationship. We estimate iFs using the CAL3QHCR line source model combined with residential populations within 5000 m of each road segment. The annual average values for the road segments range from 0.8 to 53 per million, with a mean of 12 per million. On average, 46% of the total exposure is realized within 200 m of the road segment, though this varies from 0 to 93% largely due to variable population patterns. Our findings indicate the likelihood of substantial intra-urban variability in mobile source primary PM2.5 iF that accounting for population movement with time, localized meteorological conditions, and street-canyon configurations would likely increase.

  19. B Cell Antigen Receptor Signaling and Internalization Are Mutually Exclusive Events

    PubMed Central

    Hou, Ping; Araujo, Elizabeth; Zhao, Tong; Zhang, Miao; Massenburg, Don; Veselits, Margaret; Doyle, Colleen; Dinner, Aaron R; Clark, Marcus R

    2006-01-01

    Engagement of the B cell antigen receptor initiates two concurrent processes, signaling and receptor internalization. While both are required for normal humoral immune responses, the relationship between these two processes is unknown. Herein, we demonstrate that following receptor ligation, a small subpopulation of B cell antigen receptors are inductively phosphorylated and selectively retained at the cell surface where they can serve as scaffolds for the assembly of signaling molecules. In contrast, the larger population of non-phosphorylated receptors is rapidly endocytosed. Each receptor can undergo only one of two mutually exclusive fates because the tyrosine-based motifs that mediate signaling when phosphorylated mediate internalization when not phosphorylated. Mathematical modeling indicates that the observed competition between receptor phosphorylation and internalization enhances signaling responses to low avidity ligands. PMID:16719564

  20. Distribution of messenger RNAs for D1 dopamine receptors and DARPP-32 in striatum and cerebral cortex of the cynomolgus monkey: relationship to D1 dopamine receptors.

    PubMed

    Brené, S; Hall, H; Lindefors, N; Karlsson, P; Halldin, C; Sedvall, G

    1995-07-01

    Messenger RNAs for the D1 dopamine receptor and dopamine- and cyclic AMP-regulated phosphoprotein of relative mass 32,000 (DARPP-32) were examined by in situ hybridization in the cynomolgus monkey brain. The messenger RNA distribution was compared to the distribution of D1 dopamine receptors using [3H]SCH 23390 autoradiography. In the caudate nucleus and putamen, D1 dopamine receptor messenger RNA-positive cells were unevenly distributed. Clusters of cells with an approximately three-fold higher intensity of labeling, as compared to surrounding regions, were found. Some of these D1 dopamine receptor messenger RNA intensive cell clusters in the caudate nucleus appeared to some extent to be matched to regions of higher intensity of [3H]SCH 23390 binding. The distribution of cells expressing DARPP-32 messenger RNA in the caudate nucleus and putamen was found to be non-clustered. In neocortical regions, cells of different sizes expressing D1 dopamine receptor messenger RNA were present in layers II-VI. D1 dopamine receptor messenger RNA-positive cells were most abundant in layer V. Unexpectedly, no DARPP-32 messenger RNA signal was detected in neocortex. Chronic SCH 23390 administration did not change the relative levels of messenger RNAs for the D1 dopamine receptor and DARPP-32 or [3H]SCH 23390 binding as measured by quantitative image analysis. The clustered distribution of D1 dopamine receptor messenger RNA is in contrast to that of DARPP-32 messenger RNA. This suggests that D1 dopamine receptors may play a more significant role in regulating DARPP-32 function in patch regions as compared to matrix regions. D1 dopamine receptor messenger RNA-expressing cells could also be visualized in several layers of the primate neocortex, implying that dopamine acts through D1 dopamine receptors within functionally different neuronal circuits of the neocortex.

  1. Navigating the cancer information environment: The reciprocal relationship between patient-clinician information engagement and information seeking from nonmedical sources.

    PubMed

    Moldovan-Johnson, Mihaela; Tan, Andy S L; Hornik, Robert C

    2014-01-01

    Prior theory has argued and empirical studies have shown that cancer patients rely on information from their health care providers as well as lay sources to understand and make decisions about their disease. However, research on the dynamic and interdependent nature of cancer patients' engagement with different information sources is lacking. This study tested the hypotheses that patient-clinician information engagement and information seeking from nonmedical sources influence one another longitudinally among a representative cohort of 1,293 cancer survivors in Pennsylvania. The study hypotheses were supported in a series of lagged multiple regression analyses. Baseline seeking information from nonmedical sources positively predicted subsequent patient-clinician information engagement at 1-year follow-up. The reverse relationship was also statistically significant; baseline patient-clinician information engagement positively predicted information seeking from nonmedical sources at follow-up. These findings suggest that cancer survivors move between nonmedical and clinician sources in a dynamic way to learn about their disease.

  2. Navigating the cancer information environment: The reciprocal relationship between patient-clinician information engagement and information seeking from nonmedical sources

    PubMed Central

    Moldovan-Johnson, Mihaela; Tan, Andy SL; Hornik, Robert C

    2014-01-01

    Prior theory has argued and empirical studies have shown that cancer patients rely on information from their health care providers as well as lay sources to understand and make decisions about their disease. However, research on the dynamic and interdependent nature of cancer patients’ engagement with different information sources is lacking. This study tested the hypotheses that patient-clinician information engagement and information seeking from nonmedical sources influence one another longitudinally among a representative cohort of 1,293 cancer survivors in Pennsylvania. The study hypotheses were supported in a series of lagged multiple regression analyses. Baseline seeking information from nonmedical sources positively predicted subsequent patient-clinician information engagement at one-year follow-up. The reverse relationship was also statistically significant; baseline patient-clinician information engagement positively predicted information seeking from nonmedical sources at follow-up. These findings suggest that cancer survivors move between nonmedical to clinician sources in a dynamic way to learn about their disease. PMID:24359259

  3. Structural Insights into Selective Ligand-Receptor Interactions Leading to Receptor Inactivation Utilizing Selective Melanocortin 3 Receptor Antagonists.

    PubMed

    Cai, Minying; Marelli, Udaya Kiran; Mertz, Blake; Beck, Johannes G; Opperer, Florian; Rechenmacher, Florian; Kessler, Horst; Hruby, Victor J

    2017-08-15

    Systematic N-methylated derivatives of the melanocortin receptor ligand, SHU9119, lead to multiple binding and functional selectivity toward melanocortin receptors. However, the relationship between N-methylation-induced conformational changes in the peptide backbone and side chains and melanocortin receptor selectivity is still unknown. We conducted comprehensive conformational studies in solution of two selective antagonists of the third isoform of the melanocortin receptor (hMC3R), namely, Ac-Nle-c[Asp-NMe-His 6 -d-Nal(2') 7 -NMe-Arg 8 -Trp 9 -Lys]-NH 2 (15) and Ac-Nle-c[Asp-His 6 -d-Nal(2') 7 -NMe-Arg 8 -NMe-Trp 9 -NMe-Lys]-NH 2 (17). It is known that the pharmacophore (His 6 -DNal 7 -Arg 8 -Trp 9 ) of the SHU-9119 peptides occupies a β II-turn-like region with the turn centered about DNal 7 -Arg 8 . The analogues with hMC3R selectivity showed distinct differences in the spatial arrangement of the Trp 9 side chains. In addition to our NMR studies, we also carried out molecular-level interaction studies of these two peptides at the homology model of hMC3R. Earlier chimeric human melanocortin 3 receptor studies revealed insights regarding the binding and functional sites of hMC3R selectivity. Upon docking of peptides 15 and 17 to the binding pocket of hMC3R, it was revealed that Arg 8 and Trp 9 side chains are involved in a majority of the interactions with the receptor. While Arg 8 forms polar contacts with D154 and D158 of hMC3R, Trp 9 utilizes π-π stacking interactions with F295 and F298, located on the transmembrane domain of hMC3R. It is hypothesized that as the frequency of Trp 9 -hMC3R interactions decrease, antagonistic activity increases. The absence of any interactions of the N-methyl groups with hMC3R suggests that their primary function is to modulate backbone conformations of the ligands.

  4. Structural studies of G protein-coupled receptors.

    PubMed

    Lu, Mengjie; Wu, Beili

    2016-11-01

    G protein-coupled receptors (GPCRs) comprise the largest membrane protein family. These receptors sense a variety of signaling molecules, activate multiple intracellular signal pathways, and act as the targets of over 40% of marketed drugs. Recent progress on GPCR structural studies provides invaluable insights into the structure-function relationship of the GPCR superfamily, deepening our understanding about the molecular mechanisms of GPCR signal transduction. Here, we review recent breakthroughs on GPCR structure determination and the structural features of GPCRs, and take the structures of chemokine receptor CCR5 and purinergic receptors P2Y 1 R and P2Y 12 R as examples to discuss the importance of GPCR structures on functional studies and drug discovery. In addition, we discuss the prospect of GPCR structure-based drug discovery. © 2016 IUBMB Life, 68(11):894-903, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

  5. The Relationships Between Alcohol Source, Autonomy in Brand Selection, and Brand Preference Among Youth in the USA

    PubMed Central

    Roberts, Sarah P.; Siegel, Michael B.; DeJong, William; Naimi, Timothy S.; Jernigan, David H.

    2014-01-01

    Aims: We aimed to describe the sources from which youth in the USA commonly obtain alcohol, their role in selecting the brands they drink and the relationship of these variables to their indicated alcohol brand preferences. Methods: We recruited 1031 underage drinkers in the age range of 13–20 through an internet panel managed by Knowledge Networks. Respondents completed an online survey assessing their recent brand-specific alcohol use, the source of their most recently consumed alcohol and whether the respondent or another person selected the brand they drank. Results: Alcohol sources were more often passive than transactional. Nearly equal proportions of youth reported that they did versus did not choose the brand of their most recent drink. Analysis revealed that the brand preferences of passive versus active source drinkers were highly similar, as were the brand preferences of respondent versus non-respondent choice drinkers. Stratification of respondents by age did not significantly change these results. Conclusion: Our findings suggest that youth are consuming a homogenous list of preferred brands regardless of the source of their most recently obtained alcohol or who selected the brand they drank. PMID:25113176

  6. The relationships between alcohol source, autonomy in brand selection, and brand preference among youth in the USA.

    PubMed

    Roberts, Sarah P; Siegel, Michael B; DeJong, William; Naimi, Timothy S; Jernigan, David H

    2014-01-01

    We aimed to describe the sources from which youth in the USA commonly obtain alcohol, their role in selecting the brands they drink and the relationship of these variables to their indicated alcohol brand preferences. We recruited 1031 underage drinkers in the age range of 13-20 through an internet panel managed by Knowledge Networks. Respondents completed an online survey assessing their recent brand-specific alcohol use, the source of their most recently consumed alcohol and whether the respondent or another person selected the brand they drank. Alcohol sources were more often passive than transactional. Nearly equal proportions of youth reported that they did versus did not choose the brand of their most recent drink. Analysis revealed that the brand preferences of passive versus active source drinkers were highly similar, as were the brand preferences of respondent versus non-respondent choice drinkers. Stratification of respondents by age did not significantly change these results. Our findings suggest that youth are consuming a homogenous list of preferred brands regardless of the source of their most recently obtained alcohol or who selected the brand they drank. © The Author 2014. Medical Council on Alcohol and Oxford University Press. All rights reserved.

  7. Structure-Activity Relationships of Bifunctional Cyclic Disulfide Peptides Based on Overlapping Pharmacophores at Opioid and Cholecystokinin Receptors

    PubMed Central

    Agnes, Richard S.; Ying, Jinfa; Kövér, Katalin E.; Lee, Yeon Sun; Davis, Peg; Ma, Shou-wu; Badghisi, Hamid; Porreca, Frank; Lai, Josephine; Hruby, Victor J.

    2008-01-01

    Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system, where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[D-Cys-Gly-Trp-Cys]-Asp-Phe-NH2) showed potent binding and agonist activities at δ and µ opioid receptors while displaying some binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands. PMID:18502541

  8. Research progress of the bitter taste receptor genes in primates.

    PubMed

    Feng, Ping; Luo, Rui-Jian

    2018-02-20

    Among the five basic tastes (umami, sweet, bitter, salty and sour), the perception of bitterness is believed to protect animals from digesting toxic and harmful substances, thus it is vital for animal survival. The taste of bitterness is triggered by the interaction between bitter substances and bitter taste receptors, which are encoded by Tas2rs. The gene numbers vary largely across species to meet different demands. So far, several ligands of bitter receptors have been identified in primates. They also discovered that the selective pressure of certain bitter taste receptor genes vary across taxa, genes or even different functional regions of the gene. In this review, we summarize the research progress of bitter taste receptor genes in primates by introducing the functional diversity of bitter receptors, the specific interaction between bitter taste receptors and ligands, the relationship between the evolutionary pattern of bitter taste receptors and diets, and the adaptive evolution of bitter taste receptor genes. We aim to provide a reference for further research on bitter receptor genes in primates.

  9. Characterizing Long-term Contaminant Mass Discharge and the Relationship Between Reductions in Discharge and Reductions in Mass for DNAPL Source Areas

    PubMed Central

    Matthieu, D.E.; Carroll, K.C.; Mainhagu, J.; Morrison, C.; McMillan, A.; Russo, A.; Plaschke, M.

    2013-01-01

    The objective of this study was to characterize the temporal behavior of contaminant mass discharge, and the relationship between reductions in contaminant mass discharge and reductions in contaminant mass, for a very heterogeneous, highly contaminated source-zone field site. Trichloroethene is the primary contaminant of concern, and several lines of evidence indicate the presence of organic liquid in the subsurface. The site is undergoing groundwater extraction for source control, and contaminant mass discharge has been monitored since system startup. The results show a significant reduction in contaminant mass discharge with time, decreasing from approximately 1 to 0.15 kg/d. Two methods were used to estimate the mass of contaminant present in the source area at the initiation of the remediation project. One was based on a comparison of two sets of core data, collected 3.5 years apart, which suggests that a significant (~80%) reduction in aggregate sediment-phase TCE concentrations occurred between sampling events. The second method was based on fitting the temporal contaminant mass discharge data with a simple exponential source-depletion function. Relatively similar estimates, 784 and 993 kg, respectively, were obtained with the two methods. These data were used to characterize the relationship between reductions in contaminant mass discharge (CMDR) and reductions in contaminant mass (MR). The observed curvilinear relationship exhibits a reduction in contaminant mass discharge essentially immediately upon initiation of mass reduction. This behavior is consistent with a system wherein significant quantities of mass are present in hydraulically poorly accessible domains for which mass removal is influenced by rate-limited mass transfer. The results obtained from the present study are compared to those obtained from other field studies to evaluate the impact of system properties and conditions on mass-discharge and mass-removal behavior. The results indicated that

  10. New Insights on Leucine-Rich Repeats Receptor-Like Kinase Orthologous Relationships in Angiosperms

    PubMed Central

    Dufayard, Jean-François; Bettembourg, Mathilde; Fischer, Iris; Droc, Gaetan; Guiderdoni, Emmanuel; Périn, Christophe; Chantret, Nathalie; Diévart, Anne

    2017-01-01

    Leucine-Rich Repeats Receptor-Like Kinase (LRR-RLK) genes represent a large and complex gene family in plants, mainly involved in development and stress responses. These receptors are composed of an LRR-containing extracellular domain (ECD), a transmembrane domain (TM) and an intracellular kinase domain (KD). To provide new perspectives on functional analyses of these genes in model and non-model plant species, we performed a phylogenetic analysis on 8,360 LRR-RLK receptors in 31 angiosperm genomes (8 monocots and 23 dicots). We identified 101 orthologous groups (OGs) of genes being conserved among almost all monocot and dicot species analyzed. We observed that more than 10% of these OGs are absent in the Brassicaceae species studied. We show that the ECD structural features are not always conserved among orthologs, suggesting that functions may have diverged in some OG sets. Moreover, we looked at targets of positive selection footprints in 12 pairs of OGs and noticed that depending on the subgroups, positive selection occurred more frequently either in the ECDs or in the KDs. PMID:28424707

  11. The entry of Colombian-sourced heroin into the US market: the relationship between competition, price, and purity.

    PubMed

    Rosenblum, Daniel; Unick, George Jay; Ciccarone, Daniel

    2014-01-01

    There have been large structural changes in the US heroin market over the past 20 years. Colombian-sourced heroin entered the market in the mid-1990s, followed by a large fall in the price per pure gram and the exit of Asian heroin. By the 2000s, Colombian-sourced heroin had become a monopoly on the east coast and Mexican-sourced heroin a monopoly on the west coast with competition between the two in the middle. We estimate the relationship between these changes in competitive market structure on retail-level heroin price and purity. We find that the entry of Colombian-sourced heroin is associated with less competition and a lower price per pure gram of heroin at the national level. However, there is wide variation in changes in market concentration across the US. Controlling for the national fall in the heroin price, more competition in a region or city is associated with a lower price per pure gram. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Ligand binding was acquired during evolution of nuclear receptors

    PubMed Central

    Escriva, Hector; Safi, Rachid; Hänni, Catherine; Langlois, Marie-Claire; Saumitou-Laprade, Pierre; Stehelin, Dominique; Capron, André; Pierce, Raymond; Laudet, Vincent

    1997-01-01

    The nuclear receptor (NR) superfamily comprises, in addition to ligand-activated transcription factors, members for which no ligand has been identified to date. We demonstrate that orphan receptors are randomly distributed in the evolutionary tree and that there is no relationship between the position of a given liganded receptor in the tree and the chemical nature of its ligand. NRs are specific to metazoans, as revealed by a screen of NR-related sequences in early- and non-metazoan organisms. The analysis of the NR gene duplication pattern during the evolution of metazoans shows that the present NR diversity arose from two waves of gene duplications. Strikingly, our results suggest that the ancestral NR was an orphan receptor that acquired ligand-binding ability during subsequent evolution. PMID:9192646

  13. Using a source-receptor approach to characterise VOC behaviour in a French urban area influenced by industrial emissions. Part II: source contribution assessment using the Chemical Mass Balance (CMB) model.

    PubMed

    Badol, Caroline; Locoge, Nadine; Galloo, Jean-Claude

    2008-01-25

    In Part I of this study (Badol C, Locoge N, Leonardis T, Gallo JC. Using a source-receptor approach to characterise VOC behaviour in a French urban area influenced by industrial emissions, Part I: Study area description, data set acquisition and qualitative data analysis of the data set. Sci Total Environ 2007; submitted as companion manuscript.) the study area, acquisition of the one-year data set and qualitative analysis of the data set have been described. In Part II a source profile has been established for each activity present in the study area: 6 profiles (urban heating, solvent use, natural gas leakage, biogenic emissions, gasoline evaporation and vehicle exhaust) have been extracted from literature to characterise urban sources, 7 industrial profiles have been established via canister sampling around industrial plants (hydrocarbon cracking, oil refinery, hydrocarbon storage, lubricant storage, lubricant refinery, surface treatment and metallurgy). The CMB model is briefly described and its implementation is discussed through the selection of source profiles and fitting species. Main results of CMB modellings for the Dunkerque area are presented. (1) The daily evolution of source contributions for the urban wind sector shows that the vehicle exhaust source contribution varies between 40 and 55% and its relative increase at traffic rush hours is hardly perceptible. (2) The relative contribution of vehicle exhaust varies from 55% in winter down to 30% in summer. This decrease is due to the increase of the relative contribution of hydrocarbon storage source reaching up to 20% in summer. (3) The evolution of source contributions with wind directions has confirmed that in urban wind sectors the contribution of vehicle exhaust dominate with around 45-55%. For the other wind sectors that include some industrial plants, the contribution of industrial sources is around 60% and could reach 80% for the sector 280-310 degrees , which corresponds to the most dense

  14. The Laminin Receptor Is a Cellular Attachment Receptor for Classical Swine Fever Virus

    PubMed Central

    Chen, Jianing; He, Wen-Rui; Shen, Liang; Dong, Hong; Yu, Jiahui; Wang, Xiao; Yu, Shaoxiong; Li, Yongfeng; Li, Su; Luo, Yuzi; Sun, Yuan

    2015-01-01

    protein genes, we identified the laminin receptor (LamR) to be another attachment receptor. We demonstrate the involvement of LamR together with HS in virus attachment, and we elucidate the relationship between LamR and HS. LamR also serves as an attachment receptor for many viral pathogens, including dengue virus, a fatal human flavivirus. The study will help to enhance our understanding of the life cycle of flaviviruses and the development of antiviral strategies for flaviviruses. PMID:25694590

  15. Calcitonin and calcitonin receptors: bone and beyond

    PubMed Central

    Pondel, Marc

    2000-01-01

    Calcitonin (CT), a 32 amino acid peptide hormone produced primarily by the thyroid, and its receptor (CTR) are well known for their ability to regulate osteoclast mediated bone resorption and enhance Ca2+ excretion by the kidney. However, recent studies now suggest that CT and CTRs may play an important role in a variety of processes as wide ranging as embryonic/foetal development and sperm function/physiology. In this review article, CT and CTR gene transcription, signal transduction and function are addressed. The effects of CT on the physiology of a variety of organ systems are discussed and the relationship between polymorphisms in the CTR gene and bone mineral density (BMD)/osteoporosis is examined. Recent studies demonstrating the ability of receptor activity modifying proteins (RAMPs) to post-translationally modify the calcitonin receptor-like receptor (CRLR) are detailed and studies employing transgenic mouse technology to determine the temporal and tissue specific transcriptional activity of the CTR gene in vivo are discussed. PMID:11298188

  16. Serial femtosecond crystallography datasets from G protein-coupled receptors.

    PubMed

    White, Thomas A; Barty, Anton; Liu, Wei; Ishchenko, Andrii; Zhang, Haitao; Gati, Cornelius; Zatsepin, Nadia A; Basu, Shibom; Oberthür, Dominik; Metz, Markus; Beyerlein, Kenneth R; Yoon, Chun Hong; Yefanov, Oleksandr M; James, Daniel; Wang, Dingjie; Messerschmidt, Marc; Koglin, Jason E; Boutet, Sébastien; Weierstall, Uwe; Cherezov, Vadim

    2016-08-01

    We describe the deposition of four datasets consisting of X-ray diffraction images acquired using serial femtosecond crystallography experiments on microcrystals of human G protein-coupled receptors, grown and delivered in lipidic cubic phase, at the Linac Coherent Light Source. The receptors are: the human serotonin receptor 2B in complex with an agonist ergotamine, the human δ-opioid receptor in complex with a bi-functional peptide ligand DIPP-NH2, the human smoothened receptor in complex with an antagonist cyclopamine, and finally the human angiotensin II type 1 receptor in complex with the selective antagonist ZD7155. All four datasets have been deposited, with minimal processing, in an HDF5-based file format, which can be used directly for crystallographic processing with CrystFEL or other software. We have provided processing scripts and supporting files for recent versions of CrystFEL, which can be used to validate the data.

  17. Rectification properties and Ca2+ permeability of glutamate receptor channels in hippocampal cells.

    PubMed

    Lerma, J; Morales, M; Ibarz, J M; Somohano, F

    1994-07-01

    Excitatory amino acids exert a depolarizing action on central nervous system cells through an increase in cationic conductances. Non-NMDA receptors have been considered to be selectively permeable to Na+ and K+, while Ca2+ influx has been thought to occur through the NMDA receptor subtype. Recently, however, the expression of cloned non-NMDA receptor subunits has shown that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are permeable to Ca2+ whenever the receptor lacks a particular subunit (edited GluR-B). The behaviour of recombinant glutamate receptor channels predicts that Ca2+ would only permeate through receptors that show strong inward rectification and vice versa, i.e. AMPA receptors with linear current-voltage relationships would be impermeable to Ca2+. Using the whole-cell configuration of the patch-clamp technique, we have studied the Ca2+ permeability and the rectifying properties of AMPA receptors, when activated by kainate, in hippocampal neurons kept in culture or acutely dissociated from differentiated hippocampus. Cells were classified according to whether they showed outward rectifying (type I), inward rectifying (type II) or almost linear (type III) current-voltage relationships for kainate-activated responses. AMPA receptors of type I cells (52.2%) were mostly Ca(2+)-impermeable (PCa/PCs = 0.1), while type II cells (6.5%) expressed Ca(2+)-permeable receptors (PCa/PCs = 0.9). Type III cells (41.3%) showed responses with low but not negligible Ca2+ permeability (PCa/PCs = 0.18). The degree of Ca2+ permeability and inward rectification were well correlated in cultured cells, i.e. more inward rectification corresponded to higher Ca2+ permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Structure-Activity Relationships for the Antifungal Activity of Selective Estrogen Receptor Antagonists Related to Tamoxifen

    PubMed Central

    Butts, Arielle; Martin, Jennifer A.; DiDone, Louis; Bradley, Erin K.; Mutz, Mitchell; Krysan, Damian J.

    2015-01-01

    Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold. PMID:26016941

  19. Evolution of the nuclear receptor gene superfamily.

    PubMed Central

    Laudet, V; Hänni, C; Coll, J; Catzeflis, F; Stéhelin, D

    1992-01-01

    Nuclear receptor genes represent a large family of genes encoding receptors for various hydrophobic ligands such as steroids, vitamin D, retinoic acid and thyroid hormones. This family also contains genes encoding putative receptors for unknown ligands. Nuclear receptor gene products are composed of several domains important for transcriptional activation, DNA binding (C domain), hormone binding and dimerization (E domain). It is not known whether these genes have evolved through gene duplication from a common ancestor or if their different domains came from different independent sources. To test these possibilities we have constructed and compared the phylogenetic trees derived from two different domains of 30 nuclear receptor genes. The tree built from the DNA binding C domain clearly shows a common progeny of all nuclear receptors, which can be grouped into three subfamilies: (i) thyroid hormone and retinoic acid receptors, (ii) orphan receptors and (iii) steroid hormone receptors. The tree constructed from the central part of the E domain which is implicated in transcriptional regulation and dimerization shows the same distribution in three subfamilies but two groups of receptors are in a different position from that in the C domain tree: (i) the Drosophila knirps family genes have acquired very different E domains during evolution, and (ii) the vitamin D and ecdysone receptors, as well as the FTZ-F1 and the NGF1B genes, seem to have DNA binding and hormone binding domains belonging to different classes. These data suggest a complex evolutionary history for nuclear receptor genes in which gene duplication events and swapping between domains of different origins took place. PMID:1312460

  20. Genetic variants of estrogen beta and leptin receptors may cause gynecomastia in adolescent.

    PubMed

    Eren, Erdal; Edgunlu, Tuba; Korkmaz, Huseyin Anil; Cakir, Esra Deniz Papatya; Demir, Korcan; Cetin, Esin Sakalli; Celik, Sevim Karakas

    2014-05-15

    Gynecomastia is a benign breast enlargement in males that affects approximately one-third of adolescents. The exact mechanism is not fully understood; however, it has been proposed that estrogen receptors and aromatase enzyme activity may play important roles in the pathogenesis of gynecomastia. While many studies have reported that aromatase enzyme (CYP19) gene polymorphism is associated with gynecomastia, only one study has shown a relationship between estrogen receptor (ER) alpha and beta gene polymorphism and gynecomastia. Thus, the aim of this study was to evaluate the relationships between CYP19 (rs2414096), ER alpha (rs2234693), ER beta (rs4986938), leptin (rs7799039), and leptin receptor (rs1137101) gene polymorphisms and gynecomastia. This study included 107 male adolescents with gynecomastia and 97 controls. Total serum testosterone (T) and estradiol (E2) levels were measured, and DNA was extracted from whole blood using the PCR-RFLP technique. The polymorphic distributions of CYP19, ER alpha, ER beta, leptin and leptin receptor genes were compared. The median E2 level was 12.41 (5.00-65.40) pg/ml in the control group and 16.86 (2.58-78.47) pg/ml in the study group (p<0.001). The median T level was 2.19 (0.04-7.04) ng/ml in the control group and 1.46 (0.13-12.02) ng/ml in the study group (p=0.714). There was a significant relationship between gynecomastia and leptin receptor rs1137101 (p=0.002) and ER beta receptor rs4986938 gene polymorphisms (p=0.002). According to our results, increased E2 level and ER beta gene rs4986938 polymorphism might explain why some adolescents have gynecomastia. Leptin receptor gene rs1137101 polymorphism might affect susceptibility to gynecomastia. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.

    PubMed

    Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D; Sorensen, Nicholas B; Wood, Michael S; Xiang, Zhimin; Haskell-Luevano, Carrie

    2016-07-20

    The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

  2. Sources and atmospheric transformations of semivolatile organic aerosols

    NASA Astrophysics Data System (ADS)

    Grieshop, Andrew P.

    Fine atmospheric particulate matter (PM2.5) is associated with increased mortality, a fact which led the EPA to promulgate a National Ambient Air Quality Standard (NAAQS) for PM2.5 in 1997. Organic material contributes a substantial portion of the PM2.5 mass; organic aerosols (OA) are either directly emitted (primary OA or POA) or formed via the atmospheric oxidation of volatile precursor compounds as secondary OA (SOA). The relative contributions of POA and SOA to atmospheric OA are uncertain, as are the contributions from various source classes (e.g. motor vehicles, biomass burning). This dissertation first assesses the importance of organic PM within the context of current US air pollution regulations. Most control efforts to date have focused on the inorganic component of PM. Although growing evidence strongly implicates OA, especially which from motor vehicles, in the health effects of PM, uncertain and complex source-receptor relationships for OA discourage its direct control for NAAQS compliance. Analysis of both ambient data and chemical transport modeling results indicate that OA does not play a dominant role in NAAQS violations in most areas of the country under current and likely future regulations. Therefore, new regulatory approaches will likely be required to directly address potential health impacts associated with OA. To help develop the scientific understanding needed to better regulate OA, this dissertation examined the evolution of organic aerosol emitted by combustion systems. The current conceptual model of POA is that it is non-volatile and non-reactive. Both of these assumptions were experimental investigated in this dissertation. Novel dilution measurements were carried out to investigate the gas-particle partitioning of OA at atmospherically-relevant conditions. The results demonstrate that POA from combustion sources is semivolatile. Therefore its gas-particle partitioning depends on temperature and atmospheric concentrations; heating and

  3. Mechanoreceptor afferent activity compared with receptor field dimensions and pressure changes in feline urinary bladder.

    PubMed

    Downie, J W; Armour, J A

    1992-11-01

    The relationship between vesical mechanoreceptor field dimensions and afferent nerve activity recorded in pelvic plexus nerve filaments was examined in chloralose-anesthetized cats. Orthogonal receptor field dimensions were monitored with piezoelectric ultrasonic crystals. Reflexly generated bladder contractile activity made measurements difficult, therefore data were collected from cats subjected to actual sacral rhizotomy. Afferent activity was episodic and was initiated at different pressure and receptor field dimension thresholds. Maximum afferent activity did not correlate with maximum volume or pressure. Furthermore, activity was not linearly related to intravesical pressure, receptor field dimensions, or calculated wall tension. Pressure-length hysteresis of the receptor fields occurred. The responses of identified afferent units and their associated receptor field dimensions to brief contractions elicited by the ganglion stimulant 1,1-dimethyl-4-phenylpiperazinium iodide (2.5-20 micrograms i.a.), studied under constant volume or constant pressure conditions, are compatible with bladder mechanoreceptors behaving as tension receptors. Because activity generated by bladder mechanoreceptors did not correlate in a simple fashion with intravesical pressure or receptor field dimensions, it is concluded that such receptors are influenced by the viscoelastic properties of the bladder wall. Furthermore, as a result of the heterogeneity of the bladder wall, receptor field tension appears to offer a more precise relationship with the activity of bladder wall mechanoreceptors than does intravesical pressure.

  4. Serial femtosecond crystallography datasets from G protein-coupled receptors

    PubMed Central

    White, Thomas A.; Barty, Anton; Liu, Wei; Ishchenko, Andrii; Zhang, Haitao; Gati, Cornelius; Zatsepin, Nadia A.; Basu, Shibom; Oberthür, Dominik; Metz, Markus; Beyerlein, Kenneth R.; Yoon, Chun Hong; Yefanov, Oleksandr M.; James, Daniel; Wang, Dingjie; Messerschmidt, Marc; Koglin, Jason E.; Boutet, Sébastien; Weierstall, Uwe; Cherezov, Vadim

    2016-01-01

    We describe the deposition of four datasets consisting of X-ray diffraction images acquired using serial femtosecond crystallography experiments on microcrystals of human G protein-coupled receptors, grown and delivered in lipidic cubic phase, at the Linac Coherent Light Source. The receptors are: the human serotonin receptor 2B in complex with an agonist ergotamine, the human δ-opioid receptor in complex with a bi-functional peptide ligand DIPP-NH2, the human smoothened receptor in complex with an antagonist cyclopamine, and finally the human angiotensin II type 1 receptor in complex with the selective antagonist ZD7155. All four datasets have been deposited, with minimal processing, in an HDF5-based file format, which can be used directly for crystallographic processing with CrystFEL or other software. We have provided processing scripts and supporting files for recent versions of CrystFEL, which can be used to validate the data. PMID:27479354

  5. Identification of 2-arylbenzimidazoles as potent human histamine H4 receptor ligands.

    PubMed

    Lee-Dutra, Alice; Arienti, Kristen L; Buzard, Daniel J; Hack, Michael D; Khatuya, Haripada; Desai, Pragnya J; Nguyen, Steven; Thurmond, Robin L; Karlsson, Lars; Edwards, James P; Breitenbucher, J Guy

    2006-12-01

    A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H(4) receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H(4) receptor.

  6. 5-HT7 Receptor Antagonists with an Unprecedented Selectivity Profile.

    PubMed

    Ates, Ali; Burssens, Pierre; Lorthioir, Olivier; Lo Brutto, Patrick; Dehon, Gwenael; Keyaerts, Jean; Coloretti, Francis; Lallemand, Bénédicte; Verbois, Valérie; Gillard, Michel; Vermeiren, Céline

    2018-04-23

    Selective leads: In this study, we generated a new series of serotonin 5-HT 7 receptor antagonists. Their synthesis, structure-activity relationships, and selectivity profiles are reported. This series includes 5-HT 7 antagonists with unprecedented high selectivity for the 5-HT 7 receptor, setting the stage for lead optimization of drugs acting on a range of neurological targets. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Interactions between estrogen receptors and metabotropic glutamate receptors and their impact on drug addiction in females.

    PubMed

    Tonn Eisinger, Katherine R; Gross, Kellie S; Head, Brian P; Mermelstein, Paul G

    2018-03-10

    Estrogen receptors α and β (ERα and ERβ) have a unique relationship with metabotropic glutamate receptors (mGluRs) in the female rodent brain such that estradiol is able to recruit intracellular G-protein signaling cascades to influence neuronal physiology, structure, and ultimately behavior. While this association between ERs and mGluRs exists in many cell types and brain regions, its effects are perhaps most striking in the nucleus accumbens (NAc). This review will discuss the original characterization of ER/mGluR signaling and how estradiol activity in the NAc confers increased sensitivity to drugs of abuse in females through this mechanism. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Relationship between peroxisome proliferator-activated receptor alpha activity and cellular concentration of 14 perfluoroalkyl substances in HepG2 cells.

    PubMed

    Rosenmai, Anna Kjerstine; Ahrens, Lutz; le Godec, Théo; Lundqvist, Johan; Oskarsson, Agneta

    2018-02-01

    Peroxisome proliferator-activated receptor alpha (PPARα) is a molecular target for perfluoroalkyl substances (PFASs). Little is known about the cellular uptake of PFASs and how it affects the PPARα activity. We investigated the relationship between PPARα activity and cellular concentration in HepG2 cells of 14 PFASs, including perfluoroalkyl carboxylates (PFCAs), perfluoroalkyl sulfonates and perfluorooctane sulfonamide (FOSA). Cellular concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry and PPARα activity was determined in transiently transfected cells by reporter gene assay. Cellular uptake of the PFASs was low (0.04-4.1%) with absolute cellular concentrations in the range 4-2500 ng mg -1 protein. Cellular concentration of PFCAs increased with perfluorocarbon chain length up to perfluorododecanoate. PPARα activity of PFCAs increased with chain length up to perfluorooctanoate. The maximum induction of PPARα activity was similar for short-chain (perfluorobutanoate and perfluoropentanoate) and long-chain PFCAs (perfluorododecanoate and perfluorotetradecanoate) (approximately twofold). However, PPARα activities were induced at lower cellular concentrations for the short-chain homologs compared to the long-chain homologs. Perfluorohexanoate, perfluoroheptanoate, perfluorooctanoate, perfluorononanoate (PFNA) and perfluorodecanoate induced PPARα activities >2.5-fold compared to controls. The concentration-response relationships were positive for all the tested compounds, except perfluorooctane sulfonate PFOS and FOSA, and were compound-specific, as demonstrated by differences in the estimated slopes. The relationships were steeper for PFCAs with chain lengths up to and including PFNA than for the other studied PFASs. To our knowledge, this is the first report establishing relationships between PPARα activity and cellular concentration of a broad range of PFASs. Copyright © 2017 John Wiley & Sons, Ltd.

  9. Investigation of the relationship between radon anomalıes in deep water resources near Akşehir fault zone and the radial distances of the sources to an earthquake center

    NASA Astrophysics Data System (ADS)

    Gümüş, Ayla; Yalım, Hüseyin Ali

    2018-02-01

    Radon emanation occurs all the rocks and earth containing uranium element. Anomalies in radon concentrations before earthquakes are observed in fault lines, geothermal sources, uranium deposits, volcanic movements. The aim of this study is to investigate the relationship between the radon anomalies in water resources and the radial distances of the sources to the earthquake center. For this purpose, radon concentrations of 9 different deep water sources near Akşehir fault line were determined by taking samples with monthly periods for two years. The relationship between the radon anomalies and the radial distances of the sources to the earthquake center was obtained for the sources.

  10. The Roles of Dopamine D1 Receptor on the Social Hierarchy of Rodents and Nonhuman Primates

    PubMed Central

    Yamaguchi, Yoshie; Lee, Young-A; Kato, Akemi

    2017-01-01

    Abstract Background: Although dopamine has been suggested to play a role in mediating social behaviors of individual animals, it is not clear whether such dopamine signaling contributes to attributes of social groups such as social hierarchy. Methods: In this study, the effects of the pharmacological manipulation of dopamine D1 receptor function on the social hierarchy and behavior of group-housed mice and macaques were investigated using a battery of behavioral tests. Results: D1 receptor blockade facilitated social dominance in mice at the middle, but not high or low, social rank in the groups without altering social preference among mates. In contrast, the administration of a D1 receptor antagonist in a macaque did not affect social dominance of the drug-treated animal; however, relative social dominance relationships between the drug-treated and nontreated subjects were altered indirectly through alterations of social affiliative relationships within the social group. Conclusions: These results suggest that dopamine D1 receptor signaling may be involved in social hierarchy and social relationships within a group, which may differ between rodents and primates. PMID:27927739

  11. Relationship between THMs/NDMA formation potential and molecular weight of organic compounds for source and treated water in Shanghai, China.

    PubMed

    An, Dong; Gu, Bin; Sun, Sainan; Zhang, Han; Chen, Yanan; Zhu, Huifeng; Shi, Jian; Tong, Jun

    2017-12-15

    Molecular weight (MW) distributions in source and treated water in Shanghai, China were investigated to understand the relationship between trihalomethanes formation potential/N-nitrosodimethylamine formation potential (THMFP/NDMAFP) and dissolved organic carbon (DOC) for different MW ranges (<1K, 1-10K, 10-30K, >30KDa). The result of MW distributions in source water indicated a relationship between THMFP/NDMAFP and DOC such that DOC for <1K and 1-30KDa DOC were linearly related to THMFP and NDMAFP, respectively. In treated water, >30KDa THMFP was totally removed whereas <1KDa THMFP showed linear relationships with R 2 =0.88 and 0.83 after sand and granular activated carbon (GAC) filtration, respectively. DOC content for 1-10KDa tended to form NDMA according to the results for treated water between DOC and NDMAFP (R 2 =0.94 and 0.93 for sand and GAC filtration, respectively). The results may provide researchers with targeted treatment strategies to destroy, remove, or reduce the occurrence of THMs and NDMA precursors. The findings presented in this study will be of great value in future work for selecting suitable drinking water treatment processes to minimize the formation of disinfection by-products using chlorine or chloramine disinfection. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Ligands for Ionotropic Glutamate Receptors

    PubMed Central

    Swanson, Geoffrey T.; Sakai, Ryuichi

    2010-01-01

    Marine-derived small molecules and peptides have played a central role in elaborating pharmacological specificities and neuronal functions of mammalian ionotropic glutamate receptors (iGluRs), the primary mediators of excitatory synaptic transmission in the central nervous system (CNS). As well, the pathological sequelae elicited by one class of compounds (the kainoids) constitute a widely-used animal model for human mesial temporal lobe epilepsy (mTLE). New and existing molecules could prove useful as lead compounds for the development of therapeutics for neuropathologies that have aberrant glutamatergic signaling as a central component. In this chapter we discuss natural source origins and pharmacological activities of those marine compounds that target ionotropic glutamate receptors. PMID:19184587

  13. Ligands for Ionotropic Glutamate Receptors

    NASA Astrophysics Data System (ADS)

    Swanson, Geoffrey T.; Sakai, Ryuichi

    Marine-derived small molecules and peptides have played a central role in elaborating pharmacological specificities and neuronal functions of mammalian ionotropic glutamate receptors (iGluRs), the primary mediators of excitatory syn-aptic transmission in the central nervous system (CNS). As well, the pathological sequelae elicited by one class of compounds (the kainoids) constitute a widely-used animal model for human mesial temporal lobe epilepsy (mTLE). New and existing molecules could prove useful as lead compounds for the development of therapeutics for neuropathologies that have aberrant glutamatergic signaling as a central component. In this chapter we discuss natural source origins and pharmacological activities of those marine compounds that target ionotropic glutamate receptors.

  14. INPUFF: A SINGLE SOURCE GAUSSIAN PUFF DISPERSION ALGORITHM. USER'S GUIDE

    EPA Science Inventory

    INPUFF is a Gaussian INtegrated PUFF model. The Gaussian puff diffusion equation is used to compute the contribution to the concentration at each receptor from each puff every time step. Computations in INPUFF can be made for a single point source at up to 25 receptor locations. ...

  15. Identification of atmospheric mercury sources and transport pathways on local and regional sales

    NASA Astrophysics Data System (ADS)

    Gratz, Lynne E.

    Mercury (Hg) is a hazardous air pollutant and bioaccumulative neurotoxin whose intricate atmospheric chemistry complicates our ability to define Hg source-receptor relationships on all scales. Our detailed measurements of Hg in its different forms together with atmospheric tracers have improved our understanding of Hg chemistry and transport. Daily-event precipitation samples collected from 1995 to 2006 in Underhill, VT were examined to identify Hg wet deposition trends and source influences. Analysis revealed that annual Hg deposition at this fairly remote location did not vary significantly over the 12-year period. While a decreasing trend in volume-weighted mean Hg concentration was observed, Hg wet deposition did not decline as transport of emissions from the Midwest and along the Atlantic Coast consistently contributed to the largest observed Hg wet deposition events. Receptor modeling of Hg and trace elements in precipitation indicated that ---60% of Hg wet deposition at Underhill could be attributed to emissions from coal-fired utility boilers (CFUBs), and their contribution to Hg wet deposition did not change significantly over time. Hybrid-receptor modeling further defined these CFUBs to be located predominantly in the Midwestern U.S. Atmospheric Hg chemistry and transport from the Chicago urban/industrial area was the focus of speciated Hg measurements performed in the southern Lake Michigan basin during summer 2007. Transport from Chicago, IL to Holland, MI occurred during 27% of the study period, resulting in a five-fold increase in divalent reactive gaseous Hg (RGM) at the downwind Holland site. Dispersion modeling of case study periods demonstrated that under southwesterly flow approximately half of the RGM in Holland could be attributed to primary RGM emissions from Chicago after transport and dispersion, with the remainder due to Hg0 oxidation in the atmosphere en route. Precipitation and ambient vapor phase samples were also collected in Chicago

  16. RECENT APPLICATIONS OF SOURCE APPORTIONMENT METHODS AND RELATED NEEDS

    EPA Science Inventory

    Traditional receptor modeling studies have utilized factor analysis (like principal component analysis, PCA) and/or Chemical Mass Balance (CMB) to assess source influences. The limitations with these approaches is that PCA is qualitative and CMB requires the input of source pr...

  17. Source apportionment of airborne particulates through receptor modeling: Indian scenario

    NASA Astrophysics Data System (ADS)

    Banerjee, Tirthankar; Murari, Vishnu; Kumar, Manish; Raju, M. P.

    2015-10-01

    Airborne particulate chemistry mostly governed by associated sources and apportionment of specific sources is extremely essential to delineate explicit control strategies. The present submission initially deals with the publications (1980s-2010s) of Indian origin which report regional heterogeneities of particulate concentrations with reference to associated species. Such meta-analyses clearly indicate the presence of reservoir of both primary and secondary aerosols in different geographical regions. Further, identification of specific signatory molecules for individual source category was also evaluated in terms of their scientific merit and repeatability. Source signatures mostly resemble international profile while, in selected cases lack appropriateness. In India, source apportionment (SA) of airborne particulates was initiated way back in 1985 through factor analysis, however, principal component analysis (PCA) shares a major proportion of applications (34%) followed by enrichment factor (EF, 27%), chemical mass balance (CMB, 15%) and positive matrix factorization (PMF, 9%). Mainstream SA analyses identify earth crust and road dust resuspensions (traced by Al, Ca, Fe, Na and Mg) as a principal source (6-73%) followed by vehicular emissions (traced by Fe, Cu, Pb, Cr, Ni, Mn, Ba and Zn; 5-65%), industrial emissions (traced by Co, Cr, Zn, V, Ni, Mn, Cd; 0-60%), fuel combustion (traced by K, NH4+, SO4-, As, Te, S, Mn; 4-42%), marine aerosols (traced by Na, Mg, K; 0-15%) and biomass/refuse burning (traced by Cd, V, K, Cr, As, TC, Na, K, NH4+, NO3-, OC; 1-42%). In most of the cases, temporal variations of individual source contribution for a specific geographic region exhibit radical heterogeneity possibly due to unscientific orientation of individual tracers for specific source and well exaggerated by methodological weakness, inappropriate sample size, implications of secondary aerosols and inadequate emission inventories. Conclusively, a number of challenging

  18. Airborne exposure patterns from a passenger source in aircraft cabins

    PubMed Central

    Bennett, James S.; Jones, Byron W.; Hosni, Mohammad H.; Zhang, Yuanhui; Topmiller, Jennifer L.; Dietrich, Watts L.

    2015-01-01

    Airflow is a critical factor that influences air quality, airborne contaminant distribution, and disease transmission in commercial airliner cabins. The general aircraft-cabin air-contaminant transport effect model seeks to build exposure-spatial relationships between contaminant sources and receptors, quantify the uncertainty, and provide a platform for incorporation of data from a variety of studies. Knowledge of infection risk to flight crews and passengers is needed to form a coherent response to an unfolding epidemic, and infection risk may have an airborne pathogen exposure component. The general aircraf-tcabin air-contaminant transport effect model was applied to datasets from the University of Illinois and Kansas State University and also to case study information from a flight with probable severe acute respiratory syndrome transmission. Data were fit to regression curves, where the dependent variable was contaminant concentration (normalized for source strength and ventilation rate), and the independent variable was distance between source and measurement locations. The data-driven model showed exposure to viable small droplets and post-evaporation nuclei at a source distance of several rows in a mock-up of a twin-aisle airliner with seven seats per row. Similar behavior was observed in tracer gas, particle experiments, and flight infection data for severe acute respiratory syndrome. The study supports the airborne pathway as part of the matrix of possible disease transmission modes in aircraft cabins. PMID:26526769

  19. The relationship between the height of a volcano and the depth to its magma source zone - A critical reexamination

    NASA Technical Reports Server (NTRS)

    Wilson, Lionel; Head, James W., III; Parfitt, Elisabeth A.

    1992-01-01

    The relationship between the maximum height to which a volcanic edifice is able to grow and the depth at which the partial melts providing its magma supply are formed is used to infer various aspects of the thermal and stress state of the lithosphere beneath volcanic constructs on earth, Mars, Io, and Venus. The assumptions behind this relationship are examined, and it is shown that many of them require geologically unreasonable conditions. The evidence cited in the literature for the relationship is assessed critically, and it is found that there are other factors that may explain the observations. It is concluded that volcano heights on the terrestrial planets cannot be related in any simple way to lithospheric thickness or depth to the magma source zone, and the range of other vectors controlling volcano height are reviewed.

  20. Agonists and antagonists for P2 receptors

    PubMed Central

    Jacobson, Kenneth A.; Costanzi, Stefano; Joshi, Bhalchandra V.; Besada, Pedro; Shin, Dae Hong; Ko, Hyojin; Ivanov, Andrei A.; Mamedova, Liaman

    2015-01-01

    Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. PMID:16805423

  1. DUALITY IN MULTIVARIATE RECEPTOR MODEL. (R831078)

    EPA Science Inventory

    Multivariate receptor models are used for source apportionment of multiple observations of compositional data of air pollutants that obey mass conservation. Singular value decomposition of the data leads to two sets of eigenvectors. One set of eigenvectors spans a space in whi...

  2. Species differences in the localization and number of CNS beta adrenergic receptors: Rat versus guinea pig

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Booze, R.M.; Crisostomo, E.A.; Davis, J.N.

    1989-06-01

    The localization and number of beta adrenergic receptors were directly compared in the brains of rats and guinea pigs. The time course of association and saturability of (125I)cyanopindolol (CYP) binding to slide-mounted tissue sections was similar in rats (Kd = 17 pM) and guinea pigs (Kd = 20 pM). The beta-1 and beta-2 receptor subtypes were examined through the use of highly selective unlabeled receptor antagonists, ICI 118,551 (50 nM) and ICI 89,406 (70 nM). Dramatic species differences between rats and guinea pigs were observed in the neuroanatomical regional localization of the beta adrenergic receptor subtypes. For example, in themore » thalamus prominent beta-1 and beta-2 receptor populations were identified in the rat; however, the entire thalamus of the guinea pig had few, if any, beta adrenergic receptors of either subtype. Hippocampal area CA1 had high levels of beta-2 adrenergic receptors in both rats and guinea pigs but was accompanied by a widespread distribution of beta-2 adrenergic receptors only in rats. Quantitative autoradiographic analyses of 25 selected neuroanatomical regions (1) confirmed the qualitative differences in CNS beta adrenergic receptor localization, (2) determined that guinea pigs had significantly lower levels of beta adrenergic receptors than rats and (3) indicated a differential pattern of receptor subtypes between the two species. Knowledge of species differences in receptor patterns may be useful in designing effective experiments as well as in exploring the relationships between receptor and innervation patterns. Collectively, these data suggest caution be used in extrapolation of the relationships of neurotransmitters and receptors from studies of a single species.« less

  3. Change in parenting, change in student-teacher relationships, and oxytocin receptor gene (OXTR): Testing a gene-×-environment (G×E) hypothesis in two samples.

    PubMed

    Hygen, Beate Wold; Belsky, Jay; Li, Zhi; Stenseng, Frode; Güzey, Ismail Cuneyt; Wichstrøm, Lars

    2017-07-01

    Prior research suggests that parenting affects children's relationships, including those with teachers, although there is variation across individuals in such effects. Given evidence suggesting that oxytocin may be particularly important for the quality of social relationships, we tested the hypotheses (a) that change in parenting from 4 to 6 years of age influences and predicts change in the student-teacher relationship from 6 to 8 years of age and (b) that this effect is moderated by a polymorphism related to the child's oxytocin receptor gene (OXTR), rs53576. In 2 studies, participants included, respectively, 652 socioeconomically diverse Norwegian children from a community sample (50.8% male; mean age of 54.9 months at first assessment) and 559 such children from 8 different U.S. locales (49.0% male; approximately 54 months at the first assessment). Norwegian results showed that change in parenting predicted change in student-teacher relationships, but only in the case of children homozygous for the A allele of rs53576 and in a manner consistent with differential-susceptibility theory: for AA carriers, when parenting changed for the worse, so did children's relationship with teachers, whereas when parenting changed for the better, the teacher-child relationships improved accordingly. Such G×E findings could not be replicated in the American sample. Results are discussed in terms of 2 contrasting models of Person-×-Environment interaction (differential susceptibility and diathesis stress) and potential reasons for failure to replicate. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  4. Application of Quantitative Structure–Activity Relationship Models of 5-HT1A Receptor Binding to Virtual Screening Identifies Novel and Potent 5-HT1A Ligands

    PubMed Central

    2015-01-01

    The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure–activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 μM. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs. PMID:24410373

  5. [Study on relationship between mother's animal sourced food intake during pregnancy and neonate birth weight].

    PubMed

    Yan, H; Dang, S N; Mi, B B; Qu, P F; Zhang, L; Wang, H L; Bi, Y X; Zeng, L X; Li, Q; Yan, H

    2017-05-10

    Objective: To explore the effect of maternal animal sourced food intake during pregnancy on neonate birth weight and provide scientific basis for guiding the reasonable diet intake in pregnant women and increasing neonate birth weight. Methods: Data were derived from a cross-sectional project of"the prevalence and risk factors of birth defects in Shaanxi province" , which were conducted in 30 counties in Shaanxi province from July to November in 2013. A stratified multistage random sampling method was used to select women who were pregnant between January 2010 and December 2013 for a random semi-quantitative food frequency questionnaire survey to collect the data on the frequency and amount of food consumption on animal protein sources and the data of newborns. Children aged 0-1 years and their mothers were selected as the study subjects. The generalized linear model was used to analyze the relationship between the neonate birth weight and maternal animal sourced food intake during pregnancy, and by using neonate birth weight as dependent variable, food intake frequency as independent variable, three adjustment models were established for stratified analysis. Results: Totally 11 459 participants were involved in this study. The average birth weight of newborn was (3 279.9±454.6) g, the average weekly intake of animal sourced foods was4.00 times for egg, 1.50 times for meat, 3.00 times for dairy foods, 0.50 times for fish and 5.00 times for overall animal sourced foods in pregnant women. Without stratification, three models shown that meat and overall animal sourced food intake had effects on neonate birth weight. After adjustment for gestational weeks, maternal age, social and demographic factors and others, meat intake increased by 1 time a week, the increase of neonate birth weight was about 5.26 (95 %CI : 1.32-9.20) g, and the overall animal food increased by 1 times a week, the average neonate birth weight increased by 3.24 (95 %CI : 1.09-5.39) g. Stratified

  6. PM over summertime India: Sources and trends investigated using long term measurements and multi-receptor site back trajectory analysis

    NASA Astrophysics Data System (ADS)

    Kumar, Vinod; Sarkar, Chinmoy; Sachan, Himanshu; Kumar, Devender; Sinha, Baerbel

    2013-04-01

    We apply multi-receptor site residence-time weighted concentration back trajectory analysis to a ten year data set (1991-2003) of PM10 and TSP measurement data from four Indian megacities Delhi, Mumbai, Kolkata and Chennai. The dataset was sourced from the published and peer reviewed work of Gupta and Kumar (2006). Sources and trends of PM10 and TSP during the pre-monsoon season (March-June) were investigated. Residence-time weighted concentration maps were derived using 72 hour HYSPLIT back trajectory ensemble calculations. Trajectory runs were started 100 m AGL and the observed PM monthly averages were attributed to all trajectory runs in a month and each trajectory of the ensemble runs with equal probability. For investigating trends the dataset was further subdivided into two groups of four year durations each (1992-1995 and 2000-2003). We found a linear correlation with a slope of 1.0 (R2=0.9) between estimated seasonal average TSP (2000-2003) using our approach and the measured seasonal averages (2006-2007) for Kanpur, Ahmedabad, Pune and Bangalore. A linear fit between predicted and measured PM10 concentration for 19 sites with PM10 observations of at least one seasonal average between 1999-2009 shows a slope of 1.4 (R2=0.4). For the observation period 2000-2003, the Thar Desert and Taklimakan Desert emerged as largest sources for both PM10 (>180 μg/m3 and >200 μg/m3 respectively) and TSP (>650 μg/m3 and >725 μg/m3 respectively). In-situ observation at Bikaner (central Thar Desert) and in Jhunjhunu (semi-arid site at the border of the Thar Desert) indicate that both TSP and PM10 inside the desert source region are underpredicted by a factor of 10 compared to in-situ observations while for the semi arid area bordering the desert PM10 and TSP are underpredicted by a factor of 5 and 3 respectively. This indicates that strong sources are underpredicted by a receptor site centred approach. The entire North-Western Indo-Gangetic Basin (NW-IGB), where crop

  7. Bayesian source term estimation of atmospheric releases in urban areas using LES approach.

    PubMed

    Xue, Fei; Kikumoto, Hideki; Li, Xiaofeng; Ooka, Ryozo

    2018-05-05

    The estimation of source information from limited measurements of a sensor network is a challenging inverse problem, which can be viewed as an assimilation process of the observed concentration data and the predicted concentration data. When dealing with releases in built-up areas, the predicted data are generally obtained by the Reynolds-averaged Navier-Stokes (RANS) equations, which yields building-resolving results; however, RANS-based models are outperformed by large-eddy simulation (LES) in the predictions of both airflow and dispersion. Therefore, it is important to explore the possibility of improving the estimation of the source parameters by using the LES approach. In this paper, a novel source term estimation method is proposed based on LES approach using Bayesian inference. The source-receptor relationship is obtained by solving the adjoint equations constructed using the time-averaged flow field simulated by the LES approach based on the gradient diffusion hypothesis. A wind tunnel experiment with a constant point source downwind of a single building model is used to evaluate the performance of the proposed method, which is compared with that of the existing method using a RANS model. The results show that the proposed method reduces the errors of source location and releasing strength by 77% and 28%, respectively. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology.

    PubMed

    Fuxe, K; Marcellino, D; Rivera, A; Diaz-Cabiale, Z; Filip, M; Gago, B; Roberts, D C S; Langel, U; Genedani, S; Ferraro, L; de la Calle, A; Narvaez, J; Tanganelli, S; Woods, A; Agnati, L F

    2008-08-01

    Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson's disease, schizophrenia and drug addiction or drug dependence may substantially build on the existence of intramembrane receptor-receptor interactions within dopamine receptor containing receptor mosaics (RM; dimeric or high-order receptor oligomers) where it is believed that the dopamine D(2) receptor may operate as the 'hub receptor' within these complexes. The constitutive adenosine A(2A)/dopamine D(2) RM, located in the dorsal striato-pallidal GABA neurons, are of particular interest in view of the demonstrated antagonistic A(2A)/D(2) interaction within these heteromers; an interaction that led to the suggestion and later demonstration that A(2A) antagonists could be used as novel anti-Parkinsonian drugs. Based on the likely existence of A(2A)/D(2)/mGluR5 RM located both extrasynaptically on striato-pallidal GABA neurons and on cortico-striatal glutamate terminals, multiple receptor-receptor interactions within this RM involving synergism between A(2A)/mGluR5 to counteract D(2) signaling, has led to the proposal of using combined mGluR5 and A(2A) antagonists as a future anti-Parkinsonian treatment. Based on the same RM in the ventral striato-pallidal GABA pathways, novel strategies for the treatment of schizophrenia, building on the idea that A(2A) agonists and/or mGluR5 agonists will help reduce the increased dopaminergic signaling associated with this disease, have been suggested. Such treatment may ensure the proper glutamatergic drive from the mediodorsal thalamic nucleus to the prefrontal cortex, one which is believed to be reduced in schizophrenia due to a dominance of D(2)-like signaling in the ventral striatum. Recently, A(2A) receptors also have been shown to counteract the locomotor and sensitizing actions of cocaine and increases in A(2A) receptors have also been observed in the nucleus accumbens after extended cocaine self-administration, probably

  9. Relationship of dopamine type 2 receptor binding potential with fasting neuroendocrine hormones and insulin sensitivity in human obesity.

    PubMed

    Dunn, Julia P; Kessler, Robert M; Feurer, Irene D; Volkow, Nora D; Patterson, Bruce W; Ansari, Mohammad S; Li, Rui; Marks-Shulman, Pamela; Abumrad, Naji N

    2012-05-01

    Midbrain dopamine (DA) neurons, which are involved with reward and motivation, are modulated by hormones that regulate food intake (insulin, leptin, and acyl ghrelin [AG]). We hypothesized that these hormones are associated with deficits in DA signaling in obesity. We assessed the relationships between fasting levels of insulin and leptin, and AG, BMI, and insulin sensitivity index (S(I)) with the availability of central DA type 2 receptor (D2R). We measured D2R availability using positron emission tomography and [(18)F]fallypride (radioligand that competes with endogenous DA) in lean (n = 8) and obese (n = 14) females. Fasting hormones were collected prior to scanning and S(I) was determined by modified oral glucose tolerance test. Parametric image analyses revealed associations between each metabolic measure and D2R. The most extensive findings were negative associations of AG with clusters involving the striatum and inferior temporal cortices. Regional regression analyses also found extensive negative relationships between AG and D2R in the caudate, putamen, ventral striatum (VS), amygdala, and temporal lobes. S(I) was negatively associated with D2R in the VS, while insulin was not. In the caudate, BMI and leptin were positively associated with D2R availability. The direction of associations of leptin and AG with D2R availability are consistent with their opposite effects on DA levels (decreasing and increasing, respectively). After adjusting for BMI, AG maintained a significant relationship in the VS. We hypothesize that the increased D2R availability in obese subjects reflects relatively reduced DA levels competing with the radioligand. Our findings provide evidence for an association between the neuroendocrine hormones and DA brain signaling in obese females.

  10. The changing world of G protein-coupled receptors: from monomers to dimers and receptor mosaics with allosteric receptor-receptor interactions.

    PubMed

    Fuxe, Kjell; Marcellino, Daniel; Borroto-Escuela, Dasiel Oscar; Frankowska, Malgorzata; Ferraro, Luca; Guidolin, Diego; Ciruela, Francisco; Agnati, Luigi F

    2010-10-01

    Based on indications of direct physical interactions between neuropeptide and monoamine receptors in the early 1980s, the term receptor-receptor interactions was introduced and later on the term receptor heteromerization in the early 1990s. Allosteric mechanisms allow an integrative activity to emerge either intramolecularly in G protein-coupled receptor (GPCR) monomers or intermolecularly via receptor-receptor interactions in GPCR homodimers, heterodimers, and receptor mosaics. Stable heteromers of Class A receptors may be formed that involve strong high energy arginine-phosphate electrostatic interactions. These receptor-receptor interactions markedly increase the repertoire of GPCR recognition, signaling and trafficking in which the minimal signaling unit in the GPCR homomers appears to be one receptor and one G protein. GPCR homomers and GPCR assemblies are not isolated but also directly interact with other proteins to form horizontal molecular networks at the plasma membrane.

  11. Thiourea, a ROS scavenger, regulates source-to-sink relationship to enhance crop yield and oil content in Brassica juncea (L.).

    PubMed

    Pandey, Manish; Srivastava, Ashish Kumar; D'Souza, Stanislaus Francis; Penna, Suprasanna

    2013-01-01

    In the present agricultural scenario, the major thrust is to increase crop productivity so as to ensure sustainability. In an earlier study, foliar application of thiourea (TU; a non physiological thiol based ROS scavenger) has been demonstrated to enhance the stress tolerance and yield of different crops under field condition. Towards this endeavor, present work deals with the effect of TU on photosynthetic efficiency and source-to-sink relationship of Indian mustard (Brassica juncea) for understanding its mode of action. The application of TU increased the efficiency of both PSI and PSII photosystems and vegetative growth of plant. The comparative analysis of sucrose to starch ratio and expression level of sugar transporters confirmed the higher source and sink strength in response to TU treatment. The biochemical evidence in support of this was derived from higher activities of sucrose phosphate synthase and fructose-1,6-bis-phosphatase at source; and sucrose synthase and different classes of invertases at both source and sink. This indicated an overall increase in photoassimilate level at sink. An additional contribution through pod photosynthesis was confirmed through the analysis of phosphoenol pyruvate carboxylase enzyme activity and level of organic acids. The increased photoassimilate level was also co-ordinated with acetyl coA carboxylase mediated oil biosynthesis. All these changes were ultimately reflected in the form of 10 and 20% increase in total yield and oil content, respectively under TU treatment as compared to control. Additionally, no change was observed in oil composition of seeds derived from TU treated plants. The study thus signifies the co-ordinated regulation of key steps of photosynthesis and source-to-sink relationship through the external application of TU resulting in increased crop yield and oil content.

  12. 'Struggling to be the alpha': sources of tension and intimate partner violence in same-sex relationships between men.

    PubMed

    Goldenberg, Tamar; Stephenson, Rob; Freeland, Ryan; Finneran, Catherine; Hadley, Craig

    2016-08-01

    In countries such as the USA, gay and bisexual men experience high rates of intimate partner violence. However, little is known about the factors that contribute to this form of violence. In this study, we examine gay and bisexual men's perceptions of sources of tension in same-sex male relationships and how these may contribute to intimate partner violence. We conducted seven focus-group discussions with 64 gay and bisexual men in Atlanta, GA. Focus groups examined men's reactions to the short-form revised Conflicts Tactics Scale to determine if each item was considered to be intimate partner violence if it were to occur among gay and bisexual men. Analysts completed a thematic analysis, using elements of grounded theory. The sources of tension that men identified included: gender role conflict, dyadic inequalities (e.g. differences in income, age, education), differences in 'outness' about sexual identity, substance use, jealousy and external homophobic violence. Results suggest that intimate partner violence interventions for gay and bisexual men should address behavioural factors, while also focusing on structural interventions. Interventions that aim to reduce homophobic stigma and redefine male gender roles may help to address some of the tension that contributes to intimate partner violence in same-sex male relationships.

  13. Quantitative Characterization of Shear-Induced Platelet Receptor Shedding: Glycoprotein Ibα, Glycoprotein VI, and Glycoprotein IIb/IIIa.

    PubMed

    Chen, Zengsheng; Koenig, Steven C; Slaughter, Mark S; Griffith, Bartley P; Wu, Zhongjun J

    2017-11-07

    The structural integrity of platelet receptors is essential for platelets to play the normal hemostatic function. The high non-physiologic shear stress (NPSS) commonly exists in blood-contacting medical devices and has been shown to cause platelet receptor shedding. The loss of platelet receptors may impair the normal hemostatic function of platelets. The aim of this study was to quantify NPSS-induced shedding of three key receptors on the platelet surface. Human blood was subjected to the matrix of well-defined shear stresses and exposure times, generated by using a custom-designed blood-shearing device. The expression of three key platelet receptors, glycoprotein (GP) Ibα, GPVI, and GPIIb/IIIa, in sheared blood was quantified using flow cytometry. The quantitative relationship between the loss of each of the three receptors on the platelet surface and shear condition (shear stress level and exposure time) was explored. It was found that these relationships followed well the power law functional form. The coefficients of the power law models for the shear-induced shedding of these platelet receptors were derived with coefficients of determination (R) of 0.77, 0.73, and 0.78, respectively. The power law models with these coefficients may be potentially used to predict the shear-induced platelet receptor shedding of human blood.

  14. 1,2,4-Benzothiadiazine-1,1-dioxide derivatives as ionotropic glutamate receptor ligands: synthesis and structure-activity relationships.

    PubMed

    Varano, Flavia; Catarzi, Daniela; Colotta, Vittoria; Squarcialupi, Lucia; Matucci, Rosanna

    2014-11-01

    Ionotropic glutamate receptor (iGluR) modulators, specially AMPA receptor antagonists, are potential tools for numerous therapeutic applications in neurological disorders, including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy, chronic pain, and neuropathology ensuing from cerebral ischemia or cardiac arrest. In this work, the synthesis and binding affinities at the Gly/NMDA, AMPA, and kainic acid (KA) receptors of a new series of 1,2,4-benzothiadiazine-1,1-dioxide derivatives are reported. The results show that 1,2,4-benzothiadiazine-1,1-dioxide is a new scaffold for obtaining iGluR ligands. Moreover, this work has led us to the 7-(3-formylpyrrol-1-yl)-6-trifluoromethyl substituted compound 7, which displays the highest AMPA receptor affinity and high selectivity versus the Gly/NMDA (90-fold) and KA (46-fold) receptors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Role of the metabotropic P2Y(4) receptor during hypoglycemia: cross talk with the ionotropic NMDAR1 receptor.

    PubMed

    Cavaliere, Fabio; Amadio, Susanna; Angelini, Daniela F; Sancesario, Giuseppe; Bernardi, Giorgio; Volonté, Cinzia

    2004-10-15

    It is well established that both extracellular ATP and glutamate exert a critical role during metabolic impairment, that several P2 receptor subunits are directly involved in this action and that a strong relationship exists between glutamatergic and purinergic signals. Therefore, here we studied the molecular behavior of the purinergic metabotropic P2Y(4) and the glutamatergic ionotropic NMDAR1 receptors during hypoglycemic cell death. We find that these proteins are oppositely modulated during glucose starvation (P2Y(4) is induced, whereas NMDAR1 is inhibited) and that both P2 and NMDA antagonists can restore basal protein expression levels. Moreover, double immunofluorescence experiments with confocal laser microscopy reveal co-localization at the membrane level between the P2Y(4) and NMDAR1 receptors, in both homologous (cerebellar granule neurons) and heterologous (Hek-293) cellular systems. This is furthermore confirmed by co-immunoprecipitation experiments. Finally, when we express the P2Y(4) receptor in the heterologous SH-SY5Y neuronal cell line, hypoglycemia then causes severe cell death and simultaneous downregulation of the NMDAR1 protein. In summary, our work establishes a potential molecular interplay between P2Y(4) and NMDAR1 receptors during glucose deprivation and the causative role of the P2Y(4) during cell death.

  16. The Roles of Dopamine D1 Receptor on the Social Hierarchy of Rodents and Nonhuman Primates.

    PubMed

    Yamaguchi, Yoshie; Lee, Young-A; Kato, Akemi; Goto, Yukiori

    2017-04-01

    Although dopamine has been suggested to play a role in mediating social behaviors of individual animals, it is not clear whether such dopamine signaling contributes to attributes of social groups such as social hierarchy. In this study, the effects of the pharmacological manipulation of dopamine D1 receptor function on the social hierarchy and behavior of group-housed mice and macaques were investigated using a battery of behavioral tests. D1 receptor blockade facilitated social dominance in mice at the middle, but not high or low, social rank in the groups without altering social preference among mates. In contrast, the administration of a D1 receptor antagonist in a macaque did not affect social dominance of the drug-treated animal; however, relative social dominance relationships between the drug-treated and nontreated subjects were altered indirectly through alterations of social affiliative relationships within the social group. These results suggest that dopamine D1 receptor signaling may be involved in social hierarchy and social relationships within a group, which may differ between rodents and primates. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  17. The Relationship of Health Beliefs with Information Sources and HPV Vaccine Acceptance among Young Adults in Korea.

    PubMed

    Kim, Jarim

    2018-04-04

    Despite the HPV vaccine’s efficacy in preventing cervical cancer, its coverage rates among Asians are very low. To increase immunization coverage among these populations, understanding the psychological factors that affect HPV acceptability is critical. To this end, this study examined the relationships between multidimensional health beliefs and HPV vaccine acceptance, and what information sources effectively foster HPV vaccination-related health beliefs. Data were collected using a survey of 323 undergraduate students in Korea. Results showed that perceived susceptibility, perceived severity, perceived benefits, and perceived vaccine safety concerns predicted vaccine acceptance. Multiple dimensions of perceived barriers showed differing impacts on vaccine acceptance. In addition, interpersonal information sources were effective in boosting various health beliefs for HPV vaccination. The Internet also was effective in reducing social barriers, but the effects were opposite to those of social media. Theoretical and practical implications are discussed.

  18. Positive Effect of Carbon Sources on Natural Transformation in Escherichia coli: Role of Low-Level Cyclic AMP (cAMP)-cAMP Receptor Protein in the Derepression of rpoS

    PubMed Central

    Guo, Mengyue; Wang, Huanyu; Xie, Nengbin

    2015-01-01

    ABSTRACT Natural plasmid transformation of Escherichia coli is a complex process that occurs strictly on agar plates and requires the global stress response factor σS. Here, we showed that additional carbon sources could significantly enhance the transformability of E. coli. Inactivation of phosphotransferase system genes (ptsH, ptsG, and crr) caused an increase in the transformation frequency, and the addition of cyclic AMP (cAMP) neutralized the promotional effect of carbon sources. This implies a negative role of cAMP in natural transformation. Further study showed that crp and cyaA mutations conferred a higher transformation frequency, suggesting that the cAMP-cAMP receptor protein (CRP) complex has an inhibitory effect on transformation. Moreover, we observed that rpoS is negatively regulated by cAMP-CRP in early log phase and that both crp and cyaA mutants show no transformation superiority when rpoS is knocked out. Therefore, it can be concluded that both the crp and cyaA mutations derepress rpoS expression in early log phase, whereby they aid in the promotion of natural transformation ability. We also showed that the accumulation of RpoS during early log phase can account for the enhanced transformation aroused by additional carbon sources. Our results thus demonstrated that the presence of additional carbon sources promotes competence development and natural transformation by reducing cAMP-CRP and, thus, derepressing rpoS expression during log phase. This finding could contribute to a better understanding of the relationship between nutrition state and competence, as well as the mechanism of natural plasmid transformation in E. coli. IMPORTANCE Escherichia coli, which is not usually considered to be naturally transformable, was found to spontaneously take up plasmid DNA on agar plates. Researching the mechanism of natural transformation is important for understanding the role of transformation in evolution, as well as in the transfer of pathogenicity and

  19. Evidence for the lack of spare high-affinity insulin receptors in skeletal muscle.

    PubMed Central

    Camps, M; Gumà, A; Viñals, F; Testar, X; Palacín, M; Zorzano, A

    1992-01-01

    In this study, the relationship between the concentration of extracellular insulin, insulin binding and insulin action was evaluated in skeletal muscle. Initially we investigated the dose-response relationship of insulin action using three different experimental models that are responsive to insulin, i.e. the isolated perfused rat hindquarter, incubated strips of soleus muscle, and insulin receptors partially affinity-purified from skeletal muscle. We selected as insulin-sensitive parameters glucose uptake in the perfused hindquarter, lactate production in the incubated muscle preparation, and tyrosine receptor kinase activity in the purified receptor preparation. Our results showed that the dose-response curves obtained in the perfused hindquarter and in the incubated muscle were superimposable. In contrast, the dose-response curve for insulin-stimulated receptor tyrosine kinase activity in partially purified receptors was displaced to the left compared with the curves obtained in the perfused hindquarter and in the incubated muscle. The differences between the dose-response curve for receptor tyrosine kinase and those for glucose uptake and lactate production were not explained by a substantial insulin concentration gradient between medium and interstitial space. Thus the medium/interstitial insulin concentration ratio, when assayed in the incubated intact muscle at 5 degrees C, was close to 1. We also compared the dose-response curve of insulin-stimulated receptor tyrosine kinase with the pattern of insulin-binding-site occupancy. The curve of insulin-stimulated receptor kinase activity fitted closely with the occupancy of high-affinity binding sites. In summary, assuming that the estimation of the medium/interstitial insulin concentration ratio obtained at 5 degrees C reflects the actual ratio under more physiological conditions, our results suggest that maximal insulin action is obtained in skeletal muscle at insulin concentrations which do allow full

  20. Evidence for the lack of spare high-affinity insulin receptors in skeletal muscle.

    PubMed

    Camps, M; Gumà, A; Viñals, F; Testar, X; Palacín, M; Zorzano, A

    1992-08-01

    In this study, the relationship between the concentration of extracellular insulin, insulin binding and insulin action was evaluated in skeletal muscle. Initially we investigated the dose-response relationship of insulin action using three different experimental models that are responsive to insulin, i.e. the isolated perfused rat hindquarter, incubated strips of soleus muscle, and insulin receptors partially affinity-purified from skeletal muscle. We selected as insulin-sensitive parameters glucose uptake in the perfused hindquarter, lactate production in the incubated muscle preparation, and tyrosine receptor kinase activity in the purified receptor preparation. Our results showed that the dose-response curves obtained in the perfused hindquarter and in the incubated muscle were superimposable. In contrast, the dose-response curve for insulin-stimulated receptor tyrosine kinase activity in partially purified receptors was displaced to the left compared with the curves obtained in the perfused hindquarter and in the incubated muscle. The differences between the dose-response curve for receptor tyrosine kinase and those for glucose uptake and lactate production were not explained by a substantial insulin concentration gradient between medium and interstitial space. Thus the medium/interstitial insulin concentration ratio, when assayed in the incubated intact muscle at 5 degrees C, was close to 1. We also compared the dose-response curve of insulin-stimulated receptor tyrosine kinase with the pattern of insulin-binding-site occupancy. The curve of insulin-stimulated receptor kinase activity fitted closely with the occupancy of high-affinity binding sites. In summary, assuming that the estimation of the medium/interstitial insulin concentration ratio obtained at 5 degrees C reflects the actual ratio under more physiological conditions, our results suggest that maximal insulin action is obtained in skeletal muscle at insulin concentrations which do allow full

  1. Relationship between soluble receptor for advanced glycation end products (sRAGE), body composition and fat distribution in healthy women.

    PubMed

    Dozio, Elena; Briganti, Silvia; Delnevo, Alessandra; Vianello, Elena; Ermetici, Federica; Secchi, Francesco; Sardanelli, Francesco; Morricone, Lelio; Malavazos, Alexis E; Corsi Romanelli, Massimiliano M

    2017-12-01

    Soluble receptor for advanced glycation end products (sRAGE) is a decoy receptor which sequesters RAGE ligands and acts as a cytoprotective agent. To date, it is unclear whether the lower sRAGE levels observed in obesity are a marker of increased overall adiposity or reflect increases in particular fat depots. Therefore, we evaluated in healthy women the relationship among sRAGE and indicators of adiposity, including abdominal visceral (VAT) and epicardial visceral (EAT) adipose tissues, to explore the potential role of sRAGE as an earlier biomarker of cardiometabolic risk. Plasma sRAGE levels were quantified by an enzyme-linked immunosorbent assay in 47 healthy women. Total fat mass (FM) and fat-free mass were estimated with bioimpedance analysis. Anthropometric measures and biochemical data were recorded. Subcutaneous adipose tissue, VAT and EAT volumes were measured by magnetic resonance imaging. Obese women had lower sRAGE levels compared to normal-weight women. sRAGE levels were also lower in women with a waist circumference (WC) larger than 80 cm. Correlation analyses indicated an inverse association of sRAGE with body mass index and FM. Concerning adipose tissue distribution, sRAGE inversely correlated with WC, EAT and VAT depots. In a multiple stepwise regression analysis, performed to emphasize the role of fat distribution, EAT volume was the only predictor of sRAGE. Lower sRAGE levels reflect accumulation of visceral fat mainly at the epicardial level and are present in advance of metabolic complications in adult women. sRAGE quantification might be an early marker of cardiometabolic risk.

  2. Relationship between hard X-ray and EUV sources in solar flares

    NASA Technical Reports Server (NTRS)

    Kane, S. R.; Frost, K. J.; Donnelly, R. F.

    1979-01-01

    The high time resolution hard X-ray (not less than 15 keV) observations of medium and large impulsive solar flares made with the OSO 5 satellite are compared with the simultaneous ground-based observations of 10-1030 A EUV flux made via sudden frequency deviations (SFD) at Boulder. For most flares the agreement between the times of maxima of the impulsive hard X-ray and EUV emissions is found to be consistent with earlier studies (not less than 1 s). The rise and decay times of the EUV emission are larger than the corresponding times for X-rays not less than 30 keV. When OSO 5 hard X-ray measurements are combined with those made by OGO1, OGO 3, OGO 5, and TD 1A satellites, it is found that there is a nearly linear relationship between the energy fluxes of impulsive EUV emission and X-rays not less than 10 keV over a wide range of flare magnitudes. A model involving only a 'partial precipitation' of energetic electrons and consisting of both thick and thin target hard X-ray sources is examined.

  3. DEVELOPMENT AND EVALUATION OF PM 2.5 SOURCE APPORTIONMENT METHODOLOGIES

    EPA Science Inventory

    The receptor model called Positive Matrix Factorization (PMF) has been extensively used to apportion sources of ambient fine particulate matter (PM2.5), but the accuracy of source apportionment results currently remains unknown. In addition, air quality forecast model...

  4. Emission sources estimation of size-segregated suburban aerosols measured in continental part of Balkan region using PMF5.0 multivariate receptor model

    NASA Astrophysics Data System (ADS)

    Petrovic, Srdjan; Đuričić-Milanković, Jelena; Anđelković, Ivan; Pantelić, Ana; Gambaro, Andrea; Đorđević, Dragana

    2017-04-01

    Using Low-Pressure Cascade Impactors by Dr Berner size segregated particulate matter in the size ranges: 0.27 ≤ Dp ≤ 0.53 μm, 0.53 ≤ Dp ≤ 1.06 μm, 1.06 ≤ Dp ≤ 2.09 μm, 2.09 ≤ Dp ≤ 4.11 μm, 4.11 ≤ Dp ≤ 8.11 μm and 8.11 ≤ Dp ≤ 16 μm were collected. Forty-eight-hour size segregated particulate matter samples from atmospheric aerosols in the sub-urban site of Belgrade were measured during two years (in 2012th to 2013in). ICP-MS was used to quantify next elements: Ag, Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Hg, Na, Ni, Mg, Mn, Mo, Pb, Se, Sb, Ti, Tl, V and Zn. In order to examine the number of sources and their fingerprints, EPA PMF 5.0 multivariate receptor tool was used. Error estimation methods (bootstrap, displacement, and bootstrap enhanced by displacement) in the analysis of the obtained solutions have enabled proper detection of the number and types of sources. This analysis of the results indicated the existence of four main sources that contribute to air pollution in the suburban area of Belgrade.

  5. Receptor-based 3D QSAR analysis of estrogen receptor ligands - merging the accuracy of receptor-based alignments with the computational efficiency of ligand-based methods

    NASA Astrophysics Data System (ADS)

    Sippl, Wolfgang

    2000-08-01

    One of the major challenges in computational approaches to drug design is the accurate prediction of binding affinity of biomolecules. In the present study several prediction methods for a published set of estrogen receptor ligands are investigated and compared. The binding modes of 30 ligands were determined using the docking program AutoDock and were compared with available X-ray structures of estrogen receptor-ligand complexes. On the basis of the docking results an interaction energy-based model, which uses the information of the whole ligand-receptor complex, was generated. Several parameters were modified in order to analyze their influence onto the correlation between binding affinities and calculated ligand-receptor interaction energies. The highest correlation coefficient ( r 2 = 0.617, q 2 LOO = 0.570) was obtained considering protein flexibility during the interaction energy evaluation. The second prediction method uses a combination of receptor-based and 3D quantitative structure-activity relationships (3D QSAR) methods. The ligand alignment obtained from the docking simulations was taken as basis for a comparative field analysis applying the GRID/GOLPE program. Using the interaction field derived with a water probe and applying the smart region definition (SRD) variable selection, a significant and robust model was obtained ( r 2 = 0.991, q 2 LOO = 0.921). The predictive ability of the established model was further evaluated by using a test set of six additional compounds. The comparison with the generated interaction energy-based model and with a traditional CoMFA model obtained using a ligand-based alignment ( r 2 = 0.951, q 2 LOO = 0.796) indicates that the combination of receptor-based and 3D QSAR methods is able to improve the quality of the underlying model.

  6. Bayesian source term determination with unknown covariance of measurements

    NASA Astrophysics Data System (ADS)

    Belal, Alkomiet; Tichý, Ondřej; Šmídl, Václav

    2017-04-01

    Determination of a source term of release of a hazardous material into the atmosphere is a very important task for emergency response. We are concerned with the problem of estimation of the source term in the conventional linear inverse problem, y = Mx, where the relationship between the vector of observations y is described using the source-receptor-sensitivity (SRS) matrix M and the unknown source term x. Since the system is typically ill-conditioned, the problem is recast as an optimization problem minR,B(y - Mx)TR-1(y - Mx) + xTB-1x. The first term minimizes the error of the measurements with covariance matrix R, and the second term is a regularization of the source term. There are different types of regularization arising for different choices of matrices R and B, for example, Tikhonov regularization assumes covariance matrix B as the identity matrix multiplied by scalar parameter. In this contribution, we adopt a Bayesian approach to make inference on the unknown source term x as well as unknown R and B. We assume prior on x to be a Gaussian with zero mean and unknown diagonal covariance matrix B. The covariance matrix of the likelihood R is also unknown. We consider two potential choices of the structure of the matrix R. First is the diagonal matrix and the second is a locally correlated structure using information on topology of the measuring network. Since the inference of the model is intractable, iterative variational Bayes algorithm is used for simultaneous estimation of all model parameters. The practical usefulness of our contribution is demonstrated on an application of the resulting algorithm to real data from the European Tracer Experiment (ETEX). This research is supported by EEA/Norwegian Financial Mechanism under project MSMT-28477/2014 Source-Term Determination of Radionuclide Releases by Inverse Atmospheric Dispersion Modelling (STRADI).

  7. Autoantibodies against β1 receptor and AT1 receptor in type 2 diabetes patients with left ventricular dilatation.

    PubMed

    Zhao, Linshuang; Xu, Chunyan; Xu, Jinling

    2014-01-01

    To explore the relationship between the autoantibodies against the β1 and AT1 receptors and left ventricular dilatation in patients with type 2 diabetes (T2DM). The autoantibodies against the β1 and angiotensin II type 1 (AT1) receptors of T2DM patients with and without hypertension were screened by ELISA. Multiple logistic regression was used to analyze the risk factors for left ventricular dilatation. The reversing effect of left ventricular dilatation was evaluated after receptor blocker treatment. The positive rates of autoantibodies against the β1 and AT1 receptors (43.0 and 44.1%, respectively) in T2DM patients with hypertension were significantly higher than those in normotensive patients (16.0 and 10.4%, respectively; all p < 0.01). Furthermore, among T2DM patients with hypertension, the positive rates (61.4 and 64.9%, respectively) in patients with left ventricular dilatation were remarkably higher than those with normal left ventricular dimensions (34.4 and 36.1%, respectively; all p < 0.01). The presence of β1 receptor antibody and AT1 receptor antibody were risk factors for left ventricular dilatation (p < 0.05). The curative effect of metoprolol tartrate and valsartan in reversing left ventricular hypertrophy in the group positive for autoantibodies was much better than in the negative group. The findings show that autoantibodies against the β1 and AT1 receptors may play a role in predicting left ventricular dilatation in T2DM patients in combination with hypertension. Metoprolol tartrate and valsartan are effective and safe in the treatment of these patients. © 2014 S. Karger AG, Basel.

  8. Dry season limnological conditions and basin geology exhibit complex relationships with δ13C and δ15N of carbon sources in four Neotropical floodplains.

    PubMed

    Zaia Alves, Gustavo H; Hoeinghaus, David J; Manetta, Gislaine I; Benedito, Evanilde

    2017-01-01

    Studies in freshwater ecosystems are seeking to improve understanding of carbon flow in food webs and stable isotopes have been influential in this work. However, variation in isotopic values of basal production sources could either be an asset or a hindrance depending on study objectives. We assessed the potential for basin geology and local limnological conditions to predict stable carbon and nitrogen isotope values of six carbon sources at multiple locations in four Neotropical floodplain ecosystems (Paraná, Pantanal, Araguaia, and Amazon). Limnological conditions exhibited greater variation within than among systems. δ15N differed among basins for most carbon sources, but δ13C did not (though high within-basin variability for periphyton, phytoplankton and particulate organic carbon was observed). Although δ13C and δ15N values exhibited significant correlations with some limnological factors within and among basins, those relationships differed among carbon sources. Regression trees for both carbon and nitrogen isotopes for all sources depicted complex and in some cases nested relationships, and only very limited similarity was observed among trees for different carbon sources. Although limnological conditions predicted variation in isotope values of carbon sources, we suggest the resulting models were too complex to enable mathematical corrections of source isotope values among sites based on these parameters. The importance of local conditions in determining variation in source isotope values suggest that isotopes may be useful for examining habitat use, dispersal and patch dynamics within heterogeneous floodplain ecosystems, but spatial variability in isotope values needs to be explicitly considered when testing ecosystem models of carbon flow in these systems.

  9. Glucocorticoid Receptor Related Genes: Genotype And Brain Gene Expression Relationships To Suicide And Major Depressive Disorder

    PubMed Central

    Pantazatos, Spiro P.; Huang, Yung-yu; Rosoklija, Gorazd B.; Dwork, Andrew J.; Burke, Ainsley; Arango, Victoria; Oquendo, Maria A.; Mann, J. John

    2016-01-01

    Introduction We tested the relationship between genotype, gene expression and suicidal behavior and MDD in live subjects and postmortem samples for three genes, associated with the hypothalamic-pituitary-adrenal axis, suicidal behavior and major depressive disorder (MDD); FK506 binding protein 5 (FKBP5), Spindle and kinetochore-associated protein 2 (SKA2) and Glucocorticoid Receptor (NR3C1). Materials and Methods Single-nucleotide polymorphisms (SNPs) and haplotypes were tested for association with suicidal behavior and MDD in a live (N=277) and a postmortem sample (N=209). RNA-seq was used to examine gene and isoform-level brain expression postmortem (Brodmann Area 9) (N=59). Expression quantitative trait loci (eQTL) relationships were examined using a public database (UK Brain Expression Consortium). Results We identified a haplotype within the FKBP5 gene, present in 47% of the live subjects, that was associated with increased risk of suicide attempt (OR=1.58, t=6.03, p=0.014). Six SNPs on this gene, three SNPs on SKA2 and one near NR3C1 showed before-adjustment association with attempted suicide, and two SNPs of SKA2 with suicide death, but none stayed significant after adjustment for multiple testing. Only the SKA2 SNPs were related to expression in the prefrontal cortex. One NR3C1 transcript had lower expression in suicide relative to non-suicide sudden death cases (b=-0.48, SE=0.12, t=-4.02, adjusted p=0.004). Conclusion We have identified an association of FKBP5 haplotype with risk of suicide attempt and found an association between suicide and altered NR3C1 gene expression in the prefrontal cortex. Our findings further implicate hypothalamic pituitary axis dysfunction in suicidal behavior. PMID:27030168

  10. GLUCOCORTICOID RECEPTOR-RELATED GENES: GENOTYPE AND BRAIN GENE EXPRESSION RELATIONSHIPS TO SUICIDE AND MAJOR DEPRESSIVE DISORDER.

    PubMed

    Yin, Honglei; Galfalvy, Hanga; Pantazatos, Spiro P; Huang, Yung-Yu; Rosoklija, Gorazd B; Dwork, Andrew J; Burke, Ainsley; Arango, Victoria; Oquendo, Maria A; Mann, J John

    2016-06-01

    We tested the relationship between genotype, gene expression and suicidal behavior and major depressive disorder (MDD) in live subjects and postmortem samples for three genes, associated with the hypothalamic-pituitary-adrenal axis, suicidal behavior, and MDD; FK506-binding protein 5 (FKBP5), Spindle and kinetochore-associated protein 2 (SKA2), and Glucocorticoid Receptor (NR3C1). Single-nucleotide polymorphisms (SNPs) and haplotypes were tested for association with suicidal behavior and MDD in a live (N = 277) and a postmortem sample (N = 209). RNA-seq was used to examine gene and isoform-level brain expression postmortem (Brodmann Area 9; N = 59). Expression quantitative trait loci (eQTL) relationships were examined using a public database (UK Brain Expression Consortium). We identified a haplotype within the FKBP5 gene, present in 47% of the live subjects, which was associated with increased risk of suicide attempt (OR = 1.58, t = 6.03, P = .014). Six SNPs on this gene, three SNPs on SKA2, and one near NR3C1 showed before-adjustment association with attempted suicide, and two SNPs of SKA2 with suicide death, but none stayed significant after adjustment for multiple testing. Only the SKA2 SNPs were related to expression in the prefrontal cortex (pFCTX). One NR3C1 transcript had lower expression in suicide relative to nonsuicide sudden death cases (b = -0.48, SE = 0.12, t = -4.02, adjusted P = .004). We have identified an association of FKBP5 haplotype with risk of suicide attempt and found an association between suicide and altered NR3C1 gene expression in the pFCTX. Our findings further implicate hypothalamic pituitary axis dysfunction in suicidal behavior. © 2016 Wiley Periodicals, Inc.

  11. Decreased brain sigma-1 receptor contributes to the relationship between heart failure and depression.

    PubMed

    Ito, Koji; Hirooka, Yoshitaka; Matsukawa, Ryuichi; Nakano, Masatsugu; Sunagawa, Kenji

    2012-01-01

    Depression often coexists with cardiovascular disease, such as hypertension and heart failure, in which sympathetic hyperactivation is critically involved. Reduction in the brain sigma-1 receptor (S1R) functions in depression pathogenesis via neuronal activity modulation. We hypothesized that reduced brain S1R exacerbates heart failure, especially with pressure overload via sympathetic hyperactivation and worsening depression. Male Institute of Cancer Research mice were treated with aortic banding and, 4 weeks thereafter, fed a high-salt diet for an additional 4 weeks to accelerate cardiac dysfunction (AB-H). Compared with sham-operated controls (Sham), AB-H showed augmented sympathetic activity, decreased per cent fractional shortening, increased left ventricular dimensions, and significantly lower brain S1R expression. Intracerebroventricular (ICV) infusion of S1R agonist PRE084 increased brain S1R expression, lowered sympathetic activity, and improved cardiac function in AB-H. ICV infusion of S1R antagonist BD1063 increased sympathetic activity and decreased cardiac function in Sham. Tail suspension test was used to evaluate the index of depression-like behaviour, with immobility time and strain amplitude recorded as markers of struggle activity using a force transducer. Immobility time increased and strain amplitude decreased in AB-H compared with Sham, and these changes were attenuated by ICV infusion of PRE084. These results indicate that decreased brain S1R contributes to the relationship between heart failure and depression in a mouse model of pressure overload.

  12. Recombinant Collagen Engineered to Bind to Discoidin Domain Receptor Functions as a Receptor Inhibitor*

    PubMed Central

    An, Bo; Abbonante, Vittorio; Xu, Huifang; Gavriilidou, Despoina; Yoshizumi, Ayumi; Bihan, Dominique; Farndale, Richard W.; Kaplan, David L.; Balduini, Alessandra; Leitinger, Birgit; Brodsky, Barbara

    2016-01-01

    A bacterial collagen-like protein Scl2 has been developed as a recombinant collagen model system to host human collagen ligand-binding sequences, with the goal of generating biomaterials with selective collagen bioactivities. Defined binding sites in human collagen for integrins, fibronectin, heparin, and MMP-1 have been introduced into the triple-helical domain of the bacterial collagen and led to the expected biological activities. The modular insertion of activities is extended here to the discoidin domain receptors (DDRs), which are collagen-activated receptor tyrosine kinases. Insertion of the DDR-binding sequence from human collagen III into bacterial collagen led to specific receptor binding. However, even at the highest testable concentrations, the construct was unable to stimulate DDR autophosphorylation. The recombinant collagen expressed in Escherichia coli does not contain hydroxyproline (Hyp), and complementary synthetic peptide studies showed that replacement of Hyp by Pro at the critical Gly-Val-Met-Gly-Phe-Hyp position decreased the DDR-binding affinity and consequently required a higher concentration for the induction of receptor activation. The ability of the recombinant bacterial collagen to bind the DDRs without inducing kinase activation suggested it could interfere with the interactions between animal collagen and the DDRs, and such an inhibitory role was confirmed in vitro and with a cell migration assay. This study illustrates that recombinant collagen can complement synthetic peptides in investigating structure-activity relationships, and this system has the potential for the introduction or inhibition of specific biological activities. PMID:26702058

  13. Expression of Angiotensin II Types 1 and 2 Receptors in Endometriotic Lesions.

    PubMed

    Nakao, Takehiro; Chishima, Fumihisa; Sugitani, Masahiko; Tsujimura, Ryusuke; Hayashi, Chuyu; Yamamoto, Tatsuo

    2017-01-01

    The aim of this study was to evaluate the gene and protein expression of angiotensin type (AT) 1, AT2 receptors in endometriotic lesions and its relation to prostaglandin (PG) synthases. Endometriosis samples were obtained from 32 patients with endometriotic cysts. Endometrial tissues were obtained during operations for benign gynecological conditions. The expression of the AT1 and AT2 receptor mRNA and that of PG-endoperoxide synthase 2 and microsomal PGE2 synthase-1 (mPGES-1) was examined by quantitative RT-PCR. Immunohistochemical staining was performed for these receptors. AT1 and AT2 receptor proteins were mostly located in endometrial glandular epithelium and some stromal cells. Immunoreactivity of the receptor proteins was observed in both the eutopic endometrium and endometriotic lesions. The AT1/AT2 ratio in endometriotic cysts (median 7.29, range 1.88-187.60) was significantly increased compared with that in the eutopic endometrium in the proliferative-phase in controls (median 1.01, range 0.37-2.09, p < 0.001). There was a relationship between the AT1 mRNA expression and that of mPGES-1 mRNA in the endometriotic cysts (r = 0.394089, p < 0.05). There was a significant relationship between the mRNA expression of the AT2 receptor and that of mPGES-1 in eutopic endometrium of non-endometriotic control (r = 0.610714, p < 0.05). Renin-angiotensin system may play an important role in the pathophysiology of endometriosis. © 2016 S. Karger AG, Basel.

  14. New horizons for lipoprotein receptors: communication by β-propellers

    PubMed Central

    Andersen, Olav M.; Dagil, Robert; Kragelund, Birthe B.

    2013-01-01

    The lipoprotein receptor (LR) family constitutes a large group of structurally closely related receptors with broad ligand-binding specificity. Traditionally, ligand binding to LRs has been anticipated to involve merely the complement type repeat (CR)-domains omnipresent in the family. Recently, this dogma has transformed with the observation that β-propellers of some LRs actively engage in complex formation too. Based on an in-depth decomposition of current structures and sequences, we suggest that exploitation of the β-propellers as binding targets depends on receptor subgroups. In particular, we highlight the shutter mechanism of β-propellers as a general recognition motif for NxI-containing ligands, and we present indications that the generalized β-propeller-induced ligand release mechanism is not applicable for the larger LRs. For the giant LR members, we present evidence that their β-propellers may also actively engage in ligand binding. We therefore advocate for an increased focus on solving the structure-function relationship of this group of important biological receptors. PMID:23881912

  15. μ Opioid receptor: novel antagonists and structural modeling

    NASA Astrophysics Data System (ADS)

    Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

    2016-02-01

    The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

  16. [The relationship between necroptosis and blinding eye diseases].

    PubMed

    Xie, L L; Jiang, B

    2018-03-11

    As a programmed cell death manner which is distinguished from apoptosis and autophagy, necroptosis is a newly discovered pathway of regulated necrosis that requires the protein receptor interacting protein kinases 1 and 3 and mixed lineage kinase domain-like protein. Necroptosis is mediated by death receptors, toll-like receptors and probably other mediators. Emerging evidences have delineated that necroptosis plays an important role in the occurrence and development of various blinding eye diseases. In this review, the related mechanism of necroptosis, the relationship between necroptosis and multiple blinding eye diseases, such as age-related macular degeneration, retinitis pigmentosa and glaucoma, and the potential therapeutic targets of necroptosis are discussed. (Chin J Ophthalmol, 2018, 54: 234-240) .

  17. Receptor-mediated signalling in plants: molecular patterns and programmes

    PubMed Central

    Tör, Mahmut; Lotze, Michael T.; Holton, Nicholas

    2009-01-01

    A highly evolved surveillance system in plants is able to detect a broad range of signals originating from pathogens, damaged tissues, or altered developmental processes, initiating sophisticated molecular mechanisms that result in defence, wound healing, and development. Microbe-associated molecular pattern molecules (MAMPs), damage-associated molecular pattern molecules (DAMPs), virulence factors, secreted proteins, and processed peptides can be recognized directly or indirectly by this surveillance system. Nucleotide binding-leucine rich repeat proteins (NB-LRR) are intracellular receptors and have been targeted by breeders for decades to elicit resistance to crop pathogens in the field. Receptor-like kinases (RLKs) or receptor like proteins (RLPs) are membrane bound signalling molecules with an extracellular receptor domain. They provide an early warning system for the presence of potential pathogens and activate protective immune signalling in plants. In addition, they act as a signal amplifier in the case of tissue damage, establishing symbiotic relationships and effecting developmental processes. The identification of several important ligands for the RLK-type receptors provided an opportunity to understand how plants differentiate, how they distinguish beneficial and detrimental stimuli, and how they co-ordinate the role of various types of receptors under varying environmental conditions. The diverse roles of extra-and intracellular plant receptors are examined here and the recent findings on how they promote defence and development is reviewed. PMID:19628572

  18. The Relationship of Health Beliefs with Information Sources and HPV Vaccine Acceptance among Young Adults in Korea

    PubMed Central

    Kim, Jarim

    2018-01-01

    Despite the HPV vaccine’s efficacy in preventing cervical cancer, its coverage rates among Asians are very low. To increase immunization coverage among these populations, understanding the psychological factors that affect HPV acceptability is critical. To this end, this study examined the relationships between multidimensional health beliefs and HPV vaccine acceptance, and what information sources effectively foster HPV vaccination-related health beliefs. Data were collected using a survey of 323 undergraduate students in Korea. Results showed that perceived susceptibility, perceived severity, perceived benefits, and perceived vaccine safety concerns predicted vaccine acceptance. Multiple dimensions of perceived barriers showed differing impacts on vaccine acceptance. In addition, interpersonal information sources were effective in boosting various health beliefs for HPV vaccination. The Internet also was effective in reducing social barriers, but the effects were opposite to those of social media. Theoretical and practical implications are discussed. PMID:29617313

  19. Identifying PM2.5 and PM0.1 sources for epidemiological studies in California.

    PubMed

    Hu, Jianlin; Zhang, Hongliang; Chen, Shuhua; Ying, Qi; Wiedinmyer, Christine; Vandenberghe, Francois; Kleeman, Michael J

    2014-05-06

    The University of California-Davis_Primary (UCD_P) model was applied to simultaneously track ∼ 900 source contributions to primary particulate matter (PM) in California for seven continuous years (January 1st, 2000 to December 31st, 2006). Predicted source contributions to primary PM2.5 mass, PM1.8 elemental carbon (EC), PM1.8 organic carbon (OC), PM0.1 EC, and PM0.1 OC were in general agreement with the results from previous source apportionment studies using receptor-based techniques. All sources were further subjected to a constraint check based on model performance for PM trace elemental composition. A total of 151 PM2.5 sources and 71 PM0.1 sources contained PM elements that were predicted at concentrations in general agreement with measured values at nearby monitoring sites. Significant spatial heterogeneity was predicted among the 151 PM2.5 and 71 PM0.1 source concentrations, and significantly different seasonal profiles were predicted for PM2.5 and PM0.1 in central California vs southern California. Population-weighted concentrations of PM emitted from various sources calculated using the UCD_P model spatial information differed from the central monitor estimates by up to 77% for primary PM2.5 mass and 148% for PM2.5 EC because the central monitor concentration is not representative of exposure for nearby population. The results from the UCD_P model provide enhanced source apportionment information for epidemiological studies to examine the relationship between health effects and concentrations of primary PM from individual sources.

  20. Dopamine D4 receptor gene polymorphism and personality traits in healthy volunteers.

    PubMed

    Persson, M L; Wasserman, D; Geijer, T; Frisch, A; Rockah, R; Michaelovsky, E; Apter, A; Weizman, A; Jönsson, E G; Bergman, H

    2000-01-01

    An association between long alleles of a variable number tandem repeat (VNTR) polymorphism in the dopamine receptor D4 gene and the extraversion related personality traits Excitement and Novelty Seeking has been reported in healthy subjects. In an attempt to replicate the previous findings, 256 healthy Caucasian volunteers were analysed for a potential relationship between the dopamine receptor D4 exon III VNTR polymorphism and Extraversion as assessed by the Revised Neo Personality Inventory (NEO PI-R). The present study did not yield evidence for an association between Extraversion and the dopamine receptor D4 polymorphism.

  1. Source attribution of tropospheric ozone

    NASA Astrophysics Data System (ADS)

    Butler, T. M.

    2015-12-01

    geographical regions and to emission sectors. Source-receptor relationships are defined for intercontinental transport of ozone and its precursors, and the relative contributions of NOx, methane, CO, NMVOC, and stratosphere-troposphere exchange to tropospheric background ozone are determined.

  2. Expectations for Future Relationship Satisfaction: Unique Sources and Critical Implications for Commitment

    PubMed Central

    Baker, Levi R.; McNulty, James K.; VanderDrift, Laura E.

    2017-01-01

    Contemporary perspectives on relationship commitment posit that intimates decide whether or not to maintain a relationship based on their commitment to that relationship, and that they base such commitment partially on their current satisfaction with that relationship. Nevertheless, given that ending a relationship requires knowing about both the current state of the relationship and the likely future state of the relationship, we propose that people base their commitment to a relationship more on their expected future satisfaction with the relationship than on their current satisfaction with that relationship. Six studies provided evidence for these ideas. Study 1 demonstrated that expected satisfaction is shaped by not only current satisfaction but also several unique indicators of the likelihood of future satisfaction, including anticipated life events, plans to improve the relationship, and individual differences. Then, using a combination of cross-sectional, experimental, and longitudinal methods, Studies 2–6 demonstrated that (a) expected satisfaction was a stronger predictor of relationship commitment, maintenance behaviors, and/or divorce than was current satisfaction and (b) expected satisfaction mediated the association between current satisfaction and these outcomes. These findings highlight not only the need to incorporate expected satisfaction into extent perspectives on commitment, but also the importance of expectations for decision-making processes more broadly. PMID:28368196

  3. Relationship between circulating serum osteoprotegerin and total receptor activator of nuclear κ-B ligand levels, triglycerides, and coronary calcification in postmenopausal women.

    PubMed

    Poornima, Indu G; Mackey, Rachel H; Buhari, Alhaji M; Cauley, Jane A; Matthews, Karen A; Kuller, Lewis H

    2014-07-01

    This study evaluates the relationship of blood osteoprotegerin (OPG) and receptor activator of nuclear κ-B ligand (RANKL) levels with coronary artery calcium (CAC) and cardiovascular risk factors in two studies of postmenopausal women. OPG, a marker of bone turnover, and its ligand, RANKL, may contribute to cardiovascular disease risk. We tested the hypothesis that serum OPG and RANKL levels were associated with CAC and cardiovascular disease risk factors among postmenopausal women in the Women On the Move through Activity and Nutrition Study (WOMAN Study; n = 86; mean [SD], age 58 [2.9] y) and replicated our findings in the Healthy Women Study (HWS; n = 205; mean [SD] age, 61 [2.3] y). Serum OPG, total RANKL, and CAC were measured at baseline and 48 months in the WOMAN Study and on the eighth postmenopausal visit in the HWS. In the WOMAN Study, higher OPG was associated with higher CAC, and higher total RANKL was associated with lower CAC and triglycerides. In the HWS, higher total RANKL was also associated with lower CAC and triglycerides. In logistic regression models adjusted for body mass index and triglycerides, the odds ratios (95% CIs) for CAC per unit increase in OPG were 1.78 (1.17-2.73) for the WOMAN Study and 1.02 (0.84-1.24) for the HWS, and the odds ratios (95% CIs) for CAC per unit increase in log total RANKL were 0.86 (0.64-1.17) for the WOMAN Study and 0.83 (0.72-0.96) for the HWS. The inverse association of total RANKL with CAC and triglycerides is a new finding and may have important implications given the increasing use of drugs that modify total RANKL and its receptor, receptor activator of nuclear κ-B.

  4. Structure-5-HT/D2 Receptor Affinity Relationship in a New Group of 1-Arylpiperazynylalkyl Derivatives of 8-Dialkylamino-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione.

    PubMed

    Żmudzki, Paweł; Satała, Grzegorz; Chłoń-Rzepa, Grażyna; Bojarski, Andrzej J; Kazek, Grzegorz; Siwek, Agata; Gryboś, Anna; Głuch-Lutwin, Monika; Wesołowska, Anna; Pawłowski, Maciej

    2016-10-01

    In our previous papers, we have reported that some 8-amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives possessed high affinity and displayed agonistic, partial agonistic, or antagonistic activity for serotonin 5-HT 1A and dopamine D 2 receptors. In order to examine further the influence of the substituent in the position 8 of the purine moiety and the influence of the xanthine core on the affinity for serotonin 5-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 , and dopamine D 2 receptors, two series of 1-arylpiperazynylalkyl derivatives of 8-amino-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione were synthesized. All the final compounds were investigated in in vitro competition binding experiments for the serotonin 5-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 , and dopamine D 2 receptors. The structure-affinity relationships for this group of compounds were discussed. For selected compounds, the functional assays for the 5-HT 1A and D 2 receptors were carried out. The results of the assays indicated that these groups of derivatives possessed antagonistic activity for 5-HT 1A receptors and agonistic, partial agonistic, or antagonistic activity for D 2 receptors. In total, 26 new compounds were synthesized, 20 of which were tested in in vitro binding experiments and 5 were tested in in vitro functional assays. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Evolutionary Analysis of Functional Divergence among Chemokine Receptors, Decoy Receptors, and Viral Receptors

    PubMed Central

    Daiyasu, Hiromi; Nemoto, Wataru; Toh, Hiroyuki

    2012-01-01

    Chemokine receptors (CKRs) function in the inflammatory response and in vertebrate homeostasis. Decoy and viral receptors are two types of CKR homologs with modified functions from those of the typical CKRs. The decoy receptors are able to bind ligands without signaling. On the other hand, the viral receptors show constitutive signaling without ligands. We examined the sites related to the functional difference. At first, the decoy and viral receptors were each classified into five groups, based on the molecular phylogenetic analysis. A multiple amino acid sequence alignment between each group and the CKRs was then constructed. The difference in the amino acid composition between the group and the CKRs was evaluated as the Kullback–Leibler (KL) information value at each alignment site. The KL information value is considered to reflect the difference in the functional constraints at the site. The sites with the top 5% of KL information values were selected and mapped on the structure of a CKR. The comparisons with decoy receptor groups revealed that the detected sites were biased on the intracellular side. In contrast, the sites detected from the comparisons with viral receptor groups were found on both the extracellular and intracellular sides. More sites were found in the ligand binding pocket in the analyses of the viral receptor groups, as compared to the decoy receptor groups. Some of the detected sites were located in the GPCR motifs. For example, the DRY motif of the decoy receptors was often degraded, although the motif of the viral receptors was basically conserved. The observations for the viral receptor groups suggested that the constraints in the pocket region are loose and that the sites on the intracellular side are different from those for the decoy receptors, which may be related to the constitutive signaling activity of the viral receptors. PMID:22855685

  6. Evolutionary Analysis of Functional Divergence among Chemokine Receptors, Decoy Receptors, and Viral Receptors.

    PubMed

    Daiyasu, Hiromi; Nemoto, Wataru; Toh, Hiroyuki

    2012-01-01

    Chemokine receptors (CKRs) function in the inflammatory response and in vertebrate homeostasis. Decoy and viral receptors are two types of CKR homologs with modified functions from those of the typical CKRs. The decoy receptors are able to bind ligands without signaling. On the other hand, the viral receptors show constitutive signaling without ligands. We examined the sites related to the functional difference. At first, the decoy and viral receptors were each classified into five groups, based on the molecular phylogenetic analysis. A multiple amino acid sequence alignment between each group and the CKRs was then constructed. The difference in the amino acid composition between the group and the CKRs was evaluated as the Kullback-Leibler (KL) information value at each alignment site. The KL information value is considered to reflect the difference in the functional constraints at the site. The sites with the top 5% of KL information values were selected and mapped on the structure of a CKR. The comparisons with decoy receptor groups revealed that the detected sites were biased on the intracellular side. In contrast, the sites detected from the comparisons with viral receptor groups were found on both the extracellular and intracellular sides. More sites were found in the ligand binding pocket in the analyses of the viral receptor groups, as compared to the decoy receptor groups. Some of the detected sites were located in the GPCR motifs. For example, the DRY motif of the decoy receptors was often degraded, although the motif of the viral receptors was basically conserved. The observations for the viral receptor groups suggested that the constraints in the pocket region are loose and that the sites on the intracellular side are different from those for the decoy receptors, which may be related to the constitutive signaling activity of the viral receptors.

  7. Dopamine D(3) receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans.

    PubMed

    Haadsma-Svensson, S R; Cleek, K A; Dinh, D M; Duncan, J N; Haber, C L; Huff, R M; Lajiness, M E; Nichols, N F; Smith, M W; Svensson, K A; Zaya, M J; Carlsson, A; Lin, C H

    2001-12-20

    5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D(3) receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D(3) antagonists. Thus, combinations of various alkyl groups were generally inactive at the D(3) receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D(3) binding affinity, the D(2) affinity is also enhanced, resulting in a less than 4-fold preference for the D(3) receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D(3) antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH(3).Me(2)S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et(3)SiH to give the desired product 3 in good overall yield of ( approximately 65%) from the indanone 5c.

  8. G protein-coupled estrogen receptor 1/G protein-coupled receptor 30 localizes in the plasma membrane and traffics intracellularly on cytokeratin intermediate filaments.

    PubMed

    Sandén, Caroline; Broselid, Stefan; Cornmark, Louise; Andersson, Krister; Daszkiewicz-Nilsson, Joanna; Mårtensson, Ulrika E A; Olde, Björn; Leeb-Lundberg, L M Fredrik

    2011-03-01

    G protein-coupled receptor 30 [G protein-coupled estrogen receptor 1 (GPER1)], has been introduced as a membrane estrogen receptor and a candidate cancer biomarker and therapeutic target. However, several questions surround the subcellular localization and signaling of this receptor. In native cells, including mouse myoblast C(2)C(12) cells, Madin-Darby canine kidney epithelial cells, and human ductal breast epithelial tumor T47-D cells, G-1, a GPER1 agonist, and 17β-estradiol stimulated GPER1-dependent cAMP production, a defined plasma membrane (PM) event, and recruitment of β-arrestin2 to the PM. Staining of fixed and live cells showed that GPER1 was localized both in the PM and on intracellular structures. One such intracellular structure was identified as cytokeratin (CK) intermediate filaments, including those composed of CK7 and CK8, but apparently not endoplasmic reticulum, Golgi, or microtubules. Reciprocal coimmunoprecipitation of GPER1 and CKs confirmed an association of these proteins. Live staining also showed that the PM receptors constitutively internalize apparently to reach CK filaments. Receptor localization was supported using FLAG- and hemagglutinin-tagged GPER1. We conclude that GPER1-mediated stimulation of cAMP production and β-arrestin2 recruitment occur in the PM. Furthermore, the PM receptors constitutively internalize and localize intracellularly on CK. This is the first observation that a G protein-coupled receptor is capable of associating with intermediate filaments, which may be important for GPER1 regulation in epithelial cells and the relationship of this receptor to cancer.

  9. Binding Mode and Structure-Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist.

    PubMed

    Dolciami, Daniela; Gargaro, Marco; Cerra, Bruno; Scalisi, Giulia; Bagnoli, Luana; Servillo, Giuseppe; Fazia, Maria Agnese Della; Puccetti, Paolo; Quintana, Francisco J; Fallarino, Francesca; Macchiarulo, Antonio

    2018-02-06

    Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which include metabolites of l-tryptophan (l-Trp) catabolism as endogenous ligands of the receptor. Among these, 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE) has attracted interest in the scientific community, being endowed with nontoxic, immunomodulatory, and anticancer AhR-mediated functions. So far, no information about the binding mode and interactions of ITE with AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental in validating the proposed binding mode, identifying His 285 and Tyr 316 as important key residues for ligand-dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR and characterize the relevance of specific functional groups in the chemical structure for receptor activity. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Quantitative identification of moisture sources over the Tibetan Plateau and the relationship between thermal forcing and moisture transport

    NASA Astrophysics Data System (ADS)

    Pan, Chen; Zhu, Bin; Gao, Jinhui; Kang, Hanqing; Zhu, Tong

    2018-02-01

    Despite the importance of the Tibetan Plateau (TP) to the surrounding water cycle, the moisture sources of the TP remain uncertain. In this study, the moisture sources of the TP are quantitatively identified based on a 33-year simulation with a horizontal resolution of 1.9° × 2.5° using the Community Atmosphere Model version 5.1 (CAM5.1), in which atmospheric water tracer technology is incorporated. Results demonstrate that the major moisture sources differ over the southern TP (STP) and northern TP (NTP). During the winter, Africa, the TP, and India are the dominant source regions, contributing nearly half of the water vapour over the STP. During the summer, the tropical Indian Ocean (TIO) supplies 28.5 ± 3.6% of the water vapour over the STP and becomes the dominant source region. The dominant moisture source regions of the water vapour over the NTP are Africa (19.0 ± 2.8%) during the winter and the TP (25.8 ± 2.4%) during the summer. The overall relative contribution of each source region to the precipitation is similar to the contribution to the water vapour over the TP. Like most models, CAM5.1 generally overestimates the precipitation over the TP, yielding uncertainty in the absolute contributions to the precipitation. Composite analyses exhibit significant variations in the TIO-supplied moisture transport and precipitation over the STP during the summer alongside anomalous TP heating. This relationship between moisture transport from the TIO and the TP heating primarily involves the dynamic change in the TIO-supplied moisture flux, which further controls the variation in the TIO-contributed precipitation over the STP.

  11. Dry season limnological conditions and basin geology exhibit complex relationships with δ13C and δ15N of carbon sources in four Neotropical floodplains

    PubMed Central

    Hoeinghaus, David J.; Manetta, Gislaine I.; Benedito, Evanilde

    2017-01-01

    Studies in freshwater ecosystems are seeking to improve understanding of carbon flow in food webs and stable isotopes have been influential in this work. However, variation in isotopic values of basal production sources could either be an asset or a hindrance depending on study objectives. We assessed the potential for basin geology and local limnological conditions to predict stable carbon and nitrogen isotope values of six carbon sources at multiple locations in four Neotropical floodplain ecosystems (Paraná, Pantanal, Araguaia, and Amazon). Limnological conditions exhibited greater variation within than among systems. δ15N differed among basins for most carbon sources, but δ13C did not (though high within-basin variability for periphyton, phytoplankton and particulate organic carbon was observed). Although δ13C and δ15N values exhibited significant correlations with some limnological factors within and among basins, those relationships differed among carbon sources. Regression trees for both carbon and nitrogen isotopes for all sources depicted complex and in some cases nested relationships, and only very limited similarity was observed among trees for different carbon sources. Although limnological conditions predicted variation in isotope values of carbon sources, we suggest the resulting models were too complex to enable mathematical corrections of source isotope values among sites based on these parameters. The importance of local conditions in determining variation in source isotope values suggest that isotopes may be useful for examining habitat use, dispersal and patch dynamics within heterogeneous floodplain ecosystems, but spatial variability in isotope values needs to be explicitly considered when testing ecosystem models of carbon flow in these systems. PMID:28358822

  12. Design, synthesis and biological evaluation of a bivalent micro opiate and adenosine A1 receptor antagonist.

    PubMed

    Mathew, Smitha C; Ghosh, Nandita; By, Youlet; Berthault, Aurélie; Virolleaud, Marie-Alice; Carrega, Louis; Chouraqui, Gaëlle; Commeiras, Laurent; Condo, Jocelyne; Attolini, Mireille; Gaudel-Siri, Anouk; Ruf, Jean; Parrain, Jean-Luc; Rodriguez, Jean; Guieu, Régis

    2009-12-01

    The cross talk between different membrane receptors is the source of increasing research. We designed and synthesized a new hetero-bivalent ligand that has antagonist properties on both A(1) adenosine and mu opiate receptors with a K(i) of 0.8+/-0.05 and 0.7+/-0.03 microM, respectively. This hybrid molecule increases cAMP production in cells that over express the mu receptor as well as those over expressing the A(1) adenosine receptor and reverses the antalgic effects of mu and A(1) adenosine receptor agonists in animals.

  13. Role of Epidermal Growth Factor Receptors and Their Ligands in Normal Mammary Epithelial and Breast Cancer Cells

    DTIC Science & Technology

    1997-07-01

    have an estrogen receptor and progesterone receptor negative phenotype, high proliferation rates, poor response to endocrine therapy, and reduced...mitogenic effects of estrogen, progesterone and prolactin in breast cancer cell lines (3), and part of the growth promoting effects of an activated ras...of the cases (51,52), and an inverse relationship with estrogen and progesterone receptors; in such tumors, a poor response to endocrine therapy

  14. Further characterization of benzodiazepine receptor differences in long-sleep and short-sleep mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Marley, R.J.; Stinchcomb, A.; Wehner, J.M.

    Molecular and conformational characteristics of benzodiazepine (BZ) receptors in cortex and cerebellum from long-sleep and mice were investigated using heat inactivation and beta-carboline competition techniques. To investigate differences in the allosteric coupling between GABA and BZ receptors, the protection of BZ receptors from heat inactivation, by GABA, was also evaluated. The two genotypes do not differ in the affinity or number of BZ receptors in the cortex or cerebellum. They do, however, appear to differ in the molecular structure and/or regulation of the conformational state of the receptor in the cortex, as indicated by a greater sensitivity of LS micemore » to both heat inactivation and beta-carboline competition of /sup 3/H-flunitrazepam (FNZ) binding in this region. Evidence for differences in the nature of coupling between GABA and BZ receptors is provided by the finding in that in both regions, GABA protected BZ receptors from inactivation to a greater degree in LS mice. The relationship between these differences and the multiplicity of expression of BZ receptors is discussed.« less

  15. Pharmacological characterisation of strychnine and brucine analogues at glycine and alpha7 nicotinic acetylcholine receptors.

    PubMed

    Jensen, Anders A; Gharagozloo, Parviz; Birdsall, Nigel J M; Zlotos, Darius P

    2006-06-06

    Strychnine and brucine from the plant Strychnos nux vomica have been shown to have interesting pharmacological effects on several neurotransmitter receptors, including some members of the superfamily of ligand-gated ion channels. In this study, we have characterised the pharmacological properties of tertiary and quaternary analogues as well as bisquaternary dimers of strychnine and brucine at human alpha1 and alpha1beta glycine receptors and at a chimera consisting of the amino-terminal domain of the alpha7 nicotinic receptor (containing the orthosteric ligand binding site) and the ion channel domain of the 5-HT3A serotonin receptor. Although the majority of the analogues displayed significantly increased Ki values at the glycine receptors compared to strychnine and brucine, a few retained the high antagonist potencies of the parent compounds. However, mirroring the pharmacological profiles of strychnine and brucine, none of the analogues displayed significant selectivity between the alpha1 and alpha1beta subtypes. The structure-activity relationships for the compounds at the alpha7/5-HT3 chimera were significantly different from those at the glycine receptors. Most strikingly, quaternization of strychnine and brucine with substituents possessing different steric and electronic properties completely eliminated the activity at the glycine receptors, whereas binding affinity to the alpha7/5-HT3 chimera was retained for the majority of the quaternary analogues. This study provides an insight into the structure-activity relationships for strychnine and brucine analogues at these ligand-gated ion channels.

  16. Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and opioid receptors in spinal cord nociceptive reflexes.

    PubMed

    Ramos-Zepeda, Guillermo; Herrero, Juan F

    2013-08-14

    We previously observed that the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is a very effective antinociceptive agent on intact but not on spinalized adult rats with inflammation. Since a close connection between opioid and adenosine A1 receptors has been described, we studied a possible relationship between these systems in the spinal cord. CPA-mediated antinociception was challenged by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT) and by the opioid receptor antagonist naloxone on male adult Wistar rats with carrageenan-induced inflammation. Withdrawal reflexes activated by noxious mechanical and electrical stimulation were recorded using the single motor technique in intact and sham-spinalized animals. CPA was very effective in intact and sham spinalized rats but not in spinalized animals. Full reversal of CPA antinociception was observed with i.v. 1mg/kg of naloxone but not with 20mg/kg of CPT i.v. in responses to noxious mechanical and electrical stimulation. CPT fully prevented CPA from any antinociceptive action whereas naloxone did not modify CPA activity. These results suggest a centrally-mediated action, since CPA depressed the wind-up phenomenon which is derived of the activity of spinal cord neurons. The present study provides strong in vivo evidence of an antinociceptive activity mediated by the adenosine A1 receptor system in the spinal cord, linked to an activation of opioid receptors in adult animals with inflammation. © 2013.

  17. “Struggling to be the alpha”: Sources of tension and intimate partner violence in same-sex relationships between men

    PubMed Central

    Stephenson, Rob; Freeland, Ryan; Finneran, Catherine; Hadley, Craig

    2016-01-01

    In countries such as the USA, gay and bisexual men experience high rates of intimate partner violence. However, little is known about the factors that contribute to this form of violence. In this study, we examine gay and bisexual men’s perceptions of sources of tension in same-sex male relationships and how these may contribute to intimate partner violence. We conducted seven focus group discussions with 64 gay and bisexual men in Atlanta, GA. Focus groups examined men’s reactions to the short-form revised Conflicts Tactics Scale to determine if each item was considered to be intimate partner violence if it were to occur among gay and bisexual men. Analysts completed a thematic analysis, using elements of grounded theory. The sources of tension that men identified included: gender role conflict, dyadic inequalities (e.g. differences in income, age, education), differences in ‘outness’ about sexual identity, substance use, jealousy, and external homophobic violence. Results suggest that intimate partner violence interventions for gay and bisexual men should address behavioural factors, while also focusing on structural interventions. Interventions that aim to reduce homophobic stigma and redefine male gender roles may help to address some of the tension that contributes to intimate partner violence in same-sex male relationships. PMID:26966994

  18. Exploring the relationship between social attachment and dopamine D2/3 receptor availability in the brains of healthy humans using [11C]-(+)-PHNO.

    PubMed

    Caravaggio, Fernando; Chung, Jun Ku; Gerretsen, Philip; Fervaha, Gagan; Nakajima, Shinichiro; Plitman, Eric; Iwata, Yusuke; Wilson, Alan; Graff-Guerrero, Ariel

    2017-04-01

    Differences in striatal dopamine (DA) function may be related to differences in the degree of social attachment to others. Using positron emission tomography (PET), socially detached persons demonstrate reduced DA D 2/3 receptor (D 2/3 R) availability in the striatum. However, previous PET studies have only used antagonist radiotracers for D 2/3 R and have not specifically examined regions of interest (ROIs) such as the ventral striatum (VS). In 32 healthy persons, we investigated the relationship between self-reported attachment and DA D 2/3 R availability in striatal and extrastriatal ROIs as measured using the agonist radiotracer [ 11 C]-(+)-PHNO. Surprisingly, more social attachment-as measured by the attachment subscale of the temperament and character inventory-was related to less [ 11 C]-(+)-PHNO binding in the VS (r(30) = -.43, p = .01). This relationship held in a subsample who also completed the detachment subscale of the Karolinska Scales of Personality (r(10) = .62, p = .03). However, no relationships were observed with BP ND in the dorsal striatum or D 3 R-specific ROIs. One potential explanation for these findings is that persons who are more socially detached have less endogenous DA occupying D 2/3 R in the VS. This interpretation warrants investigation by future research. These findings may help us better understand the neurochemical basis of attachment.

  19. Exploring the relationship between social attachment and dopamine D2/3 receptor availability in the brains of healthy humans using [11C]-(+)-PHNO

    PubMed Central

    Caravaggio, Fernando; Chung, Jun Ku; Gerretsen, Philip; Fervaha, Gagan; Nakajima, Shinichiro; Plitman, Eric; Iwata, Yusuke; Wilson, Alan; Graff-Guerrero, Ariel

    2017-01-01

    Differences in striatal dopamine (DA) function may be related to differences in the degree of social attachment to others. Using positron emission tomography (PET), socially detached persons demonstrate reduced DA D2/3 receptor (D2/3R) availability in the striatum. However, previous PET studies have only used antagonist radiotracers for D2/3R and have not specifically examined regions of interest (ROIs) such as the ventral striatum (VS). In 32 healthy persons, we investigated the relationship between self-reported attachment and DA D2/3R availability in striatal and extrastriatal ROIs as measured using the agonist radiotracer [11C]-(+)-PHNO. Surprisingly, more social attachment—as measured by the attachment subscale of the temperament and character inventory—was related to less [11C]-(+)-PHNO binding in the VS (r(30) =−.43, p = .01). This relationship held in a subsample who also completed the detachment subscale of the Karolinska Scales of Personality (r(10) = .62, p = .03). However, no relationships were observed with BPND in the dorsal striatum or D3R-specific ROIs. One potential explanation for these findings is that persons who are more socially detached have less endogenous DA occupying D2/3R in the VS. This interpretation warrants investigation by future research. These findings may help us better understand the neurochemical basis of attachment. PMID:26873034

  20. Comprehensive Analysis of Non-Synonymous Natural Variants of G Protein-Coupled Receptors.

    PubMed

    Kim, Hee Ryung; Duc, Nguyen Minh; Chung, Ka Young

    2018-03-01

    G protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane receptors and have vital signaling functions in various organs. Because of their critical roles in physiology and pathology, GPCRs are the most commonly used therapeutic target. It has been suggested that GPCRs undergo massive genetic variations such as genetic polymorphisms and DNA insertions or deletions. Among these genetic variations, non-synonymous natural variations change the amino acid sequence and could thus alter GPCR functions such as expression, localization, signaling, and ligand binding, which may be involved in disease development and altered responses to GPCR-targeting drugs. Despite the clinical importance of GPCRs, studies on the genotype-phenotype relationship of GPCR natural variants have been limited to a few GPCRs such as β-adrenergic receptors and opioid receptors. Comprehensive understanding of non-synonymous natural variations within GPCRs would help to predict the unknown genotype-phenotype relationship and yet-to-be-discovered natural variants. Here, we analyzed the non-synonymous natural variants of all non-olfactory GPCRs available from a public database, UniProt. The results suggest that non-synonymous natural variations occur extensively within the GPCR superfamily especially in the N-terminus and transmembrane domains. Within the transmembrane domains, natural variations observed more frequently in the conserved residues, which leads to disruption of the receptor function. Our analysis also suggests that only few non-synonymous natural variations have been studied in efforts to link the variations with functional consequences.

  1. Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome.

    PubMed

    Boule, Lisbeth A; Burke, Catherine G; Jin, Guang-Bi; Lawrence, B Paige

    2018-01-29

    The aryl hydrocarbon receptor (AHR) offers a compelling target to modulate the immune system. AHR agonists alter adaptive immune responses, but the consequences differ across studies. We report here the comparison of four agents representing different sources of AHR ligands in mice infected with influenza A virus (IAV): TCDD, prototype exogenous AHR agonist; PCB126, pollutant with documented human exposure; ITE, novel pharmaceutical; and FICZ, degradation product of tryptophan. All four compounds diminished virus-specific IgM levels and increased the proportion of regulatory T cells. TCDD, PCB126 and ITE, but not FICZ, reduced virus-specific IgG levels and CD8 + T cell responses. Similarly, ITE, PCB126, and TCDD reduced Th1 and Tfh cells, whereas FICZ increased their frequency. In Cyp1a1-deficient mice, all compounds, including FICZ, reduced the response to IAV. Conditional Ahr knockout mice revealed that all four compounds require AHR within hematopoietic cells. Thus, differences in the immune response to IAV likely reflect variances in quality, magnitude, and duration of AHR signaling. This indicates that binding affinity and metabolism may be stronger predictors of immune effects than a compound's source of origin, and that harnessing AHR will require finding a balance between dampening immune-mediated pathologies and maintaining sufficient host defenses against infection.

  2. Teachers' Source Evaluation Self-Efficacy Predicts Their Use of Relevant Source Features When Evaluating the Trustworthiness of Web Sources on Special Education

    ERIC Educational Resources Information Center

    Andreassen, Rune; Bråten, Ivar

    2013-01-01

    Building on prior research and theory concerning source evaluation and the role of self-efficacy in the context of online learning, this study investigated the relationship between teachers' beliefs about their capability to evaluate the trustworthiness of sources and their reliance on relevant source features when judging the trustworthiness…

  3. Sources of atmospheric aerosols in Ankara (Turkey) atmosphere

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tuncel, S.G.; Yatin, M.; Aras, N.K.

    1996-12-31

    Ankara was heavily polluted owing to combustion of coal and fuel oil for space heating. Air quality over the city improved after 1993 due to use of low sulfur coal and natural gas for residential heating. These regulatory actions resulted in a dramatic decrease in SO{sub 2} concentrations measured in the air quality network, after 1990. Although concentration of particulate matter also decreased in the same period, the decrease was not as dramatic as that observed in SO{sub 2} concentrations, suggesting that sources other than space heating also contribute on observed aerosol concentrations. Currently, the concentrations of suspended particles aremore » slightly below the air quality standards effective in Turkey. A better source receptor relation must be established to reduce atmospheric levels of particulate matter. In this study, sources contributing to the observed levels of particles was determined through a receptor modeling approach. Factors controlling the observed concentrations of elements and ions were determined by relating their concentrations, to source strengths and determined by relating their concentrations, to source strengths and meteorological parameters. Residential heating was found out to be the main source of anthropogenic elements in Ankara. In the second part of the study, sources contributing on observed concentrations of elements were determined by a principal component analysis and relative contribution of each source were determined by Chemical Mass Balance study. The results indicated that, the airborne soil is the most important source of aerosol in the Ankara atmosphere during summer season, but emissions from coal combustion dominates aerosol mass during winter months.« less

  4. The discovery of tropane-derived CCR5 receptor antagonists.

    PubMed

    Armour, Duncan R; de Groot, Marcel J; Price, David A; Stammen, Blanda L C; Wood, Anthony; Perros, Manos; Burt, Catherine

    2006-04-01

    The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.

  5. Study on the quantitative relationship between Agricultural water and fertilization process and non-point source pollution based on field experiments

    NASA Astrophysics Data System (ADS)

    Wang, H.; Chen, K.; Wu, Z.; Guan, X.

    2017-12-01

    In recent years, with the prominent of water environment problem and the relative increase of point source pollution governance, especially the agricultural non-point source pollution problem caused by the extensive use of fertilizers and pesticides has become increasingly aroused people's concern and attention. In order to reveal the quantitative relationship between agriculture water and fertilizer and non-point source pollution, on the basis of elm field experiment and combined with agricultural drainage irrigation model, the agricultural irrigation water and the relationship between fertilizer and fertilization scheme and non-point source pollution were analyzed and calculated by field emission intensity index. The results show that the variation of displacement varies greatly under different irrigation conditions. When the irrigation water increased from 22cm to 42cm, the irrigation water increased by 20 cm while the field displacement increased by 11.92 cm, about 66.22% of the added value of irrigation water. Then the irrigation water increased from 42 to 68, irrigation water increased 26 cm, and the field displacement increased by 22.48 cm, accounting for 86.46% of irrigation water. So there is an "inflection point" between the irrigation water amount and field displacement amount. The load intensity increases with the increase of irrigation water and shows a significant power correlation. Under the different irrigation condition, the increase amplitude of load intensity with the increase of irrigation water is different. When the irrigation water is smaller, the load intensity increase relatively less, and when the irrigation water increased to about 42 cm, the load intensity will increase considerably. In addition, there was a positive correlation between the fertilization and load intensity. The load intensity had obvious difference in different fertilization modes even with same fertilization level, in which the fertilizer field unit load intensity

  6. The Relationship of Somatotype to Source Credibility.

    ERIC Educational Resources Information Center

    Toomb, Kevin; Divers, Lawrence T.

    A study was designed to measure the effects of the source's body type--endomorph (fat), mesomorph (muscular), and ectomorph (thin)--in relation to his perceived credibility by the receiver. Five hundred subjects were randomly selected from a basic communication course and, in groups of twenty in a classroom setting, were each given a…

  7. Toward biophysical probes for the 5-HT3 receptor: structure-activity relationship study of granisetron derivatives.

    PubMed

    Vernekar, Sanjeev Kumar V; Hallaq, Hasan Y; Clarkson, Guy; Thompson, Andrew J; Silvestri, Linda; Lummis, Sarah C R; Lochner, Martin

    2010-03-11

    This report describes the synthesis and biological characterization of novel granisetron derivatives that are antagonists of the human serotonin (5-HT(3)A) receptor. Some of these substituted granisetron derivatives showed low nanomolar binding affinity and allowed the identification of positions on the granisetron core that might be used as attachment points for biophysical tags. A BODIPY fluorophore was appended to one such position and specifically bound to 5-HT(3)A receptors in mammalian cells.

  8. Toward Biophysical Probes for the 5-HT3 Receptor: Structure−Activity Relationship Study of Granisetron Derivatives

    PubMed Central

    2010-01-01

    This report describes the synthesis and biological characterization of novel granisetron derivatives that are antagonists of the human serotonin (5-HT3A) receptor. Some of these substituted granisetron derivatives showed low nanomolar binding affinity and allowed the identification of positions on the granisetron core that might be used as attachment points for biophysical tags. A BODIPY fluorophore was appended to one such position and specifically bound to 5-HT3A receptors in mammalian cells. PMID:20146481

  9. Polymorphisms in adenosine receptor genes are associated with infarct size in patients with ischemic cardiomyopathy.

    PubMed

    Tang, Z; Diamond, M A; Chen, J-M; Holly, T A; Bonow, R O; Dasgupta, A; Hyslop, T; Purzycki, A; Wagner, J; McNamara, D M; Kukulski, T; Wos, S; Velazquez, E J; Ardlie, K; Feldman, A M

    2007-10-01

    The goal of this experiment was to identify the presence of genetic variants in the adenosine receptor genes and assess their relationship to infarct size in a population of patients with ischemic cardiomyopathy. Adenosine receptors play an important role in protecting the heart during ischemia and in mediating the effects of ischemic preconditioning. We sequenced DNA samples from 273 individuals with ischemic cardiomyopathy and from 203 normal controls to identify the presence of genetic variants in the adenosine receptor genes. Subsequently, we analyzed the relationship between the identified genetic variants and infarct size, left ventricular size, and left ventricular function. Three variants in the 3'-untranslated region of the A(1)-adenosine gene (nt 1689 C/A, nt 2206 Tdel, nt 2683del36) and an informative polymorphism in the coding region of the A3-adenosine gene (nt 1509 A/C I248L) were associated with changes in infarct size. These results suggest that genetic variants in the adenosine receptor genes may predict the heart's response to ischemia or injury and might also influence an individual's response to adenosine therapy.

  10. Identification of Odorant-Receptor Interactions by Global Mapping of the Human Odorome

    PubMed Central

    Audouze, Karine; Tromelin, Anne; Le Bon, Anne Marie; Belloir, Christine; Petersen, Rasmus Koefoed; Kristiansen, Karsten; Brunak, Søren; Taboureau, Olivier

    2014-01-01

    The human olfactory system recognizes a broad spectrum of odorants using approximately 400 different olfactory receptors (hORs). Although significant improvements of heterologous expression systems used to study interactions between ORs and odorant molecules have been made, screening the olfactory repertoire of hORs remains a tremendous challenge. We therefore developed a chemical systems level approach based on protein-protein association network to investigate novel hOR-odorant relationships. Using this new approach, we proposed and validated new bioactivities for odorant molecules and OR2W1, OR51E1 and OR5P3. As it remains largely unknown how human perception of odorants influence or prevent diseases, we also developed an odorant-protein matrix to explore global relationships between chemicals, biological targets and disease susceptibilities. We successfully experimentally demonstrated interactions between odorants and the cannabinoid receptor 1 (CB1) and the peroxisome proliferator-activated receptor gamma (PPARγ). Overall, these results illustrate the potential of integrative systems chemical biology to explore the impact of odorant molecules on human health, i.e. human odorome. PMID:24695519

  11. Broadening Sources of Dignity and Affirmation in Work and Relationship

    ERIC Educational Resources Information Center

    Byars-Winston, Angela

    2012-01-01

    This article builds on assertions in Richardson's (2012, this issue) Major Contribution on counseling for work and relationship. In this reaction, I expand on the relevance and potential of the counseling for work and relationship perspective to enrich the field of counseling psychology. My comments focus on three considerations to further extend…

  12. Changes in androgen receptor, estrogen receptor alpha, and sexual behavior with aging and testosterone in male rats.

    PubMed

    Wu, Di; Gore, Andrea C

    2010-07-01

    Reproductive aging in males is characterized by a diminution in sexual behavior beginning in middle age. We investigated the relationships among testosterone, androgen receptor (AR) and estrogen receptor alpha (ERalpha) cell numbers in the hypothalamus, and their relationship to sexual performance in male rats. Young (3months) and middle-aged (12months) rats were given sexual behavior tests, then castrated and implanted with vehicle or testosterone capsules. Rats were tested again for sexual behavior. Numbers of AR and ERalpha immunoreactive cells were counted in the anteroventral periventricular nucleus and the medial preoptic nucleus, and serum hormones were measured. Middle-aged intact rats had significant impairments of all sexual behavior measures compared to young males. After castration and testosterone implantation, sexual behaviors in middle-aged males were largely comparable to those in the young males. In the hypothalamus, AR cell density was significantly (5-fold) higher, and ERalpha cell density significantly (6-fold) lower, in testosterone- than vehicle-treated males, with no age differences. Thus, restoration of serum testosterone to comparable levels in young and middle-aged rats resulted in similar preoptic AR and ERalpha cell density concomitant with a reinstatement of most behaviors. These data suggest that age-related differences in sexual behavior cannot be due to absolute levels of testosterone, and further, the middle-aged brain retains the capacity to respond to exogenous testosterone with changes in hypothalamic AR and ERalpha expression. Our finding that testosterone replacement in aging males has profound effects on hypothalamic receptors and behavior has potential medical implications for the treatment of age-related hypogonadism in men. Copyright 2010 Elsevier Inc. All rights reserved.

  13. Chemical compositions and source identification of PM₂.₅ aerosols for estimation of a diesel source surrogate.

    PubMed

    Sahu, Manoranjan; Hu, Shaohua; Ryan, Patrick H; Le Masters, Grace; Grinshpun, Sergey A; Chow, Judith C; Biswas, Pratim

    2011-06-01

    Exposure to traffic-related pollution during childhood has been associated with asthma exacerbation, and asthma incidence. The objective of the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) is to determine if the development of allergic and respiratory disease is associated with exposure to diesel engine exhaust particles. A detailed receptor model analyses was undertaken by applying positive matrix factorization (PMF) and UNMIX receptor models to two PM₂.₅ data sets: one consisting of two carbon fractions and the other of eight temperature-resolved carbon fractions. Based on the source profiles resolved from the analyses, markers of traffic-related air pollution were estimated: the elemental carbon attributed to traffic (ECAT) and elemental carbon attributed to diesel vehicle emission (ECAD). Application of UNMIX to the two data sets generated four source factors: combustion related sulfate, traffic, metal processing and soil/crustal. The PMF application generated six source factors derived from analyzing two carbon fractions and seven factors from temperature-resolved eight carbon fractions. The source factors (with source contribution estimates by mass concentrations in parentheses) are: combustion sulfate (46.8%), vegetative burning (15.8%), secondary sulfate (12.9%), diesel vehicle emission (10.9%), metal processing (7.5%), gasoline vehicle emission (5.6%) and soil/crustal (0.7%). Diesel and gasoline vehicle emission sources were separated using eight temperature-resolved organic and elemental carbon fractions. Application of PMF to both datasets also differentiated the sulfate rich source from the vegetative burning source, which are combined in a single factor by UNMIX modeling. Calculated ECAT and ECAD values at different locations indicated that traffic source impacts depend on factors such as traffic volumes, meteorological parameters, and the mode of vehicle operation apart from the proximity of the sites to highways. The difference

  14. Research on the relationship of the probe system for the swing arm profilometer based on the point source microscope

    NASA Astrophysics Data System (ADS)

    Gao, Mingxing; Jing, Hongwei; Cao, Xuedong; Chen, Lin; Yang, Jie

    2015-08-01

    When using the swing arm profilometer (SAP) to measure the aspheric mirror and the off-axis aspheric mirror, the error of the effective arm length of the SAP has an obvious influence on the measurement result. In order to reduce the influence of the effective arm length and increase the measurement accuracy of the SAP, the laser tracker is adopted to measure the effective arm length. Because the space position relationship of the probe system for the SAP is needed to measured before using the laser tracker, the point source microscope (PSM) is used to measure the space positional relationship. The measurement principle of the PSM and other applications are introduced; the accuracy and repeatability of this technology are analysed; the advantages and disadvantages of this technology are summarized.

  15. Serial Femtosecond Crystallography of G Protein-Coupled Receptors

    PubMed Central

    Liu, Wei; Wacker, Daniel; Gati, Cornelius; Han, Gye Won; James, Daniel; Wang, Dingjie; Nelson, Garrett; Weierstall, Uwe; Katritch, Vsevolod; Barty, Anton; Zatsepin, Nadia A.; Li, Dianfan; Messerschmidt, Marc; Boutet, Sébastien; Williams, Garth J.; Koglin, Jason E.; Seibert, M. Marvin; Wang, Chong; Shah, Syed T.A.; Basu, Shibom; Fromme, Raimund; Kupitz, Christopher; Rendek, Kimberley N.; Grotjohann, Ingo; Fromme, Petra; Kirian, Richard A.; Beyerlein, Kenneth R.; White, Thomas A.; Chapman, Henry N.; Caffrey, Martin; Spence, John C.H.; Stevens, Raymond C.; Cherezov, Vadim

    2014-01-01

    X-ray crystallography of G protein-coupled receptors and other membrane proteins is hampered by difficulties associated with growing sufficiently large crystals that withstand radiation damage and yield high-resolution data at synchrotron sources. Here we used an x-ray free-electron laser (XFEL) with individual 50-fs duration x-ray pulses to minimize radiation damage and obtained a high-resolution room temperature structure of a human serotonin receptor using sub-10 µm microcrystals grown in a membrane mimetic matrix known as lipidic cubic phase. Compared to the structure solved by traditional microcrystallography from cryo-cooled crystals of about two orders of magnitude larger volume, the room temperature XFEL structure displays a distinct distribution of thermal motions and conformations of residues that likely more accurately represent the receptor structure and dynamics in a cellular environment. PMID:24357322

  16. Specific olfactory receptor populations projecting to identified glomeruli in the rat olfactory bulb.

    PubMed

    Jastreboff, P J; Pedersen, P E; Greer, C A; Stewart, W B; Kauer, J S; Benson, T E; Shepherd, G M

    1984-08-01

    A critical gap exists in our knowledge of the topographical relationship between the olfactory epithelium and olfactory bulb. The present report describes the application to this problem of a method involving horseradish peroxidase conjugated to wheat germ agglutinin. This material was iontophoretically delivered to circumscribed glomeruli in the olfactory bulb and the characteristics and distribution of retrogradely labeled receptor cells were assessed. After discrete injections into small glomerular groups in the caudomedial bulb, topographically defined populations of receptor cells were labeled. Labeled receptor cell somata appeared at several levels within the epithelium. The receptor cell apical dendrites followed a tight helical course towards the surface of the epithelium. The data thus far demonstrate that functional units within the olfactory system may include not only glomeruli as previously suggested but, in addition, a corresponding matrix of receptor cells possessing functional and topographical specificity.

  17. A GIS-based atmospheric dispersion model for pollutants emitted by complex source areas.

    PubMed

    Teggi, Sergio; Costanzini, Sofia; Ghermandi, Grazia; Malagoli, Carlotta; Vinceti, Marco

    2018-01-01

    Gaussian dispersion models are widely used to simulate the concentrations and deposition fluxes of pollutants emitted by source areas. Very often, the calculation time limits the number of sources and receptors and the geometry of the sources must be simple and without holes. This paper presents CAREA, a new GIS-based Gaussian model for complex source areas. CAREA was coded in the Python language, and is largely based on a simplified formulation of the very popular and recognized AERMOD model. The model allows users to define in a GIS environment thousands of gridded or scattered receptors and thousands of complex sources with hundreds of vertices and holes. CAREA computes ground level, or near ground level, concentrations and dry deposition fluxes of pollutants. The input/output and the runs of the model can be completely managed in GIS environment (e.g. inside a GIS project). The paper presents the CAREA formulation and its applications to very complex test cases. The tests shows that the processing time are satisfactory and that the definition of sources and receptors and the output retrieval are quite easy in a GIS environment. CAREA and AERMOD are compared using simple and reproducible test cases. The comparison shows that CAREA satisfactorily reproduces AERMOD simulations and is considerably faster than AERMOD. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances

    PubMed Central

    Xu, Shi; Olenyuk, Bogdan Z.; Okamoto, Curtis T.; Hamm-Alvarez, Sarah F.

    2012-01-01

    Targeting of drugs and their carrier systems by using receptor-mediated endocytotic pathways was in its nascent stages 25 years ago. In the intervening years, an explosion of knowledge focused on design and synthesis of nanoparticulate delivery systems as well as elucidation of the cellular complexity of what was previously-termed receptor-mediated endocytosis has now created a situation when it has become possible to design and test the feasibility of delivery of highly specific nanoparticle drug carriers to specific cells and tissue. This review outlines the mechanisms governing the major modes of receptor-mediated endocytosis used in drug delivery and highlights recent approaches using these as targets for in vivo drug delivery of nanoparticles. The review also discusses some of the inherent complexity associated with the simple shift from a ligand-drug conjugate versus a ligand-nanoparticle conjugate, in terms of ligand valency and its relationship to the mode of receptor-mediated internalization. PMID:23026636

  19. Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors: Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT

    PubMed Central

    Oh, Sowon; Prasad, Vikas; Lee, Dong Soo; Baum, R. P.

    2011-01-01

    The heterogeneous nature of the neuroendocrine tumors (NET) makes it challenging to find one uniformly applicable management protocol which is especially true for diagnosis. The discovery of the overexpression of somatostatin receptors (SMS-R) on neuroendocrine tumor cells lead to the generalized and rapid acceptance of radiolabeled somatostatin receptor analogs for staging and restaging of NET as well as for Peptide Receptor Radionuclide Therapy (PRRNT) using Y-90 and Lu-177 DOTATATE/DOTATOC. In this present work we tried to look in to the effect of PRRNT on the glucose metabolism assessed by F-18 FDG PET/CT and SMS-R density assessed by Ga-68 DOTANOC PET/CT. We observed a complex relationship between the somatostatin receptor expression and glucose metabolism with only 56% (77/138) of the lesions showing match, while the others show mismatch between the receptor status and metabolism. The match between receptor expression and glucose metabolism increases with the grade of NET. In grade 3 NET, there is a concurrence between the changes in glucose metabolism and somatostatin receptor expression. PRRNT was found to be more effective in lesions with higher receptor expression. PMID:22121482

  20. An automated system for the analysis of G protein-coupled receptor transmembrane binding pockets: alignment, receptor-based pharmacophores, and their application.

    PubMed

    Kratochwil, Nicole A; Malherbe, Pari; Lindemann, Lothar; Ebeling, Martin; Hoener, Marius C; Mühlemann, Andreas; Porter, Richard H P; Stahl, Martin; Gerber, Paul R

    2005-01-01

    G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Here, a comprehensive and automated method allowing fast analysis and comparison of these putative binding pockets across the entire GPCR family is presented. The method relies on a robust alignment algorithm based on conservation indices, focusing on pharmacophore-like relationships between amino acids. Analysis of conservation patterns across the GPCR family and alignment to the rhodopsin X-ray structure allows the extraction of the amino acids lining the TM binding pocket in a so-called ligand binding pocket vector (LPV). In a second step, LPVs are translated to simple 3D receptor pharmacophore models, where each amino acid is represented by a single spherical pharmacophore feature and all atomic detail is omitted. Applications of the method include the assessment of selectivity issues, support of mutagenesis studies, and the derivation of rules for focused screening to identify chemical starting points in early drug discovery projects. Because of the coarseness of this 3D receptor pharmacophore model, however, meaningful scoring and ranking procedures of large sets of molecules are not justified. The LPV analysis of the trace amine-associated receptor family and its experimental validation is discussed as an example. The value of the 3D receptor model is demonstrated for a class C GPCR family, the metabotropic glutamate receptors.

  1. Structure-activity relationships for hallucinogenic N,N-dialkyltryptamines: photoelectron spectra and serotonin receptor affinities of methylthio and methylenedioxy derivatives

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kline, T.B.; Benington, F.; Morin, R.D.

    1982-11-01

    Serotonin receptor affinity and photelectron spectral data were obtained on a number of substituted N,N-dimethyltryptamines. Evidence is presented that electron-donating substituents in the 5-position lead to enhanced behavioral disruption activity and serotonin receptor affinity as compared to unsubstituted N,N-dimethyltryptamine and analogues substituted in the 4- or 6-position. Some correlation was found between ionization potentials and behavioral activity, which may have implications concerning the mechanism of receptor binding.

  2. Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

    PubMed Central

    2013-01-01

    Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR1, PAR2, PAR3 and PAR4, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression. PARs are characterized by a unique activation mechanism involving receptor cleavage by different proteinases at specific sites within the extracellular amino-terminus and the exposure of amino-terminal “tethered ligand“ domains that bind to and activate the cleaved receptors. After activation, the PAR family members are able to stimulate complex intracellular signalling networks via classical G protein-mediated pathways and beta-arrestin signalling. In addition, different receptor crosstalk mechanisms critically contribute to a high diversity of PAR signal transduction and receptor-trafficking processes that result in multiple physiological effects. In this review, we summarize current information about PAR-initiated physical and functional receptor interactions and their physiological and pathological roles. We focus especially on PAR homo- and heterodimerization, transactivation of receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases (RSTKs), communication with other GPCRs, toll-like receptors and NOD-like receptors, ion channel receptors, and on PAR association with cargo receptors. In addition, we discuss the suitability of these receptor interaction mechanisms as targets for modulating PAR signalling in disease. PMID:24215724

  3. SOURCE APPORTIONMENT RESULTS, UNCERTAINTIES, AND MODELING TOOLS

    EPA Science Inventory

    Advanced multivariate receptor modeling tools are available from the U.S. Environmental Protection Agency (EPA) that use only speciated sample data to identify and quantify sources of air pollution. EPA has developed both EPA Unmix and EPA Positive Matrix Factorization (PMF) and ...

  4. Prognostic value of sex-hormone receptor expression in non-muscle-invasive bladder cancer.

    PubMed

    Nam, Jong Kil; Park, Sung Woo; Lee, Sang Don; Chung, Moon Kee

    2014-09-01

    We investigated sex-hormone receptor expression as predicting factor of recurrence and progression in patients with non-muscle invasive bladder cancer. We retrospectively evaluated tumor specimens from patients treated for transitional cell carcinoma of the bladder at our institution between January 2006 and January 2011. Performing immunohistochemistry using a monoclonal androgen receptor antibody and monoclonal estrogen receptor-beta antibody on paraffin-embedded tissue sections, we assessed the relationship of immunohistochemistry results and prognostic factors such as recurrence and progression. A total of 169 patients with bladder cancer were evaluated in this study. Sixty-threepatients had expressed androgen receptors and 52 patients had estrogen receptor beta. On univariable analysis, androgen receptor expression was significant lower in recurrence rates (p=0.001), and estrogen receptor beta expression was significant higher in progression rates (p=0.004). On multivariable analysis, significant association was found between androgen receptor expression and lower recurrence rates (hazard ratio=0.500; 95% confidence interval, 0.294 to 0.852; p=0.011), but estrogen receptor beta expression was not significantly associated with progression rates. We concluded that the possibility of recurrence was low when the androgen receptor was expressed in the bladder cancer specimen and it could be the predicting factor of the stage, number of tumors, carcinoma in situ lesion and recurrence.

  5. Insights into structure–activity relationship of GABAA receptor modulating coumarins and furanocoumarins

    PubMed Central

    Singhuber, Judith; Baburin, Igor; Ecker, Gerhard F.; Kopp, Brigitte; Hering, Steffen

    2011-01-01

    The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (IGABA) by a selection of 18 coumarin derivatives on recombinant α1β2γ2S GABAA receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC50=14±1 μM) and oxypeucedanin (EC50=25±8 μM) displayed the highest efficiency with IGABA potentiation of 116±4% and 547±56%, respectively. IGABA enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 μM) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish IGABA modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin – comprising three hydrophobic and one aromatic feature – identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABAA receptor modulators. PMID:21749864

  6. Source attribution of black carbon in Arctic snow.

    PubMed

    Hegg, Dean A; Warren, Stephen G; Grenfell, Thomas C; Doherty, Sarah J; Larson, Timothy V; Clarke, Antony D

    2009-06-01

    Snow samples obtained at 36 sites in Alaska, Canada, Greenland, Russia, and the Arctic Ocean in early 2007 were analyzed for light-absorbing aerosol concentration together with a suite of associated chemical species. The light absorption data, interpreted as black carbon concentrations, and other chemical data were input into the EPA PMF 1.1 receptor model to explore the sources for black carbon in the snow. The analysis found four factors or sources: two distinct biomass burning sources, a pollution source, and a marine source. The first three of these were responsible for essentially all of the black carbon, with the two biomass sources (encompassing both open and closed combustion) together accounting for >90% of the black carbon.

  7. GABA, its receptors, and GABAergic inhibition in mouse taste buds

    PubMed Central

    Dvoryanchikov, Gennady; Huang, Yijen A; Barro-Soria, Rene; Chaudhari, Nirupa; Roper, Stephen D.

    2012-01-01

    Taste buds consist of at least three principal cell types that have different functions in processing gustatory signals — glial-like Type I cells, Receptor (Type II) cells, and Presynaptic (Type III) cells. Using a combination of Ca2+ imaging, single cell RT-PCR, and immunostaining, we show that γ-amino butyric acid (GABA) is an inhibitory transmitter in mouse taste buds, acting on GABA-A and GABA-B receptors to suppress transmitter (ATP) secretion from Receptor cells during taste stimulation. Specifically, Receptor cells express GABA-A receptor subunits β2, δ, π, as well as GABA-B receptors. In contrast, Presynaptic cells express the GABA-Aβ3 subunit and only occasionally GABA-B receptors. In keeping with the distinct expression pattern of GABA receptors in Presynaptic cells, we detected no GABAergic suppression of transmitter release from Presynaptic cells. We suggest that GABA may serve function(s) in taste buds in addition to synaptic inhibition. Finally, we also defined the source of GABA in taste buds: GABA is synthesized by GAD65 in Type I taste cells as well as by GAD67 in Presynaptic (Type III) taste cells and is stored in both those two cell types. We conclude that GABA is released during taste stimulation and possibly also during growth and differentiation of taste buds. PMID:21490220

  8. GABA, its receptors, and GABAergic inhibition in mouse taste buds.

    PubMed

    Dvoryanchikov, Gennady; Huang, Yijen A; Barro-Soria, Rene; Chaudhari, Nirupa; Roper, Stephen D

    2011-04-13

    Taste buds consist of at least three principal cell types that have different functions in processing gustatory signals: glial-like (type I) cells, receptor (type II) cells, and presynaptic (type III) cells. Using a combination of Ca2+ imaging, single-cell reverse transcriptase-PCR and immunostaining, we show that GABA is an inhibitory transmitter in mouse taste buds, acting on GABA(A) and GABA(B) receptors to suppress transmitter (ATP) secretion from receptor cells during taste stimulation. Specifically, receptor cells express GABA(A) receptor subunits β2, δ, and π, as well as GABA(B) receptors. In contrast, presynaptic cells express the GABA(A) β3 subunit and only occasionally GABA(B) receptors. In keeping with the distinct expression pattern of GABA receptors in presynaptic cells, we detected no GABAergic suppression of transmitter release from presynaptic cells. We suggest that GABA may serve function(s) in taste buds in addition to synaptic inhibition. Finally, we also defined the source of GABA in taste buds: GABA is synthesized by GAD65 in type I taste cells as well as by GAD67 in presynaptic (type III) taste cells and is stored in both those two cell types. We conclude that GABA is an inhibitory transmitter released during taste stimulation and possibly also during growth and differentiation of taste buds.

  9. Conformational states of the full-length glucagon receptor

    PubMed Central

    Yang, Linlin; Yang, Dehua; de Graaf, Chris; Moeller, Arne; West, Graham M.; Dharmarajan, Venkatasubramanian; Wang, Chong; Siu, Fai Y.; Song, Gaojie; Reedtz-Runge, Steffen; Pascal, Bruce D.; Wu, Beili; Potter, Clinton S.; Zhou, Hu; Griffin, Patrick R.; Carragher, Bridget; Yang, Huaiyu; Wang, Ming-Wei; Stevens, Raymond C.; Jiang, Hualiang

    2015-01-01

    Class B G protein-coupled receptors are composed of an extracellular domain (ECD) and a seven-transmembrane (7TM) domain, and their signalling is regulated by peptide hormones. Using a hybrid structural biology approach together with the ECD and 7TM domain crystal structures of the glucagon receptor (GCGR), we examine the relationship between full-length receptor conformation and peptide ligand binding. Molecular dynamics (MD) and disulfide crosslinking studies suggest that apo-GCGR can adopt both an open and closed conformation associated with extensive contacts between the ECD and 7TM domain. The electron microscopy (EM) map of the full-length GCGR shows how a monoclonal antibody stabilizes the ECD and 7TM domain in an elongated conformation. Hydrogen/deuterium exchange (HDX) studies and MD simulations indicate that an open conformation is also stabilized by peptide ligand binding. The combined studies reveal the open/closed states of GCGR and suggest that glucagon binds to GCGR by a conformational selection mechanism. PMID:26227798

  10. Glutamate receptor mutations in psychiatric and neurodevelopmental disorders

    PubMed Central

    Soto, David; Altafaj, Xavier; Sindreu, Carlos; Bayés, Àlex

    2014-01-01

    Alterations in glutamatergic neurotransmission have long been associated with psychiatric and neurodevelopmental disorders (PNDD), but only recent advances in high-throughput DNA sequencing have allowed interrogation of the prevalence of mutations in glutamate receptors (GluR) among afflicted individuals. In this review we discuss recent work describing GluR mutations in the context of PNDDs. Although there are no strict relationships between receptor subunit or type and disease, some interesting preliminary conclusions have arisen. Mutations in genes coding for ionotropic glutamate receptor subunits, which are central to synaptic transmission and plasticity, are mostly associated with intellectual disability and autism spectrum disorders. In contrast, mutations of metabotropic GluRs, having a role on modulating neural transmission, are preferentially associated with psychiatric disorders. Also, the prevalence of mutations among GluRs is highly heterogeneous, suggesting a critical role of certain subunits in PNDD pathophysiology. The emerging bias between GluR subtypes and specific PNDDs may have clinical implications. PMID:24605182

  11. Glutamate receptor mutations in psychiatric and neurodevelopmental disorders.

    PubMed

    Soto, David; Altafaj, Xavier; Sindreu, Carlos; Bayés, Alex

    2014-01-01

    Alterations in glutamatergic neurotransmission have long been associated with psychiatric and neurodevelopmental disorders (PNDD), but only recent advances in high-throughput DNA sequencing have allowed interrogation of the prevalence of mutations in glutamate receptors (GluR) among afflicted individuals. In this review we discuss recent work describing GluR mutations in the context of PNDDs. Although there are no strict relationships between receptor subunit or type and disease, some interesting preliminary conclusions have arisen. Mutations in genes coding for ionotropic glutamate receptor subunits, which are central to synaptic transmission and plasticity, are mostly associated with intellectual disability and autism spectrum disorders. In contrast, mutations of metabotropic GluRs, having a role on modulating neural transmission, are preferentially associated with psychiatric disorders. Also, the prevalence of mutations among GluRs is highly heterogeneous, suggesting a critical role of certain subunits in PNDD pathophysiology. The emerging bias between GluR subtypes and specific PNDDs may have clinical implications.

  12. Intracellular postsynaptic cannabinoid receptors link thyrotropin-releasing hormone receptors to TRPC-like channels in thalamic paraventricular nucleus neurons.

    PubMed

    Zhang, L; Kolaj, M; Renaud, L P

    2015-12-17

    In rat thalamic paraventricular nucleus of thalamus (PVT) neurons, activation of thyrotropin-releasing hormone (TRH) receptors enhances excitability via concurrent decrease in G protein-coupled inwardly-rectifying potassium (GIRK)-like and activation of transient receptor potential cation (TRPC)4/5-like cationic conductances. An exploration of intracellular signaling pathways revealed the TRH-induced current to be insensitive to phosphatidylinositol-specific phospholipase C (PI-PLC) inhibitors, but reduced by D609, an inhibitor of phosphatidylcholine-specific PLC (PC-PLC). A corresponding change in the I-V relationship implied suppression of the cationic component of the TRH-induced current. Diacylglycerol (DAG) is a product of the hydrolysis of PC. Studies focused on the isolated cationic component of the TRH-induced response revealed a reduction by RHC80267, an inhibitor of DAG lipase, the enzyme involved in the hydrolysis of DAG to the endocannabinoid 2-arachidonoylglycerol (2-AG). Further investigation revealed enhancement of the cationic component in the presence of either JZL184 or WWL70, inhibitors of enzymes involved in the hydrolysis of 2-AG. A decrease in the TRH-induced response was noted in the presence of rimonabant or SR144528, membrane permeable CB1 and CB2 receptor antagonists, respectively. A decrease in the TRH-induced current by intracellular, but not by bath application of the membrane impermeable peptide hemopressin, selective for CB1 receptors, suggests a postsynaptic intracellular localization of these receptors. The TRH-induced current was increased in the presence of arachidonyl-2'-chloroethylamide (ACEA) or JWH133, CB1 and CB2 receptor agonists, respectively. The PI3-kinase inhibitor LY294002, known to inhibit TRPC translocation, decreased the response to TRH. In addition, a TRH-induced enhancement of the low-threshold spike was prevented by both rimonabant, and SR144528. TRH had no influence on excitatory or inhibitory miniature

  13. VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins.

    PubMed

    Couvineau, Alain; Laburthe, Marc

    2012-05-01

    The vasoactive intestinal peptide (VIP) is a neuropeptide with wide distribution in both central and peripheral nervous systems, where it plays important regulatory role in many physiological processes. VIP displays a large biological functions including regulation of exocrine secretions, hormone release, fetal development, immune responses, etc. VIP appears to exert beneficial effect in neuro-degenerative and inflammatory diseases. The mechanism of action of VIP implicates two subtypes of receptors (VPAC1 and VPAC2), which are members of class B receptors belonging to the super-family of GPCR. This article reviews the current knowledge regarding the structure and molecular pharmacology of VPAC receptors. The structure-function relationship of VPAC1 receptor has been extensively studied, allowing to understand the molecular basis for receptor affinity, specificity, desensitization and coupling to adenylyl cyclase. Those studies have clearly demonstrated the crucial role of the N-terminal ectodomain (N-ted) of VPAC1 receptor in VIP recognition. By using different approaches including directed mutagenesis, photoaffinity labelling, NMR, molecular modelling and molecular dynamic simulation, it has been shown that the VIP molecule interacts with the N-ted of VPAC1 receptor, which is itself structured as a 'Sushi' domain. VPAC1 receptor also interacts with a few accessory proteins that play a role in cell signalling of receptors. Recent advances in the structural characterization of VPAC receptor and more generally of class B GPCRs will lead to the design of new molecules, which could have considerable interest for the treatment of inflammatory and neuro-degenerative diseases. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  14. Steroid receptors and their ligands: Effects on male gamete functions

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Aquila, Saveria; De Amicis, Francesca, E-mail: francesca.deamicis@unical.it

    In recent years a new picture of human sperm biology is emerging. It is now widely recognized that sperm contain nuclear encoded mRNA, mitochondrial encoded RNA and different transcription factors including steroid receptors, while in the past sperm were considered incapable of transcription and translation. One of the main targets of steroid hormones and their receptors is reproductive function. Expression studies on Progesterone Receptor, estrogen receptor, androgen receptor and their specific ligands, demonstrate the presence of these systems in mature spermatozoa as surface but also as nuclear conventional receptors, suggesting that both systemic and local steroid hormones, through sperm receptors,more » may influence male reproduction. However, the relationship between the signaling events modulated by steroid hormones and sperm fertilization potential as well as the possible involvement of the specific receptors are still controversial issues. The main line of this review highlights the current research in human sperm biology examining new molecular systems of response to the hormones as well as specific regulatory pathways controlling sperm cell fate and biological functions. Most significant studies regarding the identification of steroid receptors are reported and the mechanistic insights relative to signaling pathways, together with the change in sperm metabolism energy influenced by steroid hormones are discussed.The reviewed evidences suggest important effects of Progesterone, Estrogen and Testosterone and their receptors on spermatozoa and implicate the involvement of both systemic and local steroid action in the regulation of male fertility potential. - Highlights: • One of the main targets of steroid hormones and their receptors is reproductive function. • Pg/PR co-work to stimulate enzymatic activities to sustain a capacitation process. • E2/ERs regulate sperm motility, capacitation and acrosome reaction and act as survival factors.

  15. Estrogen-related receptor β (ERRβ) – renaissance receptor or receptor renaissance?

    PubMed Central

    Divekar, Shailaja D.; Tiek, Deanna M.; Fernandez, Aileen; Riggins, Rebecca B.

    2016-01-01

    Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα and ERRγ at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ, however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRβ in mouse, man, and other species, highlighting unique aspects of ERRβ biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor. PMID:27507929

  16. Presence and distribution of leptin and leptin receptor in the canine gallbladder.

    PubMed

    Lee, Sungin; Lee, Aeri; Kweon, Oh-Kyeong; Kim, Wan Hee

    2016-09-01

    The hormone leptin is produced by mature adipocytes and plays an important role in regulating food intake and energy metabolism through its interaction with the leptin receptor. In addition to roles in obesity and obesity-related diseases, leptin has been reported to affect the components and secretion of bile in leptin-deficient mice. Furthermore, gallbladder diseases such as cholelithiasis are known to be associated with serum leptin concentrations in humans. We hypothesized that the canine gallbladder is a source of leptin and that the leptin receptor may be localized in the gallbladder, where it plays a role in regulating the function of this organ. The aim of this study was to demonstrate the presence and expression patterns of leptin and its receptors in normal canine gallbladders using reverse transcriptase-PCR (RT-PCR) and immunohistochemistry. Clinically normal gallbladder tissue samples were obtained from four healthy beagle dogs with similar body condition scores. RT-PCR and sequencing of the amplified PCR products revealed the presence of leptin mRNA and its receptors in the gallbladder. Immunohistochemical investigations demonstrated the expression of leptin and its receptors in the luminal single columnar and tubuloalveolar glandular epithelial cells. In conclusion, the results of this study demonstrated the presence of leptin and its receptors in the gallbladders of dogs. Leptin and its receptor were both localized throughout the cytoplasm of luminal and glandular epithelial cells. These results suggested that the gallbladder is not only a source of leptin, but also a target of leptin though autocrine/paracrine mechanisms. The results of this study could increase the understanding of both the normal physiological functions of the gallbladder and the pathophysiological mechanisms of gallbladder diseases characterized by leptin system dysfunction. Copyright © 2016 The Authors. Published by Elsevier GmbH.. All rights reserved.

  17. Dietary Lignan Intake and Androgen Receptor Expression in Breast Tumors

    PubMed Central

    Williams, AnnaLynn M.; Bonner, Matthew; Ochs-Balcom, Heather M.; Hwang, Helena; Morrison, Carl; McCann, Susan E.

    2014-01-01

    Purpose Lignans, a class of phytoestrogen commonly found in the Western diet, have been linked to decreased breast cancer risks in epidemiologic studies. Similar to estrogen receptors, the androgen receptor (AR), a prognostic factor in breast tumors, may be affected by lignans. However, few studies have investigated this link in the context of breast cancer etiology. We evaluated the relationship between dietary lignan intake and androgen receptor expression in incident breast tumors. Methods Tumor tissue, epidemiological, and clinical data were collected from 216 women with incident, primary, histologically-confirmed breast cancer enrolled in the Roswell Park Cancer Institute (RPCI) Data Bank and BioRepository (DBBR). On average, three tumor cores from each participant were assembled into a Tissue MicroArray (TMA). After immunohistochemical staining, a trained RPCI pathologist determined AR status of each core. Lignan intake was calculated from a food frequency questionnaire collected upon enrollment into the DBBR. Results We observed a weak positive association between dietary lignans and AR expression (β (SE) 27.6 (17.0), p 0.10) and there was no significant difference in lignan intake across categories of AR expression (p=0.09, R2 =0.35). Conclusion Our results do not support a clear relationship between dietary lignan intake and AR expression. This investigation is the first, to our knowledge, to examine dietary lignan intake and AR expression in breast tumors. Further research is needed within a larger, more representative sample to determine if lignan intake is truly associated with androgen receptor expression. PMID:25471060

  18. Homology Modeling of Class A G Protein-Coupled Receptors

    PubMed Central

    Costanzi, Stefano

    2012-01-01

    G protein-coupled receptors (GPCRs) are a large superfamily of membrane bound signaling proteins that hold great pharmaceutical interest. Since experimentally elucidated structures are available only for a very limited number of receptors, homology modeling has become a widespread technique for the construction of GPCR models intended to study the structure-function relationships of the receptors and aid the discovery and development of ligands capable of modulating their activity. Through this chapter, various aspects involved in the constructions of homology models of the serpentine domain of the largest class of GPCRs, known as class A or rhodopsin family, are illustrated. In particular, the chapter provides suggestions, guidelines and critical thoughts on some of the most crucial aspect of GPCR modeling, including: collection of candidate templates and a structure-based alignment of their sequences; identification and alignment of the transmembrane helices of the query receptor to the corresponding domains of the candidate templates; selection of one or more templates receptor; election of homology or de novo modeling for the construction of specific extracellular and intracellular domains; construction of the three-dimensional models, with special consideration to extracellular regions, disulfide bridges, and interhelical cavity; validation of the models through controlled virtual screening experiments. PMID:22323225

  19. Quantitative structure-activity relationship study of P2X7 receptor inhibitors using combination of principal component analysis and artificial intelligence methods.

    PubMed

    Ahmadi, Mehdi; Shahlaei, Mohsen

    2015-01-01

    P2X7 antagonist activity for a set of 49 molecules of the P2X7 receptor antagonists, derivatives of purine, was modeled with the aid of chemometric and artificial intelligence techniques. The activity of these compounds was estimated by means of combination of principal component analysis (PCA), as a well-known data reduction method, genetic algorithm (GA), as a variable selection technique, and artificial neural network (ANN), as a non-linear modeling method. First, a linear regression, combined with PCA, (principal component regression) was operated to model the structure-activity relationships, and afterwards a combination of PCA and ANN algorithm was employed to accurately predict the biological activity of the P2X7 antagonist. PCA preserves as much of the information as possible contained in the original data set. Seven most important PC's to the studied activity were selected as the inputs of ANN box by an efficient variable selection method, GA. The best computational neural network model was a fully-connected, feed-forward model with 7-7-1 architecture. The developed ANN model was fully evaluated by different validation techniques, including internal and external validation, and chemical applicability domain. All validations showed that the constructed quantitative structure-activity relationship model suggested is robust and satisfactory.

  20. Quantitative structure–activity relationship study of P2X7 receptor inhibitors using combination of principal component analysis and artificial intelligence methods

    PubMed Central

    Ahmadi, Mehdi; Shahlaei, Mohsen

    2015-01-01

    P2X7 antagonist activity for a set of 49 molecules of the P2X7 receptor antagonists, derivatives of purine, was modeled with the aid of chemometric and artificial intelligence techniques. The activity of these compounds was estimated by means of combination of principal component analysis (PCA), as a well-known data reduction method, genetic algorithm (GA), as a variable selection technique, and artificial neural network (ANN), as a non-linear modeling method. First, a linear regression, combined with PCA, (principal component regression) was operated to model the structure–activity relationships, and afterwards a combination of PCA and ANN algorithm was employed to accurately predict the biological activity of the P2X7 antagonist. PCA preserves as much of the information as possible contained in the original data set. Seven most important PC's to the studied activity were selected as the inputs of ANN box by an efficient variable selection method, GA. The best computational neural network model was a fully-connected, feed-forward model with 7−7−1 architecture. The developed ANN model was fully evaluated by different validation techniques, including internal and external validation, and chemical applicability domain. All validations showed that the constructed quantitative structure–activity relationship model suggested is robust and satisfactory. PMID:26600858

  1. Specific olfactory receptor populations projecting to identified glomeruli in the rat olfactory bulb.

    PubMed Central

    Jastreboff, P J; Pedersen, P E; Greer, C A; Stewart, W B; Kauer, J S; Benson, T E; Shepherd, G M

    1984-01-01

    A critical gap exists in our knowledge of the topographical relationship between the olfactory epithelium and olfactory bulb. The present report describes the application to this problem of a method involving horseradish peroxidase conjugated to wheat germ agglutinin. This material was iontophoretically delivered to circumscribed glomeruli in the olfactory bulb and the characteristics and distribution of retrogradely labeled receptor cells were assessed. After discrete injections into small glomerular groups in the caudomedial bulb, topographically defined populations of receptor cells were labeled. Labeled receptor cell somata appeared at several levels within the epithelium. The receptor cell apical dendrites followed a tight helical course towards the surface of the epithelium. The data thus far demonstrate that functional units within the olfactory system may include not only glomeruli as previously suggested but, in addition, a corresponding matrix of receptor cells possessing functional and topographical specificity. Images PMID:6206495

  2. CGRP Receptor Biology: Is There More Than One Receptor?

    PubMed

    Hay, Debbie L

    2018-05-25

    Calcitonin gene-related peptide (CGRP) has many reported pharmacological actions. Can a single receptor explain all of these? This chapter outlines the molecular nature of reported CGRP binding proteins and their pharmacology. Consideration of whether CGRP has only one or has more receptors is important because of the key role that this peptide plays in migraine. It is widely thought that the calcitonin receptor-like receptor together with receptor activity-modifying protein 1 (RAMP1) is the only relevant receptor for CGRP. However, some closely related receptors also have high affinity for CGRP and it is still plausible that these play a role in CGRP biology, and in migraine. The calcitonin receptor/RAMP1 complex, which is currently called the AMY 1 receptor, seems to be the most likely candidate but more investigation is needed to determine its role.

  3. Opioid Receptor Probes Derived from Cycloaddition of the Hallucinogen Natural Product Salvinorin A†

    PubMed Central

    Lozama, Anthony; Cunningham, Christopher W.; Caspers, Michael J.; Douglas, Justin T.; Dersch, Christina M.; Rothman, Richard B.; Prisinzano, Thomas E.

    2011-01-01

    As part of our continuing efforts toward more fully understanding the structure-activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels-Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure-activity relationships of furan containing natural products. PMID:21338114

  4. Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A.

    PubMed

    Lozama, Anthony; Cunningham, Christopher W; Caspers, Michael J; Douglas, Justin T; Dersch, Christina M; Rothman, Richard B; Prisinzano, Thomas E

    2011-04-25

    As part of our continuing efforts toward more fully understanding the structure-activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels-Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure-activity relationships of furan-containing natural products.

  5. Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias

    PubMed Central

    Sengmany, K

    2015-01-01

    The metabotropic glutamate receptor subtype 5 (mGlu5) is a family C GPCR that has been implicated in various neuronal processes and, consequently, in several CNS disorders. Over the past few decades, GPCR‐based drug discovery, including that for mGlu5 receptors, has turned considerable attention to targeting allosteric binding sites. Modulation of endogenous agonists by allosteric ligands offers the advantages of spatial and temporal fine‐tuning of receptor activity, increased selectivity and reduced adverse effects with the potential to elicit improved clinical outcomes. Further, with greater appreciation of the multifaceted nature of the transduction of mGlu5 receptor signalling, it is increasingly apparent that drug discovery must take into consideration unique receptor conformations and the potential for stimulus‐bias. This novel paradigm proposes that different ligands may differentially modulate distinct signalling pathways arising from the same receptor. We review our current understanding of the complexities of mGlu5 receptor signalling and regulation, and how these relate to allosteric ligands. Ultimately, a deeper appreciation of these relationships will provide the foundation for targeted drug design of compounds with increased selectivity, not only for the desired receptor but also for the desired signalling outcome from the receptor. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein‐Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc PMID:26276909

  6. Insulin receptors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kahn, C.R.; Harrison, L.C.

    1988-01-01

    This book contains the procedure in insulin receptors. Part B: Clinical assessment, biological responses, and comparison to the IGF-1 receptor. Topics covered include: Insulin and IGF-1 receptors, Clinical assessment of receptor functions, and Biological responses.

  7. Relationship between Hard X-Ray Footpoint Sources and Photospheric Electric Currents in Solar Flares: a Statistical Study

    NASA Astrophysics Data System (ADS)

    Zimovets, I. V.; Sharykin, I. N.; Wang, R.; Liu, Y. D.; Kosovichev, A. G.

    2017-12-01

    It is believed that solar flares are a result of release of free magnetic energy contained in electric currents (ECs) flowing in active regions (ARs). However, there are still debates whether the primary energy release and acceleration of electrons take place in coronal current sheets or in chromospheric footpoints of current-carrying magnetic flux tubes (loops). We present results of an observational statistical study of spatial relationship between hard X-ray (HXR; EHXR≥50keV) footpoint sources detected by RHESSI and vertical photospheric ECs calculated using vector magnetograms obtained from the SDO/HMI data. We found that for a sample of 47 flares (from C3.0 to X3.1 class) observed on the solar disk by both instruments in 2010-2016, at least one HXR source was in a region of strong (within 20% of the maximum EC density in the corresponding ARs) vertical ECs having the form of a ribbon (79%) or an island (21%). The total vertical ECs in such HXR sources are in the range of 1010-1013 A. The EC density is in the range of 0.01-1.0 A/m2. We found no correlation between intensity of the HXR sources and the EC density. By comparing pre-flare and post-flare EC maps we did not find evidences of significant dissipation of vertical ECs in the regions corresponding to the HXR sources. In some cases, we found amplification of ECs during flares. We discuss effects of sensitivity and angular resolution of RHESSI and SDO/HMI. In general, the results indicate that there is a link between the flare HXR footpoint sources and enhanced vertical ECs in the photosphere. However, the results do not support a concept of electron acceleration by the electric field excited in footpoints of current-carrying loops due to some (e.g. Rayleigh-Taylor) instabilities (Zaitsev et al., 2016), since strong correlation between the HXR intensity and the EC density is expected in such concept.

  8. Midbrain functional connectivity and ventral striatal dopamine D2-type receptors: Link to impulsivity in methamphetamine users

    PubMed Central

    Kohno, Milky; Okita, Kyoji; Morales, Angelica M.; Robertson, Chelsea; Dean, Andy C.; Ghahremani, Dara G.; Sabb, Fred; Mandelkern, Mark A.; Bilder, Robert M.; London, Edythe D.

    2015-01-01

    Stimulant use disorders are associated with deficits in striatal dopamine receptor availability, abnormalities in mesocorticolimbic resting-state functional connectivity (RSFC), and impulsivity. In methamphetamine-dependent research participants, impulsivity is correlated negatively with striatal D2-type receptor availability, and mesocorticolimbic RSFC is stronger than in controls. The extent to which these features of methamphetamine dependence are interrelated, however, is unknown. This question was addressed in two studies. In Study 1, 19 methamphetamine-dependent and 26 healthy control subjects underwent [18F]fallypride positron emission tomography to measure ventral striatal dopamine D2-type receptor availability, indexed by binding potential (BPND), and functional magnetic resonance imaging (fMRI) to assess mesocorticolimbic RSFC, using a midbrain seed. In Study 2, an independent sample of 20 methamphetamine-dependent and 18 control subjects completed the Barratt Impulsiveness Scale in addition to fMRI. Study 1 showed a significant group by ventral striatal BPND interaction effect on RSFC, reflecting a negative relationship between ventral striatal BPND and RSFC between midbrain and striatum, orbitofrontal cortex, and insula in methamphetamine-dependent participants but a positive relationship in the control group. In Study 2, an interaction of group with RSFC on impulsivity was observed. Methamphetamine-dependent participants users exhibited a positive relationship of midbrain RSFC to the left ventral striatum with cognitive impulsivity, whereas a negative relationship was observed in healthy controls. The results indicate that ventral striatal D2-type receptor signaling may affect system-level activity within the mesocorticolimbic system, providing a functional link that may help explain high impulsivity in methamphetamine-dependent individuals. PMID:26830141

  9. Identification of source locations for atmospheric dry deposition of heavy metals during yellow-sand events in Seoul, Korea in 1998 using hybrid receptor models

    NASA Astrophysics Data System (ADS)

    Han, Young-Ji; Holsen, Thomas M.; Hopke, Philip K.; Cheong, Jang-Pyo; Kim, Ho; Yi, Seung-Muk

    2004-10-01

    Elemental dry deposition fluxes were measured using dry deposition plates from March to June 1998 in Seoul, Korea. During this spring sampling period several yellow-sand events characterized by long-range transport from China and Mongolia impacted the area. Understanding the impact of yellow-sand events on atmospheric dry deposition is critical to managing the heavy metal levels in the environment in Korea. In this study, the measured flux of a primarily crustal metal, Al and an anthropogenic metal, Pb was used with two hybrid receptor models, potential source contribution function (PSCF) and residence time weighted concentration (RTWC) for locating sources of heavy metals associated with atmospheric dry deposition fluxes during the yellow-sand events in Seoul, Korea. The PSCF using a criterion value of the 75th percentile of the measured dry deposition fluxes and RTWC results using the measured elemental dry deposition fluxes agreed well and consistently showed that there were large potential source areas in the Gobi Desert in China and Mongolia and industrial areas near Tianjin, Tangshan, and Shenyang in China. Major industrial areas of Shenyang, Fushun, and Anshan, the Central China loess plateau, the Gobi Desert, and the Alashan semi-desert in China were identified to be major source areas for the measured Pb flux in Seoul, Korea. For Al, the main industrial areas of Tangshan, Tianjin and Beijing, the Gobi Desert, the Alashan semi-desert, and the Central China loess plateau were found to be the major source areas. These results indicate that both anthropogenic sources such as industrial areas and natural sources such as deserts contribute to the high dry deposition fluxes of both Pb and Al in Seoul, Korea during yellow-sand events. RTWC resolved several high potential source areas. Modeling results indicated that the long-range transport of Al and Pb from China during yellow-sand events as well as non-yellow-sand spring daytimes increased atmospheric dry

  10. Prediction of blood-brain barrier permeation of α-adrenergic and imidazoline receptor ligands using PAMPA technique and quantitative-structure permeability relationship analysis.

    PubMed

    Vucicevic, Jelica; Nikolic, Katarina; Dobričić, Vladimir; Agbaba, Danica

    2015-02-20

    Imidazoline receptor ligands are a numerous family of biologically active compounds known to produce central hypotensive effect by interaction with both α2-adrenoreceptors (α2-AR) and imidazoline receptors (IRs). Recent hypotheses connect those ligands with several neurological disorders. Therefore some IRs ligands are examined as novel centrally acting antihypertensives and drug candidates for treatment of various neurological diseases. Effective Blood-Brain Barrier (BBB) permeability (P(e)) of 18 IRs/α-ARs ligands and 22 Central Nervous System (CNS) drugs was experimentally determined using Parallel Artificial Membrane Permeability Assay (PAMPA) and studied by the Quantitative-Structure-Permeability Relationship (QSPR) methodology. The dominant molecules/cations species of compounds have been calculated at pH = 7.4. The analyzed ligands were optimized using Density Functional Theory (B3LYP/6-31G(d,p)) included in ChemBio3D Ultra 13.0 program and molecule descriptors for optimized compounds were calculated using ChemBio3D Ultra 13.0, Dragon 6.0 and ADMET predictor 6.5 software. Effective permeability of compounds was used as dependent variable (Y), while calculated molecular parametres were used as independent variables (X) in the QSPR study. SIMCA P+ 12.0 was used for Partial Least Square (PLS) analysis, while the stepwise Multiple Linear Regression (MLR) and Artificial Neural Networks (ANN) modeling were performed using STASTICA Neural Networks 4.0. Predictive potential of the formed models was confirmed by Leave-One-Out Cross- and external-validation and the most reliable models were selected. The descriptors that are important for model building are identified as well as their influence on BBB permeability. Results of the QSPR studies could be used as time and cost efficient screening tools for evaluation of BBB permeation of novel α-adrenergic/imidazoline receptor ligands, as promising drug candidates for treatment of hypertension or neurological diseases

  11. VOCs emission rate estimate for complicated industrial area source using an inverse-dispersion calculation method: A case study on a petroleum refinery in Northern China.

    PubMed

    Wei, Wei; Lv, Zhaofeng; Yang, Gan; Cheng, Shuiyuan; Li, Yue; Wang, Litao

    2016-11-01

    This study aimed to apply an inverse-dispersion calculation method (IDM) to estimate the emission rate of volatile organic compounds (VOCs) for the complicated industrial area sources, through a case study on a petroleum refinery in Northern China. The IDM was composed of on-site monitoring of ambient VOCs concentrations and meteorological parameters around the source, calculation of the relationship coefficient γ between the source's emission rate and the ambient VOCs concentration by the ISC3 model, and estimation of the actual VOCs emission rate from the source. Targeting the studied refinery, 10 tests and 8 tests were respectively conducted in March and in June of 2014. The monitoring showed large differences in VOCs concentrations between background and downwind receptors, reaching 59.7 ppbv in March and 248.6 ppbv in June, on average. The VOCs increases at receptors mainly consisted of ethane (3.1%-22.6%), propane (3.8%-11.3%), isobutane (8.5%-10.2%), n-butane (9.9%-13.2%), isopentane (6.1%-12.9%), n-pentane (5.1%-9.7%), propylene (6.1-11.1%) and 1-butylene (1.6%-5.4%). The chemical composition of the VOCs increases in this field monitoring was similar to that of VOCs emissions from China's refineries reported, which revealed that the ambient VOCs increases were predominantly contributed by this refinery. So, we used the ISC3 model to create the relationship coefficient γ for each receptor of each test. In result, the monthly VOCs emissions from this refinery were calculated to be 183.5 ± 89.0 ton in March and 538.3 ± 281.0 ton in June. The estimate in June was greatly higher than in March, chiefly because the higher environmental temperature in summer produced more VOCs emissions from evaporation and fugitive process of the refinery. Finally, the VOCs emission factors (g VOCs/kg crude oil refined) of 0.73 ± 0.34 (in March) and 2.15 ± 1.12 (in June) were deduced for this refinery, being in the same order with previous direct

  12. Source Contributions of Urban PM2.5 in the Beijing-Tianjin-Hebei Region: Changes between 2006 and 2013 and Relative Impacts of Emissions and Meteorology

    NASA Astrophysics Data System (ADS)

    Li, X.; Zhang, Q.; Zhang, Y.; Zheng, B.; Li, M.; Wang, K.; Chen, Y.; Wallington, T. J.; Han, W.; Shen, W.; Zhang, X.; He, K.

    2015-12-01

    . The results in this study enhance the quantitative understanding of the source-receptor relationships and provide an important basis for policymaking to advance the control of PM2.5 pollution in China. Both sector-based and fuel-based source apportionment will be available to further improve the comparability with receptor model results.

  13. Roles of CLR/RAMP Receptor Signaling in Reproduction and Development

    PubMed Central

    Chang, Chia Lin; Hsu, Sheau Yu Teddy

    2016-01-01

    Adrenomedullin (ADM), calcitonin gene-related peptides (α- and β-CGRPs), and intermedin/adrenomedullin 2 (IMD/ADM2) are major regulators of vascular tone and cardiovascular development in vertebrates. Recent research into their functions in reproduction has illuminated the role of these peptides and their cognate receptors (calcitonin receptor-like receptor/receptor activity-modifying protein (CLR/RAMP) receptors) in fetal–maternal blood circulation, feto-placental development, female gamete development, and gamete movement in the oviduct. Although ADM family peptides function in a temporally and spatially specific manner in various reproductive processes, they appear to act via a similar set of second messengers, including nitric oxide, cyclic GMP, cyclic AMP, and calcium-activated potassium channels in different tissues. These discoveries supported the view that CLR/RAMP receptors were recruited to perform a variety of newly evolved reproductive functions during the evolution of internal reproduction in mammals. These advances also provided insight into how CLR/RAMP receptor signaling pathways coordinate with other physiological adaptions to accommodate the extra metabolic needs during pregnancy, and captured some important details as to how fetal–maternal vascular communications are generated in the first place. Furthermore, these findings have revealed novel, promising opportunities for the prevention and treatment of aberrant pregnancies such as pregnancy-induced hypertension, preeclampsia, and tubal ectopic pregnancy. However, significant efforts are still needed to clarify the relationships between certain components of the CLR/RAMP signaling pathway and aberrant pregnancies before CLR/RAMP receptors can become targets for clinical management. With this understanding, this review summarizes recent progresses with particular focus on clinical implications. PMID:23745703

  14. Comprehensive Support for Peer Relationships at Secondary Transition

    ERIC Educational Resources Information Center

    Keay, Andy; Lang, Jane; Frederickson, Norah

    2015-01-01

    Peer relationships represent a major source of concern to children transitioning to secondary school. They also offer a potentially important source of support to adjustment and academic progress. However, strategies to support peer relationships at secondary transition have received little attention in previous research. This semi-structured…

  15. Hmrbase: a database of hormones and their receptors

    PubMed Central

    Rashid, Mamoon; Singla, Deepak; Sharma, Arun; Kumar, Manish; Raghava, Gajendra PS

    2009-01-01

    Background Hormones are signaling molecules that play vital roles in various life processes, like growth and differentiation, physiology, and reproduction. These molecules are mostly secreted by endocrine glands, and transported to target organs through the bloodstream. Deficient, or excessive, levels of hormones are associated with several diseases such as cancer, osteoporosis, diabetes etc. Thus, it is important to collect and compile information about hormones and their receptors. Description This manuscript describes a database called Hmrbase which has been developed for managing information about hormones and their receptors. It is a highly curated database for which information has been collected from the literature and the public databases. The current version of Hmrbase contains comprehensive information about ~2000 hormones, e.g., about their function, source organism, receptors, mature sequences, structures etc. Hmrbase also contains information about ~3000 hormone receptors, in terms of amino acid sequences, subcellular localizations, ligands, and post-translational modifications etc. One of the major features of this database is that it provides data about ~4100 hormone-receptor pairs. A number of online tools have been integrated into the database, to provide the facilities like keyword search, structure-based search, mapping of a given peptide(s) on the hormone/receptor sequence, sequence similarity search. This database also provides a number of external links to other resources/databases in order to help in the retrieving of further related information. Conclusion Owing to the high impact of endocrine research in the biomedical sciences, the Hmrbase could become a leading data portal for researchers. The salient features of Hmrbase are hormone-receptor pair-related information, mapping of peptide stretches on the protein sequences of hormones and receptors, Pfam domain annotations, categorical browsing options, online data submission, Drug

  16. Variation of M3 muscarinic receptor expression in different prostate tissues and its significance.

    PubMed

    Song, Wei; Yuan, Mingzhen; Zhao, Shengtian

    2009-08-01

    To detect the expression of the muscarinic receptor (M receptor) in different prostate tissues and analyze the role of its subtype in prostatic oncogenesis. Thirty-six cases of normal prostate and benign prostatic hyperplasia, and 8 cases of prostatic tumor, were used in this study from the Shandong University, Shandong, China, between 2003-2006. The protein expressions of M1, M2, and M3 receptors in each group were determined by Western-blotting. The gene expressions of the M3 receptor and vascular endothelial growth factors (VEGF) in each group were determined by reverse transcriptase-polymerase chain reaction. The protein and gene expressions of the M3 receptor in the prostatic carcinoma group were higher than that of benign prostatic hyperplasia group (p=0.0001) and normal prostate group (p=0.0001). The M3 receptor and VEGF showed positive straight-line correlations of gene expressions with the 3 groups (r=0.4999, p=0.0001). The M3 receptor may have a close relationship with prostatic oncogenesis.

  17. Dopamine receptor activity participates in hippocampal synaptic plasticity associated with novel object recognition.

    PubMed

    Yang, Kechun; Broussard, John I; Levine, Amber T; Jenson, Daniel; Arenkiel, Benjamin R; Dani, John A

    2017-01-01

    Physiological and behavioral evidence supports that dopamine (DA) receptor signaling influences hippocampal function. While several recent studies examined how DA influences CA1 plasticity and learning, there are fewer studies investigating the influence of DA signaling to the dentate gyrus. The dentate gyrus receives convergent cortical input through the perforant path fiber tracts and has been conceptualized to detect novelty in spatial memory tasks. To test whether DA-receptor activity influences novelty-detection, we used a novel object recognition (NOR) task where mice remember previously presented objects as an indication of learning. Although DA innervation arises from other sources and the main DA signaling may be from those sources, our molecular approaches verified that midbrain dopaminergic fibers also sparsely innervate the dentate gyrus. During the NOR task, wild-type mice spent significantly more time investigating novel objects rather than previously observed objects. Dentate granule cells in slices cut from those mice showed an increased AMPA/NMDA-receptor current ratio indicative of potentiated synaptic transmission. Post-training injection of a D1-like receptor antagonist not only effectively blocked the preference for the novel objects, but also prevented the increased AMPA/NMDA ratio. Consistent with that finding, neither NOR learning nor the increase in the AMPA/NMDA ratio were observed in DA-receptor KO mice under the same experimental conditions. The results indicate that DA-receptor signaling contributes to the successful completion of the NOR task and to the associated synaptic plasticity of the dentate gyrus that likely contributes to the learning. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  18. Receptor-dependent mechanisms of glucocorticoid and dioxin-induced cleft palate

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pratt, R.M.

    1985-09-01

    Glucocorticoids (triamcinolone) and dioxins (TCDD) are highly specific teratogens in the mouse, in that cleft palate is the major malformation observed. Glucocorticoids and TCDD both readily cross the yolk sac and placenta and appear in the developing secondary palate. Structure-activity relationships for glucocorticoid- and TCDD-induced cleft palate suggest a receptor involvement. Receptors for glucocorticoids and TCDD are present in the palate and their levels in various mouse strains are highly correlated with their sensitivity to cleft palate induction. Receptors for glucocorticoids appear to be more prevalent in the palatal mesenchymal cells whereas those for TCDD are probably located in themore » palatal epithelial cells. Glucocorticoids exert their teratogenic effect on the palate by inhibiting the growth of the palatal mesenchymal cells whereas TCDD alters the terminal cell differentiation of the media palatal epithelial cells. 71 references.« less

  19. In the Blink of an Eye: Relating Positive-Feedback Sensitivity to Striatal Dopamine D2-Like Receptors through Blink Rate

    PubMed Central

    Groman, Stephanie M.; James, Alex S.; Seu, Emanuele; Tran, Steven; Clark, Taylor A.; Harpster, Sandra N.; Crawford, Maverick; Burtner, Joanna Lee; Feiler, Karen; Roth, Robert H.; Elsworth, John D.; London, Edythe D.

    2014-01-01

    For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors. PMID:25339755

  20. Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88.

    PubMed

    Dunne, Aisling; Ejdeback, Mikael; Ludidi, Phumzile L; O'Neill, Luke A J; Gay, Nicholas J

    2003-10-17

    The Toll/interleukin 1 receptor (TIR) domain is a region found in the cytoplasmic tails of members of the Toll-like receptor/interleukin-1 receptor superfamily. The domain is essential for signaling and is also found in the adaptor proteins Mal (MyD88 adaptor-like) and MyD88, which function to couple activation of the receptor to downstream signaling components. Experimental structures of two Toll/interleukin 1 receptor domains reveal a alpha-beta-fold similar to that of the bacterial chemotaxis protein CheY, and other evidence suggests that the adaptors can make heterotypic interactions with both the receptors and themselves. Here we show that the purified TIR domains of Mal and MyD88 can form stable heterodimers and also that Mal homodimers and oligomers are dissociated in the presence of ATP. To identify structural features that may contribute to the formation of signaling complexes, we produced models of the TIR domains from human Toll-like receptor 4 (TLR4), Mal, and MyD88. We found that although the overall fold is conserved the electrostatic surface potentials are quite distinct. Docking studies of the models suggest that Mal and MyD88 bind to different regions in TLRs 2 and 4, a finding consistent with a cooperative role of the two adaptors in signaling. Mal and MyD88 are predicted to interact at a third non-overlapping site, suggesting that the receptor and adaptors may form heterotetrameric complexes. The theoretical model of the interactions is supported by experimental data from glutathione S-transferase pull-downs and co-immunoprecipitations. Neither theoretical nor experimental data suggest a direct role for the conserved proline in the BB-loop in the association of TLR4, Mal, and MyD88. Finally we show a sequence relationship between the Drosophila protein Tube and Mal that may indicate a functional equivalence of these two adaptors in the Drosophila and vertebrate Toll pathways.

  1. Assessment of source-specific health effects associated with an unknown number of major sources of multiple air pollutants: a unified Bayesian approach.

    PubMed

    Park, Eun Sug; Hopke, Philip K; Oh, Man-Suk; Symanski, Elaine; Han, Daikwon; Spiegelman, Clifford H

    2014-07-01

    There has been increasing interest in assessing health effects associated with multiple air pollutants emitted by specific sources. A major difficulty with achieving this goal is that the pollution source profiles are unknown and source-specific exposures cannot be measured directly; rather, they need to be estimated by decomposing ambient measurements of multiple air pollutants. This estimation process, called multivariate receptor modeling, is challenging because of the unknown number of sources and unknown identifiability conditions (model uncertainty). The uncertainty in source-specific exposures (source contributions) as well as uncertainty in the number of major pollution sources and identifiability conditions have been largely ignored in previous studies. A multipollutant approach that can deal with model uncertainty in multivariate receptor models while simultaneously accounting for parameter uncertainty in estimated source-specific exposures in assessment of source-specific health effects is presented in this paper. The methods are applied to daily ambient air measurements of the chemical composition of fine particulate matter ([Formula: see text]), weather data, and counts of cardiovascular deaths from 1995 to 1997 for Phoenix, AZ, USA. Our approach for evaluating source-specific health effects yields not only estimates of source contributions along with their uncertainties and associated health effects estimates but also estimates of model uncertainty (posterior model probabilities) that have been ignored in previous studies. The results from our methods agreed in general with those from the previously conducted workshop/studies on the source apportionment of PM health effects in terms of number of major contributing sources, estimated source profiles, and contributions. However, some of the adverse source-specific health effects identified in the previous studies were not statistically significant in our analysis, which probably resulted because we

  2. Geometrical Relationship Between Interplanetary Flux Ropes and Their Solar Sources

    NASA Astrophysics Data System (ADS)

    Marubashi, K.; Akiyama, S.; Yashiro, S.; Gopalswamy, N.; Cho, K.-S.; Park, Y.-D.

    2015-05-01

    We investigated the physical connection between interplanetary flux ropes (IFRs) near Earth and coronal mass ejections (CMEs) by comparing the magnetic field structures of IFRs and CME source regions. The analysis is based on the list of 54 pairs of ICMEs (interplanetary coronal mass ejections) and CMEs that are taken to be the most probable solar source events. We first attempted to identify the flux rope structure in each of the 54 ICMEs by fitting models with a cylinder and torus magnetic field geometry, both with a force-free field structure. This analysis determined the possible geometries of the identified flux ropes. Then we compared the flux rope geometries with the magnetic field structure of the solar source regions. We obtained the following results: (1) Flux rope structures are seen in 51 ICMEs out of the 54. The result implies that all ICMEs have an intrinsic flux rope structure, if the three exceptional cases are attributed to unfavorable observation conditions. (2) It is possible to find flux rope geometries with the main axis orientation close to the orientation of the magnetic polarity inversion line (PIL) in the solar source regions, the differences being less than 25°. (3) The helicity sign of an IFR is strongly controlled by the location of the solar source: flux ropes with positive (negative) helicity are associated with sources in the southern (northern) hemisphere (six exceptions were found). (4) Over two-thirds of the sources in the northern hemisphere are concentrated along PILs with orientations of 45° ± 30° (measured clockwise from the east), and over two-thirds in the southern hemisphere along PILs with orientations of 135° ± 30°, both corresponding to the Hale boundaries. These results strongly support the idea that a flux rope with the main axis parallel to the PIL erupts in a CME and that the erupted flux rope propagates through the interplanetary space with its orientation maintained and is observed as an IFR.

  3. Primitive ATP-activated P2X receptors: discovery, function and pharmacology

    PubMed Central

    Fountain, Samuel J.

    2013-01-01

    Adenosine 5-triphosphate (ATP) is omnipresent in biology. It is therefore no surprise that organisms have evolved multifaceted roles for ATP, exploiting its abundance and restriction of passive diffusion across biological membranes. A striking role is the emergence of ATP as a bona fide transmitter molecule, whereby the movement of ATP across membranes serves as a chemical message through a direct ligand-receptor interaction. P2X receptors are ligand-gated ion channels that mediate fast responses to the transmitter ATP in mammalian cells including central and sensory neurons, vascular smooth muscle, endothelium, and leukocytes. Molecular cloning of P2X receptors and our understanding of structure-function relationships has provided sequence information with which to query an exponentially expanding wealth of genome sequence information including protist, early animal and human pathogen genomes. P2X receptors have now been cloned and characterized from a number of simple organisms. Such work has led to surprising new cellular roles for the P2X receptors family and an unusual phylogeny, with organisms such as Drosophila and C. elegans notably lacking P2X receptors despite retaining ionotropic receptors for other common transmitters that are present in mammals. This review will summarize current work on the evolutionary biology of P2X receptors and ATP as a signaling molecule, discuss what can be drawn from such studies when considering the action of ATP in higher animals and plants, and outline how simple organisms may be exploited experimentally to inform P2X receptor function in a wider context. PMID:24367292

  4. Heterogeneity of binding of muscarinic receptor antagonists in rat brain homogenates

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lee, J.H.; el-Fakahany, E.E.

    1985-06-01

    The binding properties of (-)-(/sup 3/H)quinuclidinyl benzilate and (/sup 3/H) N-methylscopolamine to muscarinic acetylcholine receptors have been investigated in rat brain homogenates. The binding of both antagonists demonstrated high affinity and saturability. Analysis of the binding data resulted in linear Scatchard plots. However, (-)-(/sup 3/H)quinuclidinyl benzilate showed a significantly higher maximal binding capacity than that of (/sup 3/H)N-methylscopolamine. Displacement of both ligands with several muscarinic receptor antagonists resulted in competition curves in accordance with the law of mass-action for quinuclidinyl benzilate, atropine and scopolamine. A similar profile was found for the quaternary ammonium analogs of atropine and scopolamine when (/supmore » 3/H)N-methylscopolamine was used to label the receptors. However, when these hydrophilic antagonists were used to displace (-)-(/sup 3/H) quinuclidinyl benzilate binding, they showed interaction with high- and low-affinity binding sites. On the other hand, the nonclassical muscarinic receptor antagonist, pirenzepine, was able to displace both ligands from two binding sites. The present data are discussed in terms of the relationship of this anomalous heterogenity of binding of these hydrophilic muscarinic receptor antagonists and the proposed M1 and M2 receptor subtypes.« less

  5. Winning agonistic encounters increases testosterone and androgen receptor expression in Syrian Hamsters

    PubMed Central

    Clinard, Catherine T.; Barnes, Abigail K.; Adler, Samuel G.; Cooper, Matthew A.

    2016-01-01

    Winning aggressive disputes is one of several experiences that can alter responses to future stressful events. We have previously tested dominant and subordinate male Syrian hamsters in a conditioned defeat model and found that dominant individuals show less change in behavior following social defeat stress compared to subordinates and controls, indicating a reduced conditioned defeat response. Resistance to the effects of social defeat in dominants is experience-dependent and requires the maintenance of dominance relationships for 14 days. For this study we investigated whether winning aggressive interactions increases plasma testosterone and whether repeatedly winning increases androgen receptor expression. First, male hamsters were paired in daily 10-min aggressive encounters and blood samples were collected immediately before and 15-min and 30-min after the formation of dominance relationships. Dominants showed an increase in plasma testosterone at 15-min post-interaction compared to their pre-interaction baseline, whereas subordinates and controls showed no change in plasma testosterone. Secondly, we investigated whether 14 days of dominant social status increased androgen or estrogen alpha-receptor immunoreactivity in brain regions that regulate the conditioned defeat response. Dominants showed more androgen, but not estrogen alpha, receptor immuno-positive cells in the dorsal medial amygdala (dMeA) and ventral lateral septum (vLS) compared to subordinates and controls. Finally, we showed that one day of dominant social status was insufficient to increase androgen receptor immunoreactivity compared to subordinates. These results suggest that elevated testosterone signaling at androgen receptors in the dMeA and vLS might contribute to the reduced conditioned defeat response exhibited by dominant hamsters. PMID:27619945

  6. Recombinant G protein-coupled receptor expression in Saccharomyces cerevisiae for protein characterization.

    PubMed

    Blocker, Kory M; Britton, Zachary T; Naranjo, Andrea N; McNeely, Patrick M; Young, Carissa L; Robinson, Anne S

    2015-01-01

    G protein-coupled receptors (GPCRs) are membrane proteins that mediate signaling across the cellular membrane and facilitate cellular responses to external stimuli. Due to the critical role that GPCRs play in signal transduction, therapeutics have been developed to influence GPCR function without an extensive understanding of the receptors themselves. Closing this knowledge gap is of paramount importance to improving therapeutic efficacy and specificity, where efforts to achieve this end have focused chiefly on improving our knowledge of the structure-function relationship. The purpose of this chapter is to review methods for the heterologous expression of GPCRs in Saccharomyces cerevisiae, including whole-cell assays that enable quantitation of expression, localization, and function in vivo. In addition, we describe methods for the micellular solubilization of the human adenosine A2a receptor and for reconstitution of the receptor in liposomes that have enabled its biophysical characterization. © 2015 Elsevier Inc. All rights reserved.

  7. Depressive symptoms and the relationship of inflammation to physical signs and symptoms in heart failure patients.

    PubMed

    Heo, Seongkum; Moser, Debra K; Pressler, Susan J; Dunbar, Sandra B; Dekker, Rebecca L; Lennie, Terry A

    2014-09-01

    Depressive symptoms in patients with heart failure can affect the relationship between physical signs and symptoms and inflammation. To examine the relationship between soluble tumor necrosis factor receptor I and physical signs and symptoms and the effects of depressive symptoms on this relationship in patients with heart failure. Data on physical signs and symptoms (Symptom Status Questionnaire-Heart Failure), depressive symptoms (Beck Depression Inventory-II), and levels of the receptor (blood samples) were collected from 145 patients with heart failure. Data on the receptor were square root transformed to achieve normality. Patients were divided into 2 groups according to their scores for depressive symptoms (nondepressed <14 and depressed ≥14). Hierarchical multiple regression was used to analyze the data. In the total sample, with controls for covariates, higher levels of the receptor were significantly related to more severe physical signs and symptoms (F = 7.915; P < .001). In subgroup analyses, with controls for covariates, levels of the receptor were significantly related to physical signs and symptoms only in the patients without depression (F = 3.174; P = .005). Both depressive symptoms and inflammation should be considered along with physical signs and symptoms in patients with heart failure. Further studies are needed to determine the effects of improvement in inflammation on improvement in physical signs and symptoms, with consideration given to the effects of depressive symptoms. ©2014 American Association of Critical-Care Nurses.

  8. GABA-A Receptors Mediate Tonic Inhibition and Neurosteroid Sensitivity in the Brain.

    PubMed

    Reddy, Doodipala Samba

    2018-01-01

    Neurosteroids like allopregnanolone (AP) are positive allosteric modulators of synaptic and extrasynaptic GABA-A receptors. AP and related neurosteroids exhibit a greater potency for δ-containing extrasynaptic receptors. The δGABA-A receptors, which are expressed extrasynaptically in the dentate gyrus and other regions, contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. Levels of endogenous neurosteroids fluctuate with ovarian cycle. Natural and synthetic neurosteroids maximally potentiate tonic inhibition in the hippocampus and provide robust protection against a variety of limbic seizures and status epilepticus. Recently, a consensus neurosteroid pharmacophore model has been proposed at extrasynaptic δGABA-A receptors based on structure-activity relationship for functional activation of tonic currents and seizure protection. Aside from anticonvulsant actions, neurosteroids have been found to be powerful anxiolytic and anesthetic agents. Neurosteroids and Zn 2+ have preferential affinity for δ-containing receptors. Thus, Zn 2+ can prevent neurosteroid activation of extrasynaptic δGABA-A receptor-mediated tonic inhibition. Recently, we demonstrated that Zn 2+ selectively inhibits extrasynaptic δGABA-A receptors and thereby fully prevents AP activation of tonic inhibition and seizure protection. We confirmed that neurosteroids exhibit greater sensitivity at extrasynaptic δGABA-A receptors. Overall, extrasynaptic GABA-A receptors are primary mediators of tonic inhibition in the brain and play a key role in the pathophysiology of epilepsy and other neurological disorders. © 2018 Elsevier Inc. All rights reserved.

  9. The future of type 1 cannabinoid receptor allosteric ligands.

    PubMed

    Alaverdashvili, Mariam; Laprairie, Robert B

    2018-02-01

    Allosteric modulation of the type 1 cannabinoid receptor (CB1R) holds great therapeutic potential. This is because allosteric modulators do not possess intrinsic efficacy, but instead augment (positive allosteric modulation) or diminish (negative allosteric modulation) the receptor's response to endogenous ligand. Consequently, CB1R allosteric modulators have an effect ceiling which allows for the tempering of CB1R signaling without the desensitization, tolerance, dependence, and psychoactivity associated with orthosteric compounds. Pain, movement disorders, epilepsy, obesity are all potential therapeutic targets for CB1R allosteric modulation. Several challenges exist for the development of CB1R allosteric modulators, such as receptor subtype specificity, translation to in vivo systems, and mixed allosteric/agonist/inverse agonist activity. Despite these challenges, elucidation of crystal structures of CB1R and compound design based on structure-activity relationships will advance the field. In this review, we will cover recent progress for CB1R allosteric modulators and discuss the future promise of this research.

  10. An Investigation of Faculty Relationships as a Source of Motivation for STEM Undergraduates at a Historically Black University

    NASA Astrophysics Data System (ADS)

    Mitchell, Aquila

    2011-12-01

    The expansion of STEM education and career opportunities among underrepresented populations is a national priority. Therefore, more research is needed that examines the institutional, instructional and individual factors related to African American students' success in these fields. This dissertation study was drawn from a larger mixed-methods longitudinal study (Freeman and Winston, 2007). It utilized a concurrent embedded design of mixed methods (Creswell, 2009), to investigate faculty relationships as a source of motivation for STEM undergraduates at a HBCU. Bandura's (1986) social cognitive theory was the theoretical basis for this study. The following research questions were examined: (a) What is the nature of student-faculty relationships among STEM undergraduates attending an HBCU; (b) How does the nature of faculty student relationships vary by gender and STEM major; (c) How do student-faculty relationships influence students' persistence in STEM, self-concept of ability in mathematics and in science and grade point average; and (d) Does the influence of student-faculty relationships on self-concept of ability in mathematics and in science and grade point average vary by gender and STEM major? Freshman college students (N=167) who had a declared major in STEM fall 2009 were participants in this study. Students were predominately Black/African American (82%) and predominately female (71%). The Student-Professor Interaction Scale (SPIS) was used to measure various dimensions of student-faculty interactions (Cokley, Komarraju, Rosales, et al., 2006). The Experiences with Faculty Scale (Pace & Kuh, 1998) was used to measure the frequency of student's experiences with faculty. Self-Concept of Ability Scales in Mathematics and in Science (Marsh, 1999) was used to measure students' global perception of their abilities. An open-ended question was designed to expand and provide breadth to the quantitative results. Findings indicated that student

  11. Joint explorative analysis of neuroreceptor subsystems in the human brain: application to receptor-transporter correlation using PET data.

    PubMed

    Cselényi, Zsolt; Lundberg, Johan; Halldin, Christer; Farde, Lars; Gulyás, Balázs

    2004-10-01

    Positron emission tomography (PET) has proved to be a highly successful technique in the qualitative and quantitative exploration of the human brain's neurotransmitter-receptor systems. In recent years, the number of PET radioligands, targeted to different neuroreceptor systems of the human brain, has increased considerably. This development paves the way for a simultaneous analysis of different receptor systems and subsystems in the same individual. The detailed exploration of the versatility of neuroreceptor systems requires novel technical approaches, capable of operating on huge parametric image datasets. An initial step of such explorative data processing and analysis should be the development of novel exploratory data-mining tools to gain insight into the "structure" of complex multi-individual, multi-receptor data sets. For practical reasons, a possible and feasible starting point of multi-receptor research can be the analysis of the pre- and post-synaptic binding sites of the same neurotransmitter. In the present study, we propose an unsupervised, unbiased data-mining tool for this task and demonstrate its usefulness by using quantitative receptor maps, obtained with positron emission tomography, from five healthy subjects on (pre-synaptic) serotonin transporters (5-HTT or SERT) and (post-synaptic) 5-HT(1A) receptors. Major components of the proposed technique include the projection of the input receptor maps to a feature space, the quasi-clustering and classification of projected data (neighbourhood formation), trans-individual analysis of neighbourhood properties (trajectory analysis), and the back-projection of the results of trajectory analysis to normal space (creation of multi-receptor maps). The resulting multi-receptor maps suggest that complex relationships and tendencies in the relationship between pre- and post-synaptic transporter-receptor systems can be revealed and classified by using this method. As an example, we demonstrate the regional

  12. Structural Insights into σ₁ Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations.

    PubMed

    Kurciński, Mateusz; Jarończyk, Małgorzata; Lipiński, Piotr F J; Dobrowolski, Jan Cz; Sadlej, Joanna

    2018-02-18

    Despite considerable advances over the past years in understanding the mechanisms of action and the role of the σ₁ receptor, several questions regarding this receptor remain unanswered. This receptor has been identified as a useful target for the treatment of a diverse range of diseases, from various central nervous system disorders to cancer. The recently solved issue of the crystal structure of the σ₁ receptor has made elucidating the structure-activity relationship feasible. The interaction of seven representative opioid ligands with the crystal structure of the σ₁ receptor (PDB ID: 5HK1) was simulated for the first time using molecular dynamics (MD). Analysis of the MD trajectories has provided the receptor-ligand interaction fingerprints, combining information on the crucial receptor residues and frequency of the residue-ligand contacts. The contact frequencies and the contact maps suggest that for all studied ligands, the hydrophilic (hydrogen bonding) interactions with Glu172 are an important factor for the ligands' affinities toward the σ₁ receptor. However, the hydrophobic interactions with Tyr120, Val162, Leu105, and Ile124 also significantly contribute to the ligand-receptor interplay and, in particular, differentiate the action of the agonistic morphine from the antagonistic haloperidol.

  13. Chemistry and Structure-Activity Relationships of Psychedelics.

    PubMed

    Nichols, David E

    2018-01-01

    This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT 2A receptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT 2A receptor is the principal mechanism of action for psychedelics, compounds with 5-HT 2A agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT 2A receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.

  14. Relationship between funding source and conclusion among nutrition-related scientific articles.

    PubMed

    Lesser, Lenard I; Ebbeling, Cara B; Goozner, Merrill; Wypij, David; Ludwig, David S

    2007-01-01

    Industrial support of biomedical research may bias scientific conclusions, as demonstrated by recent analyses of pharmaceutical studies. However, this issue has not been systematically examined in the area of nutrition research. The purpose of this study is to characterize financial sponsorship of scientific articles addressing the health effects of three commonly consumed beverages, and to determine how sponsorship affects published conclusions. Medline searches of worldwide literature were used to identify three article types (interventional studies, observational studies, and scientific reviews) about soft drinks, juice, and milk published between 1 January, 1999 and 31 December, 2003. Financial sponsorship and article conclusions were classified by independent groups of coinvestigators. The relationship between sponsorship and conclusions was explored by exact tests and regression analyses, controlling for covariates. 206 articles were included in the study, of which 111 declared financial sponsorship. Of these, 22% had all industry funding, 47% had no industry funding, and 32% had mixed funding. Funding source was significantly related to conclusions when considering all article types (p = 0.037). For interventional studies, the proportion with unfavorable conclusions was 0% for all industry funding versus 37% for no industry funding (p = 0.009). The odds ratio of a favorable versus unfavorable conclusion was 7.61 (95% confidence interval 1.27 to 45.73), comparing articles with all industry funding to no industry funding. Industry funding of nutrition-related scientific articles may bias conclusions in favor of sponsors' products, with potentially significant implications for public health.

  15. Taste transductions in taste receptor cells: basic tastes and moreover.

    PubMed

    Iwata, Shusuke; Yoshida, Ryusuke; Ninomiya, Yuzo

    2014-01-01

    In the oral cavity, taste receptor cells dedicate to detecting chemical compounds in foodstuffs and transmitting their signals to gustatory nerve fibers. Heretofore, five taste qualities (sweet, umami, bitter, salty and sour) are generally accepted as basic tastes. Each of these may have a specific role in the detection of nutritious and poisonous substances; sweet for carbohydrate sources of calories, umami for protein and amino acid contents, bitter for harmful compounds, salty for minerals and sour for ripeness of fruits and spoiled foods. Recent studies have revealed molecular mechanisms for reception and transduction of these five basic tastes. Sweet, umami and bitter tastes are mediated by G-protein coupled receptors (GPCRs) and second-messenger signaling cascades. Salty and sour tastes are mediated by channel-type receptors. In addition to five basic tastes, taste receptor cells may have the ability to detect fat taste, which is elicited by fatty acids, and calcium taste, which is elicited by calcium. Taste compounds eliciting either fat taste or calcium taste may be detected by specific GPCRs expressed in taste receptor cells. This review will focus on transduction mechanisms and cellular characteristics responsible for each of basic tastes, fat taste and calcium taste.

  16. Toll-like receptors (TLRs) and immune disorders.

    PubMed

    Akashi-Takamura, Sachiko; Miyake, Kensuke

    2006-10-01

    Upon the invasion of pathogens, the immune system needs to mount defense responses immediately. Over the past 10 years, Toll-like receptors (TLRs) have been discovered in mammals and defined as pathogen sensors. TLRs are considered to bind directly to ligands, discriminate them immediately, and induce defense responses when appropriate. We here review microbial recognition by TLRs, downstream signaling, and the relationship of TLRs to susceptibility to infectious diseases and immune disorders. Recent reports have revealed a requirement for co-receptors in TLR responses. A TLR signaling pathway is required for protection against infectious diseases, but excessive signaling may lead to allergies, autoimmune diseases, or atherosclerosis. In humans, several deficiencies of signaling molecules downstream of TLRs, and TLR polymorphisms that affect recognition or signaling, were reported to cause immunodeficiencies. It is important to understand how TLR signaling is controlled.

  17. The relationship between the agonist-induced activation and desensitization of the human tachykinin NK2 receptor expressed in Xenopus oocytes

    PubMed Central

    Maudsley, S; Gent, J P; Findlay, J B C; Donnelly, D

    1998-01-01

    Repeated applications of neurokinin A (NKA) to oocytes injected with 25 ng wild-type hNK2 receptor cRNA caused complete attenuation of second and subsequent NKA-induced responses while analogous experiments using repeated applications of GR64349 and [Nle10]NKA(4–10) resulted in no such desensitization. This behaviour has been previously attributed to the ability of the different ligands to stabilize different active conformations of the receptor that have differing susceptibilities to receptor kinases (Nemeth & Chollet, 1995).However, for Xenopus oocytes injected (into the nucleus) with 10 ng wild-type hNK2 receptor cDNA, a single 100 nM concentration of any of the three ligands resulted in complete desensitization to further concentrations.On the other hand, none of the ligands caused any desensitization in oocytes injected with 0.25 ng wild-type hNK2 receptor cRNA, even at concentrations up to 10 μM.The two N-terminally truncated analogues of neurokinin A have a lower efficacy than NKA and it is likely that it is this property which causes the observed differences in desensitization, rather than the formation of alternative active states of the receptor.The peak calcium-dependent chloride current is not a reliable measure of maximal receptor stimulation and efficacy is better measured in this system by studying agonist-induced desensitization.The specific adenylyl cyclase inhibitor SQ22536 can enhance NKA and GR64349-mediated desensitization which suggests that agonist-induced desensitization involves the inhibition of adenylyl cyclase and the subsequent down-regulation of the cyclic AMP-dependent protein kinase, possibly by cross-talk to a second signalling pathway. PMID:9690859

  18. Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI.

    PubMed

    Lukito, P; Wong, A; Jing, J; Arthur, J F; Marasco, S F; Murphy, D A; Bergin, P J; Shaw, J A; Collecutt, M; Andrews, R K; Gardiner, E E; Davis, A K

    2016-11-01

    Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk. Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use. Exposure of platelets to elevated shear in vitro leads to increased shedding. Objectives To investigate whether loss of platelet receptors occurs in vivo, and the relationship with acquired von Willebrand syndrome (AVWS). Methods Platelet counts, coagulation tests and von Willebrand factor (VWF) analyses were performed on samples from 21 continuous flow VAD (CF-VAD), 20 ECMO, 12 heart failure and seven aortic stenosis patients. Levels of platelet receptors were measured by flow cytometry or ELISA. Results The loss of high molecular weight VWF multimers was observed in 18 of 19 CF-VAD and 14 of 20 ECMO patients, consistent with AVWS. Platelet receptor shedding was demonstrated by elevated soluble glycoprotein (GP) VI levels in plasma and significantly reduced surface GPIbα and GPVI levels in CF-VAD and ECMO patients as compared with healthy donors. Platelet receptor levels were also significantly reduced in heart failure patients. Conclusions These data link AVWS and increased platelet receptor shedding in patients with CF-VADs or ECMO for the first time. Loss of the platelet surface receptors GPIbα and GPVI in heart failure, CF-VAD and ECMO patients may contribute to ablated platelet adhesion/activation, and limit thrombus formation under high/pathologic shear conditions. © 2016 International Society on Thrombosis and Haemostasis.

  19. PM2.5 source apportionment in a French urban coastal site under steelworks emission influences using constrained non-negative matrix factorization receptor model.

    PubMed

    Kfoury, Adib; Ledoux, Frédéric; Roche, Cloé; Delmaire, Gilles; Roussel, Gilles; Courcot, Dominique

    2016-02-01

    The constrained weighted-non-negative matrix factorization (CW-NMF) hybrid receptor model was applied to study the influence of steelmaking activities on PM2.5 (particulate matter with equivalent aerodynamic diameter less than 2.5 μm) composition in Dunkerque, Northern France. Semi-diurnal PM2.5 samples were collected using a high volume sampler in winter 2010 and spring 2011 and were analyzed for trace metals, water-soluble ions, and total carbon using inductively coupled plasma--atomic emission spectrometry (ICP-AES), ICP--mass spectrometry (ICP-MS), ionic chromatography and micro elemental carbon analyzer. The elemental composition shows that NO3(-), SO4(2-), NH4(+) and total carbon are the main PM2.5 constituents. Trace metals data were interpreted using concentration roses and both influences of integrated steelworks and electric steel plant were evidenced. The distinction between the two sources is made possible by the use Zn/Fe and Zn/Mn diagnostic ratios. Moreover Rb/Cr, Pb/Cr and Cu/Cd combination ratio are proposed to distinguish the ISW-sintering stack from the ISW-fugitive emissions. The a priori knowledge on the influencing source was introduced in the CW-NMF to guide the calculation. Eleven source profiles with various contributions were identified: 8 are characteristics of coastal urban background site profiles and 3 are related to the steelmaking activities. Between them, secondary nitrates, secondary sulfates and combustion profiles give the highest contributions and account for 93% of the PM2.5 concentration. The steelwork facilities contribute in about 2% of the total PM2.5 concentration and appear to be the main source of Cr, Cu, Fe, Mn, Zn. Copyright © 2015. Published by Elsevier B.V.

  20. Serum growth hormone (GH)-binding protein/receptor: an important determinant of GH responsiveness.

    PubMed

    Martha, P M; Reiter, E O; Dávila, N; Shaw, M A; Holcombe, J H; Baumann, G

    1992-12-01

    Individual growth rates (or responses to GH therapy) and adult heights vary over a wide range. The reasons for this variation are poorly understood. Based on the reciprocal relationship between GH production and serum GH-binding protein/receptor (GH-BP), we hypothesized that genetic growth potential was achieved by a specific combination of GH-BP/receptor and GH production in each individual. To address the question whether GH production regulates GH-BP, or vice versa, we studied GH-deficient children, where one of the parameters, GH exposure, could be controlled through exogenous administration. Forty-three untreated prepubertal GH-deficient children were studied before and after 6 and 12 months of GH replacement therapy (0.18 mg/kg.week). Growth velocity, height, bone age, weight and their respective Z scores, serum GH-BP, and serum insulin-like growth factor I (IGF-I) were measured at each time point. The patients responded with significant increases in serum IGF-I, age-adjusted growth velocity, and height (P < 10(-6) for all). Before therapy, GH-BP correlated directly with chronologic and bone age (P < 10(-4), but not with either growth velocity or IGF-I. In contrast, GH-BP correlated strongly with the response to therapy whether assessed as the incremental change in IGF-I (P < 10(-6)) or as the increase in growth velocity (P approximately 0.003). GH treatment had no consistent effect on GH-BP/receptor levels. These findings support the concept that the GH-BP/receptor endowment is characteristic for an individual and plays a pivotal role in somatic growth. The GH-BP/receptor system and its ontogeny appears relatively independent of regulation by GH. Differences in individual GH-BP/GH receptor complement account for some of the variability in the response to GH, and GH-BP levels may serve as a predictor for the degree of response. The reciprocal relationship between GH production and GH-BP in normal subjects probably results from adjustment of GH secretion to

  1. The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

    PubMed Central

    Bow, Eric W.; Rimoldi, John M.

    2016-01-01

    The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (−)-Δ9-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles. PMID:27398024

  2. Chemokine and lymph node homing receptor expression on pDC vary by graft source.

    PubMed

    Hosoba, Sakura; Harris, Wayne Ac; Lin, Kaifeng L; Waller, Edmund K

    2014-11-01

    A randomized clinical trial of BM vs. blood stem cell transplants from unrelated donors showed that more plasmacytoid dendritic cells (pDCs) in BM grafts was associated with better post-transplant survival. Here, we describe differences in homing-receptor expression on pDC to explain observed differences following BM vs. blood stem cell transplantation.

  3. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

    PubMed Central

    Meng, Jingru; Ma, Xue; Wang, Ning; Jia, Min; Bi, Long; Wang, Yunying; Li, Mingkai; Zhang, Huinan; Xue, Xiaoyan; Hou, Zheng; Zhou, Ying; Yu, Zhibin; He, Gonghao; Luo, Xiaoxing

    2016-01-01

    Summary Glucagon-like peptide 1 (GLP-1) plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4) promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These functions were accompanied by an increase in osteoblast number and serum bone formation markers, while the adipocyte number was decreased. Furthermore, GLP-1 receptor was detected in bone marrow stromal cells (BMSCs), but not in osteoblast. Activation of GLP-1 receptor by Ex-4 promoted the osteogenic differentiation and inhibited BMSC adipogenic differentiation through regulating PKA/β-catenin and PKA/PI3K/AKT/GSK3β signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provide a molecular basis for therapeutic potential of GLP-1 against osteoporosis. PMID:26947974

  4. Mood states, sympathetic activity, and in vivo beta-adrenergic receptor function in a normal population.

    PubMed

    Yu, Bum-Hee; Kang, Eun-Ho; Ziegler, Michael G; Mills, Paul J; Dimsdale, Joel E

    2008-01-01

    The purpose of this study was to examine the relationship between mood states and beta-adrenergic receptor function in a normal population. We also examined if sympathetic nervous system activity is related to mood states or beta-adrenergic receptor function. Sixty-two participants aged 25-50 years were enrolled in this study. Mood states were assessed using the Profile of Mood States (POMS). Beta-adrenergic receptor function was determined using the chronotropic 25 dose isoproterenol infusion test. Level of sympathetic nervous system activity was estimated from 24-hr urine norepinephrine excretion. Higher tension-anxiety, depression-dejection, and anger-hostility were related to decreased beta-adrenergic receptor sensitivity (i.e., higher chronotropic 25 dose values), but tension-anxiety was the only remaining independent predictor of beta-adrenergic receptor function after controlling for age, gender, ethnicity, and body mass index (BMI). Urinary norepinephrine excretion was unrelated to either mood states or beta-adrenergic receptor function. These findings replicate previous reports that anxiety is related to decreased (i.e., desensitized) beta-adrenergic receptor sensitivity, even after controlling for age, gender, ethnicity, and body mass index.

  5. Revisiting the Quinoxalinedione Scaffold in the Construction of New Ligands for the Ionotropic Glutamate Receptors.

    PubMed

    Demmer, Charles S; Rombach, David; Liu, Na; Nielsen, Birgitte; Pickering, Darryl S; Bunch, Lennart

    2017-11-15

    More than two decades ago, the quinoxalinedione scaffold was shown to act as an α-amino acid bioisoster. Following extensive structure-activity relationship (SAR) studies, the antagonists DNQX, CNQX, and NBQX in the ionotropic glutamate receptor field were identified. In this work, we revisit the quinoxalinedione scaffold and explore the incorporation of an acid functionality in the 6-position. The SAR studies disclose that by this strategy it was possible to tune in iGluR selectivity among the AMPA, NMDA, and KA receptors, and to some extent also obtain full receptor subtype selectivity. Highlights of the study of 44 new analogues are compound 2m being a high affinity ligand for native AMPA receptors (IC 50 = 0.48 μM), analogues 2e,f,h,k,v all displayed selectivity for native NMDA receptors, and compounds 2s,t,u are selective ligand for the GluK1 receptor. Most interestingly, compound 2w was shown to be a GluK3-preferring ligand with full selectivity over native AMPA, KA and NMDA receptors.

  6. PGE2 released by primary sensory neurons modulates Toll-like receptor 4 activities through an EP4 receptor-dependent process.

    PubMed

    Tse, Kai-Hei; Chow, Kevin B S; Wise, Helen

    2016-04-15

    Exogenous prostaglandin E2 (PGE2) displays mixed regulatory properties with regard to inflammatory gene expression in dorsal root ganglion (DRG) cells. We show here that endogenously-produced nanomolar concentrations of PGE2, such as that generated in response to Toll-like receptor 4 (TLR4) stimulation, inhibits both cyclooxygenase-2 (COX-2) and tumour necrosis factor alpha (TNFα) mRNA expression in DRG cells in an EP4 receptor-dependent manner. DRG neurons appear to be the major source of PGE2 in the DRG and likely serve as both an autocrine and paracrine system for limiting over-activation of both DRG neurons and glial cells in response to TLR4 stimulation. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Association of Dopamine D2 Receptor Gene with Creative Ideation

    ERIC Educational Resources Information Center

    Yu, Qi; Zhang, Shun; Zhang, Jinghuan H.

    2017-01-01

    Although several studies suggest that dopamine D2 receptor (DRD2) gene may contribute to creativity, the relationship between DRD2 and creativity still needs to be further validated. To further test the relevance of DRD2 and creativity, this study explored the association between DRD2 and creative ideation in 483 unrelated healthy Chinese…

  8. Synthetic cannabinoids: In silico prediction of the cannabinoid receptor 1 affinity by a quantitative structure-activity relationship model.

    PubMed

    Paulke, Alexander; Proschak, Ewgenij; Sommer, Kai; Achenbach, Janosch; Wunder, Cora; Toennes, Stefan W

    2016-03-14

    The number of new synthetic psychoactive compounds increase steadily. Among the group of these psychoactive compounds, the synthetic cannabinoids (SCBs) are most popular and serve as a substitute of herbal cannabis. More than 600 of these substances already exist. For some SCBs the in vitro cannabinoid receptor 1 (CB1) affinity is known, but for the majority it is unknown. A quantitative structure-activity relationship (QSAR) model was developed, which allows the determination of the SCBs affinity to CB1 (expressed as binding constant (Ki)) without reference substances. The chemically advance template search descriptor was used for vector representation of the compound structures. The similarity between two molecules was calculated using the Feature-Pair Distribution Similarity. The Ki values were calculated using the Inverse Distance Weighting method. The prediction model was validated using a cross validation procedure. The predicted Ki values of some new SCBs were in a range between 20 (considerably higher affinity to CB1 than THC) to 468 (considerably lower affinity to CB1 than THC). The present QSAR model can serve as a simple, fast and cheap tool to get a first hint of the biological activity of new synthetic cannabinoids or of other new psychoactive compounds. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. The interleukin-4 receptor: signal transduction by a hematopoietin receptor.

    PubMed

    Keegan, A D; Pierce, J H

    1994-02-01

    Over the last several years, the receptors for numerous cytokines have been molecularly characterized. Analysis of their amino acid sequences shows that some of these receptors bear certain motifs in their extracellular domains that define a family of receptors called the Hematopoietin receptor superfamily. Significant advances in characterizing the structure, function, and mechanisms of signal transduction have been made for several members of this family. The purpose of this review is to discuss the recent advances made for one of the family members, the interleukin (IL) 4 receptor. Other receptor systems have recently been reviewed elsewhere. The IL-4 receptor consists of, at the minimum, the cloned 140 kDa IL-4-binding chain with the potential for associating with other chains. The IL-4 receptor transduces its signal by activating a tyrosine kinase that phosphorylates cellular substrates, including the receptor itself, and the 170 kDa substrate called 4PS. Phosphorylated 4PS interacts with the SH2 domain of the enzyme PI-3'-kinase and increases its enzymatic activity. These early events in the IL-4 receptor initiated signaling pathway may trigger a series of signals that will ultimately lead to an IL-4 specific biologic outcome.

  10. Evolution of neuronal signalling: transmitters and receptors.

    PubMed

    Hoyle, Charles H V

    2011-11-16

    Evolution is a dynamic process during which the genome should not be regarded as a static entity. Molecular and morphological information yield insights into the evolution of species and their phylogenetic relationships, and molecular information in particular provides information into the evolution of signalling processes. Many signalling systems have their origin in primitive, even unicellular, organisms. Through time, and as organismal complexity increased, certain molecules were employed as intercellular signal molecules. In the autonomic nervous system the basic unit of chemical transmission is a ligand and its cognate receptor. The general mechanisms underlying evolution of signal molecules and their cognate receptors have their basis in the alteration of the genome. In the past this has occurred in large-scale events, represented by two or more doublings of the whole genome, or large segments of the genome, early in the deuterostome lineage, after the emergence of urochordates and cephalochordates, and before the emergence of vertebrates. These duplications were followed by extensive remodelling involving subsequent small-scale changes, ranging from point mutations to exon duplication. Concurrent with these processes was multiple gene loss so that the modern genome contains roughly the same number of genes as in early deuterostomes despite the large-scale genomic duplications. In this review, the principles that underlie evolution that have led to large and small families of autonomic neurotransmitters and their receptors are discussed, with emphasis on G protein-coupled receptors. Copyright © 2010 Elsevier B.V. All rights reserved.

  11. Dual source heat pump

    DOEpatents

    Ecker, Amir L.; Pietsch, Joseph A.

    1982-01-01

    What is disclosed is a heat pump apparatus for conditioning a fluid characterized by a fluid handler and path for circulating the fluid in heat exchange relationship with a refrigerant fluid; at least two refrigerant heat exchangers, one for effecting heat exchange with the fluid and a second for effecting heat exchange between refrigerant and a heat exchange fluid and the ambient air; a compressor for efficiently compressing the refrigerant; at least one throttling valve for throttling liquid refrigerant; a refrigerant circuit; refrigerant; a source of heat exchange fluid; heat exchange fluid circulating device and heat exchange fluid circuit for circulating the heat exchange fluid in heat exchange relationship with the refrigerant; and valves or switches for selecting the heat exchangers and direction of flow of the refrigerant therethrough for selecting a particular mode of operation. The heat exchange fluid provides energy for defrosting the second heat exchanger when operating in the air source mode and also provides a alternate source of heat.

  12. Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists.

    PubMed

    Mochizuki, Michiyo; Kori, Masakuni; Kobayashi, Katsumi; Yano, Takahiko; Sako, Yuu; Tanaka, Maiko; Kanzaki, Naoyuki; Gyorkos, Albert C; Corrette, Christopher P; Cho, Suk Young; Pratt, Scott A; Aso, Kazuyoshi

    2016-03-24

    Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research.

  13. A GIS-based time-dependent seismic source modeling of Northern Iran

    NASA Astrophysics Data System (ADS)

    Hashemi, Mahdi; Alesheikh, Ali Asghar; Zolfaghari, Mohammad Reza

    2017-01-01

    The first step in any seismic hazard study is the definition of seismogenic sources and the estimation of magnitude-frequency relationships for each source. There is as yet no standard methodology for source modeling and many researchers have worked on this topic. This study is an effort to define linear and area seismic sources for Northern Iran. The linear or fault sources are developed based on tectonic features and characteristic earthquakes while the area sources are developed based on spatial distribution of small to moderate earthquakes. Time-dependent recurrence relationships are developed for fault sources using renewal approach while time-independent frequency-magnitude relationships are proposed for area sources based on Poisson process. GIS functionalities are used in this study to introduce and incorporate spatial-temporal and geostatistical indices in delineating area seismic sources. The proposed methodology is used to model seismic sources for an area of about 500 by 400 square kilometers around Tehran. Previous researches and reports are studied to compile an earthquake/fault catalog that is as complete as possible. All events are transformed to uniform magnitude scale; duplicate events and dependent shocks are removed. Completeness and time distribution of the compiled catalog is taken into account. The proposed area and linear seismic sources in conjunction with defined recurrence relationships can be used to develop time-dependent probabilistic seismic hazard analysis of Northern Iran.

  14. Auditing Associative Relations across Two Knowledge Sources

    PubMed Central

    Vizenor, Lowell T.; Bodenreider, Olivier; McCray, Alexa T.

    2009-01-01

    Objectives This paper proposes a novel semantic method for auditing associative relations in biomedical terminologies. We tested our methodology on two Unified Medical Language System (UMLS) knowledge sources. Methods We use the UMLS semantic groups as high-level representations of the domain and range of relationships in the Metathesaurus and in the Semantic Network. A mapping created between Metathesaurus relationships and Semantic Network relationships forms the basis for comparing the signatures of a given Metathesaurus relationship to the signatures of the semantic relationship to which it is mapped. The consistency of Metathesaurus relations is studied for each relationship. Results Of the 177 associative relationships in the Metathesaurus, 84 (48%) exhibit a high degree of consistency with the corresponding Semantic Network relationships. Overall, 63% of the 1.8M associative relations in the Metathesaurus are consistent with relations in the Semantic Network. Conclusion The semantics of associative relationships in biomedical terminologies should be defined explicitly by their developers. The Semantic Network would benefit from being extended with new relationships and with new relations for some existing relationships. The UMLS editing environment could take advantage of the correspondence established between relationships in the Metathesaurus and the Semantic Network. Finally, the auditing method also yielded useful information for refining the mapping of associative relationships between the two sources. PMID:19475724

  15. Auditing SNOMED Relationships Using a Converse Abstraction Network

    PubMed Central

    Wei, Duo; Halper, Michael; Elhanan, Gai; Chen, Yan; Perl, Yehoshua; Geller, James; Spackman, Kent A.

    2009-01-01

    In SNOMED CT, a given kind of attribute relationship is defined between two hierarchies, a source and a target. Certain hierarchies (or subhierarchies) serve only as targets, with no outgoing relationships of their own. However, converse relationships—those pointing in a direction opposite to the defined relationships—while not explicitly represented in SNOMED’s inferred view, can be utilized in forming an alternative view of a source. In particular, they can help shed light on a source hierarchy’s overall relationship structure. Toward this end, an abstraction network, called the converse abstraction network (CAN), derived automatically from a given SNOMED hierarchy is presented. An auditing methodology based on the CAN is formulated. The methodology is applied to SNOMED’s Device subhierarchy and the related device relationships of the Procedure hierarchy. The results indicate that the CAN is useful in finding opportunities for refining and improving SNOMED. PMID:20351941

  16. Blocking mineralocorticoid receptors impairs, blocking glucocorticoid receptors enhances memory retrieval in humans.

    PubMed

    Rimmele, Ulrike; Besedovsky, Luciana; Lange, Tanja; Born, Jan

    2013-04-01

    Memory retrieval is impaired at very low as well as very high cortisol levels, but not at intermediate levels. This inverted-U-shaped relationship between cortisol levels and memory retrieval may originate from different roles of the mineralocorticoid (MR) and glucocorticoid receptor (GR) that bind cortisol with distinctly different affinity. Here, we examined the role of MRs and GRs in human memory retrieval using specific receptor antagonists. In two double-blind within-subject, cross-over designed studies, young healthy men were asked to retrieve emotional and neutral texts and pictures (learnt 3 days earlier) between 0745 and 0915 hours in the morning, either after administration of 400 mg of the MR blocker spironolactone vs placebo (200 mg at 2300 hours and 200 mg at 0400 hours, Study I) or after administration of the GR blocker mifepristone vs placebo (200 mg at 2300 hours, Study II). Blockade of MRs impaired free recall of both texts and pictures particularly for emotional material. In contrast, blockade of GRs resulted in better memory retrieval for pictures, with the effect being more pronounced for neutral than emotional materials. These findings indicate indeed opposing roles of MRs and GRs in memory retrieval, with optimal retrieval at intermediate cortisol levels likely mediated by high MR but concurrently low GR activation.

  17. Striatal D1- and D2-type dopamine receptors are linked to motor response inhibition in human subjects.

    PubMed

    Robertson, Chelsea L; Ishibashi, Kenji; Mandelkern, Mark A; Brown, Amira K; Ghahremani, Dara G; Sabb, Fred; Bilder, Robert; Cannon, Tyrone; Borg, Jacqueline; London, Edythe D

    2015-04-15

    Motor response inhibition is mediated by neural circuits involving dopaminergic transmission; however, the relative contributions of dopaminergic signaling via D1- and D2-type receptors are unclear. Although evidence supports dissociable contributions of D1- and D2-type receptors to response inhibition in rats and associations of D2-type receptors to response inhibition in humans, the relationship between D1-type receptors and response inhibition has not been evaluated in humans. Here, we tested whether individual differences in striatal D1- and D2-type receptors are related to response inhibition in human subjects, possibly in opposing ways. Thirty-one volunteers participated. Response inhibition was indexed by stop-signal reaction time on the stop-signal task and commission errors on the continuous performance task, and tested for association with striatal D1- and D2-type receptor availability [binding potential referred to nondisplaceable uptake (BPND)], measured using positron emission tomography with [(11)C]NNC-112 and [(18)F]fallypride, respectively. Stop-signal reaction time was negatively correlated with D1- and D2-type BPND in whole striatum, with significant relationships involving the dorsal striatum, but not the ventral striatum, and no significant correlations involving the continuous performance task. The results indicate that dopamine D1- and D2-type receptors are associated with response inhibition, and identify the dorsal striatum as an important locus of dopaminergic control in stopping. Moreover, the similar contribution of both receptor subtypes suggests the importance of a relative balance between phasic and tonic dopaminergic activity subserved by D1- and D2-type receptors, respectively, in support of response inhibition. The results also suggest that the stop-signal task and the continuous performance task use different neurochemical mechanisms subserving motor response inhibition. Copyright © 2015 the authors 0270-6474/15/355990-08$15.00/0.

  18. Global source attribution of sulfate concentration and direct and indirect radiative forcing

    NASA Astrophysics Data System (ADS)

    Yang, Yang; Wang, Hailong; Smith, Steven J.; Easter, Richard; Ma, Po-Lun; Qian, Yun; Yu, Hongbin; Li, Can; Rasch, Philip J.

    2017-07-01

    The global source-receptor relationships of sulfate concentrations, and direct and indirect radiative forcing (DRF and IRF) from 16 regions/sectors for years 2010-2014 are examined in this study through utilizing a sulfur source-tagging capability implemented in the Community Earth System Model (CESM) with winds nudged to reanalysis data. Sulfate concentrations are mostly contributed by local emissions in regions with high emissions, while over regions with relatively low SO2 emissions, the near-surface sulfate concentrations are primarily attributed to non-local sources from long-range transport. Regional source efficiencies of sulfate concentrations are higher over regions with dry atmospheric conditions and less export, suggesting that lifetime of aerosols, together with regional export, is important in determining regional air quality. The simulated global total sulfate DRF is -0.42 W m-2, with -0.31 W m-2 contributed by anthropogenic sulfate and -0.11 W m-2 contributed by natural sulfate, relative to a state with no sulfur emissions. In the Southern Hemisphere tropics, dimethyl sulfide (DMS) contributes 17-84 % to the total DRF. East Asia has the largest contribution of 20-30 % over the Northern Hemisphere mid- and high latitudes. A 20 % perturbation of sulfate and its precursor emissions gives a sulfate incremental IRF of -0.44 W m-2. DMS has the largest contribution, explaining -0.23 W m-2 of the global sulfate incremental IRF. Incremental IRF over regions in the Southern Hemisphere with low background aerosols is more sensitive to emission perturbation than that over the polluted Northern Hemisphere.

  19. No Effect of Nutritional Adenosine Receptor Antagonists on Exercise Performance in the Heat

    DTIC Science & Technology

    2008-11-01

    358–363, 1996. 11. Cook NC, Samman S. Flavonoids — chemistry , metabolism, cardiopro- tective effects, and dietary sources. Nutr Biochem 7: 66–76, 1996...metabolism and health effects of dietary flavonoids in man. Biomed Pharmacother 51: 305–310, 1997. R400 ADENOSINE RECEPTOR ANTAGONISM AND EXERCISE IN THE HEAT...Interactions of flavonoids with adenosine receptors. J Med Chem 39: 781–788, 1996. 35. MacRae HS, Mefferd KM. Dietary antioxidant supplementation com

  20. Relationship of Liver X Receptors α and Endoglin Levels in Serum and Placenta with Preeclampsia.

    PubMed

    Wang, Jing; Dong, Xing; Wu, Hong-Yan; Wu, Nan; Zhang, Xue-Jun; Wang, Xin; Shang, Li-Xin

    2016-01-01

    Liver X receptor alpha (LXRα) and endoglin have been postulated to play roles in trophoblast invasion and lipid metabolic disturbances. However, the relationship between LXRα and endoglin levels in serum and placenta of patients with preeclampsia remains poorly understood. The objective of this study was to identify correlations between LXRα, endoglin and preeclampsia and provide new feasible methods of clinical prediction and treatment for preeclampsia. We enrolled 45 patients with preeclampsia (24 with moderate preeclampsia and 21 with severe preeclampsia) and 15 normal pregnant women (control group) who were admitted to the Department of Obstetrics of the General Hospital of Beijing Command between October 2012 and July 2013 in this study. Serum and placental LXRα and endoglin levels were analyzed by enzyme-linked immunosorbent assay, real-time quantitative PCR, tissue microarray and immunohistochemistry. Serum and placental LXRα and endoglin levels were significantly higher in patients with preeclampsia than those in control group (P<0.05, each). Moreover, patients with severe preeclampsia displayed significantly higher LXRα and endoglin levels than those with moderate preeclampsia (P<0.05, each). The LXRα sensitivity, specificity and positive and negative predictive values were 66.00%, 80.00%, 89.19% and 48.48%, respectively, while those of endoglin levels were 62.00%, 85.00%, 91.18% and 47.22%, respectively. LXRα and endoglin levels in serum and placenta from patients with preeclampsia were positively correlated (serum: r = 0.486, P<0.01; placenta: r = 0.569, P<0.01). Elevated LXRα and endoglin levels may be associated with preeclampsia pathogenesis and development and could be used as potential predictors for this disorder.

  1. Forskolin-free cAMP assay for Gi-coupled receptors.

    PubMed

    Gilissen, Julie; Geubelle, Pierre; Dupuis, Nadine; Laschet, Céline; Pirotte, Bernard; Hanson, Julien

    2015-12-01

    G protein-coupled receptors (GPCRs) represent the most successful receptor family for treating human diseases. Many are poorly characterized with few ligands reported or remain completely orphans. Therefore, there is a growing need for screening-compatible and sensitive assays. Measurement of intracellular cyclic AMP (cAMP) levels is a validated strategy for measuring GPCRs activation. However, agonist ligands for Gi-coupled receptors are difficult to track because inducers such as forskolin (FSK) must be used and are sources of variations and errors. We developed a method based on the GloSensor system, a kinetic assay that consists in a luciferase fused with cAMP binding domain. As a proof of concept, we selected the succinate receptor 1 (SUCNR1 or GPR91) which could be an attractive drug target. It has never been validated as such because very few ligands have been described. Following analyses of SUCNR1 signaling pathways, we show that the GloSensor system allows real time, FSK-free detection of an agonist effect. This FSK-free agonist signal was confirmed on other Gi-coupled receptors such as CXCR4. In a test screening on SUCNR1, we compared the results obtained with a FSK vs FSK-free protocol and were able to identify agonists with both methods but with fewer false positives when measuring the basal levels. In this report, we validate a cAMP-inducer free method for the detection of Gi-coupled receptors agonists compatible with high-throughput screening. This method will facilitate the study and screening of Gi-coupled receptors for active ligands. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. The interrelationship of dopamine D2-like receptor availability in striatal and extrastriatal brain regions in healthy humans: A principal component analysis of [18F]Fallypride binding

    PubMed Central

    Zald, David H.; Woodward, Neil D.; Cowan, Ronald L.; Riccardi, Patrizia; Ansari, M. Sib; Baldwin, Ronald M.; Cowan, Ronald L.; Smith, Clarence E.; Hakyemez, Helene; Li, Rui; Kessler, Robert M.

    2010-01-01

    Individual differences in dopamine D2-like receptor availability arise across all brain regions expressing D2-like receptors. However, the inter-relationships in receptor availability across brain regions are poorly understood. To address this issue, we examined the relationship between D2-like binding potential (BPND) across striatal and extrastriatal regions in a sample of healthy participants. PET imaging was performed with the high affinity D2/D3 ligand [18F]fallypride in 45 participants. BPND images were submitted to voxel-wise principal components analysis to determine the pattern of associations across brain regions. Individual differences in D2-like BPND were explained by three distinguishable components. A single component explained almost all of the variance within the striatum, indicating that individual differences in receptor availability vary in a homogenous manner across the caudate, putamen, and ventral striatum. Cortical BPND was only modestly related to striatal BPND, and mostly loaded on a distinct component. After controlling for the general level of cortical D2-like BPND, an inverse relationship emerged between receptor availability in the striatum and the ventral temporal and ventromedial frontal cortices, suggesting possible cross-regulation of D2-like receptors in these regions. The analysis additionally revealed evidence of: 1) a distinct component involving the midbrain and limbic areas; 2) a dissociation between BPND in the medial and lateral temporal regions; and 3) a dissociation between BPND in the medial/midline and lateral thalamus. In summary, individual differences in D2-like receptor availability reflect several distinct patterns. This conclusion has significant implications for neuropsychiatric models that posit global or regionally specific relationships between dopaminergic tone and behavior. PMID:20149883

  3. The LDL receptor.

    PubMed

    Goldstein, Joseph L; Brown, Michael S

    2009-04-01

    In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

  4. Structural basis for selectivity and diversity in angiotensin II receptors

    DOE PAGES

    Zhang, Haitao; Han, Gye Won; Batyuk, Alexander; ...

    2017-04-20

    The angiotensin II receptors AT 1R and AT 2R serve as key components of the renin–angiotensin–aldosterone system. AT 1R has a central role in the regulation of blood pressure, but the function of AT 2R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT 2R bound to an AT 2R-selective ligand and to an AT 1R/AT 2R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position,more » stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure–activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Finally, our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.« less

  5. Structural basis for selectivity and diversity in angiotensin II receptors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Haitao; Han, Gye Won; Batyuk, Alexander

    The angiotensin II receptors AT 1R and AT 2R serve as key components of the renin–angiotensin–aldosterone system. AT 1R has a central role in the regulation of blood pressure, but the function of AT 2R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT 2R bound to an AT 2R-selective ligand and to an AT 1R/AT 2R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position,more » stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure–activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Finally, our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.« less

  6. The 5-HT₂C receptor agonist, lorcaserin, and the 5-HT₆ receptor antagonist, SB-742457, promote satiety; a microstructural analysis of feeding behaviour.

    PubMed

    Higgs, Suzanne; Cooper, Alison J; Barnes, Nicholas M

    2016-02-01

    Whilst the FDA-approved anorectic, lorcaserin and various 5-hydroxytryptamine (5-HT)6 receptor antagonists reduce feeding, a direct assessment of their impact upon feeding behaviour is less clear. We therefore examined the action of lorcaserin and the clinical-stage developmental candidate 5-HT6 receptor antagonist, SB-742457, upon microstructural analysis of licking behaviour. Such analysis provides a rich source of information about the mechanisms controlling food intake. The objective of the present study was to gain insight into the influence upon feeding behaviour of the 5-HT2C receptor agonist, lorcaserin and the developmental 5-HT6 receptor antagonist, SB-742457. The impact of lorcaserin and SB-742457 upon licking behaviour of non-deprived rats for a glucose solution was assessed using microstructural analysis. Lorcaserin (0.1-3.0 mg/kg) displayed a dose-dependent ability to reduce glucose consumption via reduction in the number of bouts of licking. A similar action was evident with SB-742457, but only at the lowest dose tested (3.0 mg/kg). The behavioural actions of both lorcaserin and SB-742457 demonstrate they directly promote satiety.

  7. GPCRdb: an information system for G protein-coupled receptors

    PubMed Central

    Isberg, Vignir; Mordalski, Stefan; Munk, Christian; Rataj, Krzysztof; Harpsøe, Kasper; Hauser, Alexander S.; Vroling, Bas; Bojarski, Andrzej J.; Vriend, Gert; Gloriam, David E.

    2016-01-01

    Recent developments in G protein-coupled receptor (GPCR) structural biology and pharmacology have greatly enhanced our knowledge of receptor structure-function relations, and have helped improve the scientific foundation for drug design studies. The GPCR database, GPCRdb, serves a dual role in disseminating and enabling new scientific developments by providing reference data, analysis tools and interactive diagrams. This paper highlights new features in the fifth major GPCRdb release: (i) GPCR crystal structure browsing, superposition and display of ligand interactions; (ii) direct deposition by users of point mutations and their effects on ligand binding; (iii) refined snake and helix box residue diagram looks; and (iii) phylogenetic trees with receptor classification colour schemes. Under the hood, the entire GPCRdb front- and back-ends have been re-coded within one infrastructure, ensuring a smooth browsing experience and development. GPCRdb is available at http://www.gpcrdb.org/ and it's open source code at https://bitbucket.org/gpcr/protwis. PMID:26582914

  8. Sources and processes contributing to nitrogen deposition: an adjoint model analysis applied to biodiversity hotspots worldwide.

    PubMed

    Paulot, Fabien; Jacob, Daniel J; Henze, Daven K

    2013-04-02

    Anthropogenic enrichment of reactive nitrogen (Nr) deposition is an ecological concern. We use the adjoint of a global 3-D chemical transport model (GEOS-Chem) to identify the sources and processes that control Nr deposition to an ensemble of biodiversity hotspots worldwide and two U.S. national parks (Cuyahoga and Rocky Mountain). We find that anthropogenic sources dominate deposition at all continental sites and are mainly regional (less than 1000 km) in origin. In Hawaii, Nr supply is controlled by oceanic emissions of ammonia (50%) and anthropogenic sources (50%), with important contributions from Asia and North America. Nr deposition is also sensitive in complicated ways to emissions of SO2, which affect Nr gas-aerosol partitioning, and of volatile organic compounds (VOCs), which affect oxidant concentrations and produce organic nitrate reservoirs. For example, VOC emissions generally inhibit deposition of locally emitted NOx but significantly increase Nr deposition downwind. However, in polluted boreal regions, anthropogenic VOC emissions can promote Nr deposition in winter. Uncertainties in chemical rate constants for OH + NO2 and NO2 hydrolysis also complicate the determination of source-receptor relationships for polluted sites in winter. Application of our adjoint sensitivities to the representative concentration pathways (RCPs) scenarios for 2010-2050 indicates that future decreases in Nr deposition due to NOx emission controls will be offset by concurrent increases in ammonia emissions from agriculture.

  9. Functional dissociation in sweet taste receptor neurons between and within taste organs of Drosophila

    PubMed Central

    Thoma, Vladimiros; Knapek, Stephan; Arai, Shogo; Hartl, Marion; Kohsaka, Hiroshi; Sirigrivatanawong, Pudith; Abe, Ayako; Hashimoto, Koichi; Tanimoto, Hiromu

    2016-01-01

    Finding food sources is essential for survival. Insects detect nutrients with external taste receptor neurons. Drosophila possesses multiple taste organs that are distributed throughout its body. However, the role of different taste organs in feeding remains poorly understood. By blocking subsets of sweet taste receptor neurons, we show that receptor neurons in the legs are required for immediate sugar choice. Furthermore, we identify two anatomically distinct classes of sweet taste receptor neurons in the leg. The axonal projections of one class terminate in the thoracic ganglia, whereas the other projects directly to the brain. These two classes are functionally distinct: the brain-projecting neurons are involved in feeding initiation, whereas the thoracic ganglia-projecting neurons play a role in sugar-dependent suppression of locomotion. Distinct receptor neurons for the same taste quality may coordinate early appetitive responses, taking advantage of the legs as the first appendages to contact food. PMID:26893070

  10. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(+)-PHNO.

    PubMed

    Girgis, Ragy R; Slifstein, Mark; D'Souza, Deepak; Lee, Yih; Periclou, Antonia; Ghahramani, Parviz; Laszlovszky, István; Durgam, Suresh; Adham, Nika; Nabulsi, Nabeel; Huang, Yiyun; Carson, Richard E; Kiss, Béla; Kapás, Margit; Abi-Dargham, Anissa; Rakhit, Ashok

    2016-10-01

    Second-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia. The purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia. Using [(11)C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations. A monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing. This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.

  11. The Dopamine D2 Receptor Gene in Lamprey, Its Expression in the Striatum and Cellular Effects of D2 Receptor Activation

    PubMed Central

    Robertson, Brita; Huerta-Ocampo, Icnelia; Ericsson, Jesper; Stephenson-Jones, Marcus; Pérez-Fernández, Juan; Bolam, J. Paul; Diaz-Heijtz, Rochellys; Grillner, Sten

    2012-01-01

    All basal ganglia subnuclei have recently been identified in lampreys, the phylogenetically oldest group of vertebrates. Furthermore, the interconnectivity of these nuclei is similar to mammals and tyrosine hydroxylase-positive (dopaminergic) fibers have been detected within the input layer, the striatum. Striatal processing is critically dependent on the interplay with the dopamine system, and we explore here whether D2 receptors are expressed in the lamprey striatum and their potential role. We have identified a cDNA encoding the dopamine D2 receptor from the lamprey brain and the deduced protein sequence showed close phylogenetic relationship with other vertebrate D2 receptors, and an almost 100% identity within the transmembrane domains containing the amino acids essential for dopamine binding. There was a strong and distinct expression of D2 receptor mRNA in a subpopulation of striatal neurons, and in the same region tyrosine hydroxylase-immunoreactive synaptic terminals were identified at the ultrastructural level. The synaptic incidence of tyrosine hydroxylase-immunoreactive boutons was highest in a region ventrolateral to the compact layer of striatal neurons, a region where most striatal dendrites arborise. Application of a D2 receptor agonist modulates striatal neurons by causing a reduced spike discharge and a diminished post-inhibitory rebound. We conclude that the D2 receptor gene had already evolved in the earliest group of vertebrates, cyclostomes, when they diverged from the main vertebrate line of evolution (560 mya), and that it is expressed in striatum where it exerts similar cellular effects to that in other vertebrates. These results together with our previous published data (Stephenson-Jones et al. 2011, 2012) further emphasize the high degree of conservation of the basal ganglia, also with regard to the indirect loop, and its role as a basic mechanism for action selection in all vertebrates. PMID:22563388

  12. Brian K. Kobilka and G-protein-coupled Receptors (GPCR)

    Science.gov Websites

    the laboratory's Advanced Photon Source (APS) to make the first discovery of the structure of a human the structure of β2AR at the exact moment that the protein-receptor complex signals across the carrying out its biological mission. ... In order to obtain the structure of a GPCR, Kobilka and his

  13. Brain aromatase (Cyp19A2) and estrogen receptors, in larvae and adult pejerrey fish Odontesthes bonariensis: Neuroanatomical and functional relations

    USGS Publications Warehouse

    Strobl-Mazzulla, P. H.; Lethimonier, C.; Gueguen, M.M.; Karube, M.; Fernandino, J.I.; Yoshizaki, G.; Patino, R.; Strussmann, C.A.; Kah, O.; Somoza, G.M.

    2008-01-01

    Although estrogens exert many functions on vertebrate brains, there is little information on the relationship between brain aromatase and estrogen receptors. Here, we report the cloning and characterization of two estrogen receptors, ?? and ??, in pejerrey. Both receptors' mRNAs largely overlap and were predominantly expressed in the brain, pituitary, liver, and gonads. Also brain aromatase and estrogen receptors were up-regulated in the brain of estradiol-treated males. In situ hybridization was performed to study in more detail, the distribution of the two receptors in comparison with brain aromatase mRNA in the brain of adult pejerrey. The estrogen receptors' mRNAs exhibited distinct but partially overlapping patterns of expression in the preoptic area and the mediobasal hypothalamus, as well as in the pituitary gland. Moreover, the estrogen receptor ??, but not ??, were found to be expressed in cells lining the preoptic recess, similarly as observed for brain aromatase. Finally, it was shown that the onset expression of brain aromatase and both estrogen receptors in the head of larvae preceded the morphological differentiation of the gonads. Because pejerrey sex differentiation is strongly influenced by temperature, brain aromatase expression was measured during the temperature-sensitive window and was found to be significantly higher at male-promoting temperature. Taken together these results suggest close neuroanatomical and functional relationships between brain aromatase and estrogen receptors, probably involved in the sexual differentiation of the brain and raising interesting questions on the origin (central or peripheral) of the brain aromatase substrate. ?? 2008 Elsevier Inc.

  14. Sigma-1 receptor chaperone and brain-derived neurotrophic factor: emerging links between cardiovascular disease and depression.

    PubMed

    Hashimoto, Kenji

    2013-01-01

    Epidemiological studies have demonstrated a close relationship between depression and cardiovascular disease (CVD). Although it is known that the central nervous system (CNS) contributes to this relationship, the detailed mechanisms involved in this process remain unclear. Recent studies suggest that the endoplasmic reticulum (ER) molecular chaperone sigma-1 receptor and brain-derived neurotrophic factor (BDNF) play a role in the pathophysiology of CVD and depression. Several meta-analysis studies have showed that levels of BDNF in the blood of patients with major depressive disorder (MDD) are lower than normal controls, indicating that blood BDNF might be a biomarker for depression. Furthermore, blood levels of BDNF in patients with CVD are also lower than normal controls. A recent study using conditional BDNF knock-out mice in animal models of myocardial infarction highlighted the role of CNS-mediated mechanisms in the cardioprotective effects of BDNF. In addition, a recent study shows that decreased levels of sigma-1 receptor in the mouse brain contribute to the association between heart failure and depression. Moreover, sigma-1 receptor agonists, including the endogenous neurosteroid dehydroepiandosterone (DHEA) and the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, show potent cardioprotective and antidepressive effects in rodents, via sigma-1 receptor stimulation. Interestingly, agonist activation of sigma-1 receptors increased the secretion of mature BDNF from its precursor proBDNF via chaperone activity in the ER. Given the role of ER stress in the pathophysiology of CVD and MDD, the author will discuss the potential link between sigma-1 receptors and BDNF-TrkB pathway in the pathophysiology of these two diseases. Finally, the author will make a case for potent sigma-1 receptor agonists and TrkB agonists as new potential therapeutic drugs for depressive patients with CVD. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Variant ionotropic glutamate receptors as chemosensory receptors in Drosophila

    PubMed Central

    Benton, Richard; Vannice, Kirsten S.; Gomez-Diaz, Carolina; Vosshall, Leslie B.

    2009-01-01

    Summary Ionotropic glutamate receptors (iGluRs) mediate neuronal communication at synapses throughout vertebrate and invertebrate nervous systems. We have characterized a novel family of iGluR-related genes in Drosophila, which we name Ionotropic Receptors (IRs). These receptors do not belong to the well-described Kainate, AMPA, or NMDA classes of iGluRs, and have divergent ligand-binding domains that lack their characteristic glutamate-interacting residues. IRs are expressed in a combinatorial fashion in sensory neurons that respond to many distinct odors but do not express either insect odorant receptors (ORs) or gustatory receptors (GRs). IR proteins accumulate in sensory dendrites and not at synapses. Mis-expression of IRs induces novel odor responses in ectopic neurons. Together, these results lead us to propose that the IRs comprise a novel family of chemosensory receptors. Conservation of IR/iGluR-related proteins in bacteria, plants, and animals suggests that this receptor family represents an evolutionarily ancient mechanism for sensing both internal and external chemical cues. PMID:19135896

  16. Estrogen Receptor Mutants/Variants in Human Breast Cancer.

    DTIC Science & Technology

    1996-12-01

    average 1 hour per response, including the time for reviewing instructions, searching existing data sources,gathering and maintaining the data needed...Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget, Paperwork Reduction Project (0704-0188...we identified, for the first time , the expression of exon deleted progesterone receptor (PR) mRNAs in both normal and neoplastic human breast tissues

  17. Toward better Alzheimer's research information sources for the public.

    PubMed

    Payne, Perry W

    2013-03-01

    The National Plan to Address Alzheimer's Disease calls for a new relationship between researchers and members of the public. This relationship is one that provides research information to patients and allows patients to provide ideas to researchers. One way to describe it is a "bidirectional translational relationship." Despite the numerous sources of online and offline information about Alzheimer's disease, there is no information source which currently provides this interaction. This article proposes the creation an Alzheimer's research information source dedicated to monitoring Alzheimer's research literature and providing user friendly, publicly accessible summaries of data written specifically for a lay audience. This information source should contain comprehensive, updated, user friendly, publicly available, reviews of Alzheimer's research and utilize existing online multimedia/social networking tools to provide information in useful formats that help patients, caregivers, and researchers learn rapidly from one another.

  18. Response of dissolved trace metals to land use/land cover and their source apportionment using a receptor model in a subtropic river, China.

    PubMed

    Li, Siyue; Zhang, Quanfa

    2011-06-15

    Water samples were collected for determination of dissolved trace metals in 56 sampling sites throughout the upper Han River, China. Multivariate statistical analyses including correlation analysis, stepwise multiple linear regression models, and principal component and factor analysis (PCA/FA) were employed to examine the land use influences on trace metals, and a receptor model of factor analysis-multiple linear regression (FA-MLR) was used for source identification/apportionment of anthropogenic heavy metals in the surface water of the River. Our results revealed that land use was an important factor in water metals in the snow melt flow period and land use in the riparian zone was not a better predictor of metals than land use away from the river. Urbanization in a watershed and vegetation along river networks could better explain metals, and agriculture, regardless of its relative location, however slightly explained metal variables in the upper Han River. FA-MLR analysis identified five source types of metals, and mining, fossil fuel combustion, and vehicle exhaust were the dominant pollutions in the surface waters. The results demonstrated great impacts of human activities on metal concentrations in the subtropical river of China. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. A spatial model to aggregate point-source and nonpoint-source water-quality data for large areas

    USGS Publications Warehouse

    White, D.A.; Smith, R.A.; Price, C.V.; Alexander, R.B.; Robinson, K.W.

    1992-01-01

    More objective and consistent methods are needed to assess water quality for large areas. A spatial model, one that capitalizes on the topologic relationships among spatial entities, to aggregate pollution sources from upstream drainage areas is described that can be implemented on land surfaces having heterogeneous water-pollution effects. An infrastructure of stream networks and drainage basins, derived from 1:250,000-scale digital-elevation models, define the hydrologic system in this spatial model. The spatial relationships between point- and nonpoint pollution sources and measurement locations are referenced to the hydrologic infrastructure with the aid of a geographic information system. A maximum-branching algorithm has been developed to simulate the effects of distance from a pollutant source to an arbitrary downstream location, a function traditionally employed in deterministic water quality models. ?? 1992.

  20. Nicotinic receptor abnormalities in the cerebellar cortex in autism.

    PubMed

    Lee, M; Martin-Ruiz, C; Graham, A; Court, J; Jaros, E; Perry, R; Iversen, P; Bauman, M; Perry, E

    2002-07-01

    multiple lobules throughout the vermis and hemispheres. This was more severe in one case with epilepsy, which also showed vermis folial malformation. The case with less severe Purkinje cell loss also showed cerebellar white matter thinning and demyelination. These findings indicate a loss of the cerebellar nicotinic alpha4 receptor subunit in autism which may relate to the loss of Purkinje cells, and a compensatory increase in the alpha7 subunit. It remains to be determined how these receptor abnormalities are involved in neurodevelopment in autism and what is the relationship to mental function. Since nicotinic receptor agonists enhance attentional function and also induce an elevation in the high affinity receptor, nicotinic therapy in autism may be worth considering.

  1. The evaluation of endocrine disrupting effects of tert-butylphenols towards estrogenic receptor α, androgen receptor and thyroid hormone receptor β and aquatic toxicities towards freshwater organisms.

    PubMed

    Wang, Jiaying; Wang, Jingpeng; Liu, Jinsong; Li, Jianzhi; Zhou, Lihong; Zhang, Huanxin; Sun, Jianteng; Zhuang, Shulin

    2018-05-09

    The phenolic compounds have posed public concern for potential threats to human health and ecosystem. Tert-butylphenols (TBPs), as one group of emerging contaminants, showed potential endocrine disrupting effects and aquatic toxicities. In the present study, we detected concentrations of 2,4-DTBP ranging from <0.001 to 0.057 μg/L (detection limit: 0.001 μg/L) in drinking water source from the Qiantang River in East China in April 2016. The endocrine disrupting effects of 2-TBP, 2,4-DTBP and 2,6-DTBP toward human estrogen receptor α (ERα), androgen receptor (AR) and thyroid hormone receptor β (TRβ) were evaluated using human recombinant two-hybrid yeast bioassay. Their aquatic toxicities were investigated with indicator organisms including Photobacterium phosphoreum, Vibrio fischeri and freshwater green alga Chlamydomonas reinhardtii. 2-TBP and 2,4-DTBP exhibited moderate antagonistic effects toward human ERα and AR in a concentration-dependent manner. 2-TBP significantly inhibited the light emission of P. phosphoreum. 2-TBP, 2,4-DTBP and 2,6-DTBP significantly inhibited the growth of C. reinhardtii and reduced the chlorophyll content. Our results suggest the potential adverse effects of TBPs on human health and aquatic organisms. The data will facilitate further risk assessment of TBPs and related contaminants. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Non-canonical modulators of nuclear receptors.

    PubMed

    Tice, Colin M; Zheng, Ya-Jun

    2016-09-01

    Like G protein-coupled receptors (GPCRs) and protein kinases, nuclear receptors (NRs) are a rich source of pharmaceutical targets. Over 80 NR-targeting drugs have been approved for 18 NRs. The focus of drug discovery in NRs has hitherto been on identifying ligands that bind to the canonical ligand binding pockets of the C-terminal ligand binding domains (LBDs). Due to the development of drug resistance and selectivity concerns, there has been considerable interest in exploring other, non-canonical ligand binding sites. Unfortunately, the potencies of compounds binding at other sites have generally not been sufficient for clinical development. However, the situation has changed dramatically over the last 3years, as compounds with sufficient potency have been reported for several NR targets. Here we review recent developments in this area from a medicinal chemistry point of view in the hope of stimulating further interest in this area of research. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Function and structure in glycine receptors and some of their relatives.

    PubMed

    Colquhoun, David; Sivilotti, Lucia G

    2004-06-01

    In the field of ligand-gated ion channels, recent developments, both in the knowledge of structure and in the measurement of function at the single-channel level, have allowed a sensible start to be made on understanding the relationship between structure and function in these proteins. In this review, the cases of glycine, nicotinic ACh and glutamate receptors are compared and contrasted, and problems such as how binding of agonist causes the channel to open, and why partial agonists are partial, are considered. Some observations, both structural and functional, suggest that more attention needs to be paid to conformational changes that occur before the channel opens. Such changes might account for the interaction found between subunits of the glycine receptor while it is still shut and, perhaps, the agonist-dependent structural changes seen in AMPA receptors. They might also complicate our understanding of the binding-gating problem.

  4. Defining the relationship between individuals’ aggregate and maximum source-specific exposures

    EPA Science Inventory

    The concepts of aggregate and source-specific exposures play an important role in chemical risk management. The concepts of aggregate and source-specific exposures play an important role in chemical risk management. Aggregate exposure to a chemical refers to combined exposures fr...

  5. Painful purinergic receptors.

    PubMed

    Donnelly-Roberts, Diana; McGaraughty, Steve; Shieh, Char-Chang; Honore, Prisca; Jarvis, Michael F

    2008-02-01

    Multiple P2 receptor-mediated mechanisms exist by which ATP can alter nociceptive sensitivity following tissue injury. Evidence from a variety of experimental strategies, including genetic disruption studies and the development of selective antagonists, has indicated that the activation of P2X receptor subtypes, including P2X(3), P2X(2/3), P2X(4) and P2X(7), and P2Y (e.g., P2Y(2)) receptors, can modulate pain. For example, administration of a selective P2X(3) antagonist, A-317491, has been shown to effectively block both hyperalgesia and allodynia in different animal models of pathological pain. Intrathecally delivered antisense oligonucleotides targeting P2X(4) receptors decrease tactile allodynia following nerve injury. Selective antagonists for the P2X(7) receptor also reduce sensitization in animal models of inflammatory and neuropathic pain, providing evidence that purinergic glial-neural interactions are important modulators of noxious sensory neurotransmission. Furthermore, activation of P2Y(2) receptors leads to sensitization of polymodal transient receptor potential-1 receptors. Thus, ATP acting at multiple purinergic receptors, either directly on neurons (e.g., P2X(3), P2X(2/3), and P2Y receptors) or indirectly through neural-glial cell interactions (P2X(4) and P2X(7) receptors), alters nociceptive sensitivity. The development of selective antagonists for some of these P2 receptors has greatly aided investigations into the nociceptive role of ATP. This perspective highlights some of the recent advances to identify selective P2 receptor ligands, which has enhanced the investigation of ATP-related modulation of pain sensitivity.

  6. Beyond small molecule SAR – using the dopamine D3 receptor crystal structure to guide drug design

    PubMed Central

    Keck, Thomas M.; Burzynski, Caitlin; Shi, Lei; Newman, Amy Hauck

    2016-01-01

    The dopamine D3 receptor is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, restless leg syndrome, and drug addiction. The high protein sequence homology between the D3 and D2 receptors has posed a challenge to developing D3 receptor-selective ligands whose behavioral actions can be attributed to D3 receptor engagement, in vivo. However, through primarily small molecule structure-activity relationship (SAR) studies, a variety of chemical scaffolds have been discovered over the past two decades that have resulted in several D3 receptor-selective ligands with high affinity and in vivo activity. Nevertheless, viable clinical candidates remain limited. The recent determination of the high-resolution crystal structure of the D3 receptor has invigorated structure-based drug design, providing refinements to the molecular dynamic models and testable predictions about receptor-ligand interactions. This review will highlight recent preclinical and clinical studies demonstrating potential utility of D3 receptor-selective ligands in the treatment of addiction. In addition, new structure-based rational drug design strategies for D3 receptor-selective ligands that complement traditional small molecule SAR to improve the selectivity and directed efficacy profiles are examined. PMID:24484980

  7. Altered 5-HT2A Receptor Binding after Recovery from Bulimia-Type Anorexia Nervosa: Relationships to Harm Avoidance and Drive for Thinness

    PubMed Central

    Bailer, Ursula F; Price, Julie C; Meltzer, Carolyn C; Mathis, Chester A; Frank, Guido K; Weissfeld, Lisa; McConaha, Claire W; Henry, Shannan E; Brooks-Achenbach, Sarah; Barbarich, Nicole C; Kaye, Walter H

    2015-01-01

    Several lines of evidence suggest that a disturbance of serotonin neuronal pathways may contribute to the pathogenesis of anorexia nervosa (AN) and bulimia nervosa (BN). This study applied positron emission tomography (PET) to investigate the brain serotonin 2A (5-HT2A) receptor, which could contribute to disturbances of appetite and behavior in AN and BN. To avoid the confounding effects of malnutrition, we studied 10 women recovered from bulimia-type AN (REC AN–BN, >1 year normal weight, regular menstrual cycles, no binging, or purging) compared with 16 healthy control women (CW) using PET imaging and a specific 5-HT2A receptor antagonist, [18F]altanserin. REC AN–BN women had significantly reduced [18F]altanserin binding potential relative to CW in the left subgenual cingulate, the left parietal cortex, and the right occipital cortex. [18F]altanserin binding potential was positively related to harm avoidance and negatively related to novelty seeking in cingulate and temporal regions only in REC AN–BN subjects. In addition, REC AN–BN had negative relationships between [18F]altanserin binding potential and drive for thinness in several cortical regions. In conclusion, this study extends research suggesting that altered 5-HT neuronal system activity persists after recovery from bulimia-type AN, particularly in subgenual cingulate regions. Altered 5-HT neurotransmission after recovery also supports the possibility that this may be a trait-related disturbance that contributes to the pathophysiology of eating disorders. It is possible that subgenual cingulate findings are not specific for AN–BN, but may be related to the high incidence of lifetime major depressive disorder diagnosis in these subjects. PMID:15054474

  8. The potent free radical scavenger alpha-lipoic acid improves memory in aged mice: putative relationship to NMDA receptor deficits.

    PubMed

    Stoll, S; Hartmann, H; Cohen, S A; Müller, W E

    1993-12-01

    alpha-Lipoic acid (alpha-LA) improved longer-term memory of aged female NMRI mice in the habituation in the open field test at a dose of 100 mg/kg body weight for 15 days. In a separate experiment, no such effect could be found for young mice. alpha-LA alleviated age-related NMDA receptor deficits (Bmax) without changing muscarinic, benzodiazepine, and alpha 2-adrenergic receptor deficits in aged mice. The carbachol-stimulated accumulation of inositol monophosphates was not changed by the treatment with alpha-LA. These results give tentative support to the hypothesis that alpha-LA improves memory in aged mice, probably by a partial compensation of NMDA receptor deficits. Possible modes of action of alpha-LA based on its free radical scavenger properties are discussed in relation to the membrane hypothesis of aging.

  9. Characterization of the Distance Relationship Between Localized Serotonin Receptors and Glia Cells on Fluorescence Microscopy Images of Brain Tissue.

    PubMed

    Jacak, Jaroslaw; Schaller, Susanne; Borgmann, Daniela; Winkler, Stephan M

    2015-08-01

    We here present two new methods for the characterization of fluorescent localization microscopy images obtained from immunostained brain tissue sections. Direct stochastic optical reconstruction microscopy images of 5-HT1A serotonin receptors and glial fibrillary acidic proteins in healthy cryopreserved brain tissues are analyzed. In detail, we here present two image processing methods for characterizing differences in receptor distribution on glial cells and their distribution on neural cells: One variant relies on skeleton extraction and adaptive thresholding, the other on k-means based discrete layer segmentation. Experimental results show that both methods can be applied for distinguishing classes of images with respect to serotonin receptor distribution. Quantification of nanoscopic changes in relative protein expression on particular cell types can be used to analyze degeneration in tissues caused by diseases or medical treatment.

  10. Allosteric nature of P2X receptor activation probed by photoaffinity labelling

    PubMed Central

    Bhargava, Y; Rettinger, J; Mourot, A

    2012-01-01

    BACKGROUND AND PURPOSE In P2X receptors, agonist binding at the interface between neighbouring subunits is efficiently transduced to ion channel gating. However, the relationship between binding and gating is difficult to study because agonists continuously bind and unbind. Here, we covalently incorporated agonists in the binding pocket of P2X receptors and examined how binding site occupancy affects the ability of the channel to gate. EXPERIMENTAL APPROACH We used a strategy for tethering agonists to their ATP-binding pocket, while simultaneously probing ion channel gating using electrophysiology. The agonist 2′,3′-O-(4-benzoylbenzoyl)-ATP (BzATP), a photoaffinity analogue of ATP, enabled us to trap rat homomeric P2X2 receptor and a P2X2/1 receptor chimera in different agonist-bound states. UV light was used to control the degree of covalent occupancy of the receptors. KEY RESULTS Irradiation of the P2X2/1 receptor chimera – BzATP complex resulted in a persistent current that lasted even after extensive washout, consistent with photochemical tethering of the agonist BzATP and trapping of the receptors in an open state. Partial labelling with BzATP primed subsequent agonist binding and modulated gating efficiency for both full and partial agonists. CONCLUSIONS AND IMPLICATIONS Our photolabelling strategy provides new molecular insights into the activation mechanism of the P2X receptor. We show here that priming with full agonist molecules leads to an increase in gating efficiency after subsequent agonist binding. PMID:22725669

  11. Regional source identification using Lagrangian stochastic particle dispersion and HYSPLIT backward-trajectory models.

    PubMed

    Koracin, Darko; Vellore, Ramesh; Lowenthal, Douglas H; Watson, John G; Koracin, Julide; McCord, Travis; DuBois, David W; Chen, L W Antony; Kumar, Naresh; Knipping, Eladio M; Wheeler, Neil J M; Craig, Kenneth; Reid, Stephen

    2011-06-01

    The main objective of this study was to investigate the capabilities of the receptor-oriented inverse mode Lagrangian Stochastic Particle Dispersion Model (LSPDM) with the 12-km resolution Mesoscale Model 5 (MM5) wind field input for the assessment of source identification from seven regions impacting two receptors located in the eastern United States. The LSPDM analysis was compared with a standard version of the Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) single-particle backward-trajectory analysis using inputs from MM5 and the Eta Data Assimilation System (EDAS) with horizontal grid resolutions of 12 and 80 km, respectively. The analysis included four 7-day summertime events in 2002; residence times in the modeling domain were computed from the inverse LSPDM runs and HYPSLIT-simulated backward trajectories started from receptor-source heights of 100, 500, 1000, 1500, and 3000 m. Statistics were derived using normalized values of LSPDM- and HYSPLIT-predicted residence times versus Community Multiscale Air Quality model-predicted sulfate concentrations used as baseline information. From 40 cases considered, the LSPDM identified first- and second-ranked emission region influences in 37 cases, whereas HYSPLIT-MM5 (HYSPLIT-EDAS) identified the sources in 21 (16) cases. The LSPDM produced a higher overall correlation coefficient (0.89) compared with HYSPLIT (0.55-0.62). The improvement of using the LSPDM is also seen in the overall normalized root mean square error values of 0.17 for LSPDM compared with 0.30-0.32 for HYSPLIT. The HYSPLIT backward trajectories generally tend to underestimate near-receptor sources because of a lack of stochastic dispersion of the backward trajectories and to overestimate distant sources because of a lack of treatment of dispersion. Additionally, the HYSPLIT backward trajectories showed a lack of consistency in the results obtained from different single vertical levels for starting the backward trajectories. To

  12. Addictive drugs and their relationship with infectious diseases.

    PubMed

    Friedman, Herman; Pross, Susan; Klein, Thomas W

    2006-08-01

    The use of drugs of abuse, both recreationally and medicinally, may be related to serious public health concerns. There is a relationship between addictive drugs of abuse such as alcohol and nicotine in cigarette smoke, as well as illegal drugs such as opiates, cocaine and marijuana, and increased susceptibility to infections. The nature and mechanisms of immunomodulation induced by such drugs of abuse are described in this review. The effects of opiates and marijuana, using animal models as well as in vitro studies with immune cells from experimental animals and humans, have shown that immunomodulation induced by these drugs is mainly receptor-mediated, either directly by interaction with specific receptors on immune cells or indirectly by reaction with similar receptors on cells of the nervous system. Similar studies also show that cocaine and nicotine have marked immunomodulatory effects, which are mainly receptor-mediated. Both cocaine, an illegal drug, and nicotine, a widely used legal addictive component of cigarettes, are markedly immunomodulatory and increase susceptibility to infection. The nature and mechanism of immunomodulation induced by alcohol, the most widely used addictive substance of abuse, are similar but immunomodulatory effects, although not receptor-mediated. The many research studies on the effects of these drugs on immunity and increased susceptibility to infectious diseases, including AIDS, are providing a better understanding of the complex interactions between immunity, infections and substance abuse.

  13. The insulin receptor.

    PubMed

    Kaplan, S A

    1984-03-01

    Cells are endowed with specific cognitive molecules that function as receptors for hormones, neurotransmitters, and other intercellular messengers. The receptor molecules may be present in the plasma membrane, cytoplasm, or nucleus. When occupied by the messenger, the receptor is coupled to the cellular machinery that responds to the message-bearing molecules. For some hormones the events following attachment of the messenger to the receptor are well known. An example is the generation of cAMP after combination of glucagon with its receptor and the series of steps culminating in activation of phosphorylase. In the case of many other messengers, including insulin, the nature of these coupling steps is not known. Receptors are subject to the regulatory processes of synthesis, degradation, and conformational change; alterations in receptor properties may have significant effects on the qualitative and quantitative responses of the cell to the extracellular messenger. The insulin receptor is located in the plasma membrane, is composed of two pairs of subunits, and has a molecular weight of about 350,000. It is located in cells such as adipocytes, hepatocytes, and skeletal muscle cells as well as in cells not considered to be typical target organ cells. Insulin receptors in nonfetal cells are downregulated by exposure of the cells to high concentrations of insulin. Other factors that regulate insulin binding include muscular exercise, diet, thyroid hormones, glucocorticoids, androgens, estrogens, and cyclic nucleotides. The fetus has high concentrations of insulin receptors in several tissues. These begin to appear early in fetal life and may outnumber those found in adult tissues. Fetal insulin receptors are unusual in that they may not undergo downregulation but may experience the opposite when exposed to insulin in high concentrations. Thus the offspring of a mother with poorly controlled diabetes may be placed in double jeopardy by fetal hyperinsulinemia and

  14. Design and synthesis of small molecule agonists of EphA2 receptor.

    PubMed

    Petty, Aaron; Idippily, Nethrie; Bobba, Viharika; Geldenhuys, Werner J; Zhong, Bo; Su, Bin; Wang, Bingcheng

    2018-01-01

    Ligand-independent activation of EphA2 receptor kinase promotes cancer metastasis and invasion. Activating EphA2 receptor tyrosine kinase with small molecule agonist is a novel strategy to treat EphA2 overexpressing cancer. In this study, we performed a lead optimization of a small molecule Doxazosin that was identified as an EphA2 receptor agonist. 33 new analogs were developed and evaluated; a structure-activity relationship was summarized based on the EphA2 activation of these derivatives. Two new derivative compounds 24 and 27 showed much improved activity compared to Doxazosin. Compound 24 possesses a bulky amide moiety, and compound 27 has a dimeric structure that is very different to the parental compound. Compound 27 with a twelve-carbon linker of the dimer activated the kinase and induced receptor internalization and cell death with the best potency. Another dimer with a six-carbon linker has significantly reduced potency compared to the dimer with a longer linker, suggesting that the length of the linker is critical for the activity of the dimeric agonist. To explore the receptor binding characteristics of the new molecules, we applied a docking study to examine how the small molecule binds to the EphA2 receptor. The results reveal that compounds 24 and 27 form more hydrogen bonds to EphA2 than Doxazosin, suggesting that they may have higher binding affinity to the receptor. Published by Elsevier Masson SAS.

  15. Intralobular ducts of human major salivary glands contain leptin and its receptor.

    PubMed

    De Matteis, R; Puxeddu, R; Riva, A; Cinti, S

    2002-11-01

    Leptin, a 16-kDa hormone, plays an important role in the control of food intake and in energy homeostasis both in rodents and in man. Leptin is mainly produced and secreted by adipocytes, but other tissues and gastric glands have also recently been shown to produce it in a dual (endocrine and exocrine) mode. In addition, a leptin receptor has been detected in taste cells of mouse circumvallate papillae and in rat intestinal epithelium. These data prompted us to carry out a detailed study of human salivary glands as potential leptin-producing organs. Biopsies of salivary glands (submandibular and parotid) obtained from male and female patients during surgery for different clinical indications were subjected to immunohistochemical study for the presence of leptin, its functional receptor, insulin and glucagon. The presence and cellular distribution of glucocorticoid receptor in leptin-secreting cells were also investigated. Double immunohistochemical staining (silver-gold intensification and avidin-biotin-peroxidase) was used for the visualization of glucocorticoid receptor and leptin labelling, respectively. The results show that intralobular duct cells of submandibular and parotid glands are immunoreactive for leptin, leptin receptor and glucagon but not for insulin. Leptin was also detected in some microglobules in whole saliva obtained from four healthy volunteers. Co-localization for leptin, leptin receptor and glucocorticoid receptor in the same cell type suggested a functional relationship between glucocorticoid hormone and leptin secretion also at the level of the salivary glands.

  16. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Farde, L.; Wiesel, F.A.; Halldin, C.

    1988-01-01

    Using positron emission tomography and the carbon 11-labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11-raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy wasmore » found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline.« less

  17. Constitutively active 5-HT2/α1 receptors facilitate muscle spasms after human spinal cord injury

    PubMed Central

    D'Amico, Jessica M.; Murray, Katherine C.; Li, Yaqing; Chan, K. Ming; Finlay, Mark G.; Bennett, David J.

    2013-01-01

    In animals, the recovery of motoneuron excitability in the months following a complete spinal cord injury is mediated, in part, by increases in constitutive serotonin (5-HT2) and norepinephrine (α1) receptor activity, which facilitates the reactivation of calcium-mediated persistent inward currents (CaPICs) without the ligands serotonin and norepinephrine below the injury. In this study we sought evidence for a similar role of constitutive monoamine receptor activity in the development of spasticity in human spinal cord injury. In chronically injured participants with partially preserved sensory and motor function, the serotonin reuptake inhibitor citalopram facilitated long-lasting reflex responses (spasms) previously shown to be mediated by CaPICs, suggesting that in incomplete spinal cord injury, functional descending sources of monoamines are present to activate monoamine receptors below the lesion. However, in participants with motor or motor/sensory complete injuries, the inverse agonist cyproheptadine, which blocks both ligand and constitutive 5-HT2/α1 receptor activity, decreased long-lasting reflexes, whereas the neutral antagonist chlorpromazine, which only blocks ligand activation of these receptors, had no effect. When tested in noninjured control participants having functional descending sources of monoamines, chlorpromazine was effective in reducing CaPIC-mediated motor unit activity. On the basis of these combined results, it appears that in severe spinal cord injury, facilitation of persistent inward currents and muscle spasms is mainly mediated by the activation of constitutive 5-HT2 and α1 receptor activity. Drugs that more selectively block these constitutively active monoamine receptors may provide better oral control of spasticity, especially in motor complete spinal cord injury where reducing motoneuron excitability is the primary goal. PMID:23221402

  18. Water Quality Assessment of River Soan (Pakistan) and Source Apportionment of Pollution Sources Through Receptor Modeling.

    PubMed

    Nazeer, Summya; Ali, Zeshan; Malik, Riffat Naseem

    2016-07-01

    The present study was designed to determine the spatiotemporal patterns in water quality of River Soan using multivariate statistics. A total of 26 sites were surveyed along River Soan and its associated tributaries during pre- and post-monsoon seasons in 2008. Hierarchical agglomerative cluster analysis (HACA) classified sampling sites into three groups according to their degree of pollution, which ranged from least to high degradation of water quality. Discriminant function analysis (DFA) revealed that alkalinity, orthophosphates, nitrates, ammonia, salinity, and Cd were variables that significantly discriminate among three groups identified by HACA. Temporal trends as identified through DFA revealed that COD, DO, pH, Cu, Cd, and Cr could be attributed for major seasonal variations in water quality. PCA/FA identified six factors as potential sources of pollution of River Soan. Absolute principal component scores using multiple regression method (APCS-MLR) further explained the percent contribution from each source. Heavy metals were largely added through industrial activities (28 %) and sewage waste (28 %), nutrients through agriculture runoff (35 %) and sewage waste (28 %), organic pollution through sewage waste (27 %) and urban runoff (17 %) and macroelements through urban runoff (39 %), and mineralization and sewage waste (30 %). The present study showed that anthropogenic activities are the major source of variations in River Soan. In order to address the water quality issues, implementation of effective waste management measures are needed.

  19. Improved binding affinity and interesting selectivities of aminopyrimidine-bearing carbohydrate receptors in comparison with their aminopyridine analogues.

    PubMed

    Lippe, Jan; Seichter, Wilhelm; Mazik, Monika

    2015-12-28

    Due to the problems with the exact prediction of the binding properties of an artificial carbohydrate receptor, the identification of characteristic structural features, having the ability to influence the binding properties in a predictable way, is of high importance. The purpose of our investigation was to examine whether the previously observed higher affinity of 2-aminopyrimidine-bearing carbohydrate receptors in comparison with aminopyridine substituted analogues represents a general tendency of aminopyrimidine-bearing compounds. Systematic binding studies on new compounds consisting of 2-aminopyrimidine groups confirmed such a tendency and allowed the identification of interesting structure-activity relationships. Receptors having different symmetries showed systematic preferences for specific glycosides, which are remarkable for such simple receptor systems. Particularly suitable receptor architectures for the recognition of selected glycosides were identified and represent a valuable base for further developments in this field.

  20. Agonism and Antagonism at the Insulin Receptor

    PubMed Central

    Knudsen, Louise; Hansen, Bo Falck; Jensen, Pia; Pedersen, Thomas Åskov; Vestergaard, Kirsten; Schäffer, Lauge; Blagoev, Blagoy; Oleksiewicz, Martin B.; Kiselyov, Vladislav V.; De Meyts, Pierre

    2012-01-01

    Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B’29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR antagonist, exhibited partial agonistic effects in the 1–10 nM range, showing altogether a bell-shaped dose-response curve. Intriguingly, the agonistic effects of S961 were seen only on mitogenic endpoints (3H-thymidine incorporation), and not on metabolic endpoints (14C-glucose incorporation in adipocytes and muscle cells). The agonistic effects of S961 were observed in 3 independent cell lines, with complete concordance between mitogenicity (3H-thymidine incorporation) and phosphorylation of the IR and Akt. Together with the B29-B’29 crosslinked dimer, S961 is a rare example of a mixed agonist/antagonist for the human IR. A plausible mechanistic explanation based on the bivalent crosslinking model of IR activation is proposed. PMID:23300584

  1. Learning the Semantics of Structured Data Sources

    ERIC Educational Resources Information Center

    Taheriyan, Mohsen

    2015-01-01

    Information sources such as relational databases, spreadsheets, XML, JSON, and Web APIs contain a tremendous amount of structured data, however, they rarely provide a semantic model to describe their contents. Semantic models of data sources capture the intended meaning of data sources by mapping them to the concepts and relationships defined by a…

  2. Heat shock proteins and toll-like receptors.

    PubMed

    Asea, Alexzander

    2008-01-01

    Researchers have only just begun to elucidate the relationship between heat shock proteins (HSP) and Toll-like receptors (TLR). HSP were originally described as an intracellular molecular chaperone of naïve, aberrantly folded, or mutated proteins and primarily implicated as a cytoprotective protein when cells are exposed to stressful stimuli. However, recent studies have ascribed novel functions to the Hsp70 protein depending on its localization: Surface-bound Hsp70 specifically activate natural killer (NK) cells, while Hsp70 released into the extracellular milieu specifically bind to Toll-like receptors (TLR) 2 and 4 on antigen-presenting cells (APC) and exerts immunoregulatory effects, including upregulation of adhesion molecules, co-stimulatory molecule expression, and cytokine and chemokine release-a process known as the chaperokine activity of Hsp70. This chapter discusses the most recent advances in the understanding of heat shock protein (HSP) and TLR interactions in general and highlights recent findings that demonstrate Hsp70 is a ligand for TLR and its biological significance.

  3. Anticancer molecules targeting fibroblast growth factor receptors.

    PubMed

    Liang, Guang; Liu, Zhiguo; Wu, Jianzhang; Cai, Yuepiao; Li, Xiaokun

    2012-10-01

    The fibroblast growth factor receptor (FGFR) family includes four highly conserved receptor tyrosine kinases: FGFR1-4. Upon ligand binding, FGFRs activate an array of downstream signaling pathways, such as the mitogen activated protein kinase (MAPK) and the phosphoinositide-3-kinase (PI3K)/Akt pathways. These FGFR cascades play crucial roles in tumor cell proliferation, angiogenesis, migration, and survival. The combination of knockdown studies and pharmaceutical inhibition in preclinical models demonstrates that FGFRs are attractive targets for therapeutic intervention in cancer. Multiple FGFR inhibitors with various structural skeletons have been designed, synthesized, and evaluated. Reviews on FGFRs have recently focused on FGFR signaling, pathophysiology, and functions in cancer or other diseases. In this article, we review recent advances in structure-activity relationships (SAR) of FGFR inhibitors, as well as the FGFR-targeting drug design strategies currently employed in targeting deregulated FGFRs by antibodies and small molecule inhibitors. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Muscarinic acetylcholine receptor subtype 4 is essential for cholinergic stimulation of duodenal bicarbonate secretion in mice - relationship to D cell/somatostatin.

    PubMed

    Takeuchi, K; Kita, K; Takahashi, K; Aihara, E; Hayashi, S

    2015-06-01

    We investigated the roles of muscarinic (M) acetylcholine receptor subtype in the cholinergic stimulation of duodenal HCO3(-) secretion using knockout (KO) mice. Wild-type and M1-M5 KO C57BL/6J mice were used. The duodenal mucosa was mounted on an Ussing chamber, and HCO3(-) secretion was measured at pH 7.0 using a pH-stat method in vitro. Carbachol (CCh) or other agents were added to the serosal side. CCh dose-dependently stimulated HCO3(-) secretion in wild-type mice, and this effect was completely inhibited in the presence of atropine. The HCO3(-) response to CCh in wild-type mice was also inhibited by pirenzepine (M1 antagonist), 4DAMP (M3 antagonist), and tropicamide (M4 antagonist), but not by methoctramine (M2 antagonist). CCh stimulated HCO3(-) secretion in M2 and M5 KO animals as effectively as in WT mice; however, this stimulatory effect was significantly attenuated in M1, M3, and M4 KO mice. The decrease observed in the CCh-stimulated HCO3(-) response in M4 KO mice was reversed by the co-application of CYN154806, a somatostatin receptor type 2 (SST2) antagonist. Octreotide (a somatostatin analogue) decreased the basal and CCh-stimulated secretion of HCO3(-) in wild-type mice. The co-localized expression of somatostatin and M4 receptors was confirmed immunohistologically in the duodenum. We concluded that the duodenal HCO3(-) response to CCh was directly mediated by M1/M3 receptors and indirectly modified by M4 receptors. The activation of M4 receptors was assumed to inhibit the release of somatostatin from D cells and potentiate the HCO3(-) response by removing the negative influence of somatostatin via the activation of SST2 receptors.

  5. The two-state dimer receptor model: a general model for receptor dimers.

    PubMed

    Franco, Rafael; Casadó, Vicent; Mallol, Josefa; Ferrada, Carla; Ferré, Sergi; Fuxe, Kjell; Cortés, Antoni; Ciruela, Francisco; Lluis, Carmen; Canela, Enric I

    2006-06-01

    Nonlinear Scatchard plots are often found for agonist binding to G-protein-coupled receptors. Because there is clear evidence of receptor dimerization, these nonlinear Scatchard plots can reflect cooperativity on agonist binding to the two binding sites in the dimer. According to this, the "two-state dimer receptor model" has been recently derived. In this article, the performance of the model has been analyzed in fitting data of agonist binding to A(1) adenosine receptors, which are an example of receptor displaying concave downward Scatchard plots. Analysis of agonist/antagonist competition data for dopamine D(1) receptors using the two-state dimer receptor model has also been performed. Although fitting to the two-state dimer receptor model was similar to the fitting to the "two-independent-site receptor model", the former is simpler, and a discrimination test selects the two-state dimer receptor model as the best. This model was also very robust in fitting data of estrogen binding to the estrogen receptor, for which Scatchard plots are concave upward. On the one hand, the model would predict the already demonstrated existence of estrogen receptor dimers. On the other hand, the model would predict that concave upward Scatchard plots reflect positive cooperativity, which can be neither predicted nor explained by assuming the existence of two different affinity states. In summary, the two-state dimer receptor model is good for fitting data of binding to dimeric receptors displaying either linear, concave upward, or concave downward Scatchard plots.

  6. A nontoxic pain killer designed by modeling of pathological receptor conformations.

    PubMed

    Spahn, V; Del Vecchio, G; Labuz, D; Rodriguez-Gaztelumendi, A; Massaly, N; Temp, J; Durmaz, V; Sabri, P; Reidelbach, M; Machelska, H; Weber, M; Stein, C

    2017-03-03

    Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological (rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral μ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro . It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential. Copyright © 2017, American Association for the Advancement of Science.

  7. Is desire for social relationships mediated by the serotonergic system in the prefrontal cortex? An [(18)F]setoperone PET study.

    PubMed

    Gerretsen, Philip; Graff-Guerrero, Ariel; Menon, Mahesh; Pollock, Bruce G; Kapur, Shitij; Vasdev, Neil; Houle, Sylvain; Mamo, David

    2010-01-01

    Social behavior and desire for social relationships have been independently linked to the serotonergic system, the prefrontal cortex, especially the orbitofrontal cortex (OFC), and the anterior cingulate cortex (ACC). The goal of this study was to explore the role of serotonin 5HT(2A) receptors in these brain regions in forming and maintaining close interpersonal relationships. Twenty-four healthy subjects completed the Temperament and Character Inventory (TCI) prior to undergoing [(18)F]setoperone brain positron emission tomography (PET) to measure serotonin 5HT(2A) receptor availability within the OFC (BA 11 and 47) and ACC (BA 32). We explored the relationship between desire for social relationships, as measured by the TCI reward dependence (RD) scale, and 5HT(2A) receptor non-displaceable binding potential (BP(nd)) in these regions. Scores of RD were negatively correlated with 5HT(2A) BP(nd) in the ACC (BA 32, r = -.528, p = .012) and OFC (BA 11, r = -.489, p = .021; BA 47, r = -.501, p = .017). These correlations were corroborated by a voxel-wise analysis. These results suggest that the serotonergic system may have a regulatory effect on the OFC and ACC for establishing and maintaining social relationships.

  8. IL-8 expression and its possible relationship with estrogen-receptor-negative status of breast cancer cells

    PubMed Central

    Freund, Ariane; Chauveau, Corine; Brouillet, Jean-Paul; Lucas, Annick; Lacroix, Matthieu; Licznar, Anne; Vignon, Françoise; Lazennec, Gwendal

    2003-01-01

    Estrogen receptor (ER) status is an important parameter in breast cancer management as ER-positive breast cancers have a better prognosis than ER-negative tumors. This difference comes essentially from the lower aggressiveness and invasiveness of ER-positive tumors. Here, we demonstrate, that IL-8 was clearly overexpressed in most ER-negative breast, ovary cell lines and breast tumor samples tested, whereas no significant IL-8 level could be detected in ER-positive breast or ovarian cell lines. We have also cloned human IL-8 from ER-negative MDA-MB-231 cells and we show that IL-8 produced by breast cancer cells is identical to monocyte-derived IL-8. Interestingly, the invasion potential of ER-negative breast cancer cells is associated at least in part with expression of interleukin-8 (IL-8), but not with IL-8 receptors levels. Moreover, IL-8 increases the invasiveness of ER-positive breast cancer cells by 2 fold, thus confirming the invasion-promoting role of IL-8. On the other hand, exogenous expression of estrogen receptors in ER-negative cells led to a decrease of IL-8 levels. In summary, our data show that IL-8 expression is negatively linked to ER-status of breast and ovarian cancer cells. We also support the idea that IL-8 expression is associated with a higher invasiveness potential of cancer cells in vitro, which suggests that IL-8 could be a novel marker of tumor aggressiveness. PMID:12527894

  9. Selective antagonism of AMPA receptors unmasks kainate receptor-mediated responses in hippocampal neurons.

    PubMed

    Paternain, A V; Morales, M; Lerma, J

    1995-01-01

    Although both protein and mRNAs for kainate receptor subunits are abundant in several brain regions, the responsiveness of AMPA receptors to kainate has made it difficult to demonstrate the presence of functional kainate-type receptors in native cells. Recently, however, we have shown that many hippocampal neurons in culture express glutamate receptors of the kainate type. The large nondesensitizing response that kainate induces at AMPA receptors precludes detection and analysis of smaller, rapidly desensitizing currents induced by kainate at kainate receptors. Consequently, the functional significance of these strongly desensitizing glutamate receptors remains enigmatic. We report here that the family of new noncompetitive antagonists of AMPA receptors (GYKI 52466 and 53655) minimally affects kainate-induced responses at kainate receptors while completely blocking AMPA receptor-mediated currents, making it possible to separate the responses mediated by each receptor. These compounds will allow determination of the role played by kainate receptors in synaptic transmission and plasticity in the mammalian brain, as well as evaluation of their involvement in neurotoxicity.

  10. A Modeling System to Examine Near-Road and Near-Source Air Toxics for Community-Scale Cumulative Assessments.

    EPA Science Inventory

    Cumulative assessments consider a range of potential stressors that might impact the health of a receptor, such as a local neighborhood or wetland area. When receptors are located near pollution sources such as highways or ports (within 500-1,000 m), then they could be at risk of...

  11. The Relationship Between Partial Contaminant Source Zone Remediation and Groundwater Plume Attenuation

    NASA Astrophysics Data System (ADS)

    Falta, R. W.

    2004-05-01

    Analytical solutions are developed that relate changes in the contaminant mass in a source area to the behavior of biologically reactive dissolved contaminant groundwater plumes. Based on data from field experiments, laboratory experiments, numerical streamtube models, and numerical multiphase flow models, the chemical discharge from a source region is assumed to be a nonlinear power function of the fraction of contaminant mass removed from the source zone. This function can approximately represent source zone mass discharge behavior over a wide range of site conditions ranging from simple homogeneous systems, to complex heterogeneous systems. A mass balance on the source zone with advective transport and first order decay leads to a nonlinear differential equation that is solved analytically to provide a prediction of the time-dependent contaminant mass discharge leaving the source zone. The solution for source zone mass discharge is coupled semi-analytically with a modified version of the Domenico (1987) analytical solution for three-dimensional reactive advective and dispersive transport in groundwater. The semi-analytical model then employs the BIOCHLOR (Aziz et al., 2000; Sun et al., 1999) transformations to model sequential first order parent-daughter biological decay reactions of chlorinated ethenes and ethanes in the groundwater plume. The resulting semi-analytic model thus allows for transient simulation of complex source zone behavior that is fully coupled to a dissolved contaminant plume undergoing sequential biological reactions. Analyses of several realistic scenarios show that substantial changes in the ground water plume can result from the partial removal of contaminant mass from the source zone. These results, however, are sensitive to the nature of the source mass reduction-source discharge reduction curve, and to the rates of degradation of the primary contaminant and its daughter products in the ground water plume. Aziz, C.E., C.J. Newell, J

  12. Ocular Purine Receptors as Drug Targets in the Eye

    PubMed Central

    Civan, Mortimer M.

    2016-01-01

    Abstract Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A1, A2A, and A3. An A1AR agonist is in clinical trials for glaucoma, A2AAR reduces neuroinflammation, A3AR protects retinal ganglion cells from apoptosis, and both A3AR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y2 and P2Y6, lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases. PMID:27574786

  13. Ocular Purine Receptors as Drug Targets in the Eye.

    PubMed

    Jacobson, Kenneth A; Civan, Mortimer M

    2016-10-01

    Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A 1 , A 2A , and A 3 . An A 1 AR agonist is in clinical trials for glaucoma, A 2A AR reduces neuroinflammation, A 3 AR protects retinal ganglion cells from apoptosis, and both A 3 AR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y 2 and P2Y 6 , lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.

  14. Mercury in the Gulf of Mexico: sources to receptors.

    PubMed

    Harris, Reed; Pollman, Curtis; Landing, William; Evans, David; Axelrad, Donald; Hutchinson, David; Morey, Steven L; Rumbold, Darren; Dukhovskoy, Dmitry; Adams, Douglas H; Vijayaraghavan, Krish; Holmes, Christopher; Atkinson, R Dwight; Myers, Tom; Sunderland, Elsie

    2012-11-01

    Gulf of Mexico (Gulf) fisheries account for 41% of the U.S. marine recreational fish catch and 16% of the nation's marine commercial fish landings. Mercury (Hg) concentrations are elevated in some fish species in the Gulf, including king mackerel, sharks, and tilefish. All five Gulf states have fish consumption advisories based on Hg. Per-capita fish consumption in the Gulf region is elevated compared to the U.S. national average, and recreational fishers in the region have a potential for greater MeHg exposure due to higher levels of fish consumption. Atmospheric wet Hg deposition is estimated to be higher in the Gulf region compared to most other areas in the U.S., but the largest source of Hg to the Gulf as a whole is the Atlantic Ocean (>90%) via large flows associated with the Loop Current. Redistribution of atmospheric, Atlantic and terrestrial Hg inputs to the Gulf occurs via large scale water circulation patterns, and further work is needed to refine estimates of the relative importance of these Hg sources in terms of contributing to fish Hg levels in different regions of the Gulf. Measurements are needed to better quantify external loads, in-situ concentrations, and fluxes of total Hg and methylmercury in the water column, sediments, and food web. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Determining Mass and Persistence of a Reactive Brominated-Solvent DNAPL Source Using Mass Depletion-Mass Flux Reduction Relationships During Pumping

    NASA Astrophysics Data System (ADS)

    Johnston, C. D.; Davis, G. B.; Bastow, T.; Annable, M. D.; Trefry, M. G.; Furness, A.; Geste, Y.; Woodbury, R.; Rhodes, S.

    2011-12-01

    Measures of the source mass and depletion characteristics of recalcitrant dense non-aqueous phase liquid (DNAPL) contaminants are critical elements for assessing performance of remediation efforts. This is in addition to understanding the relationships between source mass depletion and changes to dissolved contaminant concentration and mass flux in groundwater. Here we present results of applying analytical source-depletion concepts to pumping from within the DNAPL source zone of a 10-m thick heterogeneous layered aquifer to estimate the original source mass and characterise the time trajectory of source depletion and mass flux in groundwater. The multi-component, reactive DNAPL source consisted of the brominated solvent tetrabromoethane (TBA) and its transformation products (mostly tribromoethene - TriBE). Coring and multi-level groundwater sampling indicated the DNAPL to be mainly in lower-permeability layers, suggesting the source had already undergone appreciable depletion. Four simplified source dissolution models (exponential, power function, error function and rational mass) were able to describe the concentration history of the total molar concentration of brominated organics in extracted groundwater during 285 days of pumping. Approximately 152 kg of brominated compounds were extracted. The lack of significant kinetic mass transfer limitations in pumped concentrations was notable. This was despite the heterogeneous layering in the aquifer and distribution of DNAPL. There was little to choose between the model fits to pumped concentration time series. The variance of groundwater velocities in the aquifer determined during a partitioning inter-well tracer test (PITT) were used to parameterise the models. However, the models were found to be relatively insensitive to this parameter. All models indicated an initial source mass around 250 kg which compared favourably to an estimate of 220 kg derived from the PITT. The extrapolated concentrations from the

  16. Structural insights into the interaction of IL-33 with its receptors.

    PubMed

    Liu, Xi; Hammel, Michal; He, Yanfeng; Tainer, John A; Jeng, U-Ser; Zhang, Linqi; Wang, Shuying; Wang, Xinquan

    2013-09-10

    Interleukin (IL)-33 is an important member of the IL-1 family that has pleiotropic activities in innate and adaptive immune responses in host defense and disease. It signals through its ligand-binding primary receptor ST2 and IL-1 receptor accessory protein (IL-1RAcP), both of which are members of the IL-1 receptor family. To clarify the interaction of IL-33 with its receptors, we determined the crystal structure of IL-33 in complex with the ectodomain of ST2 at a resolution of 3.27 Å. Coupled with structure-based mutagenesis and binding assay, the structural results define the molecular mechanism by which ST2 specifically recognizes IL-33. Structural comparison with other ligand-receptor complexes in the IL-1 family indicates that surface-charge complementarity is critical in determining ligand-binding specificity of IL-1 primary receptors. Combined crystallography and small-angle X-ray-scattering studies reveal that ST2 possesses hinge flexibility between the D3 domain and D1D2 module, whereas IL-1RAcP exhibits a rigid conformation in the unbound state in solution. The molecular flexibility of ST2 provides structural insights into domain-level conformational change of IL-1 primary receptors upon ligand binding, and the rigidity of IL-1RAcP explains its inability to bind ligands directly. The solution architecture of IL-33-ST2-IL-1RAcP complex from small-angle X-ray-scattering analysis resembles IL-1β-IL-1RII-IL-1RAcP and IL-1β-IL-1RI-IL-1RAcP crystal structures. The collective results confer IL-33 structure-function relationships, supporting and extending a general model for ligand-receptor assembly and activation in the IL-1 family.

  17. A competitive binding model predicts the response of mammalian olfactory receptors to mixtures

    NASA Astrophysics Data System (ADS)

    Singh, Vijay; Murphy, Nicolle; Mainland, Joel; Balasubramanian, Vijay

    Most natural odors are complex mixtures of many odorants, but due to the large number of possible mixtures only a small fraction can be studied experimentally. To get a realistic understanding of the olfactory system we need methods to predict responses to complex mixtures from single odorant responses. Focusing on mammalian olfactory receptors (ORs in mouse and human), we propose a simple biophysical model for odor-receptor interactions where only one odor molecule can bind to a receptor at a time. The resulting competition for occupancy of the receptor accounts for the experimentally observed nonlinear mixture responses. We first fit a dose-response relationship to individual odor responses and then use those parameters in a competitive binding model to predict mixture responses. With no additional parameters, the model predicts responses of 15 (of 18 tested) receptors to within 10 - 30 % of the observed values, for mixtures with 2, 3 and 12 odorants chosen from a panel of 30. Extensions of our basic model with odorant interactions lead to additional nonlinearities observed in mixture response like suppression, cooperativity, and overshadowing. Our model provides a systematic framework for characterizing and parameterizing such mixing nonlinearities from mixture response data.

  18. Melanocortin Antagonist Tetrapeptides with Minimal Agonist Activity at the Mouse Melanocortin-3 Receptor

    PubMed Central

    2014-01-01

    The melanocortin system regulates many important functions in the body. There are five melanocortin G protein-coupled receptor subtypes known to date. Herein, we report a structure–activity relationship (SAR) study of a tetrapeptide lead discovered through a double substitution strategy at the melanocortin core His-Phe-Arg-Trp sequence. Several compounds were identified with micromolar agonist activity at the mouse melanocortin-1 (mMC1R) and mouse melanocortin-5 receptor (mMC5R) subtypes, weak antagonist activity at the mouse melanocortin-3 receptor (mMC3R), and potent antagonist activity at the mouse melanocortin-4 receptor (mMC4R). Two compounds (2 and 3) were nanomolar mMC4R antagonists with no mMC3R antagonist activity observed. Additionally, we identified three tetrapeptide MC3R antagonists (1, 6, and 7) that possess minimal mMC3R agonist activity only at 100 μM, not commonly observed for mMC3R/mMC4R antagonists. These novel molecular templates have the potential as molecular probes to better differentiate the roles of the centrally expressed MC3 and MC4 receptors. PMID:25699138

  19. Blocking Mineralocorticoid Receptors Impairs, Blocking Glucocorticoid Receptors Enhances Memory Retrieval in Humans

    PubMed Central

    Rimmele, Ulrike; Besedovsky, Luciana; Lange, Tanja; Born, Jan

    2013-01-01

    Memory retrieval is impaired at very low as well as very high cortisol levels, but not at intermediate levels. This inverted-U-shaped relationship between cortisol levels and memory retrieval may originate from different roles of the mineralocorticoid (MR) and glucocorticoid receptor (GR) that bind cortisol with distinctly different affinity. Here, we examined the role of MRs and GRs in human memory retrieval using specific receptor antagonists. In two double-blind within-subject, cross-over designed studies, young healthy men were asked to retrieve emotional and neutral texts and pictures (learnt 3 days earlier) between 0745 and 0915 hours in the morning, either after administration of 400 mg of the MR blocker spironolactone vs placebo (200 mg at 2300 hours and 200 mg at 0400 hours, Study I) or after administration of the GR blocker mifepristone vs placebo (200 mg at 2300 hours, Study II). Blockade of MRs impaired free recall of both texts and pictures particularly for emotional material. In contrast, blockade of GRs resulted in better memory retrieval for pictures, with the effect being more pronounced for neutral than emotional materials. These findings indicate indeed opposing roles of MRs and GRs in memory retrieval, with optimal retrieval at intermediate cortisol levels likely mediated by high MR but concurrently low GR activation. PMID:23303058

  20. Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures.

    PubMed

    Rosenthaler, Sarah; Pöhn, Birgit; Kolmanz, Caroline; Huu, Chi Nguyen; Krewenka, Christopher; Huber, Alexandra; Kranner, Barbara; Rausch, Wolf-Dieter; Moldzio, Rudolf

    2014-01-01

    Phytocannabinoids are potential candidates for neurodegenerative disease treatment. Nonetheless, the exact mode of action of major phytocannabinoids has to be elucidated, but both, receptor and non-receptor mediated effects are discussed. Focusing on the often presumed structure-affinity-relationship, Ki values of phytocannabinoids cannabidiol (CBD), cannabidivarin (CBDV), cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN), THC acid (THCA) and THC to human CB1 and CB2 receptors were detected by using competitive inhibition between radioligand [(3)H]CP-55,940 and the phytocannabinoids. The resulting Ki values to CB1 range from 23.5 nM (THCA) to 14711 nM (CBDV), whereas Ki values to CB2 range from 8.5 nM (THC) to 574.2 nM (CBDV). To study the relationship between binding affinity and effects on neurons, we investigated possible CB1 related cytotoxic properties in murine mesencephalic primary cell cultures and N18TG2 neuroblastoma cell line. Most of the phytocannabinoids did not affect the number of dopaminergic neurons in primary cultures, whereas propidium iodide and resazurin formation assays revealed cytotoxic properties of CBN, CBDV and CBG. However, THC showed positive effects on N18TG2 cell viability at a concentration of 10 μM, whereas CBC and THCA also displayed slightly positive activities. These findings are not linked to the receptor binding affinity therewith pointing to another mechanism than a receptor mediated one. [Corrected] Copyright © 2014 Elsevier Inc. All rights reserved.