Differences in the Pathways of Proteins Unfolding Induced by Urea and Guanidine Hydrochloride: Molten Globule State and Aggregates

PubMed Central

Povarova, Olga I.; Kuznetsova, Irina M.; Turoverov, Konstantin K.

2010-01-01

It was shown that at low concentrations guanidine hydrochloride (GdnHCl) can cause aggregation of proteins in partially folded state and that fluorescent dye 1-anilinonaphthalene-8-sulfonic acid (ANS) binds with these aggregates rather than with hydrophobic clusters on the surface of protein in molten globule state. That is why the increase in ANS fluorescence intensity is often recorded in the pathway of protein denaturation by GdnHCl, but not by urea. So what was previously believed to be the molten globule state in the pathway of protein denaturation by GdnHCl, in reality, for some proteins represents the aggregates of partially folded molecules. PMID:21152408

Regional projections of the likelihood of very large wildland fires under a changing climate in the contiguous Western United States

Treesearch

Donald McKenzie; John T. Abatzoglou; E. Natasha Stavros; Narasimhan K. Larkin

2014-01-01

Seasonal changes in the climatic potential for very large wildfires (VLWF >= 50,000 ac~20,234 ha) across the western contiguous United States are projected over the 21st century using generalized linear models and downscaled climate projections for two representative concentration pathways (RCPs). Significant (p

Climate, ocean circulation, and sea level changes under stabilization and overshoot pathways to 1.5 K warming

NASA Astrophysics Data System (ADS)

Palter, Jaime B.; Frölicher, Thomas L.; Paynter, David; John, Jasmin G.

2018-06-01

The Paris Agreement has initiated a scientific debate on the role that carbon removal - or net negative emissions - might play in achieving less than 1.5 K of global mean surface warming by 2100. Here, we probe the sensitivity of a comprehensive Earth system model (GFDL-ESM2M) to three different atmospheric CO2 concentration pathways, two of which arrive at 1.5 K of warming in 2100 by very different pathways. We run five ensemble members of each of these simulations: (1) a standard Representative Concentration Pathway (RCP4.5) scenario, which produces 2 K of surface warming by 2100 in our model; (2) a stabilization pathway in which atmospheric CO2 concentration never exceeds 440 ppm and the global mean temperature rise is approximately 1.5 K by 2100; and (3) an overshoot pathway that passes through 2 K of warming at mid-century, before ramping down atmospheric CO2 concentrations, as if using carbon removal, to end at 1.5 K of warming at 2100. Although the global mean surface temperature change in response to the overshoot pathway is similar to the stabilization pathway in 2100, this similarity belies several important differences in other climate metrics, such as warming over land masses, the strength of the Atlantic Meridional Overturning Circulation (AMOC), ocean acidification, sea ice coverage, and the global mean sea level change and its regional expressions. In 2100, the overshoot ensemble shows a greater global steric sea level rise and weaker AMOC mass transport than in the stabilization scenario, with both of these metrics close to the ensemble mean of RCP4.5. There is strong ocean surface cooling in the North Atlantic Ocean and Southern Ocean in response to overshoot forcing due to perturbations in the ocean circulation. Thus, overshoot forcing in this model reduces the rate of sea ice loss in the Labrador, Nordic, Ross, and Weddell seas relative to the stabilized pathway, suggesting a negative radiative feedback in response to the early rapid warming. Finally, the ocean perturbation in response to warming leads to strong pathway dependence of sea level rise in northern North American cities, with overshoot forcing producing up to 10 cm of additional sea level rise by 2100 relative to stabilization forcing.

Specificity of EIA immunoassay for complement factor Bb testing.

PubMed

Pavlov, Igor Y; De Forest, Nikol; Delgado, Julio C

2011-01-01

During the alternative complement pathway activation, factor B is cleaved in two fragments, Ba and Bb. Concentration of those fragments is about 2 logs lower than of factor B present in the blood, which makes fragment detection challenging because of potential cross-reactivity. Lack of information on Bb assay cross-reactivity stimulated the authors to investigate this issue. We ran 109 healthy donor EDTA plasmas and 80 sera samples with both factor B immunodiffusion (The Binding Site) and Quidel Bb EIA assays. During the study it was shown that physiological concentrations of gently purified factor B demonstrated approximately 0.15% cross-reactivity in the Quidel Bb EIA assay. We also observed that Bb concentration in serum is higher than in plasma due to complement activation during clot formation which let us use sera as samples representing complement activated state. Our study demonstrated that despite the potential 0.15% cross-reactivity between endogenous factor B and cleaved Bb molecule, measuring plasma concentrations of factor Bb is adequate to evaluate the activation of the alternative complement pathway.

Quantitative trait loci and metabolic pathways: genetic control of the concentration of maysin, a corn earworm resistance factor, in maize silks.

PubMed Central

Byrne, P F; McMullen, M D; Snook, M E; Musket, T A; Theuri, J M; Widstrom, N W; Wiseman, B R; Coe, E H

1996-01-01

Interpretation of quantitative trait locus (QTL) studies of agronomic traits is limited by lack of knowledge of biochemical pathways leading to trait expression. To more fully elucidate the biological significance of detected QTL, we chose a trait that is the product of a well-characterized pathway, namely the concentration of maysin, a C-glycosyl flavone, in silks of maize, Zea mays L. Maysin is a host-plant resistance factor against the corn earworm, Helicoverpa zea (Boddie). We determined silk maysin concentrations and restriction fragment length polymorphism genotypes at flavonoid pathway loci or linked markers for 285 F2 plants derived from the cross of lines GT114 and GT119. Single-factor analysis of variance indicated that the p1 region on chromosome 1 accounted for 58.0% of the phenotypic variance and showed additive gene action. The p1 locus is a transcription activator for portions of the flavonoid pathway. A second QTL, represented by marker umc 105a near the brown pericarp1 locus on chromosome 9, accounted for 10.8% of the variance. Gene action of this region was dominant for low maysin, but was only expressed in the presence of a functional p1 allele. The model explaining the greatest proportion of phenotypic variance (75.9%) included p1, umc105a, umc166b (chromosome 1), r1 (chromosome 10), and two epistatic interaction terms, p1 x umc105a and p1 x r1. Our results provide evidence that regulatory loci have a central role and that there is a complex interplay among different branches of the flavonoid pathway in the expression of this trait. PMID:11607699

Anthropogenic Emissions Shift Pathways of Organic PM1 Production in Amazonia

NASA Astrophysics Data System (ADS)

de Sá, S. S.; Palm, B. B.; Campuzano-Jost, P.; Day, D. A.; Hu, W.; Jimenez, J. L.; Newburn, M. K.; Alexander, M. L. L.; Isaacman-VanWertz, G. A.; Yee, L.; Goldstein, A. H.; Brito, J.; Carbone, S.; Artaxo, P.; Springston, S. R.; Souza, R. A. F. D.; Manzi, A. O.; Surratt, J. D.; Martin, S. T.

2016-12-01

As part of GoAmazon2014/5, a high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS) was deployed to characterize the composition of fine-mode particulate matter (PM) and provide insights into the production of organic PM in the central Amazon basin, Brazil. Through a combination of meteorology, emissions, and chemistry, the T3 research site (located 70 km downwind of Manaus) was affected by biogenic emissions from the tropical rainforest that were periodically mixed with urban outflow from the Manaus metropolitan area as well as with biomass burning plumes. Results from the T3 site are presented in the context of measurements at T0a (ATTO) and T2, representing predominantly clean and polluted conditions, respectively. At T3, the non-refractory PM1 mass concentration was dominated by the organic component in both the wet and dry seasons (80% by mass). The analysis of the results aims at delineating the anthropogenic impact on the measurements, especially focusing on the effect of NOx emissions on the formation of organic PM. Positive matrix factorization (PMF) analysis is applied to the time series of mass spectra of the organic component of PM1. The resulting factors provide information on the relative and time-varying contributions of different sources and pathways to organic PM production. The time trend of the different statistical factors is investigated against co-located measurements, and compared between background and polluted conditions. Results suggest that polluted conditions are associated with higher organic mass concentrations, with some pathways being favored under those conditions while others are inhibited. This analysis and results represent a step toward the goal of improving the understanding of anthropogenic influences on the mass concentrations and composition of PM1 in Amazonia.

Projection of Future Mortality Due to Temperature and Population Changes under Representative Concentration Pathways and Shared Socioeconomic Pathways

PubMed Central

Lee, Jae Young; Kim, Ejin; Lee, Woo-Seop; Chae, Yeora; Kim, Ho

2018-01-01

The Paris Agreement aims to limit the global temperature increase to below 2 °C above pre-industrial levels and to pursue efforts to limit the increase to even below 1.5 °C. Now, it should be asked what benefits are in pursuing these two targets. In this study, we assessed the temperature–mortality relationship using a distributed lag non-linear model in seven major cities of South Korea. Then, we projected future temperature-attributable mortality under different Representative Concentration Pathway (RCP) and Shared Socioeconomic Pathway (SSP) scenarios for those cities. Mortality was projected to increase by 1.53 under the RCP 4.5 (temperature increase by 2.83 °C) and 3.3 under the RCP 8.5 (temperature increase by 5.10 °C) until the 2090s, as compared to baseline (1991–2015) mortality. However, future mortality is expected to increase by less than 1.13 and 1.26 if the 1.5 °C and 2 °C increase targets are met, respectively, under the RCP 4.5. Achieving the more ambitious target of 1.5 °C will reduce mortality by 12%, when compared to the 2 °C target. When we estimated future mortality due to both temperature and population changes, the future mortality was found to be increased by 2.07 and 3.85 for the 1.5 °C and 2 °C temperature increases, respectively, under the RCP 4.5. These increases can be attributed to a growing proportion of elderly population, who is more vulnerable to high temperatures. Meeting the target of 1.5 °C will be particularly beneficial for rapidly aging societies, including South Korea. PMID:29690535

AgMIP 1.5°C Assessment: Mitigation and Adaptation at Coordinated Global and Regional Scales

NASA Astrophysics Data System (ADS)

Rosenzweig, C.

2016-12-01

The AgMIP 1.5°C Coordinated Global and Regional Integrated Assessments of Climate Change and Food Security (AgMIP 1.5 CGRA) is linking site-based crop and livestock models with similar models run on global grids, and then links these biophysical components with economics models and nutrition metrics at regional and global scales. The AgMIP 1.5 CGRA assessment brings together experts in climate, crop, livestock, economics, nutrition, and food security to define the 1.5°C Protocols and guide the process throughout the assessment. Scenarios are designed to consistently combine elements of intertwined storylines of future society including socioeconomic development (Shared Socioeconomic Pathways), greenhouse gas concentrations (Representative Concentration Pathways), and specific pathways of agricultural sector development (Representative Agricultural Pathways). Shared Climate Policy Assumptions will be extended to provide additional agricultural detail on mitigation and adaptation strategies. The multi-model, multi-disciplinary, multi-scale integrated assessment framework is using scenarios of economic development, adaptation, mitigation, food policy, and food security. These coordinated assessments are grounded in the expertise of AgMIP partners around the world, leading to more consistent results and messages for stakeholders, policymakers, and the scientific community. The early inclusion of nutrition and food security experts has helped to ensure that assessment outputs include important metrics upon which investment and policy decisions may be based. The CGRA builds upon existing AgMIP research groups (e.g., the AgMIP Wheat Team and the AgMIP Global Gridded Crop Modeling Initiative; GGCMI) and regional programs (e.g., AgMIP Regional Teams in Sub-Saharan Africa and South Asia), with new protocols for cross-scale and cross-disciplinary linkages to ensure the propagation of expert judgment and consistent assumptions.

Projection of Future Mortality Due to Temperature and Population Changes under Representative Concentration Pathways and Shared Socioeconomic Pathways.

PubMed

Lee, Jae Young; Kim, Ejin; Lee, Woo-Seop; Chae, Yeora; Kim, Ho

2018-04-21

The Paris Agreement aims to limit the global temperature increase to below 2 °C above pre-industrial levels and to pursue efforts to limit the increase to even below 1.5 °C. Now, it should be asked what benefits are in pursuing these two targets. In this study, we assessed the temperature⁻mortality relationship using a distributed lag non-linear model in seven major cities of South Korea. Then, we projected future temperature-attributable mortality under different Representative Concentration Pathway (RCP) and Shared Socioeconomic Pathway (SSP) scenarios for those cities. Mortality was projected to increase by 1.53 under the RCP 4.5 (temperature increase by 2.83 °C) and 3.3 under the RCP 8.5 (temperature increase by 5.10 °C) until the 2090s, as compared to baseline (1991⁻2015) mortality. However, future mortality is expected to increase by less than 1.13 and 1.26 if the 1.5 °C and 2 °C increase targets are met, respectively, under the RCP 4.5. Achieving the more ambitious target of 1.5 °C will reduce mortality by 12%, when compared to the 2 °C target. When we estimated future mortality due to both temperature and population changes, the future mortality was found to be increased by 2.07 and 3.85 for the 1.5 °C and 2 °C temperature increases, respectively, under the RCP 4.5. These increases can be attributed to a growing proportion of elderly population, who is more vulnerable to high temperatures. Meeting the target of 1.5 °C will be particularly beneficial for rapidly aging societies, including South Korea.

Spatially resolved estimation of ozone-related mortality in the United States under two representative concentration pathways (RCPs) and their uncertainty

DOE PAGES

Kim, Young-Min; Zhou, Ying; Gao, Yang; ...

2014-11-16

We report that the spatial pattern of the uncertainty in air pollution-related health impacts due to climate change has rarely been studied due to the lack of high-resolution model simulations, especially under the Representative Concentration Pathways (RCPs), the latest greenhouse gas emission pathways. We estimated future tropospheric ozone (O 3) and related excess mortality and evaluated the associated uncertainties in the continental United States under RCPs. Based on dynamically downscaled climate model simulations, we calculated changes in O 3 level at 12 km resolution between the future (2057 and 2059) and base years (2001–2004) under a low-to-medium emission scenario (RCP4.5)more » and a fossil fuel intensive emission scenario (RCP8.5). We then estimated the excess mortality attributable to changes in O 3. Finally, we analyzed the sensitivity of the excess mortality estimates to the input variables and the uncertainty in the excess mortality estimation using Monte Carlo simulations. O 3-related premature deaths in the continental U.S. were estimated to be 1312 deaths/year under RCP8.5 (95 % confidence interval (CI): 427 to 2198) and ₋2118 deaths/year under RCP4.5 (95 % CI: ₋3021 to ₋1216), when allowing for climate change and emissions reduction. The uncertainty of O 3-related excess mortality estimates was mainly caused by RCP emissions pathways. Finally, excess mortality estimates attributable to the combined effect of climate and emission changes on O 3 as well as the associated uncertainties vary substantially in space and so do the most influential input variables. Spatially resolved data is crucial to develop effective community level mitigation and adaptation policy.« less

Spatially resolved estimation of ozone-related mortality in the United States under two representative concentration pathways (RCPs) and their uncertainty

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

Kim, Young-Min; Zhou, Ying; Gao, Yang

We report that the spatial pattern of the uncertainty in air pollution-related health impacts due to climate change has rarely been studied due to the lack of high-resolution model simulations, especially under the Representative Concentration Pathways (RCPs), the latest greenhouse gas emission pathways. We estimated future tropospheric ozone (O 3) and related excess mortality and evaluated the associated uncertainties in the continental United States under RCPs. Based on dynamically downscaled climate model simulations, we calculated changes in O 3 level at 12 km resolution between the future (2057 and 2059) and base years (2001–2004) under a low-to-medium emission scenario (RCP4.5)more » and a fossil fuel intensive emission scenario (RCP8.5). We then estimated the excess mortality attributable to changes in O 3. Finally, we analyzed the sensitivity of the excess mortality estimates to the input variables and the uncertainty in the excess mortality estimation using Monte Carlo simulations. O 3-related premature deaths in the continental U.S. were estimated to be 1312 deaths/year under RCP8.5 (95 % confidence interval (CI): 427 to 2198) and ₋2118 deaths/year under RCP4.5 (95 % CI: ₋3021 to ₋1216), when allowing for climate change and emissions reduction. The uncertainty of O 3-related excess mortality estimates was mainly caused by RCP emissions pathways. Finally, excess mortality estimates attributable to the combined effect of climate and emission changes on O 3 as well as the associated uncertainties vary substantially in space and so do the most influential input variables. Spatially resolved data is crucial to develop effective community level mitigation and adaptation policy.« less

Impacts devalue the potential of large-scale terrestrial CO2 removal through biomass plantations

NASA Astrophysics Data System (ADS)

Boysen, L. R.; Lucht, W.; Gerten, D.; Heck, V.

2016-09-01

Large-scale biomass plantations (BPs) are often considered a feasible and safe climate engineering proposal for extracting carbon from the atmosphere and, thereby, reducing global mean temperatures. However, the capacity of such terrestrial carbon dioxide removal (tCDR) strategies and their larger Earth system impacts remain to be comprehensively studied—even more so under higher carbon emissions and progressing climate change. Here, we use a spatially explicit process-based biosphere model to systematically quantify the potentials and trade-offs of a range of BP scenarios dedicated to tCDR, representing different assumptions about which areas are convertible. Based on a moderate CO2 concentration pathway resulting in a global mean warming of 2.5 °C above preindustrial level by the end of this century—similar to the Representative Concentration Pathway (RCP) 4.5—we assume tCDR to be implemented when a warming of 1.5 °C is reached in year 2038. Our results show that BPs can slow down the progression of increasing cumulative carbon in the atmosphere only sufficiently if emissions are reduced simultaneously like in the underlying RCP4.5 trajectory. The potential of tCDR to balance additional, unabated emissions leading towards a business-as-usual pathway alike RCP8.5 is therefore very limited. Furthermore, in the required large-scale applications, these plantations would induce significant trade-offs with food production and biodiversity and exert impacts on forest extent, biogeochemical cycles and biogeophysical properties.

A Surface "Superconvergence" Pathway Connecting the South Indian Ocean to the Subtropical South Pacific Gyre

NASA Astrophysics Data System (ADS)

Maes, C.; Grima, N.; Blanke, B.; Martinez, E.; Paviet-Salomon, T.; Huck, T.

2018-02-01

We study the dispersion and convergence of marine floating material by surface currents from a model reanalysis that represents explicitly mesoscale eddy variability. Lagrangian experiments about the long-term evolution (29 years) of an initially homogeneous concentration of particles are performed at global scale with horizontal current at one fourth degree resolution and refreshed daily over the 1985-2013 period. Results not only confirm and document the five known sites of surface convergence at the scale of individual oceanic basins but also reveal a convergent pathway connecting the South Indian subtropical region with the convergence zone of the South Pacific through the Great Australian Bight, the Tasman Sea, and the southwest Pacific Ocean. This "superconvergent" pathway at the ocean surface is robust and permanent over a distance longer than 8,000 km. The current variability is crucial to sustain this pathway.

Quantifying the percentage of methane formation via acetoclastic and syntrophic acetate oxidation pathways in anaerobic digesters.

PubMed

Jiang, Ying; Banks, Charles; Zhang, Yue; Heaven, Sonia; Longhurst, Philip

2018-01-01

Ammonia concentration is one of the key factors influencing the methanogenic community composition and dominant methanogenic pathway in anaerobic digesters. This study adopted a radiolabelling technique using [2- 14 C] acetate to investigate the relationship between total ammonia nitrogen (TAN) and the methanogenic pathway. The radiolabelling experiments determined the ratio of 14 CO 2 and 14 CH 4 in the biogas which was used to quantitatively determine the percentage of CH 4 derived from acetoclastic and syntrophic acetate oxidation routes, respectively. This technique was performed on a selection of mesophilic digesters representing samples of low to high TAN concentrations (0.2-11.1gkg -1 wet weight). In high TAN digesters, the ratio between 14 CO 2 and 14 CH 4 was in the range 2.1-3.0; indicating 68-75% of methane was produced via the hydrogenotrophic route; whereas in low ammonia samples the ratio was 0.1-0.3, indicating 9-23% of methane was produced by the hydrogenotrophic route. These findings have been confirmed further by phylogenetic studies. Copyright © 2017. Published by Elsevier Ltd.

Marine Plastic Pollution in Waters around Australia: Characteristics, Concentrations, and Pathways

PubMed Central

Reisser, Julia; Shaw, Jeremy; Wilcox, Chris; Hardesty, Britta Denise; Proietti, Maira; Thums, Michele; Pattiaratchi, Charitha

2013-01-01

Plastics represent the vast majority of human-made debris present in the oceans. However, their characteristics, accumulation zones, and transport pathways remain poorly assessed. We characterised and estimated the concentration of marine plastics in waters around Australia using surface net tows, and inferred their potential pathways using particle-tracking models and real drifter trajectories. The 839 marine plastics recorded were predominantly small fragments (“microplastics”, median length = 2.8 mm, mean length = 4.9 mm) resulting from the breakdown of larger objects made of polyethylene and polypropylene (e.g. packaging and fishing items). Mean sea surface plastic concentration was 4256.4 pieces km−2, and after incorporating the effect of vertical wind mixing, this value increased to 8966.3 pieces km−2. These plastics appear to be associated with a wide range of ocean currents that connect the sampled sites to their international and domestic sources, including populated areas of Australia's east coast. This study shows that plastic contamination levels in surface waters of Australia are similar to those in the Caribbean Sea and Gulf of Maine, but considerably lower than those found in the subtropical gyres and Mediterranean Sea. Microplastics such as the ones described here have the potential to affect organisms ranging from megafauna to small fish and zooplankton. PMID:24312224

Marine plastic pollution in waters around Australia: characteristics, concentrations, and pathways.

PubMed

Reisser, Julia; Shaw, Jeremy; Wilcox, Chris; Hardesty, Britta Denise; Proietti, Maira; Thums, Michele; Pattiaratchi, Charitha

2013-01-01

Plastics represent the vast majority of human-made debris present in the oceans. However, their characteristics, accumulation zones, and transport pathways remain poorly assessed. We characterised and estimated the concentration of marine plastics in waters around Australia using surface net tows, and inferred their potential pathways using particle-tracking models and real drifter trajectories. The 839 marine plastics recorded were predominantly small fragments ("microplastics", median length = 2.8 mm, mean length = 4.9 mm) resulting from the breakdown of larger objects made of polyethylene and polypropylene (e.g. packaging and fishing items). Mean sea surface plastic concentration was 4256.4 pieces km(-2), and after incorporating the effect of vertical wind mixing, this value increased to 8966.3 pieces km(-2). These plastics appear to be associated with a wide range of ocean currents that connect the sampled sites to their international and domestic sources, including populated areas of Australia's east coast. This study shows that plastic contamination levels in surface waters of Australia are similar to those in the Caribbean Sea and Gulf of Maine, but considerably lower than those found in the subtropical gyres and Mediterranean Sea. Microplastics such as the ones described here have the potential to affect organisms ranging from megafauna to small fish and zooplankton.

Cellular proteostasis: degradation of misfolded proteins by lysosomes

PubMed Central

Jackson, Matthew P.

2016-01-01

Proteostasis refers to the regulation of the cellular concentration, folding, interactions and localization of each of the proteins that comprise the proteome. One essential element of proteostasis is the disposal of misfolded proteins by the cellular pathways of protein degradation. Lysosomes are an important site for the degradation of misfolded proteins, which are trafficked to this organelle by the pathways of macroautophagy, chaperone-mediated autophagy and endocytosis. Conversely, amyloid diseases represent a failure in proteostasis, in which proteins misfold, forming amyloid deposits that are not degraded effectively by cells. Amyloid may then exacerbate this failure by disrupting autophagy and lysosomal proteolysis. However, targeting the pathways that regulate autophagy and the biogenesis of lysosomes may present approaches that can rescue cells from the deleterious effects of amyloidogenic proteins. PMID:27744333

Pathway-based approaches for assessment of real-time exposure to an estrogenic wastewater treatment plant effluent on fathead minnow reproduction

USGS Publications Warehouse

Cavallin, Jenna E.; Jensen, Kathleen M.; Kahl, Michael D.; Villeneuve, Daniel L.; Lee, Kathy E.; Schroeder, Anthony L.; Mayasich, Joe; Eid, Evan P.; Nelson, Krysta R.; Milsk, Rebecca Y.; Blackwell, Brett R.; Berninger, Jason P.; LaLone, Carlie A.; Blanskma, Chad; Jicha, Terri M.; Elonen, Colleen M.; Johnson, Rodney C.; Ankley, Gerald T.

2016-01-01

Wastewater treatment plant (WWTP) effluents are known contributors of chemical mixtures into the environment. Of particular concern are endocrine-disrupting compounds, such as estrogens, which can affect the hypothalamic-pituitary-gonadal axis function in exposed organisms. The present study examined reproductive effects in fathead minnows exposed for 21 d to a historically estrogenic WWTP effluent. Fathead minnow breeding pairs were held in control water or 1 of 3 effluent concentrations (5%, 20%, and 100%) in a novel onsite, flow-through system providing real-time exposure. The authors examined molecular and biochemical endpoints representing key events along adverse outcome pathways linking estrogen receptor activation and other molecular initiating events to reproductive impairment. In addition, the authors used chemical analysis of the effluent to construct a chemical-gene interaction network to aid in targeted gene expression analyses and identifying potentially impacted biological pathways. Cumulative fecundity was significantly reduced in fish exposed to 100% effluent but increased in those exposed to 20% effluent, the approximate dilution factor in the receiving waters. Plasma vitellogenin concentrations in males increased in a dose-dependent manner with effluent concentration; however, male fertility was not impacted. Although in vitro analyses, analytical chemistry, and biomarker responses confirmed the effluent was estrogenic, estrogen receptor agonists were unlikely the primary driver of impaired reproduction. The results provide insights into the significance of pathway-based effects with regard to predicting adverse reproductive outcomes.

Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer

PubMed Central

2013-01-01

Introduction The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in cancer cells through numerous mutations and epigenetic changes. The recent development of inhibitors targeting different components of the PI3K pathway may represent a valuable treatment alternative. However, predicting efficacy of these drugs is challenging, and methods for therapy monitoring are needed. Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype, frequently associated with PI3K pathway activation. The objectives of this study were to quantify the PI3K pathway activity in tissue sections from xenografts representing basal-like and luminal-like breast cancer before and immediately after treatment with PI3K inhibitors, and to identify metabolic biomarkers for treatment response. Methods Tumor-bearing animals (n = 8 per treatment group) received MK-2206 (120 mg/kg/day) or BEZ235 (50 mg/kg/day) for 3 days. Activity in the PI3K/Akt/mammalian target of rapamycin pathway in xenografts and human biopsies was evaluated using a novel method for semiquantitative assessment of Aktser473 phosphorylation. Metabolic changes were assessed by ex vivo high-resolution magic angle spinning magnetic resonance spectroscopy. Results Using a novel dual near-infrared immunofluorescent imaging method, basal-like xenografts had a 4.5-fold higher baseline level of pAktser473 than luminal-like xenografts. Following treatment, basal-like xenografts demonstrated reduced levels of pAktser473 and decreased proliferation. This correlated with metabolic changes, as both MK-2206 and BEZ235 reduced lactate concentration and increased phosphocholine concentration in the basal-like tumors. BEZ235 also caused increased glucose and glycerophosphocholine concentrations. No response to treatment or change in metabolic profile was seen in luminal-like xenografts. Analyzing tumor sections from five patients with BLBC demonstrated that two of these patients had an elevated pAktser473 level. Conclusion The activity of the PI3K pathway can be determined in tissue sections by quantitative imaging using an antibody towards pAktser473. Long-term treatment with MK-2206 or BEZ235 resulted in significant growth inhibition in basal-like, but not luminal-like, xenografts. This indicates that PI3K inhibitors may have selective efficacy in basal-like breast cancer with increased PI3K signaling, and identifies lactate, phosphocholine and glycerophosphocholine as potential metabolic biomarkers for early therapy monitoring. In human biopsies, variable pAktser473 levels were observed, suggesting heterogeneous PI3K signaling activity in BLBC. PMID:23448424

The Impact of Emission and Climate Change on Ozone in the United States under Representative Concentration Pathways (RCPs)

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

Gao, Yang; Fu, Joshua S.; Drake, John B.

Dynamical downscaling was applied in this study to link the global climate-chemistry model Community Atmosphere Model (CAM-Chem) with the regional models: Weather Research and Forecasting (WRF) Model and Community Multi-scale Air Quality (CMAQ). Two Representative Concentration Pathway (RCP) scenarios (RCP 4.5 and RCP 8.5) were used to evaluate the climate impact on ozone concentrations in 2050s. Ozone concentrations in the lower-mid troposphere (surface to ~300 hPa), from mid- to high latitudes in the Northern Hemisphere (NH), show decreasing trends in RCP 4.5 between 2000s and 2050s, with the largest decrease of 4-10 ppbv occurring in the summer and the fall;more » and increasing trends (2-12 ppbv) in RCP 8.5 resulting from the increased methane emissions. In RCP 8.5, methane emissions increase by ~60% by the end of 2050s, accounting for more than 90% of ozone increases in summer and fall, and 60-80% in spring and winter. Under the RCP 4.5 scenario, in the summer when photochemical reactions are the most active, the large ozone precursor emissions reduction leads to the greatest decrease of downscaled surface ozone concentrations, ranging from 6 to 10 ppbv. However, a few major cities show ozone increases of 3 to 7 ppbv due to weakened NO titration. Under the RCP 8.5 scenario, in winter, downscaled ozone concentrations increase across nearly the entire continental US in winter, ranging from 3 to 10 ppbv due to increased methane emissions and enhanced stratosphere-troposphere exchange (STE). More intense heat waves are projected to occur by the end of 2050s in RCP 8.5, leading to more than 8 ppbv of the maximum daily 8-hour daily average (MDA8) ozone during the heat wave days than other days; this indicates the dramatic impact heat waves exert on high frequency ozone events.« less

Internal Dose from Food and Drink Ingestion in the Early Phase after the Accident

NASA Astrophysics Data System (ADS)

Kawai, Masaki; Yoshizawa, Nobuaki; Hirakawa, Sachiko; Murakami, Kana; Takizawa, Mari; Sato, Osamu; Takagi, Shunji; Miyatake, Hirokazu; Takahashi, Tomoyuki; Suzuki, Gen

2017-09-01

Activity concentrations in food and drink, represented by water and vegetables, have been monitored continuously since the Fukushima Daiichi Nuclear Power Plant accident, with a focus on radioactive cesium. On the other hand, iodine-131 was not measured systematically in the early phase after the accident. The activity concentrations of iodine-131 in food and drink are important to estimate internal exposure due to ingestion pathway. When the internal dose from ingestion in the evacuation areas is estimated, water is considered as the main ingestion pathway. In this study, we estimated the values of activity concentrations in water in the early phase after the accident, using a compartment model as an estimation method. The model uses measurement values of activity concentration and deposition rate of iodine-131 onto the ground, which is calculated from an atmospheric dispersion simulation. The model considers how drinking water would be affected by radionuclides deposited into water. We estimated the activity concentrations of water on Kawamata town and Minamisouma city during March of 2011 and the committed effective doses were 0.08 mSv and 0.06 mSv. We calculated the transfer parameters in the model for estimating the activity concentrations in the areas with a small amount of measurement data. In addition, we estimated the committed effective doses from vegetables using atmospheric dispersion simulation and FARMLAND model in case of eating certain vegetables as option information.

Trends in Public and Global Health Education among Nationally Recognized Undergraduate Liberal Arts Colleges in the United States.

PubMed

Robinson, Patrick A; Orroth, Kate K; Stutts, Lauren A; Baron, Patrick A; Wessner, David R

2018-05-01

The prevalence of public health and global health (PH/GH) curricular offerings appear to be increasing in terms of undergraduate curricula and in the context of liberal arts education in the United States. Liberal arts colleges (LACs) represent stand-alone institutions, which exclusively focus on undergraduate education. The objective of this study was to assess the prevalence of PH/GH study pathways and PH/GH course offerings among LACs. All LACs identified through the US News and World Report (USNWR) college rankings were contacted with a survey about the following: formal majors, minors, or concentrations in PH/GH; independent study (IS) pathways for PH/GH; specific PH/GH courses offered; and the number of students graduating in 2016, 2017, and 2018 with formal and IS degrees in PH/GH. Demographic characteristics of the colleges came from the USNWR database. Almost half (43%) of all LACs in our sample offer a PH/GH major, minor, concentration, or IS pathway. Almost all (90%) colleges offer at least one course in PH/GH. Approximately 2,000 students attending these LACs pursued or are pursuing graduation with majors, minors, or concentrations in PH/GH for the years 2016-2018. The number of students pursuing formal PH/GH programs has increased by 25% from 2016 to 2018. Student interest in public health is rising in U.S. LACs, with more students seeking formal curricular or IS PH degree pathways. Public health messages are prevalent even among institutions without formal programs. Colleges without programs should consider integrating public health into their curriculum.

The psychoactive pollutant fluoxetine compromises antipredator behaviour in fish.

PubMed

Martin, Jake M; Saaristo, Minna; Bertram, Michael G; Lewis, Phoebe J; Coggan, Timothy L; Clarke, Bradley O; Wong, Bob B M

2017-03-01

Pharmaceuticals are increasingly being detected in aquatic ecosystems worldwide. Particularly concerning are pharmaceutical pollutants that can adversely impact exposed wildlife, even at extremely low concentrations. One such contaminant is the widely prescribed antidepressant fluoxetine, which can disrupt neurotransmission and behavioural pathways in wildlife. Despite this, relatively limited research has addressed the behavioural impacts of fluoxetine at ecologically realistic exposure concentrations. Here, we show that 28-day fluoxetine exposure at two ecologically relevant dosages-one representing low surface water concentrations and another representing high effluent flow concentrations-alters antipredator behaviour in Eastern mosquitofish (Gambusia holbrooki). We found that fluoxetine exposure at the lower dosage resulted in increased activity levels irrespective of the presence or absence of a predatory dragonfly nymph (Hemianax papuensis). Additionally, irrespective of exposure concentration, fluoxetine-exposed fish entered the predator 'strike zone' more rapidly. In a separate experiment, fluoxetine exposure reduced mosquitofish freezing behaviour-a common antipredator strategy-following a simulated predator strike, although, in females, this reduction in behaviour was seen only at the lower dosage. Together, our findings suggest that fluoxetine can cause both non-monotonic and sex-dependent shifts in behaviour. Further, they demonstrate that exposure to fluoxetine at environmentally realistic concentrations can alter antipredator behaviour, with important repercussions for organismal fitness. Copyright © 2016 Elsevier Ltd. All rights reserved.

Implications of alternative assumptions regarding future air pollution control in scenarios similar to the Representative Concentration Pathways

NASA Astrophysics Data System (ADS)

Chuwah, Clifford; van Noije, Twan; van Vuuren, Detlef P.; Hazeleger, Wilco; Strunk, Achim; Deetman, Sebastiaan; Beltran, Angelica Mendoza; van Vliet, Jasper

2013-11-01

The uncertain, future development of emissions of short-lived trace gases and aerosols forms a key factor for future air quality and climate forcing. The Representative Concentration Pathways (RCPs) only explore part of this range as they all assume that worldwide ambitious air pollution control policies will be implemented. In this study, we explore how different assumptions on future air pollution policy and climate policy lead to different concentrations of air pollutants for a set of RCP-like scenarios developed using the IMAGE model. These scenarios combine low and high air pollution variants of the scenarios with radiative forcing targets in 2100 of 2.6 W m-2 and 6.0 W m-2. Simulations using the global atmospheric chemistry and transport model TM5 for the present-day climate show that both climate mitigation and air pollution control policies have large-scale effects on pollutant concentrations, often of similar magnitude. If no further air pollution policies would be implemented, pollution levels could be considerably higher than in the RCPs, especially in Asia. Air pollution control measures could significantly reduce the warming by tropospheric ozone and black carbon and the cooling by sulphate by 2020, and in the longer term contribute to enhanced warming by methane. These effects tend to cancel each other on a global scale. According to our estimates the effect of the worldwide implementation of air pollution control measures on the total global mean direct radiative forcing in 2050 is +0.09 W m-2 in the 6.0 W m-2 scenario and -0.16 W m-2 in the 2.6 W m-2 scenario.

Electrochemical treatment of iopromide under conditions of reverse osmosis concentrates--elucidation of the degradation pathway.

PubMed

Lütke Eversloh, C; Henning, N; Schulz, M; Ternes, T A

2014-01-01

Application of reverse osmosis for the reuse of treated wastewater on the one hand offers a way to provide high quality effluent waters. On the other hand reverse osmosis concentrates exhibiting highly concentrated contaminants are produced simultaneously. Electrochemical treatment of those concentrates is regarded as one possible answer to the problem of their disposal into surface waters. Nevertheless, due to the diversity of direct and indirect degradation processes during electrolysis, special care has to be taken about the formation of toxic transformation products (TPs). In this study the electrochemical transformation of the X-ray contrast medium iopromide was investigated as a representative of biologically persistent compounds. For this purpose, anodic oxidation at boron doped diamond as well as cathodic reduction using a platinum electrode were considered. Kinetic analyses revealed a transformation of 100 μM iopromide with first order kinetic constants between 0.6 and 1.6 × 10(-4) s(-1) at the beginning and a subsequent increase of the reaction order due to the influence of secondary oxidants formed during electrolysis. Mineralization up to 96% was achieved after about 7.5 h. At shorter treatment times several oxidatively and reductively formed transformation products were detected, whereas deiodinated iopromide represented the major fraction. Nevertheless, the latter exhibited negligible toxicological relevance according to tests on vibrio fisheri. Additional experiments utilizing a divided cell setup enabled the elucidation of the transformation pathway, whereas emerging TPs could be identified by means of high resolution mass spectrometry and MS(n)-fragmentations. During electrolysis the iodine released from Iopromide was found to 90% as iodide and to 10% as iodate even in the open cell experiments, limiting the potential formation of toxic iodo-disinfection by-products. Chlorinated TPs were not found. Copyright © 2013. Published by Elsevier Ltd.

The arginine-creatine pathway is disturbed in children and adolescents with renal transplants.

PubMed

Andrade, Fernando; Rodríguez-Soriano, Juan; Prieto, José Angel; Elorz, Javier; Aguirre, Mireia; Ariceta, Gema; Martin, Sergio; Sanjurjo, Pablo; Aldámiz-Echevarría, Luis

2008-08-01

Cardiovascular disease is an important cause of morbidity in recipients of renal transplants. The aim of the present study was to analyze the status of the arginine-creatine pathway in such patients, given the relationship between the arginine metabolism and both renal function and the methionine-homocysteine cycle. Twenty-nine children and adolescents (median age 13, range 6-18 years), who had received a renal allograft 14.5-82.0 months before, were recruited for the study. On immunosuppressive therapy, all patients evidenced an adequate level of renal function. Plasma concentrations of homocysteine and glycine were significantly higher, whereas urinary excretions of guanidinoacetate and creatine were significantly lower than controls. Urinary excretions of guanidinoacetate and creatine correlated positively with creatinine clearance. Urinary excretion of creatine was negatively correlated with plasma concentration of homocysteine. The demonstration of disturbances in the arginine-creatine pathway in patients with well-functioning renal transplants and in absence of chronic renal failure represents a novel finding. We speculate that the low urinary excretion of guanidinoacetate and creatine is probably related to the nephrotoxic effect of immunosuppressive therapy and to defective methylation associated with the presence of hyperhomocysteinemia.

Machine learning assembly landscapes from particle tracking data.

PubMed

Long, Andrew W; Zhang, Jie; Granick, Steve; Ferguson, Andrew L

2015-11-07

Bottom-up self-assembly offers a powerful route for the fabrication of novel structural and functional materials. Rational engineering of self-assembling systems requires understanding of the accessible aggregation states and the structural assembly pathways. In this work, we apply nonlinear machine learning to experimental particle tracking data to infer low-dimensional assembly landscapes mapping the morphology, stability, and assembly pathways of accessible aggregates as a function of experimental conditions. To the best of our knowledge, this represents the first time that collective order parameters and assembly landscapes have been inferred directly from experimental data. We apply this technique to the nonequilibrium self-assembly of metallodielectric Janus colloids in an oscillating electric field, and quantify the impact of field strength, oscillation frequency, and salt concentration on the dominant assembly pathways and terminal aggregates. This combined computational and experimental framework furnishes new understanding of self-assembling systems, and quantitatively informs rational engineering of experimental conditions to drive assembly along desired aggregation pathways.

Activity and diversity of aerobic methanotrophs in a coastal marine oxygen minimum zone

NASA Astrophysics Data System (ADS)

Padilla, C. C.; Bristow, L. A.; Sarode, N. D.; Garcia-Robledo, E.; Girguis, P. R.; Thamdrup, B.; Stewart, F. J.

2016-02-01

The pelagic ocean is a sink for the potent greenhouse gas methane, with methane consumption regulated primarily by aerobic methane-oxidizing bacteria (MOB). Marine oxygen minimum zones (OMZs) contain the largest pool of pelagic methane in the oceans but remain largely unexplored for their potential to harbor MOB communities and contribute to methane cycling. Here, we present meta-omic and geochemical evidence that aerobic MOB are present and active in a coastal OMZ, in Golfo Dulce, Costa Rica. Oxygen concentrations were < 50 nM below 85 m, and sulfide accumulated below 140 m, with methane concentrations ranging from trace levels above the oxycline to 78 nM at 180 m. The upper OMZ (90 m) was characterized by an abundant MOB and methylotroph community representing diverse lineages of the Methylophilaceae, Methylophaga, and Methylococcales. Of these, Type I methanotrophs of the Order Methylococcales dominated , representing >5% of total 16S rRNA genes and >19% of 16S rRNA transcripts. This peak in ribosomal abundance and activity was affiliated with methane oxidation rates of 2.6 ± 0.7 nM d-1, measured in seawater incubations with estimated O2 concentrations of 50 nM. Rates fell to zero with the addition of acetylene, an inhibitor of aerobic methanotrophy. In contrast, methane oxidation was below detection at lower depths in the OMZ (100 m and 120 m). Metatranscriptome sequencing indicated a peak at 90 m in the expression of pathways essential to Methylococcales, including aerobic methanotrophy and the RuMP pathway of carbon assimilation, as well as the serine pathway of Type II methanotrophs. Preliminary analysis of single-cell genomes suggests distinct adaptations by Methylococcales from the Golfo Dulce, helping explain the persistence of putative aerobic methanotrophs under very low oxygen in this OMZ. Taken together, these data suggest the boundary layers of OMZs, despite extreme oxygen depletion, are a niche for aerobic MOBs and therefore potentially important zones of pelagic methane loss.

The abandoned ice sheet base at Camp Century, Greenland, in a warming climate

NASA Astrophysics Data System (ADS)

Colgan, William; Machguth, Horst; MacFerrin, Mike; Colgan, Jeff D.; As, Dirk; MacGregor, Joseph A.

2016-08-01

In 1959 the U.S. Army Corps of Engineers built Camp Century beneath the surface of the northwestern Greenland Ice Sheet. There they studied the feasibility of deploying ballistic missiles within the ice sheet. The base and its wastes were abandoned with minimal decommissioning in 1967, under the assumption they would be preserved for eternity by perpetually accumulating snowfall. Here we show that a transition in ice sheet surface mass balance at Camp Century from net accumulation to net ablation is plausible within the next 75 years, under a business-as-usual anthropogenic emissions scenario (Representative Concentration Pathway 8.5). Net ablation would guarantee the eventual remobilization of physical, chemical, biological, and radiological wastes abandoned at the site. While Camp Century and four other contemporaneous ice sheet bases were legally established under a Danish-U.S. treaty, the potential remobilization of their abandoned wastes, previously regarded as sequestered, represents an entirely new pathway of political dispute resulting from climate change.

The Abandoned Ice Sheet Base at Camp Century, Greenland, in a Warming Climate

NASA Technical Reports Server (NTRS)

Colgan, William; Machguth, Horst; Macferrin, Mike; Colgan, Jeff D.; Van As, Dirk; Macgregor, Joseph A.

2016-01-01

In 1959 the U.S. Army Corps of Engineers built Camp Century beneath the surface of the northwestern Greenland Ice Sheet. There they studied the feasibility of deploying ballistic missiles within the ice sheet. The base and its wastes were abandoned with minimal decommissioning in 1967, under the assumption they would be preserved for eternity by perpetually accumulating snowfall. Here we show that a transition in ice sheet surface mass balance at Camp Century from net accumulation to net ablation is plausible within the next 75years, under a business-as-usual anthropogenic emissions scenario (Representative Concentration Pathway 8.5). Net ablation would guarantee the eventual remobilization of physical, chemical, biological, and radiological wastes abandoned at the site. While Camp Century and four other contemporaneous ice sheet bases were legally established under a Danish-U.S. treaty, the potential remobilization of their abandoned wastes, previously regarded as sequestered, represents an entirely new pathway of political dispute resulting from climate change.

Formal modeling of a system of chemical reactions under uncertainty.

PubMed

Ghosh, Krishnendu; Schlipf, John

2014-10-01

We describe a novel formalism representing a system of chemical reactions, with imprecise rates of reactions and concentrations of chemicals, and describe a model reduction method, pruning, based on the chemical properties. We present two algorithms, midpoint approximation and interval approximation, for construction of efficient model abstractions with uncertainty in data. We evaluate computational feasibility by posing queries in computation tree logic (CTL) on a prototype of extracellular-signal-regulated kinase (ERK) pathway.

SITE SPECIFIC REFERENCE PERSON PARAMETERS AND DERIVED CONCENTRATION STANDARDS FOR THE SAVANNAH RIVER SITE

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

Jannik, T.

2013-03-14

The purpose of this report is twofold. The first is to develop a set of behavioral parameters for a reference person specific for the Savannah River Site (SRS) such that the parameters can be used to determine dose to members of the public in compliance with Department of Energy (DOE) Order 458.1 “Radiation Protection of the Public and the Environment.” A reference person is a hypothetical, gender and age aggregation of human physical and physiological characteristics arrived at by international consensus for the purpose of standardizing radiation dose calculations. DOE O 458.1 states that compliance with the annual dose limitmore » of 100 mrem (1 mSv) to a member of the public may be demonstrated by calculating the dose to the maximally exposed individual (MEI) or to a representative person. Historically, for dose compliance, SRS has used the MEI concept, which uses adult dose coefficients and adult male usage parameters. Beginning with the 2012 annual site environmental report, SRS will be using the representative person concept for dose compliance. The dose to a representative person will be based on 1) the SRS-specific reference person usage parameters at the 95th percentile of appropriate national or regional data, which are documented in this report, 2) the reference person (gender and age averaged) ingestion and inhalation dose coefficients provided in DOE Derived Concentration Technical Standard (DOE-STD-1196-2011), and 3) the external dose coefficients provided in the DC_PAK3 toolbox. The second purpose of this report is to develop SRS-specific derived concentration standards (DCSs) for all applicable food ingestion pathways, ground shine, and water submersion. The DCS is the concentration of a particular radionuclide in water, in air, or on the ground that results in a member of the public receiving 100 mrem (1 mSv) effective dose following continuous exposure for one year. In DOE-STD-1196-2011, DCSs were developed for the ingestion of water, inhalation of air and submersion in air pathways, only. These DCSs are required by DOE O 458.1 to be used at all DOE sites in the design and conduct of radiological environmental protection programs. In this report, DCSs for the following additional pathways were considered and documented: ingestion of meat, dairy, grains, produce (fruits and vegetables), seafood, submersion in water and ground shine. These additional DCSs were developed using the same methods as in DOE-STD-1196-2011 and will be used at SRS, where appropriate, as screening and reference values.« less

Bioaugmentation of Syntrophic Acetate-Oxidizing Culture in Biogas Reactors Exposed to Increasing Levels of Ammonia

PubMed Central

Westerholm, Maria; Levén, Lotta

2012-01-01

The importance of syntrophic acetate oxidation for process stability in methanogenic systems operating at high ammonia concentrations has previously been emphasized. In this study we investigated bioaugmentation of syntrophic acetate-oxidizing (SAO) cultures as a possible method for decreasing the adaptation period of biogas reactors operating at gradually increased ammonia concentrations (1.5 to 11 g NH4+-N/liter). Whole stillage and cattle manure were codigested semicontinuously for about 460 days in four mesophilic anaerobic laboratory-scale reactors, and a fixed volume of SAO culture was added daily to two of the reactors. Reactor performance was evaluated in terms of biogas productivity, methane content, pH, alkalinity, and volatile fatty acid (VFA) content. The decomposition pathway of acetate was analyzed by isotopic tracer experiments, and population dynamics were monitored by quantitative PCR analyses. A shift in dominance from aceticlastic methanogenesis to SAO occurred simultaneously in all reactors, indicating no influence by bioaugmentation on the prevailing pathway. Higher abundances of Clostridium ultunense and Tepidanaerobacter acetatoxydans were associated with bioaugmentation, but no influence on Syntrophaceticus schinkii or the methanogenic population was distinguished. Overloading or accumulation of VFA did not cause notable dynamic effects on the population. Instead, the ammonia concentration had a substantial impact on the abundance level of the microorganisms surveyed. The addition of SAO culture did not affect process performance or stability against ammonia inhibition, and all four reactors deteriorated at high ammonia concentrations. Consequently, these findings further demonstrate the strong influence of ammonia on the methane-producing consortia and on the representative methanization pathway in mesophilic biogas reactors. PMID:22923397

Molecular Pathways: Gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention

PubMed Central

Bultman, Scott J.

2013-01-01

Gene-environment interactions are so numerous and biologically complicated that it can be challenging to understand their role in cancer. However, dietary fiber and colorectal cancer prevention may represent a tractable model system. Fiber is fermented by colonic bacteria into short-chain fatty acids such as butyrate. One molecular pathway that has emerged involves butyrate having differential effects depending on its concentration and the metabolic state of the cell. Low-moderate concentrations, which are present near the base of colonic crypts, are readily metabolized in the mitochondria to stimulate cell proliferation via energetics. Higher concentrations, which are present near the lumen, exceed the metabolic capacity of the colonocyte. Unmetabolized butyrate enters the nucleus and functions as a histone deacetylase (HDAC) inhibitor that epigenetically regulates gene expression to inhibit cell proliferation and induce apoptosis as the colonocytes exfoliate into the lumen. Butyrate may therefore play a role in normal homeostasis by promoting turnover of the colonic epithelium. Because cancerous colonocytes undergo the Warburg effect, their preferred energy source is glucose instead of butyrate. Consequently, even moderate concentrations of butyrate accumulate in cancerous colonocytes and function as HDAC inhibitors to inhibit cell proliferation and induce apoptosis. These findings implicate a bacterial metabolite with metaboloepigenetic properties in tumor suppression. PMID:24270685

Climate simulations and projections with a super-parameterized climate model

DOE PAGES

Stan, Cristiana; Xu, Li

2014-07-01

The mean climate and its variability are analyzed in a suite of numerical experiments with a fully coupled general circulation model in which subgrid-scale moist convection is explicitly represented through embedded 2D cloud-system resolving models. Control simulations forced by the present day, fixed atmospheric carbon dioxide concentration are conducted using two horizontal resolutions and validated against observations and reanalyses. The mean state simulated by the higher resolution configuration has smaller biases. Climate variability also shows some sensitivity to resolution but not as uniform as in the case of mean state. The interannual and seasonal variability are better represented in themore » simulation at lower resolution whereas the subseasonal variability is more accurate in the higher resolution simulation. The equilibrium climate sensitivity of the model is estimated from a simulation forced by an abrupt quadrupling of the atmospheric carbon dioxide concentration. The equilibrium climate sensitivity temperature of the model is 2.77 °C, and this value is slightly smaller than the mean value (3.37 °C) of contemporary models using conventional representation of cloud processes. As a result, the climate change simulation forced by the representative concentration pathway 8.5 scenario projects an increase in the frequency of severe droughts over most of the North America.« less

Anthropogenic Emissions Change the Amount and Composition of Organic PM1 in Amazonia

NASA Astrophysics Data System (ADS)

de Sá, S. S.; Palm, B. B.; Campuzano Jost, P.; Day, D. A.; Hu, W.; Isaacman-VanWertz, G. A.; Yee, L.; Wernis, R. A.; Thalman, R.; Brito, J.; Carbone, S.; Artaxo, P.; Goldstein, A. H.; Manzi, A. O.; Souza, R. A. F. D.; Wang, J.; Alexander, M. L. L.; Jimenez, J. L.; Martin, S. T.

2017-12-01

The Amazon forest, while one of the few regions on the globe where pristine conditions may still prevail, has experienced rapid changes due to increasing urbanization in the past decades. Manaus, a Brazilian city of 2-million people in the central Amazon basin, releases a pollution plume over the forest, potentially affecting the production pathways of particulate matter (PM) in the region. As part of GoAmazon2014/5, a high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS) and a suite of other gas and particle-phase instruments were deployed at the T3 research site, 70 km downwind of Manaus, during the wet and dry seasons. Through a combination of meteorology, emissions, and chemistry, the T3 site was affected by a mixture of biogenic emissions from the tropical rainforest, urban outflow from the Manaus metropolitan area and biomass burning plumes. Results from the T3 site are presented in the context of measurements at T0a/T0t and T2, sites representing predominantly clean and polluted conditions, respectively. The organic component consistently represented on average 70-80% of the PM1 mass concentration across sites and seasons, and constitutes the focus of this work. Positive matrix factorization (PMF) analysis was applied to the time series of organic mass spectra. The resulting factors, which included the so-called IEPOX-SOA, MO-OOA, LO-OOA, BBOA, Fac91 and HOA, provide information on the relative contributions of different sources and pathways to organic PM production. In addition, Fuzzy c-means clustering was applied to the time series of pollution indicators, including concentrations of NOy, total particle number, ozone and sulfate, in order to better understand the convoluted influences of different processes and airmass origin to each point in time. Through combination of the PMF and Fuzzy c-means analyses, insights are drawn about the relative composition of organic PM1 at varying degrees of influence of biogenic and anthropogenic processes. Results suggest that polluted conditions are associated with higher organic mass concentrations, with certain pathways being favored to the detriment of others. This analysis and results represent a step toward the goal of improving the understanding of anthropogenic influences on the production of PM1 in Amazonia.

Global wheat production potentials and management flexibility under the representative concentration pathways

NASA Astrophysics Data System (ADS)

Balkovič, Juraj; van der Velde, Marijn; Skalský, Rastislav; Xiong, Wei; Folberth, Christian; Khabarov, Nikolay; Smirnov, Alexey; Mueller, Nathaniel D.; Obersteiner, Michael

2014-11-01

Wheat is the third largest crop globally and an essential source of calories in human diets. Maintaining and increasing global wheat production is therefore strongly linked to food security. A large geographic variation in wheat yields across similar climates points to sizeable yield gaps in many nations, and indicates a regionally variable flexibility to increase wheat production. Wheat is particularly sensitive to a changing climate thus limiting management opportunities to enable (sustainable) intensification with potentially significant implications for future wheat production. We present a comprehensive global evaluation of future wheat yields and production under distinct Representative Concentration Pathways (RCPs) using the Environmental Policy Integrated Climate (EPIC) agro-ecosystem model. We project, in a geographically explicit manner, future wheat production pathways for rainfed and irrigated wheat systems. We explore agricultural management flexibility by quantifying the development of wheat yield potentials under current, rainfed, exploitable (given current irrigation infrastructure), and irrigated intensification levels. Globally, because of climate change, wheat production under conventional management (around the year 2000) would decrease across all RCPs by 37 to 52 and 54 to 103 Mt in the 2050s and 2090s, respectively. However, the exploitable and potential production gap will stay above 350 and 580 Mt, respectively, for all RCPs and time horizons, indicating that negative impacts of climate change can globally be offset by adequate intensification using currently existing irrigation infrastructure and nutrient additions. Future world wheat production on cropland already under cultivation can be increased by ~ 35% through intensified fertilization and ~ 50% through increased fertilization and extended irrigation, if sufficient water would be available. Significant potential can still be exploited, especially in rainfed wheat systems in Russia, Eastern Europe and North America.

Shock and Rarefaction Waves in a Heterogeneous Mantle

NASA Astrophysics Data System (ADS)

Jordan, J.; Hesse, M. A.

2012-12-01

We explore the effect of heterogeneities on partial melting and melt migration during active upwelling in the Earth's mantle. We have constructed simple, explicit nonlinear models in one dimension to examine heterogeneity and its dynamic affects on porosity, temperature and the magnesium number in a partially molten, porous medium comprised of olivine. The composition of the melt and solid are defined by a closed, binary phase diagram for a simplified, two-component olivine system. The two-component solid solution is represented by a phase loop where concentrations 0 and 1 to correspond to fayalite and forsterite, respectively. For analysis, we examine an advective system with a Riemann initial condition. Chromatographic tools and theory have primarily been used to track large, rare earth elements as tracers. In our case, we employ these theoretical tools to highlight the importance of the magnesium number, enthalpy and overall heterogeneity in the dynamics of melt migration. We calculate the eigenvectors and eigenvalues in the concentration-enthalpy space in order to glean the characteristics of the waves emerging the Riemann step. Analysis on Riemann problems of this nature shows us that the composition-enthalpy waves can be represented by self-similar solutions. The eigenvalues of the composition-enthalpy system represent the characteristic wave propagation speeds of the compositions and enthalpy through the domain. Furthermore, the corresponding eigenvectors are the directions of variation, or ``pathways," in concentration-enthalpy space that the characteristic waves follow. In the two-component system, the Riemann problem yields two waves connected by an intermediate concentration-enthalpy state determined by the intersections of the integral curves of the eigenvectors emanating from both the initial and boundary states. The first wave, ``slow path," and second wave, ``fast path," follow the aformentioned pathways set by the eigenvectors. The slow path wave has a zero eigenvalue, corresponding to a wave speed of zero, which preserves a residual imprint of the initial condition. Freezing fronts textemdash those that result in a negative change in porositytextemdash feature fast path waves that travel as shocks, whereas the fast path waves of melting fronts travel as spreading, rarefaction waves.

The Blood Exposome and Its Role in Discovering Causes of Disease

PubMed Central

Barupal, Dinesh K.; Wishart, David; Vineis, Paolo; Scalbert, Augustin

2014-01-01

Background: Since 2001, researchers have examined the human genome (G) mainly to discover causes of disease, despite evidence that G explains relatively little risk. We posit that unexplained disease risks are caused by the exposome (E; representing all exposures) and G × E interactions. Thus, etiologic research has been hampered by scientists’ continuing reliance on low-tech methods to characterize E compared with high-tech omics for characterizing G. Objectives: Because exposures are inherently chemical in nature and arise from both endogenous and exogenous sources, blood specimens can be used to characterize exposomes. To explore the “blood exposome” and its connection to disease, we sought human blood concentrations of many chemicals, along with their sources, evidence of chronic-disease risks, and numbers of metabolic pathways. Methods: From the literature we obtained human blood concentrations of 1,561 small molecules and metals derived from foods, drugs, pollutants, and endogenous processes. We mapped chemical similarities after weighting by blood concentrations, disease-risk citations, and numbers of human metabolic pathways. Results: Blood concentrations spanned 11 orders of magnitude and were indistinguishable for endogenous and food chemicals and drugs, whereas those of pollutants were 1,000 times lower. Chemical similarities mapped by disease risks were equally distributed by source categories, but those mapped by metabolic pathways were dominated by endogenous molecules and essential nutrients. Conclusions: For studies of disease etiology, the complexity of human exposures motivates characterization of the blood exposome, which includes all biologically active chemicals. Because most small molecules in blood are not human metabolites, investigations of causal pathways should expand beyond the endogenous metabolome. Citation: Rappaport SM, Barupal DK, Wishart D, Vineis P, Scalbert A. 2014. The blood exposome and its role in discovering causes of disease. Environ Health Perspect 122:769–774; http://dx.doi.org/10.1289/ehp.1308015 PMID:24659601

Combinations of physiologic estrogens with xenoestrogens alter calcium and kinase responses, prolactin release, and membrane estrogen receptor trafficking in rat pituitary cells

PubMed Central

2010-01-01

Background Xenoestrogens such as alkylphenols and the structurally related plastic byproduct bisphenol A have recently been shown to act potently via nongenomic signaling pathways and the membrane version of estrogen receptor-α. Though the responses to these compounds are typically measured individually, they usually contaminate organisms that already have endogenous estrogens present. Therefore, we used quantitative medium-throughput screening assays to measure the effects of physiologic estrogens in combination with these xenoestrogens. Methods We studied the effects of low concentrations of endogenous estrogens (estradiol, estriol, and estrone) at 10 pM (representing pre-development levels), and 1 nM (representing higher cycle-dependent and pregnancy levels) in combinations with the same levels of xenoestrogens in GH3/B6/F10 pituitary cells. These levels of xenoestrogens represent extremely low contamination levels. We monitored calcium entry into cells using Fura-2 fluorescence imaging of single cells. Prolactin release was measured by radio-immunoassay. Extracellular-regulated kinase (1 and 2) phospho-activations and the levels of three estrogen receptors in the cell membrane (ERα, ERβ, and GPER) were measured using a quantitative plate immunoassay of fixed cells either permeabilized or nonpermeabilized (respectively). Results All xenoestrogens caused responses at these concentrations, and had disruptive effects on the actions of physiologic estrogens. Xenoestrogens reduced the % of cells that responded to estradiol via calcium channel opening. They also inhibited the activation (phosphorylation) of extracellular-regulated kinases at some concentrations. They either inhibited or enhanced rapid prolactin release, depending upon concentration. These latter two dose-responses were nonmonotonic, a characteristic of nongenomic estrogenic responses. Conclusions Responses mediated by endogenous estrogens representing different life stages are vulnerable to very low concentrations of these structurally related xenoestrogens. Because of their non-classical dose-responses, they must be studied in detail to pinpoint effective concentrations and the directions of response changes. PMID:20950447

Identification of differential pathways in papillary thyroid carcinoma utilizing pathway co-expression analysis.

PubMed

Qiu, Wei-Hai; Chen, Gui-Yan; Cui, Lu; Zhang, Ting-Ming; Wei, Feng; Yang, Yong

2016-01-01

To identify differential pathways between papillary thyroid carcinoma (PTC) patients and normal controls utilizing a novel method which combined pathway with co-expression network. The proposed method included three steps. In the first step, we conducted pretreatments for background pathways and gained representative pathways in PTC. Subsequently, a co-expression network for representative pathways was constructed using empirical Bayes (EB) approach to assign a weight value for each pathway. Finally, random model was extracted to set the thresholds of identifying differential pathways. We obtained 1267 representative pathways and their weight values based on the co-expressed pathway network, and then by meeting the criterion (Weight > 0.0296), 87 differential pathways in total across PTC patients and normal controls were identified. The top three ranked differential pathways were CREB phosphorylation, attachment of GPI anchor to urokinase plasminogen activator receptor (uPAR) and loss of function of SMAD2/3 in cancer. In conclusion, we successfully identified differential pathways (such as CREB phosphorylation, attachment of GPI anchor to uPAR and post-translational modification: synthesis of GPI-anchored proteins) for PTC using the proposed pathway co-expression method, and these pathways might be potential biomarkers for target therapy and detection of PTC.

Flexible parameter-sparse global temperature time profiles that stabilise at 1.5 and 2.0 °C

NASA Astrophysics Data System (ADS)

Huntingford, Chris; Yang, Hui; Harper, Anna; Cox, Peter M.; Gedney, Nicola; Burke, Eleanor J.; Lowe, Jason A.; Hayman, Garry; Collins, William J.; Smith, Stephen M.; Comyn-Platt, Edward

2017-07-01

The meeting of the United Nations Framework Convention on Climate Change (UNFCCC) in December 2015 committed parties at the convention to hold the rise in global average temperature to well below 2.0 °C above pre-industrial levels. It also committed the parties to pursue efforts to limit warming to 1.5 °C. This leads to two key questions. First, what extent of emissions reduction will achieve either target? Second, what is the benefit of the reduced climate impacts from keeping warming at or below 1.5 °C? To provide answers, climate model simulations need to follow trajectories consistent with these global temperature limits. It is useful to operate models in an inverse mode to make model-specific estimates of greenhouse gas (GHG) concentration pathways consistent with the prescribed temperature profiles. Further inversion derives related emissions pathways for these concentrations. For this to happen, and to enable climate research centres to compare GHG concentrations and emissions estimates, common temperature trajectory scenarios are required. Here we define algebraic curves that asymptote to a stabilised limit, while also matching the magnitude and gradient of recent warming levels. The curves are deliberately parameter-sparse, needing the prescription of just two parameters plus the final temperature. Yet despite this simplicity, they can allow for temperature overshoot and for generational changes, for which more effort to decelerate warming change needs to be made by future generations. The curves capture temperature profiles from the existing Representative Concentration Pathway (RCP2.6) scenario projections by a range of different Earth system models (ESMs), which have warming amounts towards the lower levels of those that society is discussing.

Bacillus thuringiensis Crystal Protein Cry6Aa Triggers Caenorhabditis elegans Necrosis Pathway Mediated by Aspartic Protease (ASP-1)

PubMed Central

Zhang, Fengjuan; Peng, Donghai; Cheng, Chunsheng; Zhou, Wei; Ju, Shouyong; Wan, Danfeng; Yu, Ziquan; Shi, Jianwei; Deng, Yaoyao; Wang, Fenshan; Ye, Xiaobo; Hu, Zhenfei; Lin, Jian; Ruan, Lifang; Sun, Ming

2016-01-01

Cell death plays an important role in host-pathogen interactions. Crystal proteins (toxins) are essential components of Bacillus thuringiensis (Bt) biological pesticides because of their specific toxicity against insects and nematodes. However, the mode of action by which crystal toxins to induce cell death is not completely understood. Here we show that crystal toxin triggers cell death by necrosis signaling pathway using crystal toxin Cry6Aa-Caenorhabditis elegans toxin-host interaction system, which involves an increase in concentrations of cytoplasmic calcium, lysosomal lyses, uptake of propidium iodide, and burst of death fluorescence. We find that a deficiency in the necrosis pathway confers tolerance to Cry6Aa toxin. Intriguingly, the necrosis pathway is specifically triggered by Cry6Aa, not by Cry5Ba, whose amino acid sequence is different from that of Cry6Aa. Furthermore, Cry6Aa-induced necrosis pathway requires aspartic protease (ASP-1). In addition, ASP-1 protects Cry6Aa from over-degradation in C. elegans. This is the first demonstration that deficiency in necrosis pathway confers tolerance to Bt crystal protein, and that Cry6A triggers necrosis represents a newly added necrosis paradigm in the C. elegans. Understanding this model could lead to new strategies for nematode control. PMID:26795495

Carbon residence time dominates uncertainty in terrestrial vegetation responses to future climate and atmospheric CO2.

PubMed

Friend, Andrew D; Lucht, Wolfgang; Rademacher, Tim T; Keribin, Rozenn; Betts, Richard; Cadule, Patricia; Ciais, Philippe; Clark, Douglas B; Dankers, Rutger; Falloon, Pete D; Ito, Akihiko; Kahana, Ron; Kleidon, Axel; Lomas, Mark R; Nishina, Kazuya; Ostberg, Sebastian; Pavlick, Ryan; Peylin, Philippe; Schaphoff, Sibyll; Vuichard, Nicolas; Warszawski, Lila; Wiltshire, Andy; Woodward, F Ian

2014-03-04

Future climate change and increasing atmospheric CO2 are expected to cause major changes in vegetation structure and function over large fractions of the global land surface. Seven global vegetation models are used to analyze possible responses to future climate simulated by a range of general circulation models run under all four representative concentration pathway scenarios of changing concentrations of greenhouse gases. All 110 simulations predict an increase in global vegetation carbon to 2100, but with substantial variation between vegetation models. For example, at 4 °C of global land surface warming (510-758 ppm of CO2), vegetation carbon increases by 52-477 Pg C (224 Pg C mean), mainly due to CO2 fertilization of photosynthesis. Simulations agree on large regional increases across much of the boreal forest, western Amazonia, central Africa, western China, and southeast Asia, with reductions across southwestern North America, central South America, southern Mediterranean areas, southwestern Africa, and southwestern Australia. Four vegetation models display discontinuities across 4 °C of warming, indicating global thresholds in the balance of positive and negative influences on productivity and biomass. In contrast to previous global vegetation model studies, we emphasize the importance of uncertainties in projected changes in carbon residence times. We find, when all seven models are considered for one representative concentration pathway × general circulation model combination, such uncertainties explain 30% more variation in modeled vegetation carbon change than responses of net primary productivity alone, increasing to 151% for non-HYBRID4 models. A change in research priorities away from production and toward structural dynamics and demographic processes is recommended.

Contribution of various carbon sources toward isoprene biosynthesis in poplar leaves mediated by altered atmospheric CO2 concentrations.

PubMed

Trowbridge, Amy M; Asensio, Dolores; Eller, Allyson S D; Way, Danielle A; Wilkinson, Michael J; Schnitzler, Jörg-Peter; Jackson, Robert B; Monson, Russell K

2012-01-01

Biogenically released isoprene plays important roles in both tropospheric photochemistry and plant metabolism. We performed a (13)CO(2)-labeling study using proton-transfer-reaction mass spectrometry (PTR-MS) to examine the kinetics of recently assimilated photosynthate into isoprene emitted from poplar (Populus × canescens) trees grown and measured at different atmospheric CO(2) concentrations. This is the first study to explicitly consider the effects of altered atmospheric CO(2) concentration on carbon partitioning to isoprene biosynthesis. We studied changes in the proportion of labeled carbon as a function of time in two mass fragments, M41(+), which represents, in part, substrate derived from pyruvate, and M69(+), which represents the whole unlabeled isoprene molecule. We observed a trend of slower (13)C incorporation into isoprene carbon derived from pyruvate, consistent with the previously hypothesized origin of chloroplastic pyruvate from cytosolic phosphenolpyruvate (PEP). Trees grown under sub-ambient CO(2) (190 ppmv) had rates of isoprene emission and rates of labeling of M41(+) and M69(+) that were nearly twice those observed in trees grown under elevated CO(2) (590 ppmv). However, they also demonstrated the lowest proportion of completely labeled isoprene molecules. These results suggest that under reduced atmospheric CO(2) availability, more carbon from stored/older carbon sources is involved in isoprene biosynthesis, and this carbon most likely enters the isoprene biosynthesis pathway through the pyruvate substrate. We offer direct evidence that extra-chloroplastic rather than chloroplastic carbon sources are mobilized to increase the availability of pyruvate required to up-regulate the isoprene biosynthesis pathway when trees are grown under sub-ambient CO(2).

Contribution of Various Carbon Sources Toward Isoprene Biosynthesis in Poplar Leaves Mediated by Altered Atmospheric CO2 Concentrations

PubMed Central

Trowbridge, Amy M.; Asensio, Dolores; Eller, Allyson S. D.; Way, Danielle A.; Wilkinson, Michael J.; Schnitzler, Jörg-Peter; Jackson, Robert B.; Monson, Russell K.

2012-01-01

Biogenically released isoprene plays important roles in both tropospheric photochemistry and plant metabolism. We performed a 13CO2-labeling study using proton-transfer-reaction mass spectrometry (PTR-MS) to examine the kinetics of recently assimilated photosynthate into isoprene emitted from poplar (Populus × canescens) trees grown and measured at different atmospheric CO2 concentrations. This is the first study to explicitly consider the effects of altered atmospheric CO2 concentration on carbon partitioning to isoprene biosynthesis. We studied changes in the proportion of labeled carbon as a function of time in two mass fragments, M41+, which represents, in part, substrate derived from pyruvate, and M69+, which represents the whole unlabeled isoprene molecule. We observed a trend of slower 13C incorporation into isoprene carbon derived from pyruvate, consistent with the previously hypothesized origin of chloroplastic pyruvate from cytosolic phosphenolpyruvate (PEP). Trees grown under sub-ambient CO2 (190 ppmv) had rates of isoprene emission and rates of labeling of M41+ and M69+ that were nearly twice those observed in trees grown under elevated CO2 (590 ppmv). However, they also demonstrated the lowest proportion of completely labeled isoprene molecules. These results suggest that under reduced atmospheric CO2 availability, more carbon from stored/older carbon sources is involved in isoprene biosynthesis, and this carbon most likely enters the isoprene biosynthesis pathway through the pyruvate substrate. We offer direct evidence that extra-chloroplastic rather than chloroplastic carbon sources are mobilized to increase the availability of pyruvate required to up-regulate the isoprene biosynthesis pathway when trees are grown under sub-ambient CO2. PMID:22384238

Carbon residence time dominates uncertainty in terrestrial vegetation responses to future climate and atmospheric CO2

PubMed Central

Friend, Andrew D.; Lucht, Wolfgang; Rademacher, Tim T.; Keribin, Rozenn; Betts, Richard; Cadule, Patricia; Ciais, Philippe; Clark, Douglas B.; Dankers, Rutger; Falloon, Pete D.; Ito, Akihiko; Kahana, Ron; Kleidon, Axel; Lomas, Mark R.; Nishina, Kazuya; Ostberg, Sebastian; Pavlick, Ryan; Peylin, Philippe; Schaphoff, Sibyll; Vuichard, Nicolas; Warszawski, Lila; Wiltshire, Andy; Woodward, F. Ian

2014-01-01

Future climate change and increasing atmospheric CO2 are expected to cause major changes in vegetation structure and function over large fractions of the global land surface. Seven global vegetation models are used to analyze possible responses to future climate simulated by a range of general circulation models run under all four representative concentration pathway scenarios of changing concentrations of greenhouse gases. All 110 simulations predict an increase in global vegetation carbon to 2100, but with substantial variation between vegetation models. For example, at 4 °C of global land surface warming (510–758 ppm of CO2), vegetation carbon increases by 52–477 Pg C (224 Pg C mean), mainly due to CO2 fertilization of photosynthesis. Simulations agree on large regional increases across much of the boreal forest, western Amazonia, central Africa, western China, and southeast Asia, with reductions across southwestern North America, central South America, southern Mediterranean areas, southwestern Africa, and southwestern Australia. Four vegetation models display discontinuities across 4 °C of warming, indicating global thresholds in the balance of positive and negative influences on productivity and biomass. In contrast to previous global vegetation model studies, we emphasize the importance of uncertainties in projected changes in carbon residence times. We find, when all seven models are considered for one representative concentration pathway × general circulation model combination, such uncertainties explain 30% more variation in modeled vegetation carbon change than responses of net primary productivity alone, increasing to 151% for non-HYBRID4 models. A change in research priorities away from production and toward structural dynamics and demographic processes is recommended. PMID:24344265

Estimation of Throughfall and Stemflow Bacterial Flux in a Subtropical Oak-Cedar Forest

NASA Astrophysics Data System (ADS)

Bittar, Thais B.; Pound, Preston; Whitetree, Ansley; Moore, L. Dean; Van Stan, John T.

2018-02-01

Transport pathways of microbes between ecosystem spheres (atmosphere, phyllosphere, and pedosphere) represent major fluxes in nutrient cycles and have the potential to affect microbially mediated biogeochemical processes. Novel data on bacterial fluxes from the phyllosphere to the pedosphere during rainfall via throughfall (rain dripping from/through the canopy) and stemflow (rain funneled down tree stems) are reported. Bacterial concentrations were quantified using flow cytometry and validated with quantitative polymerase chain reaction assays in rainfall samples from an oak-cedar forest in coastal Georgia (southeastern U.S.). Bacteria concentrations (cells mL-1) and storm-normalized fluxes (cells m-2 h-1, cells m-2 mm-1) were greater for cedar versus oak. Total bacterial flux was 1.5 × 1016 cells ha-1 yr-1. These previously unexamined bacterial fluxes are interpreted in the context of major elemental pools and fluxes in forests and could represent inoculum-level sources of bacteria (if alive), and organic matter and inorganic solute inputs (if lysed) to soils.

Meeting the Radiative Forcing Targets of the Representative Concentration Pathways with Agricultural Climate Impacts

NASA Astrophysics Data System (ADS)

Kyle, P.; Müller, C.; Calvin, K. V.; Thomson, A. M.

2013-12-01

The Representative Concentration Pathways (RCPs) have formed the basis for much of the current scientific understanding of future climate change impacts and mitigation. However, the emissions scenarios underlying the RCPs were produced by integrated assessment models that did not include impacts of future climate change on the modeled evolution of the agricultural and energy systems. Given the prominent role of bioenergy in greenhouse gas emissions mitigation, and given the importance of land-use-related emissions in determining future atmospheric CO2 concentrations, it is possible that agricultural climate impacts may cause significant changes to the means and costs of mitigating greenhouse gas emissions. This study builds on several international modeling exercises aimed at improving understanding of climate change impacts--CMIP-5 and ISI-MIP--that have generated global gridded climate impacts on yields of major agricultural crops in each of the four RCPs. We use the climate outcomes from the HadGEM2-ES climate model, and the agricultural yield outcomes from the LPJmL crop growth model to inform inputs to the GCAM integrated assessment model, allowing analysis of how agricultural climate impacts may affect the long-term global and regional strategies for achieving the greenhouse gas concentration pathways of the RCPs. Our results indicate that for this combination of models and emissions scenarios, strongly negative climate impacts on several major commodity classes--prominently cereals and oil seeds, and particularly in the high-radiative-forcing RCPs--lead to a long-term increase in cropland and therefore land-use-related CO2 emissions. All else equal, this increases the emissions mitigation burden on the rest of the system, and therefore increases total net costs of emissions mitigation. However, the future climate change impacts on C4 bioenergy crops tend to be positive, limiting the shock of agricultural climate impacts on the modeled energy supply and demand systems. As well, endogenous adaptation in the agricultural sector--mostly through inter-regional shifting in production and changes in trade patterns--limits the shock of climate impacts to consumers. Global average climate impacts on wheat yields for the four emissions scenarios, using base-year weights (asterisks) and using the endogenous land allocations in GCAM (filled diamonds)

Amino Acid Starvation Induced by Protease Inhibition Produces Differential Alterations in Redox Status and the Thiol Proteome in Organogenesis-Stage Rat Embryos and Visceral Yolk Sacs

PubMed Central

Harris, Craig; Jilek, Joseph L.; Sant, Karilyn E.; Pohl, Jan; Reed, Matthew; Hansen, Jason M.

2015-01-01

The process of embryonic nutrition in rodent conceptuses during organogenesis has been shown to involve a dominant histiotrophic mechanism where essential developmental substrates and micronutrients are supplied as whole maternal proteins or cargoes associated with proteins. The histiotrophic nutrition pathways (HNP) responsible for uptake and initial processing of proteins across maternal-conceptal interfaces involve uptake via receptor mediated endocytosis and protein degradation via lysosomal proteolysis. Chemical inhibition of either process can lead to growth deficits and malformation in the embryo (EMB), but selective inhibition of either HNP component will elicit a different subset of developmental perturbations. In vitro, whole embryo culture (WEC) exposure of GD10 or GD11 rat conceptuses to the natural protease inhibitor, leupeptin, leads to significant reductions in all measured embryonic growth parameters as well as a myriad of other effects. Leupeptin doses of 10 μM or 20 μM over a 26 hr period (GD10-GD11) and 50 μM over a 3 hr pulse period produced significant decreases in the clearance of FITC-albumin from culture media. The near complete loss of acid soluble fluorescence and increased total visceral yolk sac (VYS) protein content confirmed the selective inhibition of proteolysis. Inhibition of lysosomal proteolysis thus deprives the developing EMB of essential nutrient amino acids producing conditions akin to amino acid starvation, but may also cause direct effects on pathways critical for normal growth and differentiation. Following leupeptin exposure for 26 or 6 hr, total glutathione (GSH) concentrations dropped significantly in the VYS, but only slightly in yolk sac (YSF) and amniotic (AF) fluids. Cys concentrations increased in VYS and EMB, but dropped in YSF and AF fluids. Redox potentials (Eh) for the GSSG/GSH redox couple trended significantly toward the positive, confirming the net oxidation of conceptual tissues following leupeptin treatment. Analysis of the thiol proteome showed few alterations to specific pathways mapped to the KEGG Pathway database, but did reveal significant increases in concentrations of proteins associated with glycolysis/gluconeogenesis in the VYS and decreased concentrations proteins associated with ribosome biogenesis and function in the EMB. A subset of proteins elevated by >2-23 fold in the VYS were identified as serum (blood) proteins and represent the maternal-side proteins captured by the VYS and which are not degraded in the lysosomes as a result of leupeptin’s inhibitory action. The observed constellation of proteins decreased in the EMB by leupeptin represent proteins from several adaptive pathways that are commonly altered in responses to amino acid starvation. These studies show clear differential responses to protease inhibition in VYS and EMB during organogenesis and suggest the possibility for additional roles of redox regulation, cellular adaptations and metabolic insufficiency caused by protease inhibition. PMID:26365578

Pharmaceuticals in water, fish and osprey nestlings in Delaware River and Bay

USGS Publications Warehouse

Bean, Thomas G.; Rattner, Barnett A.; Lazarus, Rebecca S.; Day, Daniel D.; Burket, S. Rebekah; Brooks, Bryan W.; Haddad, Samuel P.; Bowerman, William W.

2018-01-01

Exposure of wildlife to Active Pharmaceutical Ingredients (APIs) is likely to occur but studies of risk are limited. One exposure pathway that has received attention is trophic transfer of APIs in a water-fish-osprey food chain. Samples of water, fish plasma and osprey plasma were collected from Delaware River and Bay, and analyzed for 21 APIs. Only 2 of 21 analytes exceeded method detection limits in osprey plasma (acetaminophen and diclofenac) with plasma levels typically 2–3 orders of magnitude below human therapeutic concentrations (HTC). We built upon a screening level model used to predict osprey exposure to APIs in Chesapeake Bay and evaluated whether exposure levels could have been predicted in Delaware Bay had we just measured concentrations in water or fish. Use of surface water and BCFs did not predict API concentrations in fish well, likely due to fish movement patterns, and partitioning and bioaccumulation uncertainties associated with these ionizable chemicals. Input of highest measured API concentration in fish plasma combined with pharmacokinetic data accurately predicted that diclofenac and acetaminophen would be the APIs most likely detected in osprey plasma. For the majority of APIs modeled, levels were not predicted to exceed 1 ng/mL or method detection limits in osprey plasma. Based on the target analytes examined, there is little evidence that APIs represent a significant risk to ospreys nesting in Delaware Bay. If an API is present in fish orders of magnitude below HTC, sampling of fish-eating birds is unlikely to be necessary. However, several human pharmaceuticals accumulated in fish plasma within a recommended safety factor for HTC. It is now important to expand the scope of diet-based API exposure modeling to include alternative exposure pathways (e.g., uptake from landfills, dumps and wastewater treatment plants) and geographic locations (developing countries) where API contamination of the environment may represent greater risk.

Dihydroartemisinin inhibits the mammalian target of rapamycin-mediated signaling pathways in tumor cells

PubMed Central

Huang, Shile

2014-01-01

Dihydroartemisinin (DHA), an antimalarial drug, has previously unrecognized anticancer activity, and is in clinical trials as a new anticancer agent for skin, lung, colon and breast cancer treatment. However, the anticancer mechanism is not well understood. Here, we show that DHA inhibited proliferation and induced apoptosis in rhabdomyosarcoma (Rh30 and RD) cells, and concurrently inhibited the signaling pathways mediated by the mammalian target of rapamycin (mTOR), a central controller for cell proliferation and survival, at concentrations (<3 μM) that are pharmacologically achievable. Of interest, in contrast to the effects of conventional mTOR inhibitors (rapalogs), DHA potently inhibited mTORC1-mediated phosphorylation of p70 S6 kinase 1 and eukaryotic initiation factor 4E binding protein 1 but did not obviously affect mTORC2-mediated phosphorylation of Akt. The results suggest that DHA may represent a novel class of mTORC1 inhibitor and may execute its anticancer activity primarily by blocking mTORC1-mediated signaling pathways in the tumor cells. PMID:23929438

Air pathway effects of nuclear materials production at the Hanford Site, 1983 to 1992

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

Patton, G.W.; Cooper, A.T.

1993-10-01

This report describes the air pathway effects of Hanford Site operations from 1983 to 1992 on the local environment by summarizing the air concentrations of selected radionuclides at both onsite and offsite locations, comparing trends in environment concentrations to changing facility emissions, and briefly describing trends in the radiological dose to the hypothetical maximally exposed member of the public. The years 1983 to 1992 represent the last Hanford Site plutonium production campaign, and this report deals mainly with the air pathway effects from the 200 Areas, in which the major contributors to radiological emissions were located. An additional purpose formore » report was to review the environmental data for a long period of time to provide insight not available in an annual report format. The sampling and analytical systems used by the Surface Environmental Surveillance Project (SESP) to collect air samples during the period of this report were sufficiently sensitive to observe locally elevated concentrations of selected radionuclides near onsite source of emission as well as observing elevated levels, compared to distant locations, of some radionuclides at the down wind perimeter. The US DOE Derived Concentration Guides (DCGs) for airborne radionuclides were not exceeded for any air sample collected during 1983 to 1992, with annual average concentrations of all radionuclides at the downwind perimeter being considerably below the DCG values. Air emissions at the Hanford Site during the period of this report were dominated by releases from the PUREX Plant, with {sup 85}Kr being the major release on a curie basis and {sup 129}I being the major release on a radiological dose basis. The estimated potential radiological dose from Hanford Site point source emissions to the hypothetical maximally exposed individual (MEI) ranged from 0. 02 to 0.22 mrem/yr (effective dose equivalent), which is well below the DOE radiation limit to the public of 100 mrem/yr.« less

Evaluating officially reported polycyclic aromatic hydrocarbon emissions in the Athabasca oil sands region with a multimedia fate model.

PubMed

Parajulee, Abha; Wania, Frank

2014-03-04

Emissions of organic substances with potential toxicity to humans and the environment are a major concern surrounding the rapid industrial development in the Athabasca oil sands region (AOSR). Although concentrations of polycyclic aromatic hydrocarbons (PAHs) in some environmental samples have been reported, a comprehensive picture of organic contaminant sources, pathways, and sinks within the AOSR has yet to be elucidated. We sought to use a dynamic multimedia environmental fate model to reconcile the emissions and residue levels reported for three representative PAHs in the AOSR. Data describing emissions to air compiled from two official sources result in simulated concentrations in air, soil, water, and foliage that tend to fall close to or below the minimum measured concentrations of phenanthrene, pyrene, and benzo(a)pyrene in the environment. Accounting for evaporative emissions (e.g., from tailings pond disposal) provides a more realistic representation of PAH distribution in the AOSR. Such indirect emissions to air were found to be a greater contributor of PAHs to the AOSR atmosphere relative to reported direct emissions to air. The indirect pathway transporting uncontrolled releases of PAHs to aquatic systems via the atmosphere may be as significant a contributor of PAHs to aquatic systems as other supply pathways. Emission density estimates for the three PAHs that account for tailings pond disposal are much closer to estimated global averages than estimates based on the available emissions datasets, which fall close to the global minima. Our results highlight the need for improved accounting of PAH emissions from oil sands operations, especially in light of continued expansion of these operations.

Novel Pathways for Injury from Offshore Oil Spills: Direct, Sublethal and Indirect Effects of the Deepwater Horizon Oil Spill on Pelagic Sargassum Communities

PubMed Central

Powers, Sean P.; Hernandez, Frank J.; Condon, Robert H.; Drymon, J. Marcus; Free, Christopher M.

2013-01-01

The pelagic brown alga Sargassum forms an oasis of biodiversity and productivity in an otherwise featureless ocean surface. The vast pool of oil resulting from the Deepwater Horizon oil spill came into contact with a large portion of the Gulf of Mexico’s floating Sargassum mats. Aerial surveys performed during and after the oil spill show compelling evidence of loss and subsequent recovery of Sargassum. Expanding on the trends observed in the aerial surveys, we conducted a series of mesocosm experiments to test the effect of oil and dispersants on the vertical position and weight of the Sargassum complex (Sargassum natans and S. fluitans), as well as on the dissolved oxygen concentrations surrounding the algae. Dispersant and dispersed-oil had significant effects on the vertical position of both species of Sargassum over a period of 72 hours. Similarly, dissolved oxygen concentrations were lowest in dispersant and dispersed-oil treatments, respectively. Cumulatively, our findings suggest three pathways for oil-spill related injury: (1) Sargassum accumulated oil on the surface exposing animals to high concentrations of contaminants; (2) application of dispersant sank Sargassum, thus removing the habitat and potentially transporting oil and dispersant vertically; and (3) low oxygen surrounded the habitat potentially stressing animals that reside in the alga. These pathways represent direct, sublethal, and indirect effects of oil and dispersant release that minimize the ecosystem services provided by floating Sargassum – the latter two effects are rarely considered in assessing impacts of oil spills or response procedures. PMID:24086378

Novel pathways for injury from offshore oil spills: direct, sublethal and indirect effects of the Deepwater Horizon oil spill on pelagic Sargassum communities.

PubMed

Powers, Sean P; Hernandez, Frank J; Condon, Robert H; Drymon, J Marcus; Free, Christopher M

2013-01-01

The pelagic brown alga Sargassum forms an oasis of biodiversity and productivity in an otherwise featureless ocean surface. The vast pool of oil resulting from the Deepwater Horizon oil spill came into contact with a large portion of the Gulf of Mexico's floating Sargassum mats. Aerial surveys performed during and after the oil spill show compelling evidence of loss and subsequent recovery of Sargassum. Expanding on the trends observed in the aerial surveys, we conducted a series of mesocosm experiments to test the effect of oil and dispersants on the vertical position and weight of the Sargassum complex (Sargassum natans and S. fluitans), as well as on the dissolved oxygen concentrations surrounding the algae. Dispersant and dispersed-oil had significant effects on the vertical position of both species of Sargassum over a period of 72 hours. Similarly, dissolved oxygen concentrations were lowest in dispersant and dispersed-oil treatments, respectively. Cumulatively, our findings suggest three pathways for oil-spill related injury: (1) Sargassum accumulated oil on the surface exposing animals to high concentrations of contaminants; (2) application of dispersant sank Sargassum, thus removing the habitat and potentially transporting oil and dispersant vertically; and (3) low oxygen surrounded the habitat potentially stressing animals that reside in the alga. These pathways represent direct, sublethal, and indirect effects of oil and dispersant release that minimize the ecosystem services provided by floating Sargassum - the latter two effects are rarely considered in assessing impacts of oil spills or response procedures.

Reversal of Increasing Tropical Ocean Hypoxia Trends With Sustained Climate Warming

NASA Astrophysics Data System (ADS)

Fu, Weiwei; Primeau, Francois; Keith Moore, J.; Lindsay, Keith; Randerson, James T.

2018-04-01

Dissolved oxygen (O2) is essential for the survival of marine animals. Climate change impacts on future oxygen distributions could modify species biogeography, trophic interactions, biodiversity, and biogeochemistry. The Coupled Model Intercomparison Project Phase 5 models predict a decreasing trend in marine O2 over the 21st century. Here we show that this increasing hypoxia trend reverses in the tropics after 2100 in the Community Earth System Model forced by atmospheric CO2 from the Representative Concentration Pathway 8.5 and Extended Concentration Pathway 8.5. In tropical intermediate waters between 200 and 1,000 m, the model predicts a steady decline of O2 and an expansion of oxygen minimum zones (OMZs) during the 21st century. By 2150, however, the trend reverses with oxygen concentration increasing and OMZ volume shrinking through 2300. A novel five-box model approach in conjunction with output from the full Earth system model is used to separate the contributions of biological and physical processes to the trends in tropical oxygen. The tropical O2 recovery is caused mainly by reductions in tropical biological export, coupled with a modest increase in ventilation after 2200. The time-evolving oxygen distribution impacts marine nitrogen cycling, with potentially important climate feedbacks.

Leaching of dissolved phosphorus from tile-drained agricultural areas.

PubMed

Andersen, H E; Windolf, J; Kronvang, B

2016-01-01

We investigated leaching of dissolved phosphorus (P) from 45 tile-drains representing animal husbandry farms in all regions of Denmark. Leaching of P via tile-drains exhibits a high degree of spatial heterogeneity with a low concentration in the majority of tile-drains and few tile-drains (15% in our investigation) having high to very high concentration of dissolved P. The share of dissolved organic P (DOP) was high (up to 96%). Leaching of DOP has hitherto been a somewhat overlooked P loss pathway in Danish soils and the mechanisms of mobilization and transport of DOP needs more investigation. We found a high correlation between Olsen-P and water extractable P. Water extractable P is regarded as an indicator of risk of loss of dissolved P. Our findings indicate that Olsen-P, which is measured routinely in Danish agricultural soils, may be a useful proxy for the P leaching potential of soils. However, we found no straight-forward correlation between leaching potential of the top soil layer (expressed as either degree of P saturation, Olsen-P or water extractable P) and the measured concentration of dissolved P in the tile-drain. This underlines that not only the source of P but also the P loss pathway must be taken into account when evaluating the risk of P loss.

Precise metabolic engineering of carotenoid biosynthesis in Escherichia coli towards a low-cost biosensor.

PubMed

Watstein, Daniel M; McNerney, Monica P; Styczynski, Mark P

2015-09-01

Micronutrient deficiencies, including zinc deficiency, are responsible for hundreds of thousands of deaths annually. A key obstacle to allocating scarce treatment resources is the ability to measure population blood micronutrient status inexpensively and quickly enough to identify those who most need treatment. This paper develops a metabolically engineered strain of Escherichia coli to produce different colored pigments (violacein, lycopene, and β-carotene) in response to different extracellular zinc levels, for eventual use in an inexpensive blood zinc diagnostic test. However, obtaining discrete color states in the carotenoid pathway required precise engineering of metabolism to prevent reaction at low zinc concentrations but allow complete reaction at higher concentrations, and all under the constraints of natural regulator limitations. Hence, the metabolic engineering challenge was not to improve titer, but to enable precise control of pathway state. A combination of gene dosage, post-transcriptional, and post-translational regulation was necessary to allow visible color change over physiologically relevant ranges representing a small fraction of the regulator's dynamic response range, with further tuning possible by modulation of precursor availability. As metabolic engineering expands its applications and develops more complex systems, tight control of system components will likely become increasingly necessary, and the approach presented here can be generalized to other natural sensing systems for precise control of pathway state. Copyright © 2015 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Scholarly Concentration Program Development: A Generalizable, Data-Driven Approach.

PubMed

Burk-Rafel, Jesse; Mullan, Patricia B; Wagenschutz, Heather; Pulst-Korenberg, Alexandra; Skye, Eric; Davis, Matthew M

2016-11-01

Scholarly concentration programs-also known as scholarly projects, pathways, tracks, or pursuits-are increasingly common in U.S. medical schools. However, systematic, data-driven program development methods have not been described. The authors examined scholarly concentration programs at U.S. medical schools that U.S. News & World Report ranked as top 25 for research or primary care (n = 43 institutions), coding concentrations and mission statements. Subsequently, the authors conducted a targeted needs assessment via a student-led, institution-wide survey, eliciting learners' preferences for 10 "Pathways" (i.e., concentrations) and 30 "Topics" (i.e., potential content) augmenting core curricula at their institution. Exploratory factor analysis (EFA) and a capacity optimization algorithm characterized best institutional options for learner-focused Pathway development. The authors identified scholarly concentration programs at 32 of 43 medical schools (74%), comprising 199 distinct concentrations (mean concentrations per program: 6.2, mode: 5, range: 1-16). Thematic analysis identified 10 content domains; most common were "Global/Public Health" (30 institutions; 94%) and "Clinical/Translational Research" (26 institutions; 81%). The institutional needs assessment (n = 468 medical students; response rate 60% overall, 97% among first-year students) demonstrated myriad student preferences for Pathways and Topics. EFA of Topic preferences identified eight factors, systematically related to Pathway preferences, informing content development. Capacity modeling indicated that offering six Pathways could guarantee 95% of first-year students (162/171) their first- or second-choice Pathway. This study demonstrates a generalizable, data-driven approach to scholarly concentration program development that reflects student preferences and institutional strengths, while optimizing program diversity within capacity constraints.

Leachate pre-treatment strategies before recirculation in landfill bioreactors.

PubMed

Vigneron, V; Bouchez, T; Bureau, C; Mailly, N; Mazeas, L; Duquennoi, C; Audic, J M; Hébé, L; Bernet, N

2005-01-01

Nitrified leachate recirculation represents a promising strategy for a more sustainable landfill management. Our objective was to determine the reactions involved in nitrate reduction in municipal solid waste batch biodegradation tests. Anaerobic digestion of waste in the three control reactors showed a good reproducibility. In two test reactors, nitrate was added at various moments of the waste degradation process. We observed that: (1) H2S concentration controlled the nitrate reduction pathway: above a certain threshold of H2S, dissimilatory nitrate reduction to ammonium (DNRA) replaced denitrification. (2) N2O/N2 ratio varied with the organic carbon concentration: the lower the easily biodegradable carbon concentration, the higher the N2O/N2 ratio. (3) N2 was consumed after denitrification. The possibility of a nitrogen fixation reaction in the presence of NH4 is discussed. Nitrified leachate recirculation during acidogenesis should be avoided because of higher H2S production which could induce DNRA.

TiO2 used as photocatalyst for rhodamine B degradation under solar radiation

NASA Astrophysics Data System (ADS)

Ariyanti, Dessy; Maillot, Mathilde; Gao, Wei

2017-07-01

Transition metal oxide photocatalysis is a relatively new method representing advanced oxidation process to be applied in industrial wastewater treatment especially for degradation of organic pollutants. We investigate TiO2 as a photocatalyst for the photocatalytic degradation of Rhodamine B (RhB) under simulated sunlight. Various parameters and their effectiveness have been studied. The effects of processing parameters including catalyst loading and feed concentration were investigated; and the degradation pathway was proposed based on the UHPLC-MS analysis. The result showed that a higher kinetic rate can be obtained by employing low catalyst loading and feed concentration, i.e., 0.5 g/L of TiO2 loading and 5 ppm of RhB concentration, respectively. For this particular system, the optimum degradation rate (k) can achieve 0.297/min. The effectiveness of solar light-TiO2 system for RhB degradation shows this method can be used for wastewater treatment.

Future Water Scarcity and Potential Effects on Food Production under Climate Change in the Yellow River Basin

NASA Astrophysics Data System (ADS)

Tang, Q.; Yin, Y. Y.; Liu, X.; Zhang, X.

2016-12-01

Increasing population and socio-economic development have put great pressure on water resources of the Yellow River Basin. The anticipated climate and socio-economic changes may further increase water stress. In this study, we assess water scarcity under climate change and various socio-economic pathways with an emphasis on the impact of water shortages on food production. The water demands in the 21st century are projected under the new developed Shared Socio-economic Pathways (SSPs). The renewable water supply is estimated from the climate projections under the Representative Concentration Pathways (RCP) 8.5. The agricultural water use is assumed to have the lowest priority of all water consumers when water shortage occurs. The results show that the water demands in domestic and industrial sectors would grow rapidly. As more water resources would be occupied by domestic and industrial sectors, a portion of irrigated land would have to be converted to rain-fed agriculture which would lead to more than a reduction in food production under various socio-economic pathways. This study highlights the links between water, food and ecosystems in a changing environment and suggests that trade-offs should be considered when developing regional adaptation strategies.

Anti-inflammatory salicylate treatment alters the metabolic adaptations to lactation in dairy cattle

PubMed Central

Farney, Jaymelynn K.; Mamedova, Laman K.; Coetzee, Johann F.; KuKanich, Butch; Sordillo, Lorraine M.; Stoakes, Sara K.; Minton, J. Ernest; Hollis, Larry C.

2013-01-01

Adapting to the lactating state requires metabolic adjustments in multiple tissues, especially in the dairy cow, which must meet glucose demands that can exceed 5 kg/day in the face of negligible gastrointestinal glucose absorption. These challenges are met through the process of homeorhesis, the alteration of metabolic setpoints to adapt to a shift in physiological state. To investigate the role of inflammation-associated pathways in these homeorhetic adaptations, we treated cows with the nonsteroidal anti-inflammatory drug sodium salicylate (SS) for the first 7 days of lactation. Administration of SS decreased liver TNF-α mRNA and marginally decreased plasma TNF-α concentration, but plasma eicosanoids and liver NF-κB activity were unaltered during treatment. Despite the mild impact on these inflammatory markers, SS clearly altered metabolic function. Plasma glucose concentration was decreased by SS, but this was not explained by a shift in hepatic gluconeogenic gene expression or by altered milk lactose secretion. Insulin concentrations decreased in SS-treated cows on day 7 compared with controls, which was consistent with the decline in plasma glucose concentration. The revised quantitative insulin sensitivity check index (RQUICKI) was then used to assess whether altered insulin sensitivity may have influenced glucose utilization rate with SS. The RQUICKI estimate of insulin sensitivity was significantly elevated by SS on day 7, coincident with the decline in plasma glucose concentration. Salicylate prevented postpartum insulin resistance, likely causing excessive glucose utilization in peripheral tissues and hypoglycemia. These results represent the first evidence that inflammation-associated pathways are involved in homeorhetic adaptations to lactation. PMID:23678026

The Development of Molybdenum Speciation as a Paleoredox Tool

NASA Astrophysics Data System (ADS)

Rodley, J.; Peacock, C.; Mosselmans, J. F. W.; Poulton, S.

2017-12-01

The redox state of the oceans has changed throughout geological time and an understanding of these changes is essential to elucidate links between ocean chemistry, climate and life. Due to its abundance in seawater and redox-sensitive nature, molybdenum has enormous potential as a paleoredox proxy. Although a significant amount of research has been done on molybdenum in ancient and modern sediments in terms of its concentrations and isotopic ratios there remains a limited understanding of the drawdown mechanisms of molybdenum under different redox conditions restricting its use in identifying a range of redox states. In order to address these uncertainties, we have developed a novel sequential extraction technique to examine molybdenum concentrations in six sediment fractions from modern samples that represent oxic, nitrogenous, ferruginous and euxinic environments. In addition we use µ-XRF and µ-XANES synchrotron spectroscopy to examine the molybdenum speciation within these fractions and environments. To interpret our µ-XANES data we have developed an extensive library of molybdenum XANES standards that represent molybdenum sequestration by the sediment fractions identified from the sequential extraction. To further verify our synchrotron results we developed a series of µ-XANES micro-column experiments to examine preferential uptake pathways of molybdenum to different sediment phases under a euxinic water column. The initial data from both the sequential extraction and µ-XANES methods indicate that molybdenum is not limited to a single burial pathway in any of the redox environments. We find that each of the redox environments can be characterised by a limited set of molybdenum phase associations, with molybdenum adsorption to pyrite likely the dominant burial pathway. These findings agree with existing research for molybdenum speciation in euxinic environments suggesting that both pyrite and sulphidised organic matter act as important molybdenum sinks. Our new research shows that pyrite is also an important sink for molybdenum in other redox environments.

Engineering Bacteria to Search for Specific Concentrations of Molecules by a Systematic Synthetic Biology Design Method

PubMed Central

Chen, Bor-Sen

2016-01-01

Bacteria navigate environments full of various chemicals to seek favorable places for survival by controlling the flagella’s rotation using a complicated signal transduction pathway. By influencing the pathway, bacteria can be engineered to search for specific molecules, which has great potential for application to biomedicine and bioremediation. In this study, genetic circuits were constructed to make bacteria search for a specific molecule at particular concentrations in their environment through a synthetic biology method. In addition, by replacing the “brake component” in the synthetic circuit with some specific sensitivities, the bacteria can be engineered to locate areas containing specific concentrations of the molecule. Measured by the swarm assay qualitatively and microfluidic techniques quantitatively, the characteristics of each “brake component” were identified and represented by a mathematical model. Furthermore, we established another mathematical model to anticipate the characteristics of the “brake component”. Based on this model, an abundant component library can be established to provide adequate component selection for different searching conditions without identifying all components individually. Finally, a systematic design procedure was proposed. Following this systematic procedure, one can design a genetic circuit for bacteria to rapidly search for and locate different concentrations of particular molecules by selecting the most adequate “brake component” in the library. Moreover, following simple procedures, one can also establish an exclusive component library suitable for other cultivated environments, promoter systems, or bacterial strains. PMID:27096615

Concentration dependent transcriptome responses of zebrafish embryos after exposure to cadmium, cobalt and copper.

PubMed

Sonnack, Laura; Klawonn, Thorsten; Kriehuber, Ralf; Hollert, Henner; Schäfers, Christoph; Fenske, Martina

2017-12-01

Environmental metals are known to cause harmful effects to fish of which many molecular mechanisms still require elucidation. Particularly concentration dependence of gene expression effects is unclear. Focusing on this matter, zebrafish embryo toxicity tests were used in combination with transcriptomics. Embryos were exposed to three concentrations of copper (CuSO 4 ), cadmium (CdCl 2 ) and cobalt (CoSO 4 ) from just after fertilization until the end of the 48hpf pre- and 96hpf post-hatch stage. The RNA was then analyzed on Agilent's Zebrafish (V3, 4×44K) arrays. Enrichment for GO terms of biological processes illustrated for cadmium that most affected GO terms were represented in all three concentrations, while for cobalt and copper most GO terms were represented in the lowest test concentration only. This suggested a different response to the non-essential cadmium than cobalt and copper. In cobalt and copper treated embryos, many developmental and cellular processes as well as the Wnt and Notch signaling pathways, were found significantly enriched. Also, different exposure concentrations affected varied functional networks. In contrast, the largest clusters of enriched GO terms for all three concentrations of cadmium included responses to cadmium ion, metal ion, xenobiotic stimulus, stress and chemicals. However, concentration dependence of mRNA levels was evident for several genes in all metal exposures. Some of these genes may be indicative of the mechanisms of action of the individual metals in zebrafish embryos. Real-time quantitative RT-PCR (qRT-PCR) verified the microarray data for mmp9, mt2, cldnb and nkx2.2a. Copyright © 2017 Elsevier Inc. All rights reserved.

Concentration dependent switch in the kinetic pathway of lysozyme fibrillation: Spectroscopic and microscopic analysis

NASA Astrophysics Data System (ADS)

Kiran Kumar, E.; Prasad, Deepak Kumar; Prakash Prabhu, N.

2017-08-01

Formation of amyloid fibrils is found to be a general tendency of many proteins. Investigating the kinetic mechanisms and structural features of the intermediates and the final fibrillar state is essential to understand their role in amyloid diseases. Lysozyme, a notable model protein for amyloidogenic studies, readily formed fibrils in vitro at neutral pH in the presence of urea. It, however, showed two different kinetic pathways under varying urea concentrations when probed with thioflavin T (ThT) fluorescence. In 2 M urea, lysozyme followed a nucleation-dependent fibril formation pathway which was not altered by varying the protein concentration from 2 mg/ml to 8 mg/ml. In 4 M urea, the protein exhibited concentration dependent change in the mechanism. At lower protein concentrations, lysozyme formed fibrils without any detectable nuclei (nucleation-independent polymerization pathway). When the concentration of the protein was increased above 3 mg/ml, the protein followed nucleation-dependent polymerization pathway as observed in the case of 2 M urea condition. This was further verified using microscopic images of the fibrils. The kinetic parameters such as lag time, elongation rate, and fibrillation half-time, which were derived from ThT fluorescence changes, showed linear dependency against the initial protein concentration suggested that under the nucleation-dependent pathway conditions, the protein followed primary-nucleation mechanism without any significant secondary nucleation events. The results also suggested that the differences in the initial protein conformation might alter the mechanism of fibrillation; however, at the higher protein concentrations lysozyme shifted to nucleation-dependent pathway.

Potential physiological effects of pharmaceutical compounds in Atlantic salmon (Salmo salar) implied by transcriptomic analysis.

PubMed

Hampel, Miriam; Alonso, Esteban; Aparicio, Irene; Bron, James E; Santos, Juan Luis; Taggart, John B; Leaver, Michael J

2010-05-01

Pharmaceuticals are emerging pollutants widely used in everyday urban activities which can be detected in surface, ground, and drinking waters. Their presence is derived from consumption of medicines, disposal of expired medications, release of treated and untreated urban effluents, and from the pharmaceutical industry. Their growing use has become an alarming environmental problem which potentially will become dangerous in the future. However, there is still a lack of knowledge about long-term effects in non-target organisms as well as for human health. Toxicity testing has indicated a relatively low acute toxicity to fish species, but no information is available on possible sublethal effects. This study provides data on the physiological pathways involved in the exposure of Atlantic salmon as representative test species to three pharmaceutical compounds found in ground, surface, and drinking waters based on the evaluation of the xenobiotic-induced impairment resulting in the activation and silencing of specific genes. Individuals of Atlantic salmon (Salmo salar) parr were exposed during 5 days to environmentally relevant concentrations of three representative pharmaceutical compounds with high consumption rates: the analgesic acetaminophen (54.77+/-34.67 microg L(-1)), the anticonvulsant carbamazepine (7.85+/-0.13 microg L(-1)), and the beta-blocker atenolol (11.08+/-7.98 microg L(-1)). Five immature males were selected for transcriptome analysis in brain tissues by means of a 17k salmon cDNA microarray. For this purpose, mRNA was isolated and reverse-transcribed into cDNA which was labeled with fluorescent dyes and hybridized against a common pool to the arrays. Lists of significantly up- and down-regulated candidate genes were submitted to KEGG (Kyoto Encyclopedia of Genes and Genomes) in order to analyze for induced pathways and to evaluate the usefulness of this method in cases of not completely annotated test organisms. Exposure during 5 days to environmentally relevant concentrations of the selected pharmaceutical compounds acetaminophen, carbamazepine, and atenolol produced differences in the expression of 659, 700, and 480 candidate genes, respectively. KEGG annotation numbers (KO annotations) were obtained for between 26.57% and 33.33% of these differently expressed genes per treatment in comparison to non-exposure conditions. Pathways that showed to be induced did not always follow previously reported targets or metabolic routes for the employed treatments; however, several other pathways have been found (four or more features) to be significantly induced. Energy-related pathways have been altered under exposure in all the selected treatments, indicating a possible energy budget leakage due to additional processes resulting from the exposure to environmental contaminants. Observed induction of pathways may indicate additional processes involved in the mode of action of the selected pharmaceuticals which may not have been detected with conventional methods like quantitative PCR in which only suspected features are analyzed punctually for effects. The employment of novel high-throughput screening techniques in combination with global pathway analysis methods, even if the organism is not completely annotated, allows the examination of a much broader range of candidates for potential effects of exposure at the gene level. The continuously growing number of annotations of representative species relevant for environmental quality testing is facilitating pathway analysis processes for not completely annotated organisms. KEGG has shown to be a useful tool for the analysis of induced pathways from data generated by microarray techniques with the selected pharmaceutical contaminants acetaminophen, carbamazepine, and atenolol, but further studies have to be carried out in order to determine if a similar expression pattern in terms of fold change quantity and pathways is observed after long-term exposure. Together with the information obtained in this study, it will then be possible to evaluate the potential risk that the continuous release of these compounds may have on the environment and ecosystem functioning.

Evaluating officially reported polycyclic aromatic hydrocarbon emissions in the Athabasca oil sands region with a multimedia fate model

PubMed Central

Parajulee, Abha; Wania, Frank

2014-01-01

Emissions of organic substances with potential toxicity to humans and the environment are a major concern surrounding the rapid industrial development in the Athabasca oil sands region (AOSR). Although concentrations of polycyclic aromatic hydrocarbons (PAHs) in some environmental samples have been reported, a comprehensive picture of organic contaminant sources, pathways, and sinks within the AOSR has yet to be elucidated. We sought to use a dynamic multimedia environmental fate model to reconcile the emissions and residue levels reported for three representative PAHs in the AOSR. Data describing emissions to air compiled from two official sources result in simulated concentrations in air, soil, water, and foliage that tend to fall close to or below the minimum measured concentrations of phenanthrene, pyrene, and benzo(a)pyrene in the environment. Accounting for evaporative emissions (e.g., from tailings pond disposal) provides a more realistic representation of PAH distribution in the AOSR. Such indirect emissions to air were found to be a greater contributor of PAHs to the AOSR atmosphere relative to reported direct emissions to air. The indirect pathway transporting uncontrolled releases of PAHs to aquatic systems via the atmosphere may be as significant a contributor of PAHs to aquatic systems as other supply pathways. Emission density estimates for the three PAHs that account for tailings pond disposal are much closer to estimated global averages than estimates based on the available emissions datasets, which fall close to the global minima. Our results highlight the need for improved accounting of PAH emissions from oil sands operations, especially in light of continued expansion of these operations. PMID:24596429

The Global Food System as a Transport Pathway for Hazardous Chemicals: The Missing Link between Emissions and Exposure.

PubMed

Ng, Carla A; von Goetz, Natalie

2017-01-01

Food is a major pathway for human exposure to hazardous chemicals. The modern food system is becoming increasingly complex and globalized, but models for food-borne exposure typically assume locally derived diets or use concentrations directly measured in foods without accounting for food origin. Such approaches may not reflect actual chemical intakes because concentrations depend on food origin, and representative analysis is seldom available. Processing, packaging, storage, and transportation also impart different chemicals to food and are not yet adequately addressed. Thus, the link between environmental emissions and realistic human exposure is effectively broken. We discuss the need for a fully integrated treatment of the modern industrialized food system, and we propose strategies for using existing models and relevant supporting data sources to track chemicals during production, processing, packaging, storage, and transport. Fate and bioaccumulation models describe how chemicals distribute in the environment and accumulate through local food webs. Human exposure models can use concentrations in food to determine body burdens based on individual or population characteristics. New models now include the impacts of processing and packaging but are far from comprehensive. We propose to close the gap between emissions and exposure by utilizing a wider variety of models and data sources, including global food trade data, processing, and packaging models. A comprehensive approach that takes into account the complexity of the modern global food system is essential to enable better prediction of human exposure to chemicals in food, sound risk assessments, and more focused risk abatement strategies. Citation: Ng CA, von Goetz N. 2017. The global food system as a transport pathway for hazardous chemicals: the missing link between emissions and exposure. Environ Health Perspect 125:1-7; http://dx.doi.org/10.1289/EHP168.

Impact of Climate Change on Potential Distribution of Chinese Caterpillar Fungus (Ophiocordyceps sinensis) in Nepal Himalaya

PubMed Central

Shrestha, Uttam Babu; Bawa, Kamaljit S.

2014-01-01

Climate change has already impacted ecosystems and species and substantial impacts of climate change in the future are expected. Species distribution modeling is widely used to map the current potential distribution of species as well as to model the impact of future climate change on distribution of species. Mapping current distribution is useful for conservation planning and understanding the change in distribution impacted by climate change is important for mitigation of future biodiversity losses. However, the current distribution of Chinese caterpillar fungus, a flagship species of the Himalaya with very high economic value, is unknown. Nor do we know the potential changes in suitable habitat of Chinese caterpillar fungus caused by future climate change. We used MaxEnt modeling to predict current distribution and changes in the future distributions of Chinese caterpillar fungus in three future climate change trajectories based on representative concentration pathways (RCPs: RCP 2.6, RCP 4.5, and RCP 6.0) in three different time periods (2030, 2050, and 2070) using species occurrence points, bioclimatic variables, and altitude. About 6.02% (8,989 km2) area of the Nepal Himalaya is suitable for Chinese caterpillar fungus habitat. Our model showed that across all future climate change trajectories over three different time periods, the area of predicted suitable habitat of Chinese caterpillar fungus would expand, with 0.11–4.87% expansion over current suitable habitat. Depending upon the representative concentration pathways, we observed both increase and decrease in average elevation of the suitable habitat range of the species. PMID:25180515

Impact of climate change on potential distribution of Chinese caterpillar fungus (Ophiocordyceps sinensis) in Nepal Himalaya.

PubMed

Shrestha, Uttam Babu; Bawa, Kamaljit S

2014-01-01

Climate change has already impacted ecosystems and species and substantial impacts of climate change in the future are expected. Species distribution modeling is widely used to map the current potential distribution of species as well as to model the impact of future climate change on distribution of species. Mapping current distribution is useful for conservation planning and understanding the change in distribution impacted by climate change is important for mitigation of future biodiversity losses. However, the current distribution of Chinese caterpillar fungus, a flagship species of the Himalaya with very high economic value, is unknown. Nor do we know the potential changes in suitable habitat of Chinese caterpillar fungus caused by future climate change. We used MaxEnt modeling to predict current distribution and changes in the future distributions of Chinese caterpillar fungus in three future climate change trajectories based on representative concentration pathways (RCPs: RCP 2.6, RCP 4.5, and RCP 6.0) in three different time periods (2030, 2050, and 2070) using species occurrence points, bioclimatic variables, and altitude. About 6.02% (8,989 km2) area of the Nepal Himalaya is suitable for Chinese caterpillar fungus habitat. Our model showed that across all future climate change trajectories over three different time periods, the area of predicted suitable habitat of Chinese caterpillar fungus would expand, with 0.11-4.87% expansion over current suitable habitat. Depending upon the representative concentration pathways, we observed both increase and decrease in average elevation of the suitable habitat range of the species.

The potential impacts of 21st century climatic and population changes on human exposure to the virus vector mosquito Aedes aegypti.

PubMed

Monaghan, A J; Sampson, K M; Steinhoff, D F; Ernst, K C; Ebi, K L; Jones, B; Hayden, M H

2018-02-01

The mosquito Aedes (Ae). aegypti transmits the viruses that cause dengue and chikungunya, two globally-important vector-borne diseases. We investigate how choosing alternate emissions and/or socioeconomic pathways may modulate future human exposure to Ae. aegypti . Occurrence patterns for Ae. aegypti for 2061-2080 are mapped globally using empirically downscaled air temperature and precipitation projections from the Community Earth System Model, for the Representative Concentration Pathway (RCP) 4.5 and 8.5 scenarios. Population growth is quantified using gridded global population projections consistent with two Shared Socioeconomic Pathways (SSPs), SSP3 and SSP5. Change scenarios are compared to a 1950-2000 reference period. A global land area of 56.9 M km 2 is climatically suitable for Ae. aegypti during the reference period, and is projected to increase by 8% (RCP4.5) to 13% (RCP8.5) by 2061-2080. The annual average number of people exposed globally to Ae. aegypti for the reference period is 3794 M, a value projected to statistically significantly increase by 298-460 M (8-12%) by 2061-2080 if only climate change is considered, and by 4805-5084 M (127-134%) for SSP3 and 2232-2483 M (59-65%) for SSP5 considering both climate and population change (lower and upper values of each range represent RCP4.5 and RCP8.5 respectively). Thus, taking the lower-emissions RCP4.5 pathway instead of RCP8.5 may mitigate future human exposure to Ae. aegypti globally, but the effect of population growth on exposure will likely be larger. Regionally, Australia, Europe and North America are projected to have the largest percentage increases in human exposure to Ae. aegypti considering only climate change.

The aqueous photolysis of α-pinene in solution with humic acid

USGS Publications Warehouse

Goldberg, Marvin C.; Cunningham, Kirkwood M.; Aiken, George R.; Weiner, Eugene R.; ,

1992-01-01

Terpenes are produced abundantly by environmental processes but are found in very low concentrations in natural waters. Aqueous photolysis of solutions containing α-pinene, a representative terpene, in the presence of humic acid resulted in degradation of the pinene. Comparison of this reaction to photolysis of α-pinene in the presence of methylene blue leads to the conclusion that the reactive pathway for the abiotic degradation of α-pinene is due to reaction with singlet oxygen produced by irradiation of the humic material. The initial product of single oxygen and α-pinene is a hydroperoxide. Since humic materials are prevalent in most natural waters, this mechanism of photodecomposition for α-pinene probably also applies to other terpenes in surface waters and may be reasonably considered to contribute to their low environmental concentration.

Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure

PubMed Central

Thomas, Reuben; Hubbard, Alan E.; McHale, Cliona M.; Zhang, Luoping; Rappaport, Stephen M.; Lan, Qing; Rothman, Nathaniel; Vermeulen, Roel; Guyton, Kathryn Z.; Jinot, Jennifer; Sonawane, Babasaheb R.; Smith, Martyn T.

2014-01-01

Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from <1 ppm to >10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings. PMID:24786086

Installation Restoration Program. Remedial Investigation Report: Minnesota Air National Guard Base Duluth International Airport, Duluth, Minnesota. Volume 7

DTIC Science & Technology

1990-01-01

Selection of Indicator Chemicals 6-36 6.2.2 Estimation of Exposure Point Concentrations or Emission Rates 6-38 6.2.2.1 Exposure Pathway Analysis 6-38...Exposure Point Concentrations or Emission Rates 6-50 j 6.3.2.1 Exposure Pathway Analysis 6-52 6.3.2.2 Exposure Point Concentrations 6-55 6.3.2.3...Exposure Point Concentrations or Emission Rates 6-62 6.4.2.1 Exposure Pathway Analysis 6-62 6.4.2.2 Exposure Point Concentrations 6-69 6.4.2.3

Exploring Inflammatory Disease Drug Effects on Neutrophil Function

PubMed Central

Wu, Xiaojie; Kim, Donghyuk; Young, Ashlyn T.; Haynes, Christy L.

2014-01-01

Neutrophils are critical inflammatory cells; thus, it is important to characterize the effects of drugs on neutrophil function in the context of inflammatory diseases. Herein, chemically guided neutrophil migration, known as chemotaxis, is studied in the context of drug treatment at the single cell level using a microfluidic platform, complemented by cell viability assays and calcium imaging. Three representative drugs known to inhibit surface receptor expression, signaling enzyme activity, and the elevation of intracellular Ca2+ levels, each playing a significant role in neutrophil chemotactic pathways, are used to examine the in vitro drug effects on cellular behaviors. The microfluidic device establishes a stable concentration gradient of chemokines across a cell culture chamber so that neutrophil migration can be monitored under various drug-exposure conditions. Different time- and concentration-dependent regulatory effects were observed by comparing the motility, polarization, and effectiveness of neutrophil chemotaxis in response to the three drugs. Viability assays revealed distinct drug capabilities in reducing neutrophil viability while calcium imaging clarified the role of Ca2+ in the neutrophil chemotactic pathway. This study provides mechanistic insight into the drug effects on neutrophil function, facilitating comparison of current and potential pharmaceutical approaches. PMID:24946254

Comparative Phytonutrient Analysis of Broccoli By-Products: The Potentials for Broccoli By-Product Utilization.

PubMed

Liu, Mengpei; Zhang, Lihua; Ser, Suk Lan; Cumming, Jonathan R; Ku, Kang-Mo

2018-04-13

The phytonutrient concentrations of broccoli ( Brassica oleracea var. italica) florets, stems, and leaves were compared to evaluate the value of stem and leaf by-products as a source of valuable nutrients. Primary metabolites, including amino acids, organic acids, and sugars, as well as glucosinolates, carotenoids, chlorophylls, vitamins E and K, essential mineral elements, total phenolic content, antioxidant activity, and expression of glucosinolate biosynthesis and hydrolysis genes were quantified from the different broccoli tissues. Broccoli florets had higher concentrations of amino acids, glucoraphanin, and neoglucobrassicin compared to other tissues, whereas leaves were higher in carotenoids, chlorophylls, vitamins E and K, total phenolic content, and antioxidant activity. Leaves were also good sources of calcium and manganese compared to other tissues. Stems had the lowest nitrile formation from glucosinolate. Each tissue exhibited specific core gene expression profiles supporting glucosinolate metabolism, with different gene homologs expressed in florets, stems, and leaves, which suggests that tissue-specific pathways function to support primary and secondary metabolic pathways in broccoli. This comprehensive nutrient and bioactive compound profile represents a useful resource for the evaluation of broccoli by-product utilization in the human diet, and as feedstocks for bioactive compounds for industry.

Butyrate-Induced Transcriptional Changes in Human Colonic Mucosa

PubMed Central

Vanhoutvin, Steven A. L. W.; Troost, Freddy J.; Hamer, Henrike M.; Lindsey, Patrick J.; Koek, Ger H.; Jonkers, Daisy M. A. E.; Kodde, Andrea; Venema, Koen; Brummer, Robert J. M.

2009-01-01

Background Fermentation of dietary fiber in the colon results in the production of short chain fatty acids (mainly propionate, butyrate and acetate). Butyrate modulates a wide range of processes, but its mechanism of action is mostly unknown. This study aimed to determine the effects of butyrate on the transcriptional regulation of human colonic mucosa in vivo. Methodology/Principal Findings Five hundred genes were found to be differentially expressed after a two week daily butyrate administration with enemas. Pathway analysis showed that the butyrate intervention mainly resulted in an increased transcriptional regulation of the pathways representing fatty acid oxidation, electron transport chain and oxidative stress. In addition, several genes associated with epithelial integrity and apoptosis, were found to be differentially expressed after the butyrate intervention. Conclusions/Significance Colonic administration of butyrate in concentrations that can be achieved by consumption of a high-fiber diet enhances the maintenance of colonic homeostasis in healthy subjects, by regulating fatty acid metabolism, electron transport and oxidative stress pathways on the transcriptional level and provide for the first time, detailed molecular insight in the transcriptional response of gut mucosa to butyrate. PMID:19707587

Transport of regional pollutants through a remote trans-Himalayan valley in Nepal

NASA Astrophysics Data System (ADS)

Dhungel, Shradda; Kathayat, Bhogendra; Mahata, Khadak; Panday, Arnico

2018-01-01

Anthropogenic emissions from the combustion of fossil fuels and biomass in Asia have increased in recent years. High concentrations of reactive trace gases and light-absorbing and light-scattering particles from these sources form persistent haze layers, also known as atmospheric brown clouds, over the Indo-Gangetic plains (IGP) from December through early June. Models and satellite imagery suggest that strong wind systems within deep Himalayan valleys are major pathways by which pollutants from the IGP are transported to the higher Himalaya. However, observational evidence of the transport of polluted air masses through Himalayan valleys has been lacking to date. To evaluate this pathway, we measured black carbon (BC), ozone (O3), and associated meteorological conditions within the Kali Gandaki Valley (KGV), Nepal, from January 2013 to July 2015. BC and O3 varied over both diurnal and seasonal cycles. Relative to nighttime, mean BC and O3 concentrations within the valley were higher during daytime when the up-valley flow (average velocity of 17 m s-1) dominated. BC and O3 concentrations also varied seasonally with minima during the monsoon season (July to September). Concentrations of both species subsequently increased post-monsoon and peaked during March to May. Average concentrations for O3 during the seasonally representative months of April, August, and November were 41.7, 24.5, and 29.4 ppbv, respectively, while the corresponding BC concentrations were 1.17, 0.24, and 1.01 µg m-3, respectively. Up-valley fluxes of BC were significantly greater than down-valley fluxes during all seasons. In addition, frequent episodes of BC concentrations 2-3 times higher than average persisted from several days to a week during non-monsoon months. Our observations of increases in BC concentration and fluxes in the valley, particularly during pre-monsoon, provide evidence that trans-Himalayan valleys are important conduits for transport of pollutants from the IGP to the higher Himalaya.

New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer

PubMed Central

La Regina, Giuseppe; Bai, Ruoli; Coluccia, Antonio; Famiglini, Valeria; Pelliccia, Sveva; Passacantilli, Sara; Mazzoccoli, Carmela; Ruggieri, Vitalba; Sisinni, Lorenza; Bolognesi, Alessio; Rensen, Whilelmina Maria; Miele, Andrea; Nalli, Marianna; Alfonsi, Romina; Di Marcotullio, Lucia; Gulino, Alberto; Brancale, Andrea; Novellino, Ettore; Dondio, Giulio; Vultaggio, Stefania; Varasi, Mario; Mercurio, Ciro; Hamel, Ernest; Lavia, Patrizia; Silvestri, Romano

2014-01-01

We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway. PMID:25025991

Proteomic responses of BEAS-2B cells to nontoxic and toxic chromium: Protein indicators of cytotoxicity conversion.

PubMed

Bruno, Maribel; Ross, Jeffrey; Ge, Yue

2016-12-15

Hexavalent chromium (Cr (VI)) is an environmental human carcinogen which primarily targets lungs. Among a variety of toxic mechanisms, disruption of biological pathways via translational and post-translational modifications represents a key mechanism through which Cr (VI) induces cytotoxicity and carcinogenesis. To identify those disruptions which are altered in response to cytotoxic Cr (VI) exposures, we measured and compared cytotoxicity and changes in expression and phosphorylation status of 15 critical biochemical pathway regulators in human BEAS-2B cells exposed for 48h to a non-toxic concentration (0.3μM) and a toxic concentration (1.8μM) of Cr (VI) by ELISA techniques. In addition, 43 functional proteins which may be altered in response to pathway signaling changes were identified using two dimensional electrophoresis (2-DE) and mass spectrometry. The proteins and fold changes observed in cells exposed to the non-toxic dose of Cr (VI) (0.3μM) were not necessarily the same as those found in the toxic one (1.8μM). A subset of signaling proteins that were correlated with the cytotoxic responses of human BEAS-2B cells to Cr (VI) treatments were identified. These proteins include regulators of glycolysis, glycogen synthase kinase 3 beta (GSK3β) and phosphoprotein 70 ribosomal protein s6 kinase (p70S6K), a signaling protein associated with oxidative stress and inflammation responses, JNK and metal regulatory transcription factor 1 (MTF-1), and a source of ubiquitin for signaling targeted protein degradation, polyubiquitin C (UBC). In addition, two dimensional gel electrophoresis (2-DE) was applied to identify key alterations in biochemical pathways differentiating between cytotoxic and non-cytotoxic exposures to Cr (VI), including glycolysis and gluconeogenesis, protein degradation, inflammation, and oxidative stress. Published by Elsevier Ireland Ltd.

Coral bleaching under unconventional scenarios of climate warming and ocean acidification

NASA Astrophysics Data System (ADS)

Kwiatkowski, Lester; Cox, Peter; Halloran, Paul R.; Mumby, Peter J.; Wiltshire, Andy J.

2015-08-01

Elevated sea surface temperatures have been shown to cause mass coral bleaching. Widespread bleaching, affecting >90% of global coral reefs and causing coral degradation, has been projected to occur by 2050 under all climate forcing pathways adopted by the IPCC for use within the Fifth Assessment Report. These pathways include an extremely ambitious pathway aimed to limit global mean temperature rise to 2 °C (ref. ; Representative Concentration Pathway 2.6--RCP2.6), which assumes full participation in emissions reductions by all countries, and even the possibility of negative emissions. The conclusions drawn from this body of work, which applied widely used algorithms to estimate coral bleaching, are that we must either accept that the loss of a large percentage of the world’s coral reefs is inevitable, or consider technological solutions to buy those reefs time until atmospheric CO2 concentrations can be reduced. Here we analyse the potential for geoengineering, through stratospheric aerosol-based solar radiation management (SRM), to reduce the extent of global coral bleaching relative to ambitious climate mitigation. Exploring the common criticism of geoengineering--that ocean acidification and its impacts will continue unabated--we focus on the sensitivity of results to the aragonite saturation state dependence of bleaching. We do not, however, address the additional detrimental impacts of ocean acidification on processes such as coral calcification that will further determine the benefit to corals of any SRM-based scenario. Despite the sensitivity of thermal bleaching thresholds to ocean acidification being uncertain, stabilizing radiative forcing at 2020 levels through SRM reduces the risk of global bleaching relative to RCP2.6 under all acidification-bleaching relationships analysed.

Mapping biological process relationships and disease perturbations within a pathway network.

PubMed

Stoney, Ruth; Robertson, David L; Nenadic, Goran; Schwartz, Jean-Marc

2018-01-01

Molecular interaction networks are routinely used to map the organization of cellular function. Edges represent interactions between genes, proteins, or metabolites. However, in living cells, molecular interactions are dynamic, necessitating context-dependent models. Contextual information can be integrated into molecular interaction networks through the inclusion of additional molecular data, but there are concerns about completeness and relevance of this data. We developed an approach for representing the organization of human cellular processes using pathways as the nodes in a network. Pathways represent spatial and temporal sets of context-dependent interactions, generating a high-level network when linked together, which incorporates contextual information without the need for molecular interaction data. Analysis of the pathway network revealed linked communities representing functional relationships, comparable to those found in molecular networks, including metabolism, signaling, immunity, and the cell cycle. We mapped a range of diseases onto this network and find that pathways associated with diseases tend to be functionally connected, highlighting the perturbed functions that result in disease phenotypes. We demonstrated that disease pathways cluster within the network. We then examined the distribution of cancer pathways and showed that cancer pathways tend to localize within the signaling, DNA processes and immune modules, although some cancer-associated nodes are found in other network regions. Altogether, we generated a high-confidence functional network, which avoids some of the shortcomings faced by conventional molecular models. Our representation provides an intuitive functional interpretation of cellular organization, which relies only on high-quality pathway and Gene Ontology data. The network is available at https://data.mendeley.com/datasets/3pbwkxjxg9/1.

Targeting of the Glutathione, Thioredoxin, and Nrf2 Antioxidant Systems in Head and Neck Cancer.

PubMed

Roh, Jong-Lyel; Jang, Hyejin; Kim, Eun Hye; Shin, Daiha

2017-07-10

The glutathione (GSH), thioredoxin (Trx), and Nrf2 systems represent a major defense against reactive oxygen species (ROS), the cellular imbalance of which in cancer promotes growth and therapeutic resistance. This study investigated whether targeting the GSH, Trx, and Nrf2 antioxidant systems effectively eliminated head and neck cancer (HNC). At high concentrations, auranofin, but not buthionine sulfoximine (BSO) alone, decreased the viability of HNC, whereas even at low concentrations, auranofin plus BSO synergized to kill HNC cells. Dual silencing of the genes for GCLM and TrxR1 induced GSH depletion, Trx activity inhibition, and ROS accumulation, synergistically killing HNC cells. Inhibition of the GSH and Trx systems resulted in activation of the Nrf2-antioxidant response element (ARE) pathway, which may result in suboptimal GSH and Trx inhibition where HNC is resistant. Genetic inhibition of Nrf2 and/or HO-1 or trigonelline enhanced growth suppression, ROS accumulation, and cell death from GSH and Trx inhibition. The in vivo effects of GSH, Trx, and Nrf2 system inhibition were confirmed in a mouse HNC xenograft model by achieving growth inhibition >60% compared with those of control. Innovations: This study is the first to show that triple inhibition of GSH, Trx, and Nrf2 pathways could be an effective method to overcome the resistance of HNC. Inhibition of the Nrf2-ARE pathway in addition to dual inhibition of the GSH and Trx antioxidant systems can effectively eliminate resistant HNC. Antioxid. Redox Signal. 27, 106-114.

Responses of metabolic pathways to polycyclic aromatic compounds in flounder following oil spill in the Baltic Sea near the Estonian coast.

PubMed

Kreitsberg, Randel; Zemit, Irina; Freiberg, Rene; Tambets, Meelis; Tuvikene, Arvo

2010-09-15

In January 2006 an oil spill that involved approximately 40tons of heavy fuel oil affected more than 30km of the north-west coast of Estonia. The aquatic pollution of the coastal area of the Baltic Sea was monitored by measuring the content of selected polycyclic aromatic hydrocarbons (PAHs and PAH metabolites) in flounder (Platichthys flesus trachurus Duncker). One hundred and thirty-one fish were collected: muscle and liver tissues were analyzed by high-performance liquid chromatography (HPLC); bile and urine samples were analyzed using fixed wavelengths fluorescence. Fifteen different types of PAHs were analyzed in liver and muscle, and four types of PAH metabolites were analyzed in bile and urine (2-, 3-, 4- and 5-ringed PAH metabolites represented by naphthalene, phenanthrene, pyrene and benzo(a)pyrene). Fluorescence analyses were carried out using excitation/emission wavelength pairs: 290/380, 256/380, 341/383 and 380/430nm, respectively. There was a time-dependent decrease of PAH concentrations in liver (83%), bile (82%) and urine (113%). HPLC analysis of muscle tissues demonstrated low concentrations of single PAHs, but a decrease of concentrations during the study period was not observed. During the analyses concentrations of PAH metabolites in bile and urine were compared. Liver metabolic transformation activity is believed to exceed that of the kidney but the analyses demonstrated high metabolite concentration in fish urine, particularly of 4- and 5-ring PAH metabolites. The results indicate remarkable buffer capacity of hydrodynamically active sea as well as considerable importance of kidney-urine metabolic pathways in flounder physiology. 2010 Elsevier B.V. All rights reserved.

Relative importance of methylotrophic methanogenesis in sediments of the Western Mediterranean Sea

NASA Astrophysics Data System (ADS)

Zhuang, Guang-Chao; Heuer, Verena B.; Lazar, Cassandre S.; Goldhammer, Tobias; Wendt, Jenny; Samarkin, Vladimir A.; Elvert, Marcus; Teske, Andreas P.; Joye, Samantha B.; Hinrichs, Kai-Uwe

2018-03-01

Microbial production of methane is an important terminal metabolic process during organic matter degradation in marine sediments. It is generally acknowledged that hydrogenotrophic and acetoclastic methanogenesis constitute the dominant pathways of methane production; the importance of methanogenesis from methylated compounds remains poorly understood. We conducted various biogeochemical and molecular genetic analyses to characterize substrate availability, rates of methanogenesis, and methanogen community composition, and further evaluated the contribution of different substrates and pathways for methane production in deltaic surface and subsurface sediments of the Western Mediterranean Sea. Major substrates representing three methanogenic pathways, including H2, acetate, and methanol, trimethylamine (TMA), and dimethylsulfide (DMS), were detected in the pore waters and sediments, and exhibited variability over depth and between sites. In accompanying incubation experiments, methanogenesis rates from various 14C labeled substrates varied as well, suggesting that environmental factors, such as sulfate concentration and organic matter quality, could significantly influence the relative importance of individual pathway. In particular, methylotrophic and hydrogenotrophic methanogenesis contributed to the presence of micromolar methane concentrations in the sulfate reduction zone, with methanogenesis from methanol accounting for up to 98% of the total methane production in the topmost surface sediment. In the sulfate-depleted zone, hydrogenotrophic methanogenesis was the dominant methanogenic pathway (67-98%), and enhanced methane production from acetate was observed in organic-rich sediment (up to 31%). Methyl coenzyme M reductase gene (mcrA) analysis revealed that the composition of methanogenic communities was generally consistent with the distribution of methanogenic activity from different substrates. This study provides the first quantitative assessment of methylotrophic methanogenesis in marine sediments and has important implications for marine methane cycling. The occurrence of methylotrophic methanogenesis in surface sediments could fuel the anaerobic oxidation of methane (AOM) in the shallow sulfate reduction zone. Release of methane produced from methylotrophic methanogenesis could be a source of methane efflux to the water column, thus influencing the benthic methane budgets.

Effects of model structural uncertainty on carbon cycle projections: biological nitrogen fixation as a case study

NASA Astrophysics Data System (ADS)

Wieder, William R.; Cleveland, Cory C.; Lawrence, David M.; Bonan, Gordon B.

2015-04-01

Uncertainties in terrestrial carbon (C) cycle projections increase uncertainty of potential climate feedbacks. Efforts to improve model performance often include increased representation of biogeochemical processes, such as coupled carbon-nitrogen (N) cycles. In doing so, models are becoming more complex, generating structural uncertainties in model form that reflect incomplete knowledge of how to represent underlying processes. Here, we explore structural uncertainties associated with biological nitrogen fixation (BNF) and quantify their effects on C cycle projections. We find that alternative plausible structures to represent BNF result in nearly equivalent terrestrial C fluxes and pools through the twentieth century, but the strength of the terrestrial C sink varies by nearly a third (50 Pg C) by the end of the twenty-first century under a business-as-usual climate change scenario representative concentration pathway 8.5. These results indicate that actual uncertainty in future C cycle projections may be larger than previously estimated, and this uncertainty will limit C cycle projections until model structures can be evaluated and refined.

Yeast pheromone pathway modeling using Petri nets

PubMed Central

2014-01-01

Background Our environment is composed of biological components of varying magnitude. The relationships between the different biological elements can be represented as a biological network. The process of mating in S. cerevisiae is initiated by secretion of pheromone by one of the cells. Our interest lies in one particular question: how does a cell dynamically adapt the pathway to continue mating under severe environmental changes or under mutation (which might result in the loss of functionality of some proteins known to participate in the pheromone pathway). Our work attempts to answer this question. To achieve this, we first propose a model to simulate the pheromone pathway using Petri nets. Petri nets are directed graphs that can be used for describing and modeling systems characterized as concurrent, asynchronous, distributed, parallel, non-deterministic, and/or stochastic. We then analyze our Petri net-based model of the pathway to investigate the following: 1) Given the model of the pheromone response pathway, under what conditions does the cell respond positively, i.e., mate? 2) What kinds of perturbations in the cell would result in changing a negative response to a positive one? Method In our model, we classify proteins into two categories: core component proteins (set ψ) and additional proteins (set λ). We randomly generate our model's parameters in repeated simulations. To simulate the pathway, we carry out three different experiments. In the experiments, we simply change the concentration of the additional proteins (λ) available to the cell. The concentration of proteins in ψ is varied consistently from 300 to 400. In Experiment 1, the range of values for λ is set to be 100 to 150. In Experiment 2, it is set to be 151 to 200. In Experiment 3, the set λ is further split into σ and ς, with the idea that proteins in σ are more important than those in ς. The range of values for σ is set to be between 151 to 200 while that of ς is 100 to 150. Decision trees were derived from each of the first two experiments to allow us to more easily analyze the conditions under which the pheromone is expressed. Conclusion The simulation results reveal that a cell can overcome the detrimental effects of the conditions by using more concentration of additional proteins in λ. The first two experiments provide evidence that employing more concentration of proteins might be one of the ways that the cell uses to adapt itself in inhibiting conditions to facilitate mating. The results of the third experiment reveal that in some case the protein set σ is sufficient in regulating the response of the cell. Results of Experiments 4 and 5 reveal that there are certain conditions (parameters) in the model that are more important in determining whether a cell will respond positively or not. PMID:25080237

Yeast pheromone pathway modeling using Petri nets.

PubMed

Majumdar, Abhishek; Scott, Stephen D; Deogun, Jitender S; Harris, Steven

2014-01-01

Our environment is composed of biological components of varying magnitude. The relationships between the different biological elements can be represented as a biological network. The process of mating in S. cerevisiae is initiated by secretion of pheromone by one of the cells. Our interest lies in one particular question: how does a cell dynamically adapt the pathway to continue mating under severe environmental changes or under mutation (which might result in the loss of functionality of some proteins known to participate in the pheromone pathway). Our work attempts to answer this question. To achieve this, we first propose a model to simulate the pheromone pathway using Petri nets. Petri nets are directed graphs that can be used for describing and modeling systems characterized as concurrent, asynchronous, distributed, parallel, non-deterministic, and/or stochastic. We then analyze our Petri net-based model of the pathway to investigate the following: 1) Given the model of the pheromone response pathway, under what conditions does the cell respond positively, i.e., mate? 2) What kinds of perturbations in the cell would result in changing a negative response to a positive one? In our model, we classify proteins into two categories: core component proteins (set ψ) and additional proteins (set λ). We randomly generate our model's parameters in repeated simulations. To simulate the pathway, we carry out three different experiments. In the experiments, we simply change the concentration of the additional proteins (λ) available to the cell. The concentration of proteins in ψ is varied consistently from 300 to 400. In Experiment 1, the range of values for λ is set to be 100 to 150. In Experiment 2, it is set to be 151 to 200. In Experiment 3, the set λ is further split into σ and ς, with the idea that proteins in σ are more important than those in ς. The range of values for σ is set to be between 151 to 200 while that of ς is 100 to 150. Decision trees were derived from each of the first two experiments to allow us to more easily analyze the conditions under which the pheromone is expressed. The simulation results reveal that a cell can overcome the detrimental effects of the conditions by using more concentration of additional proteins in λ. The first two experiments provide evidence that employing more concentration of proteins might be one of the ways that the cell uses to adapt itself in inhibiting conditions to facilitate mating. The results of the third experiment reveal that in some case the protein set σ is sufficient in regulating the response of the cell. Results of Experiments 4 and 5 reveal that there are certain conditions (parameters) in the model that are more important in determining whether a cell will respond positively or not.

Temporal variability of indoor air concentrations under natural conditions in a house overlying a dilute chlorinated solvent groundwater plume.

PubMed

Holton, Chase; Luo, Hong; Dahlen, Paul; Gorder, Kyle; Dettenmaier, Erik; Johnson, Paul C

2013-01-01

Current vapor intrusion (VI) pathway assessment heavily weights concentrations from infrequent (monthly-seasonal) 24 h indoor air samples. This study collected a long-term and high-frequency data set that can be used to assess indoor air sampling strategies for answering key pathway assessment questions like: "Is VI occurring?", and "Will VI impacts exceed thresholds of concern?". Indoor air sampling was conducted for 2.5 years at 2-4 h intervals in a house overlying a dilute chlorinated solvent plume (10-50 μg/L TCE). Indoor air concentrations varied by 3 orders of magnitude (<0.01-10 ppbv TCE) with two recurring behaviors. The VI-active behavior, which was prevalent in fall, winter, and spring involved time-varying impacts intermixed with sporadic periods of inactivity; the VI-dormant behavior, which was prevalent in the summer, involved long periods of inactivity with sporadic VI impacts. These data were used to study outcomes of three simple sparse data sampling plans; the probabilities of false-negative and false-positive decisions were dependent on the ratio of the (action level/true mean of the data), the number of exceedances needed, and the sampling strategy. The analysis also suggested a significant potential for poor characterization of long-term mean concentrations with sparse sampling plans. The results point to a need for additional dense data sets and further investigation into the robustness of possible VI assessment paradigms. As this is the first data set of its kind, it is unknown if the results are representative of other VI-sites.

Future supply and demand of net primary production in the Sahel

NASA Astrophysics Data System (ADS)

Sallaba, Florian; Olin, Stefan; Engström, Kerstin; Abdi, Abdulhakim M.; Boke-Olén, Niklas; Lehsten, Veiko; Ardö, Jonas; Seaquist, Jonathan W.

2017-12-01

In the 21st century, climate change in combination with increasing demand, mainly from population growth, will exert greater pressure on the ecosystems of the Sahel to supply food and feed resources. The balance between supply and demand, defined as the annual biomass required for human consumption, serves as a key metric for quantifying basic resource shortfalls over broad regions.Here we apply an exploratory modelling framework to analyse the variations in the timing and geography of different NPP (net primary production) supply-demand scenarios, with distinct assumptions determining supply and demand, for the 21st century Sahel. We achieve this by coupling a simple NPP supply model forced with projections from four representative concentration pathways with a global, reduced-complexity demand model driven by socio-economic data and assumptions derived from five shared socio-economic pathways.For the scenario that deviates least from current socio-economic and climate trends, we find that per capita NPP begins to outstrip supply in the 2040s, while by 2050 half the countries in the Sahel experience NPP shortfalls. We also find that despite variations in the timing of the onset of NPP shortfalls, demand cannot consistently be met across the majority of scenarios. Moreover, large between-country variations are shown across the scenarios, in which by the year 2050 some countries consistently experience shortage or surplus, while others shift from surplus to shortage. At the local level (i.e. grid cell), hotspots of total NPP shortfall consistently occur in the same locations across all scenarios but vary in size and magnitude. These hotspots are linked to population density and high demand. For all scenarios, total simulated NPP supply doubles by 2050 but is outpaced by increasing demand due to a combination of population growth and the adoption of diets rich in animal products. Finally, variations in the timing of the onset and end of supply shortfalls stem from the assumptions that underpin the shared socio-economic pathways rather than the representative concentration pathways.Our results suggest that the UN sustainable development goals for eradicating hunger are at high risk for failure. This emphasizes the importance of policy interventions such as the implementation of sustainable and healthy diets, family planning, reducing yield gaps, and encouraging the transfer of resources to impoverished areas via trade relations.

Specific Inhibition of the Cyanide-insensitive Respiratory Pathway in Plant Mitochondria by Hydroxamic Acids

PubMed Central

Schonbaum, Gregory R.; Bonner, Walter D.; Storey, Bayard T.; Bahr, James T.

1971-01-01

Hydroxamic acids, R-CONHOH, are inhibitors specific to the respiratory pathway through the alternate, cyanide-insensitive terminal oxidase of plant mitochondria. The nature of the R group in these compounds affects the concentration at which the hydroxamic acids are effective, but it appears that all hydroxamic acids inhibit if high enough concentrations are used. The benzhydroxamic acids are effective at relatively low concentrations; of these, the most effective are m-chlorobenzhydroxamic acid and m-iodobenzhydroxamic acid. The concentrations required for half-maximal inhibition of the alternate oxidase pathway in mung bean (Phaseolus aureus) mitochondria are 0.03 mm for m-chlorobenzhydroxamic acid and 0.02 mm for m-iodobenzhydroxamic acid. With skunk cabbage (Symplocarpus foetidus) mitochondria, the required concentrations are 0.16 for m-chlorobenzhydroxamic acid and 0.05 for m-iodobenzhydroxamic acid. At concentrations which inhibit completely the alternate oxidase pathway, these two compounds have no discernible effect on either the respiratory pathway through cytochrome oxidase, or on the energy coupling reactions of these mitochondria. These inhibitors make it possible to isolate the two respiratory pathways and study their mode of action separately. These inhibitors also enhance an electron paramagnetic resonance signal near g = 2 in anaerobic, submitochondrial particles from skunk cabbage, which appears to be specific to the alternate oxidase and thus provides a means for its assay. PMID:5543780

Steady-State Serum T3 Concentrations for 48 Hours Following the Oral Administration of a Single Dose of 3,5,3'-Triiodothyronine Sulfate (T3S).

PubMed

Santini, Ferruccio; Giannetti, Monica; Ricco, Ilaria; Querci, Giorgia; Saponati, Giorgio; Bokor, Daniela; Rivolta, Giovanni; Bussi, Simona; Braverman, Lewis E; Vitti, Paolo; Pinchera, Aldo

2014-07-01

Sulfate conjugation of thyroid hormones is an alternate metabolic pathway that facilitates the biliary and urinary excretion of iodothyronines and enhances their deiodination rate, leading to the generation of inactive metabolites. A desulfating pathway reverses this process, and thyromimetic effects have been observed following the parenteral administration of 3,5,3'-triiodothyronine (T3) sulfate (T3S) in rats. The present study investigated whether T3S is absorbed after oral administration in humans and if it represents a source of T3. Twenty-eight hypothyroid patients (7 men and 21 women; mean age, 44 ± 11 years) who had a thyroidectomy for thyroid carcinoma were enrolled. Replacement thyroid hormone therapy was withdrawn (42 days for thyroxine, 14 days for T3) prior to 131I remnant ablation. A single oral dose of 20, 40, 80 (4 patients/group), or 160 μg (16 patients/group) of T3S was administered 3 days before the planned administration of 131I. Blood samples for serum T3S and total T3 (TT3) concentrations were obtained at various times up to 48 hours after T3S administration. At all T3S doses, serum T3S concentrations increased, reaching a peak at 2 to 4 hours and progressively returning to basal levels within 8 to 24 hours. The T3S maximum concentration (Cmax) and area under the 0- to 48-hour concentration-time curve (AUC0-48h) were directly and significantly related to the administered dose. An increase in serum TT3 concentration was observed (significant after 1 hour), and the concentration increased further at 2 and 4 hours and then remained steady up to 48 hours after T3S administration. There was a significant direct correlation between the TT3 AUC0-48h and the administered dose of T3S. No changes in serum free thyroxine (T4) concentrations during the entire study period were observed, whereas serum thyroid-stimulating hormone levels increased slightly at 48 hours, but this was not related to the dose of T3S. No adverse events were reported. (1) T3S is absorbed following oral administration in hypothyroid humans; (2) after a single oral dose, T3S is converted to T3 in a dose-dependent manner, resulting in steady-state serum T3 concentrations for 48 hours; (3) T3S may represent a new agent in combination with T4 in the therapy of hypothyroidism, if similar conversion of T3S to T3 can be demonstrated in euthyroid patients who are already taking T4.

BioPAX – A community standard for pathway data sharing

PubMed Central

Demir, Emek; Cary, Michael P.; Paley, Suzanne; Fukuda, Ken; Lemer, Christian; Vastrik, Imre; Wu, Guanming; D’Eustachio, Peter; Schaefer, Carl; Luciano, Joanne; Schacherer, Frank; Martinez-Flores, Irma; Hu, Zhenjun; Jimenez-Jacinto, Veronica; Joshi-Tope, Geeta; Kandasamy, Kumaran; Lopez-Fuentes, Alejandra C.; Mi, Huaiyu; Pichler, Elgar; Rodchenkov, Igor; Splendiani, Andrea; Tkachev, Sasha; Zucker, Jeremy; Gopinath, Gopal; Rajasimha, Harsha; Ramakrishnan, Ranjani; Shah, Imran; Syed, Mustafa; Anwar, Nadia; Babur, Ozgun; Blinov, Michael; Brauner, Erik; Corwin, Dan; Donaldson, Sylva; Gibbons, Frank; Goldberg, Robert; Hornbeck, Peter; Luna, Augustin; Murray-Rust, Peter; Neumann, Eric; Reubenacker, Oliver; Samwald, Matthias; van Iersel, Martijn; Wimalaratne, Sarala; Allen, Keith; Braun, Burk; Whirl-Carrillo, Michelle; Dahlquist, Kam; Finney, Andrew; Gillespie, Marc; Glass, Elizabeth; Gong, Li; Haw, Robin; Honig, Michael; Hubaut, Olivier; Kane, David; Krupa, Shiva; Kutmon, Martina; Leonard, Julie; Marks, Debbie; Merberg, David; Petri, Victoria; Pico, Alex; Ravenscroft, Dean; Ren, Liya; Shah, Nigam; Sunshine, Margot; Tang, Rebecca; Whaley, Ryan; Letovksy, Stan; Buetow, Kenneth H.; Rzhetsky, Andrey; Schachter, Vincent; Sobral, Bruno S.; Dogrusoz, Ugur; McWeeney, Shannon; Aladjem, Mirit; Birney, Ewan; Collado-Vides, Julio; Goto, Susumu; Hucka, Michael; Le Novère, Nicolas; Maltsev, Natalia; Pandey, Akhilesh; Thomas, Paul; Wingender, Edgar; Karp, Peter D.; Sander, Chris; Bader, Gary D.

2010-01-01

BioPAX (Biological Pathway Exchange) is a standard language to represent biological pathways at the molecular and cellular level. Its major use is to facilitate the exchange of pathway data (http://www.biopax.org). Pathway data captures our understanding of biological processes, but its rapid growth necessitates development of databases and computational tools to aid interpretation. However, the current fragmentation of pathway information across many databases with incompatible formats presents barriers to its effective use. BioPAX solves this problem by making pathway data substantially easier to collect, index, interpret and share. BioPAX can represent metabolic and signaling pathways, molecular and genetic interactions and gene regulation networks. BioPAX was created through a community process. Through BioPAX, millions of interactions organized into thousands of pathways across many organisms, from a growing number of sources, are available. Thus, large amounts of pathway data are available in a computable form to support visualization, analysis and biological discovery. PMID:20829833

Mass fluxes of organic pollutants between groundwater, streambed sediments and surface water

NASA Astrophysics Data System (ADS)

Schirmer, Mario; Kalbus, Edda; Schmidt, Christian

2010-05-01

Rivers and groundwater are commonly hydraulically connected and thus also pollutants migrate between one and the other. Particularly in small lowland streams, pollutant transport by discharging groundwater can deteriorate the surface water quality. Moreover, in urban and industrial areas streambed sediments are often polluted with a variety of organic and inorganic substances. For planning measures to improve surface water quality or to mitigate pollutant migration, it is an essential prerequisite to understand pollutant pathways and mass fluxes between the stream, the streambed sediment and the connected aquifer. We present methodological approaches and results of a study conducted at a small man-made stream located in the industrial area of Bitterfeld-Wolfen, Germany. This site is characterized by a diffuse groundwater contamination with a variety of aliphatic and aromatic organic substances. The underlying approach of this study was to quantify the mass fluxes between the aquifer, the streambed and the stream by combining high-resolution with integral monitoring approaches. Magnitudes and pattern of water fluxes were obtained by mapping streambed temperatures. The method was applied to a reach of 280 m in length. The mass fluxes from the aquifer towards the stream were estimated by combining the water fluxes with representative, average pollutant concentrations. The concentrations were obtained from an integral pumping test with four simultaneously pumped wells operated for the period of five days. For monochlorobenzene (MCB), the main groundwater pollutant at the site, the resulting average mass flux from the aquifer towards the stream was estimated to 724 µg/m²/d. Mass flux calculations with average aqueous concentrations of MCB in the streambed were found to be higher than those originating from the aquifer. Consequently, the streambed sediments represent a secondary pollutant source for the surface water. Pollutant concentrations in the streambed were lower at locations with high groundwater discharge and vice versa. Hence, the spatial heterogeneity of water fluxes must be considered when mass fluxes between surface water and streambed sediments are assessed. River restoration could improve the structural state of rivers and may thus result in an enhanced biodegradation of organic pollutants in the streambed. However, before any physical measure is applied a profound knowledge of pollutant concentration and pathways is required in order to avoid mobilization of sediment-bound pollutants.

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

Hill, David P.; D’Eustachio, Peter; Berardini, Tanya Z.

The concept of a biological pathway, an ordered sequence of molecular transformations, is used to collect and represent molecular knowledge for a broad span of organismal biology. Representations of biomedical pathways typically are rich but idiosyncratic presentations of organized knowledge about individual pathways. Meanwhile, biomedical ontologies and associated annotation files are powerful tools that organize molecular information in a logically rigorous form to support computational analysis. The Gene Ontology (GO), representing Molecular Functions, Biological Processes and Cellular Components, incorporates many aspects of biological pathways within its ontological representations. Here we present a methodology for extending and refining the classes inmore » the GO for more comprehensive, consistent and integrated representation of pathways, leveraging knowledge embedded in current pathway representations such as those in the Reactome Knowledgebase and MetaCyc. With carbohydrate metabolic pathways as a use case, we discuss how our representation supports the integration of variant pathway classes into a unified ontological structure that can be used for data comparison and analysis.« less

TELOMERE AND TELOMERASE MODULATION BY BERGAMOT POLYPHENOLIC FRACTION IN EXPERIMENTAL PHOTOAGEING IN HUMAN KERATINOCYTES.

PubMed

Nisticò, S; Ehrlich, J; Gliozzi, M; Maiuolo, J; Del Duca, E; Muscoli, C; Mollace, V

2015-01-01

Photoageing represents the addition of extrinsic chronic ultraviolet radiation-induced damage on intrinsic ageing and accounts for most age-associated changes in skin appearance. In this study, we evaluated the effect of 38% BPF, a highly concentrated extract of the bergamot fruit (Citrus bergamia) on UVB-induced photoageing by examining inflammatory cytokine expression, telomere length/telomerase alterations and cellular viability in human immortalized HaCaT keratinocytes. Our results suggest that 38% BPF protects HaCaT cells against UVB-induced oxidative stress and markers of photoageing in a dose-dependent manner and could be a useful supplement in skin care products. Together with antioxidant properties, BPF, a highly concentrated extract of the bergamot fruit, appears to modulate basic cellular signal transduction pathways leading to anti-proliferative, anti-aging and immune modulating responses.

Ethoprophos fate on soil-water interface and effects on non-target terrestrial and aquatic biota under Mediterranean crop-based scenarios.

PubMed

Leitão, Sara; Moreira-Santos, Matilde; Van den Brink, Paul J; Ribeiro, Rui; José Cerejeira, M; Sousa, José Paulo

2014-05-01

The present study aimed to assess the environmental fate of the insecticide and nematicide ethoprophos in the soil-water interface following the pesticide application in simulated maize and potato crops under Mediterranean agricultural conditions, particularly of irrigation. Focus was given to the soil-water transfer pathways (leaching and runoff), to the pesticide transport in soil between pesticide application (crop row) and non-application areas (between crop rows), as well as to toxic effects of the various matrices on terrestrial and aquatic biota. A semi-field methodology mimicking a "worst-case" ethoprophos application (twice the recommended dosage for maize and potato crops: 100% concentration v/v) in agricultural field situations was used, in order to mimic a possible misuse by the farmer under realistic conditions. A rainfall was simulated under a slope of 20° for both crop-based scenarios. Soil and water samples were collected for the analysis of pesticide residues. Ecotoxicity of soil and aquatic samples was assessed by performing lethal and sublethal bioassays with organisms from different trophic levels: the collembolan Folsomia candida, the earthworm Eisenia andrei and the cladoceran Daphnia magna. Although the majority of ethoprophos sorbed to the soil application area, pesticide concentrations were detected in all water matrices illustrating pesticide transfer pathways of water contamination between environmental compartments. Leaching to groundwater proved to be an important transfer pathway of ethoprophos under both crop-based scenarios, as it resulted in high pesticide concentration in leachates from Maize (130µgL(-1)) and Potato (630µgL(-1)) crop scenarios, respectively. Ethoprophos application at the Potato crop scenario caused more toxic effects on terrestrial and aquatic biota than at the Maize scenario at the recommended dosage and lower concentrations. In both crop-based scenarios, ethoprophos moved with the irrigation water flow to the soil between the crop rows where no pesticide was applied, causing toxic effects on terrestrial organisms. The two simulated agricultural crop-based scenarios had the merit to illustrate the importance of transfer pathways of pesticides from soil to groundwater through leaching and from crop rows to the surrounding soil areas in a soil-water interface environment, which is representative for irrigated agricultural crops under Mediterranean conditions. Copyright © 2014 Elsevier Inc. All rights reserved.

Relative contributions of four exposure pathways to influenza infection risk.

PubMed

Nicas, Mark; Jones, Rachael M

2009-09-01

The relative contribution of four influenza virus exposure pathways-(1) virus-contaminated hand contact with facial membranes, (2) inhalation of respirable cough particles, (3) inhalation of inspirable cough particles, and (4) spray of cough droplets onto facial membranes-must be quantified to determine the potential efficacy of nonpharmaceutical interventions of transmission. We used a mathematical model to estimate the relative contributions of the four pathways to infection risk in the context of a person attending a bed-ridden family member ill with influenza. Considering the uncertainties in the sparse human subject influenza dose-response data, we assumed alternative ratios of 3,200:1 and 1:1 for the infectivity of inhaled respirable virus to intranasally instilled virus. For the 3,200:1 ratio, pathways (1), (2), and (4) contribute substantially to influenza risk: at a virus saliva concentration of 10(6) mL(-1), pathways (1), (2), (3), and (4) contribute, respectively, 31%, 17%, 0.52%, and 52% of the infection risk. With increasing virus concentrations, pathway (2) increases in importance, while pathway (4) decreases in importance. In contrast, for the 1:1 infectivity ratio, pathway (1) is the most important overall: at a virus saliva concentration of 10(6) mL(-1), pathways (1), (2), (3), and (4) contribute, respectively, 93%, 0.037%, 3.3%, and 3.7% of the infection risk. With increasing virus concentrations, pathway (3) increases in importance, while pathway (4) decreases in importance. Given the sparse knowledge concerning influenza dose and infectivity via different exposure pathways, nonpharmaceutical interventions for influenza should simultaneously address potential exposure via hand contact to the face, inhalation, and droplet spray.

Platelet-released growth factors inhibit proliferation of primary keratinocytes in vitro.

PubMed

Bayer, Andreas; Tohidnezhad, Mersedeh; Berndt, Rouven; Lippross, Sebastian; Behrendt, Peter; Klüter, Tim; Pufe, Thomas; Jahr, Holger; Cremer, Jochen; Rademacher, Franziska; Simanski, Maren; Gläser, Regine; Harder, Jürgen

2018-01-01

Autologous thrombocyte concentrate lysates as platelet-released growth factors (PRGF) or Vivostat Platelet Rich Fibrin (PRF ® ) represent important tools in modern wound therapy, especially in the treatment of chronic, hard-to-heal or infected wounds. Nevertheless, underlying cellular and molecular mechanisms of the beneficial clinical effects of a local wound therapy with autologous thrombocyte concentrate lysates are poorly understood. Recently, we have demonstrated that PRGF induces antimicrobial peptides in primary keratinocytes and accelerates keratinocytes' differentiation. In the present study we analyzed the influence of PRGF on primary human keratinocytes' proliferation. Using the molecular proliferation marker Ki-67 we observed a concentration- and time dependent inhibition of Ki-67 gene expression in PRGF treated primary keratinocytes. These effects were independent from the EGFR- and the IL-6-R pathway. Inhibition of primary keratinocytes' proliferation by PRGF treatment was confirmed in colorimetric cell proliferation assays. Together, these data indicate that the clinically observed positive effects of autologous thrombocytes concentrates in the treatment of chronic, hard-to-heal wounds are not based on an increased keratinocytes proliferation. Copyright © 2017 Elsevier GmbH. All rights reserved.

ALTERATIONS IN BRAIN CREATINE CONCENTRATIONS UNDER LONG-TERM SOCIAL ISOLATION (EXPERIMENTAL STUDY).

PubMed

Koshoridze, N; Kuchukashvili, Z; Menabde, K; Lekiashvili, Sh; Koshoridze, M

2016-02-01

Stress represents one of the main problems of modern humanity. This study was done for understanding more clearly alterations in creatine content of the brain under psycho-emotional stress induced by long-term social isolation. It was shown that under 30 days social isolation creatine amount in the brain was arisen, while decreasing concentrations of synthesizing enzymes (AGAT, GAMT) and creatine transporter protein (CrT). Another important point was that such changes were accompanied by down-regulation of creatine kinase (CK), therefore the enzyme's concentration was lowered. In addition, it was observed that content of phosphocreatine (PCr) and ATP were also reduced, thus indicating down-regulation of energy metabolism of brain that is really a crucial point for its normal functioning. To sum up the results it can be underlined that long-term social isolation has negative influence on energy metabolism of brain; and as a result reduce ATP content, while increase of free creatine concentration, supposedly maintaining maximal balance for ATP amount, but here must be also noted that up-regulated oxidative pathways might have impact on blood brain barrier, resulting on its permeability.

Impacts of artificial ocean alkalinization on the carbon cycle and climate in Earth system simulations

NASA Astrophysics Data System (ADS)

González, Miriam Ferrer; Ilyina, Tatiana

2016-06-01

Using the state-of-the-art emissions-driven Max Planck Institute Earth system model, we explore the impacts of artificial ocean alkalinization (AOA) with a scenario based on the Representative Concentration Pathway (RCP) framework. Addition of 114 Pmol of alkalinity to the surface ocean stabilizes atmospheric CO2 concentration to RCP4.5 levels under RCP8.5 emissions. This scenario removes 940 GtC from the atmosphere and mitigates 1.5 K of global warming within this century. The climate adjusts to the lower CO2 concentration preventing the loss of sea ice and high sea level rise. Seawater pH and the carbonate saturation state (Ω) rise substantially above levels of the current decade. Pronounced differences in regional sensitivities to AOA are projected, with the Arctic Ocean and tropical oceans emerging as hot spots for biogeochemical changes induced by AOA. Thus, the CO2 mitigation potential of AOA comes at a price of an unprecedented ocean biogeochemistry perturbation with unknown ecological consequences.

How will SOA change in the future?: SOA IN THE FUTURE

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

Lin, Guangxing; Penner, Joyce E.; Zhou, Cheng

2016-02-17

Secondary organic aerosol (SOA) plays a significant role in the Earth system by altering its radiative balance. Here we use an Earth system model coupled with an explicit SOA formation module to estimate the response of SOA concentrations to changes in climate, anthropogenic emissions, and human land use in the future. We find that climate change is the major driver for SOA change under the representative concentration pathways for the 8.5 future scenario. Climate change increases isoprene emission rate by 18% with the effect of temperature increases outweighing that of the CO2 inhibition effect. Annual mean global SOA mass ismore » increased by 25% as a result of climate change. However, anthropogenic emissions and land use change decrease SOA. The net effect is that future global SOA burden in 2100 is nearly the same as that of the present day. The SOA concentrations over the Northern Hemisphere are predicted to decline in the future due to the control of sulfur emissions.« less

Spatiotemporal analysis of projected impacts of climate change on the major C3 and C4 crop yield under representative concentration pathway 4.5: Insight from the coasts of Tamil Nadu, South India

PubMed Central

A, Ramachandran; Praveen, Dhanya; R, Jaganathan; D, RajaLakshmi; K, Palanivelu

2017-01-01

India's dependence on a climate sensitive sector like agriculture makes it highly vulnerable to its impacts. However, agriculture is highly heterogeneous across the country owing to regional disparities in exposure, sensitivity, and adaptive capacity. It is essential to know and quantify the possible impacts of changes in climate on crop yield for successful agricultural management and planning at a local scale. The Hadley Centre Global Environment Model version 2-Earth System (HadGEM-ES) was employed to generate regional climate projections for the study area using the Regional Climate Model (RCM) RegCM4.4. The dynamics in potential impacts at the sub-district level were evaluated using the Representative Concentration Pathway 4.5 (RCPs). The aim of this study was to simulate the crop yield under a plausible change in climate for the coastal areas of South India through the end of this century. The crop simulation model, the Decision Support System for Agrotechnology Transfer (DSSAT) 4.5, was used to understand the plausible impacts on the major crop yields of rice, groundnuts, and sugarcane under the RCP 4.5 trajectory. The findings reveal that under the RCP 4.5 scenario there will be decreases in the major C3 and C4 crop yields in the study area. This would affect not only the local food security, but the livelihood security as well. This necessitates timely planning to achieve sustainable crop productivity and livelihood security. On the other hand, this situation warrants appropriate adaptations and policy intervention at the sub-district level for achieving sustainable crop productivity in the future. PMID:28753605

Spatiotemporal analysis of projected impacts of climate change on the major C3 and C4 crop yield under representative concentration pathway 4.5: Insight from the coasts of Tamil Nadu, South India.

PubMed

A, Ramachandran; Praveen, Dhanya; R, Jaganathan; D, RajaLakshmi; K, Palanivelu

2017-01-01

India's dependence on a climate sensitive sector like agriculture makes it highly vulnerable to its impacts. However, agriculture is highly heterogeneous across the country owing to regional disparities in exposure, sensitivity, and adaptive capacity. It is essential to know and quantify the possible impacts of changes in climate on crop yield for successful agricultural management and planning at a local scale. The Hadley Centre Global Environment Model version 2-Earth System (HadGEM-ES) was employed to generate regional climate projections for the study area using the Regional Climate Model (RCM) RegCM4.4. The dynamics in potential impacts at the sub-district level were evaluated using the Representative Concentration Pathway 4.5 (RCPs). The aim of this study was to simulate the crop yield under a plausible change in climate for the coastal areas of South India through the end of this century. The crop simulation model, the Decision Support System for Agrotechnology Transfer (DSSAT) 4.5, was used to understand the plausible impacts on the major crop yields of rice, groundnuts, and sugarcane under the RCP 4.5 trajectory. The findings reveal that under the RCP 4.5 scenario there will be decreases in the major C3 and C4 crop yields in the study area. This would affect not only the local food security, but the livelihood security as well. This necessitates timely planning to achieve sustainable crop productivity and livelihood security. On the other hand, this situation warrants appropriate adaptations and policy intervention at the sub-district level for achieving sustainable crop productivity in the future.

The Soil Microbial Response to a Massive Natural Gas Leak

NASA Astrophysics Data System (ADS)

Tavormina, P. L.; Newman, S.; Shen, L.; Connon, S. A.; Okumura, M.; Orphan, V. J.

2016-12-01

The 2015/2016 gas leak in the Porter Ranch community (Southern California) was the largest natural gas leak in US history. While considerable attention has focused on the amount of methane released to the atmosphere and the effects of other gas components on human well-being, less attention has been given to the response of soil microbes to this event. These microbes represent natural pathways for utilization of C1 compounds in soils and, possibly, untapped potential to remediate natural and anthropogenic gas emissions. We monitored onsite and background soil methane concentrations and microbial communities during and following the Porter Ranch gas leak. Soil core samples (25cm depth, collected twice monthly beginning in January 2016) were preserved for DNA, RNA, microscopic, stable isotope probing, and chromatographic methods. Simultaneously to coring, gas from soil pore spaces was collected for cavity ringdown spectroscopy to measure carbon dioxide, methane and ethane concentrations, and estimate corresponding isotopic values in carbon dioxide and methane. By pairing these measurements with high throughput sequencing, transcript analysis, and cultivation, we demonstrate discrete shifts in the total microbial community in surface (0 - 5 cm) and deep (20 - 25 cm) soils. Importantly, we find that methane consumption likely occurred in surface soils during and following the leak. The lineages most significantly correlated with elevated methane from the leak event were five orders of magnitude more abundant near the leak event in space and time, indicating a microbial bloom. These lineages are previously unrecognized members of Sphingomonadaceae, and they encode at least two biochemical pathways for methane oxidation. Cultivation of the first representative of this group now allows more detailed investigation into its capacity for microbially-mediated soil methane oxidation and mitigation.

Modulation of Ergot Alkaloids in a Grass-Endophyte Symbiosis by Alteration of mRNA Concentrations of an Ergot Alkaloid Synthesis Gene.

PubMed

Mulinti, Prashanthi; Florea, Simona; Schardl, Christopher L; Panaccione, Daniel G

2016-06-22

The profile of ergot alkaloids in perennial ryegrass (Lolium perenne) containing the endophytic fungus Epichloë typhina × festucae includes high concentrations of the early pathway metabolites ergotryptamine and chanoclavine-I in addition to the pathway end-product ergovaline. Because these alkaloids differ in activity, we investigated strategies to alter their relative concentrations. An RNAi-based approach reduced the concentration of mRNA from the gene easA, which encodes an enzyme required for a ring closure that separates ergotryptamine and chanoclavine-I from ergovaline. Lower easA mRNA concentrations correlated with lower concentrations of ergovaline and higher concentrations of ergotryptamine and chanoclavine-I. Overexpression of easA led to higher concentrations of ergovaline in leaf blades but not in pseudostems; concentrations of the early pathway metabolites were not altered in overexpression strains. The data indicate that altering the concentration of mRNA from a single gene can change alkaloid flux, but the magnitude of the change was limited and variable.

THE ADVERSE OUTCOME PATHWAY (AOP) FRAMEWORK: A FRAMEWORK FOR ORGANIZING BIOLOGICAL KNOWLEDGE LEADING TO HEALTH RISKS.

EPA Science Inventory

An Adverse Outcome Pathway (AOP) represents the organization of current and newly acquired knowledge of biological pathways. These pathways contain a series of nodes (Key Events, KEs) that when sufficiently altered influence the next node on the pathway, beginning from an Molecul...

Modeling biochemical pathways in the gene ontology

DOE PAGES

Hill, David P.; D’Eustachio, Peter; Berardini, Tanya Z.; ...

2016-09-01

The concept of a biological pathway, an ordered sequence of molecular transformations, is used to collect and represent molecular knowledge for a broad span of organismal biology. Representations of biomedical pathways typically are rich but idiosyncratic presentations of organized knowledge about individual pathways. Meanwhile, biomedical ontologies and associated annotation files are powerful tools that organize molecular information in a logically rigorous form to support computational analysis. The Gene Ontology (GO), representing Molecular Functions, Biological Processes and Cellular Components, incorporates many aspects of biological pathways within its ontological representations. Here we present a methodology for extending and refining the classes inmore » the GO for more comprehensive, consistent and integrated representation of pathways, leveraging knowledge embedded in current pathway representations such as those in the Reactome Knowledgebase and MetaCyc. With carbohydrate metabolic pathways as a use case, we discuss how our representation supports the integration of variant pathway classes into a unified ontological structure that can be used for data comparison and analysis.« less

Heat Shock Protein HSP27 Secretion by Ovarian Cancer Cells Is Linked to Intracellular Expression Levels, Occurs Independently of the Endoplasmic Reticulum Pathway and HSP27's Phosphorylation Status, and Is Mediated by Exosome Liberation

PubMed Central

Klinkmann, Gerd; Diesing, Karoline; Koensgen, Dominique; Burchardt, Martin

2017-01-01

The heat shock protein HSP27 has been correlated in ovarian cancer (OC) patients with aggressiveness and chemoresistance and, therefore, represents a promising potential biomarker for OC diagnosis, prognosis, and treatment response. Notably, secretion of soluble HSP27 has been described by a few cell types and may take place as well in OC cells. Therefore, we studied HSP27 secretion mechanisms under diverse cellular conditions in an OC cell model system. Secretion of HSP27 was characterized after overexpression of HSP27 by transfected plasmids and after heat shock. Intra- and extracellular HSP27 amounts were assessed by Western blotting and ELISA. Protein secretion was blocked by brefeldin A and the impact of the HSP27 phosphorylation status was analyzed overexpressing HSP27 phosphomutants. The present study demonstrated that HSP27 secretion by OVCAR-3 and SK-OV-3 cells depends on intracellular HSP27 concentrations. Moreover, HSP27 secretion is independent of the endoplasmic reticulum secretory pathway and HSP27 phosphorylation. Notably, analysis of OC cell-born exosomes not only confirmed the concentration-dependent correlation of HSP27 expression and secretion but also demonstrated a concentration-dependent incorporation of HSP27 protein into exosomes. Thus, secreted HSP27 may become more important as an extracellular factor which controls the tumor microenvironment and might be a noninvasive biomarker. PMID:28325957

Heat Shock Protein HSP27 Secretion by Ovarian Cancer Cells Is Linked to Intracellular Expression Levels, Occurs Independently of the Endoplasmic Reticulum Pathway and HSP27's Phosphorylation Status, and Is Mediated by Exosome Liberation.

PubMed

Stope, Matthias B; Klinkmann, Gerd; Diesing, Karoline; Koensgen, Dominique; Burchardt, Martin; Mustea, Alexander

2017-01-01

The heat shock protein HSP27 has been correlated in ovarian cancer (OC) patients with aggressiveness and chemoresistance and, therefore, represents a promising potential biomarker for OC diagnosis, prognosis, and treatment response. Notably, secretion of soluble HSP27 has been described by a few cell types and may take place as well in OC cells. Therefore, we studied HSP27 secretion mechanisms under diverse cellular conditions in an OC cell model system. Secretion of HSP27 was characterized after overexpression of HSP27 by transfected plasmids and after heat shock. Intra- and extracellular HSP27 amounts were assessed by Western blotting and ELISA. Protein secretion was blocked by brefeldin A and the impact of the HSP27 phosphorylation status was analyzed overexpressing HSP27 phosphomutants. The present study demonstrated that HSP27 secretion by OVCAR-3 and SK-OV-3 cells depends on intracellular HSP27 concentrations. Moreover, HSP27 secretion is independent of the endoplasmic reticulum secretory pathway and HSP27 phosphorylation. Notably, analysis of OC cell-born exosomes not only confirmed the concentration-dependent correlation of HSP27 expression and secretion but also demonstrated a concentration-dependent incorporation of HSP27 protein into exosomes. Thus, secreted HSP27 may become more important as an extracellular factor which controls the tumor microenvironment and might be a noninvasive biomarker.

High-Throughput Screening and Quantitative Chemical Ranking for Sodium-Iodide Symporter Inhibitors in ToxCast Phase I Chemical Library.

PubMed

Wang, Jun; Hallinger, Daniel R; Murr, Ashley S; Buckalew, Angela R; Simmons, Steven O; Laws, Susan C; Stoker, Tammy E

2018-05-01

Thyroid uptake of iodide via the sodium-iodide symporter (NIS) is the first step in the biosynthesis of thyroid hormones that are critical for health and development in humans and wildlife. Despite having long been a known target of endocrine disrupting chemicals such as perchlorate, information regarding NIS inhibition activity is still unavailable for the vast majority of environmental chemicals. This study applied a previously validated high-throughput approach to screen for NIS inhibitors in the ToxCast phase I library, representing 293 important environmental chemicals. Here 310 blinded samples were screened in a tiered-approach using an initial single-concentration (100 μM) radioactive-iodide uptake (RAIU) assay, followed by 169 samples further evaluated in multi-concentration (0.001 μM-100 μM) testing in parallel RAIU and cell viability assays. A novel chemical ranking system that incorporates multi-concentration RAIU and cytotoxicity responses was also developed as a standardized method for chemical prioritization in current and future screenings. Representative chemical responses and thyroid effects of high-ranking chemicals are further discussed. This study significantly expands current knowledge of NIS inhibition potential in environmental chemicals and provides critical support to U.S. EPA's Endocrine Disruptor Screening Program (EDSP) initiative to expand coverage of thyroid molecular targets, as well as the development of thyroid adverse outcome pathways (AOPs).

Inorganic elements in green sea turtles (Chelonia mydas): relationships among external and internal tissues

USGS Publications Warehouse

Faust, Derek R.; Hooper, Michael J.; Cobb, George P.; Barnes, Melanie; Shaver, Donna; Ertolacci, Shauna; Smith, Philip N.

2014-01-01

Inorganic elements from anthropogenic sources have entered marine environments worldwide and are detectable in marine organisms, including sea turtles. Threatened and endangered classifications of sea turtles have heretofore made assessments of contaminant concentrations difficult because of regulatory restrictions on obtaining samples using nonlethal techniques. In the present study, claw and skin biopsy samples were examined as potential indicators of internal tissue burdens in green sea turtles (Chelonia mydas). Significant relationships were observed between claw and liver, and claw and muscle concentrations of mercury, nickel, arsenic, and selenium (p < 0.05). Similarly, significant relationships were observed between skin biopsy concentrations and those in liver, kidney, and muscle tissues for mercury, arsenic, selenium, and vanadium (p < 0.05). Concentrations of arsenic, barium, chromium, nickel, strontium, vanadium, and zinc in claws and skin biopsies were substantially elevated when compared with all other tissues, indicating that these highly keratinized tissues may represent sequestration or excretion pathways. Correlations between standard carapace length and cobalt, lead, and manganese concentrations were observed (p < 0.05), indicating that tissue concentrations of these elements may be related to age and size. Results suggest that claws may indeed be useful indicators of mercury and nickel concentrations in liver and muscle tissues, whereas skin biopsy inorganic element concentrations may be better suited as indicators of mercury, selenium, and vanadium concentrations in liver, kidney, and muscle tissues of green sea turtles.

Using the New Scenarios Framework to Inform Climate Change Adaptation Policy in Finland

NASA Astrophysics Data System (ADS)

Carter, T. R.

2013-12-01

In 2005, Finland was among the first countries in the world to develop a national climate change adaptation strategy (Marttila et al., 2005). This included a characterization of future changes in climate and socioeconomic conditions using scenarios based on the IPCC Special Report on Emissions Scenarios (SRES - IPCC, 2000). Following a government evaluation of the strategy, completion of a national adaptation research programme, and in light of the recent European Union adaptation strategy, the Finnish strategy is now under revision. As part of this revision process, the New Scenario Framework (Moss et al., 2010) is being used to guide the mapping of future conditions in Finland out to the end of the 21st century. Future Finnish climate is being analysed using the CMIP5 climate model simulations (Taylor et al., 2012), including downscaled information based on regional climate model projections in the EURO-CORDEX project (Vautard et al., 2013). All projections are forced by the Representative Concentration Pathways (RCPs - van Vuuren et al., 2011). Socioeconomic scenarios are also being developed by outlining alternative pathways that reflect national social, economic, environmental and planning goals. These are designed according to the Shared Socioeconomic Pathway (SSP) framework of challenges to adaptation and mitigation (Kriegler et al., 2012). Work is in progress to characterize these pathways, mainly qualitatively, for different sectors in Finland. Preliminary results of the conceptual scenario development phase will be presented in this session. These initial ideas will be exchanged with representatives of ministries, regional government and key stakeholder groups. The eventual form and number of scenarios that appear in the revised strategy will be determined following a formal review of the draft document to be prepared in 2014. Future work could include quantification of scenarios, possibly mapping them onto the specific SSP worlds. This would then provide a firm basis for future climate change impact, adaptation and vulnerability assessments, offering RCP/SSP-based scenarios that are not only related to the global New Scenarios Framework, but are also recognised by national policy makers and key stakeholders, via the revised national climate change adaptation strategy. References IPCC (2000) Special Report on Emissions Scenarios: A Special Report of Working Group III of the Intergovernmental Panel on Climate Change. [Nakićenović, N. et al. (eds.)]. Cambridge University Press, 600 pp. Kriegler E et al. (2012) The need for and use of socio-economic scenarios for climate change analysis: A new approach based on shared socio-economic pathways. Glob. Envir. Change 22:807-822. Marttila V et al. (2005) Finland's National Strategy for Adaptation to Climate Change, MMM publications 1a/2005, Ministry of Agriculture and Forestry, Helsinki, Finland, 280 pp. Moss RH et al. (2010) The next generation of scenarios for climate change research and assessment. Nature 463:747-756. Taylor KE et al. (2012) A summary of the CMIP5 experiment design. BAMS 93:485-498. van Vuuren DP et al. (2011) The representative concentration pathways: an overview. Clim. Change 109:5-31. Vautard R et al. (2013) The simulation of European heat waves from an ensemble of regional climate models within the EURO-CORDEX project. Clim. Dyn. doi:10.1007/s00382-013-1714-z

DNA assembler, an in vivo genetic method for rapid construction of biochemical pathways

PubMed Central

Shao, Zengyi; Zhao, Hua; Zhao, Huimin

2009-01-01

The assembly of large recombinant DNA encoding a whole biochemical pathway or genome represents a significant challenge. Here, we report a new method, DNA assembler, which allows the assembly of an entire biochemical pathway in a single step via in vivo homologous recombination in Saccharomyces cerevisiae. We show that DNA assembler can rapidly assemble a functional d-xylose utilization pathway (∼9 kb DNA consisting of three genes), a functional zeaxanthin biosynthesis pathway (∼11 kb DNA consisting of five genes) and a functional combined d-xylose utilization and zeaxanthin biosynthesis pathway (∼19 kb consisting of eight genes) with high efficiencies (70–100%) either on a plasmid or on a yeast chromosome. As this new method only requires simple DNA preparation and one-step yeast transformation, it represents a powerful tool in the construction of biochemical pathways for synthetic biology, metabolic engineering and functional genomics studies. PMID:19074487

Characterisation of transcriptional responses to dioxins and dioxin-like contaminants in roach (Rutilus rutilus) using whole transcriptome analysis.

PubMed

Brinkmann, Markus; Koglin, Sven; Eisner, Bryanna; Wiseman, Steve; Hecker, Markus; Eichbaum, Kathrin; Thalmann, Beat; Buchinger, Sebastian; Reifferscheid, Georg; Hollert, Henner

2016-01-15

There is significant concern regarding the contamination of riverine sediments with dioxins and dioxin-like compounds (DLCs), including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs) and some polycyclic aromatic hydrocarbons (PAHs). The majority of studies investigating the ecotoxicology of DLCs in fish have focused on a few standard model species. However, there is significant uncertainty as to whether these model species are representative of native river fish, particularly in Europe. In this study, the transcriptional responses following exposure to equipotent concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), PCB 156 or the dioxin-like PAH, benzo[k]fluoranthene (BkF), were investigated in juvenile roach (Rutilus rutilus), a fish species that constitutes a large proportion of the fish biomass in freshwater bodies throughout Europe. To this end, RNA sequencing analysis was used to comprehensively characterise the molecular mechanisms and pathways of toxicity of these DLCs. Whole transcriptome analyses using ClueGO software revealed that DLCs have the potential to disrupt a number of important processes, including energy metabolism, oogenesis, the immune system, apoptosis and the response to oxidative stress. However, despite using equipotent concentrations, there was very little conservation of the transcriptional responses observed in fish exposed to different DLCs. TCDD provoked significant specific changes in the levels of transcripts related to immunotoxicity and carbohydrate metabolism, while PCB 156 caused virtually no specific effects. Exposure to BkF affected the most diverse suite of molecular functions and biological processes, including blood coagulation, oxidative stress responses, unspecific responses to organic or inorganic substances/stimuli, cellular redox homeostasis and specific receptor pathways. To our knowledge, this is the first study of the transcriptome-wide effects of different classes of DLCs in fish. These findings represent an important step towards describing complete toxicity pathways of DLCs, which will be important in the context of informing risk assessments of DLC toxicity in native fish species. Copyright © 2015 Elsevier B.V. All rights reserved.

Ab Initio-Based Kinetic Modeling for the Design of Molecular Catalysts: The Case of H 2 Production Electrocatalysts

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

Ho, Ming-Hsun; Rousseau, Roger; Roberts, John A. S.

2015-09-04

Design of fast, efficient electrocatalysts for energy production and energy utilization requires a systematic approach to predict and tune the energetics of reaction intermediates and the kinetic barriers between them as well as to tune reaction conditions (e.g., concentration of reactants, acidity of the reaction medium, and applied electric potential). Thermodynamics schemes based on the knowledge of pKa values, hydride donor ability, redox potentials, and other relevant thermodynamic properties have been demonstrated to be very effective for exploring possible reaction pathways. We seek to identify high-energy intermediates, which may represent a catalytic bottleneck, and low-energy intermediates, which may represent amore » thermodynamic sink. In this study, working on a well-established Ni-based bioinspired electrocatalyst for H2 production, we performed a detailed kinetic analysis of the catalytic pathways to assess the limitations of our current (standard state) thermodynamic analysis with respect to prediction of optimal catalyst performance. To this end, we developed a microkinetic model based on extensive ab initio simulations. The model was validated against available experimental data, and it reproduces remarkably well the observed turnover rate as a function of the acid concentration and catalytic conditions, providing valuable information on the main factors limiting catalysis. Using this kinetic analysis as a reference, we show that indeed a purely thermodynamic analysis of the possible reaction pathways provides us with valuable information, such as a qualitative picture of the species involved during catalysis, identification of the possible branching points, and the origin of the observed overpotential, which are critical insights for electrocatalyst design. However, a significant limitation of this approach is understanding how these insights relate to rate, which is an equally critical piece of information. Taking our analysis a step further, we show that the kinetic model can easily be extended to different catalytic conditions by using linear free energy relationships for activation barriers based on simple thermodynamics quantities, such as pKa values. We also outline a possible procedure to extend it to other catalytic platforms, making it a general and effective way to design catalysts with improved performance.« less

Temperature Rise and Allowable Carbon Emissions for the RCP2.6 Scenario

NASA Astrophysics Data System (ADS)

Tachiiri, K.; Hargreaves, J. C.; Annan, J. D.; Huntingford, C.; Kawamiya, M.

2012-12-01

Climate research centres are running Earth System Models (ESMs) forced by Representative Concentration Pathway (RCP) scenarios. While these GCM studies increase process based knowledge, the number of simulations is small, making it difficult to interpret the resulting distribution of responses in a probabilistic way. We use a probabilistic framework to estimate the range of future temperature change and allowable emissions for a low mitigation CO2 concentration pathway RCP 2.6. Uncertainty is initially estimated by allowing modelled equilibrium climate sensitivity, aerosol forcing and intrinsic physical and biogeochemical processes to vary within widely accepted ranges. Results are then further constrained by extensive use of contemporary measurements. Despite this, the resulting range of temperatures for RCP 2.6 remains large. The predicted peak global temperature increase, reached around 2100, from pre-industrial is 0.8 - 1.9 K and 1.0 - 1.9 K (95% range) for the unconstrained and the constrained cases, respectively. Allowable emissions at the time of peak emission period is projected as 6.0 - 10.8 PgC yr-1 and 7.4 - 10.2 PgC yr-1 for each case. After year 2100, negative net emissions are required with a probability of some 84 %, and related uncertainty in cumulative emissions is large.

Vitamin D pathway gene polymorphisms affecting daclatasvir plasma concentration at 2 weeks and 1 month of therapy.

PubMed

Cusato, Jessica; Nicolò, Amedeo De; Boglione, Lucio; Favata, Fabio; Ariaudo, Alessandra; Pinna, Simone Mornese; Carcieri, Chiara; Guido, Federica; Cariti, Giuseppe; Perri, Giovanni Di; D'Avolio, Antonio

2018-06-01

Vitamin D (VD) influences genetic expression through its receptor (VDR). VD pathway gene polymorphisms seem to influence antiviral drug pharmacokinetics and therapeutic outcome/toxicity. We investigated the association between daclatasvir (DCV) plasma concentrations and genetic variants (SNPs) associated with the VD pathway. Chronic hepatitis C patients treated with DCV from 2014 to 2016 were included. Genotypes were assessed through real-time PCR and plasma concentrations through liquid chromatography. A total of 52 patients were analyzed. DCV levels were influenced by CYP24A1 rs2248359T>C polymorphism at 2 weeks and VDR Cdx2 A>G at 1 month of treatment. Linear regression analysis showed baseline BMI, alanine aminotransferase and hematocrit as significant predictors of DCV concentrations at 2 weeks, BMI and hematocrit at baseline, VDR Cdx2 AG/GG and FokI TC/CC at 1 month. These results showed a possible role of VD pathway gene polymorphisms in influencing DCV plasma concentrations, but further studies are required.

Characterizing phosphorus dynamics in tile-drained agricultural fieldsof eastern Wisconsin

USGS Publications Warehouse

Madison, Allison; Ruark, Matthew; Stuntebeck, Todd D.; Komiskey, Matthew J.; Good, Laura W.; Drummy, Nancy; Cooley, Eric

2014-01-01

Artificial subsurface drainage provides an avenue for the rapid transfer of phosphorus (P) from agricultural fields to surface waters. This is of particular interest in eastern Wisconsin, where there is a concentrated population of dairy farms and high clay content soils prone to macropore development. Through collaboration with private landowners, surface and tile drainage was measured and analyzed for dissolved reactive P (DRP) and total P (TP) losses at four field sites in eastern Wisconsin between 2005 and 2009. These sites, which received frequent manure applications, represent a range of crop management practices which include: two chisel plowed corn fields (CP1, CP2), a no-till corn–soybean field (NT), and a grazed pasture (GP). Subsurface drainage was the dominant pathway of water loss at each site accounting for 66–96% of total water discharge. Average annual flow-weighted (FW) TP concentrations were 0.88, 0.57, 0.21, and 1.32 mg L−1 for sites CP1, CP2, NT, and GP, respectively. Low TP concentrations at the NT site were due to tile drain interception of groundwater flow where large volumes of tile drainage water diluted the FW-TP concentrations. Subsurface pathways contributed between 17% and 41% of the TP loss across sites. On a drainage event basis, total drainage explained between 36% and 72% of the event DRP loads across CP1, CP2, and GP; there was no relationship between event drainflow and event DRP load at the NT site. Manure applications did not consistently increase P concentrations in drainflow, but annual FW-P concentrations were greater in years receiving manure applications compared to years without manure application. Based on these field measures, P losses from tile drainage must be integrated into field level P budgets and P loss calculations on heavily manured soils, while also acknowledging the unique drainage patterns observed in eastern Wisconsin.

Characterizing phosphorus dynamics in tile-drained agricultural fields of eastern Wisconsin

NASA Astrophysics Data System (ADS)

Madison, Allison M.; Ruark, Matthew D.; Stuntebeck, Todd D.; Komiskey, Matthew J.; Good, Lara W.; Drummy, Nancy; Cooley, Eric T.

2014-11-01

Artificial subsurface drainage provides an avenue for the rapid transfer of phosphorus (P) from agricultural fields to surface waters. This is of particular interest in eastern Wisconsin, where there is a concentrated population of dairy farms and high clay content soils prone to macropore development. Through collaboration with private landowners, surface and tile drainage was measured and analyzed for dissolved reactive P (DRP) and total P (TP) losses at four field sites in eastern Wisconsin between 2005 and 2009. These sites, which received frequent manure applications, represent a range of crop management practices which include: two chisel plowed corn fields (CP1, CP2), a no-till corn-soybean field (NT), and a grazed pasture (GP). Subsurface drainage was the dominant pathway of water loss at each site accounting for 66-96% of total water discharge. Average annual flow-weighted (FW) TP concentrations were 0.88, 0.57, 0.21, and 1.32 mg L-1 for sites CP1, CP2, NT, and GP, respectively. Low TP concentrations at the NT site were due to tile drain interception of groundwater flow where large volumes of tile drainage water diluted the FW-TP concentrations. Subsurface pathways contributed between 17% and 41% of the TP loss across sites. On a drainage event basis, total drainage explained between 36% and 72% of the event DRP loads across CP1, CP2, and GP; there was no relationship between event drainflow and event DRP load at the NT site. Manure applications did not consistently increase P concentrations in drainflow, but annual FW-P concentrations were greater in years receiving manure applications compared to years without manure application. Based on these field measures, P losses from tile drainage must be integrated into field level P budgets and P loss calculations on heavily manured soils, while also acknowledging the unique drainage patterns observed in eastern Wisconsin.

Impact of mesophyll diffusion on estimated global land CO 2 fertilization

DOE PAGES

Sun, Ying; Gu, Lianhong; Dickinson, Robert E.; ...

2014-10-13

In C 3 plants, CO 2 concentrations drop considerably along mesophyll diffusion pathways from substomatal cavities to chloroplasts where CO 2 assimilation occurs. Global carbon cycle models have not explicitly represented this internal drawdown and so overestimate CO 2 available for carboxylation and underestimate photosynthetic responsiveness to atmospheric CO 2. An explicit consideration of mesophyll diffusion increases the modeled cumulative CO 2 fertilization effect (CFE) for global gross primary production (GPP) from 915 PgC to 1057 PgC for the period of 1901 to 2010. This increase represents a 16% correction, large enough to explain the persistent overestimation of growth ratesmore » of historical atmospheric CO 2 by Earth System Models. Without this correction, the CFE for global GPP is underestimated by 0.05 PgC yr -1ppm -1. This finding implies that the contemporary terrestrial biosphere is more CO 2-limited than previously thought.« less

Differentially expressed genes and pathways induced by organophosphates in human neuroblastoma cells.

PubMed

Li, Tianwei; Zhao, Hongtao; Hung, Guo-Chiuan; Han, Jing; Tsai, Shien; Li, Bingjie; Zhang, Jing; Puri, Raj K; Lo, Shyh-Ching

2012-12-01

Organophosphates (OPs) are toxic chemicals commonly used as pesticides and herbicides. Some OPs are highly toxic to humans and have been used in warfare and terrorist attacks. In order to elucidate the molecular mechanisms of injury caused by OPs, the differentially expressed genes were analyzed in human SK-N-SH neuroblastoma cells induced by three OPs. The SK-N-SH cells were treated with one of the three OPs, chlorpyrifos, dichlorvos or methamidophos at LC20 (high-dose), the concentration causing 20% cell death, as well as 1/20 of LC20 (low-dose), a sub-lethal concentration with no detectable cell death, for 24 h. The genome-wide gene changes were identified by Agilent Microarray System, and analyzed by microarray analysis tools. The analysis revealed neuroblastoma cells treated with the high doses of all three OPs markedly activated cell apoptosis and inhibited cell growth and proliferation genes, which would most likely lead to the process of cell death. Interestingly, the analysis also revealed significant decrease in expressions of many genes in a specific spliceosome pathway in cells treated with the low doses of all three different OPs. The change of spliceosome pathway may represent an important mechanism of injury in neuronal cells exposed to low doses of various OPs. In addition to unraveling a potentially different form of OP pathogenesis, this finding could provide a new diagnostic marker in assessing OP-associated injury in cells or tissues. In addition, these results could also contribute to the development of new prevention and/or therapeutic regimens against OP toxicity.

Cholesterol accumulation in tissues of the Niemann-pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ.

PubMed

Xie, C; Turley, S D; Dietschy, J M

1999-10-12

Niemann-Pick type C (NPC) disease is associated with the accumulation of unesterified cholesterol in nearly all tissues and with progressive neurodegeneration. A murine model of this disease, the NPC mouse, was used to determine whether this sequestered cholesterol represented sterol carried in low density lipoprotein (LDL) and chylomicrons (CMs) taken up into the tissues through the coated-pit pathway. By 7 weeks of age, the sterol pool in the NPC mice had increased from 2,165 to 5,669 mg/kg body weight because of the daily sequestration of 67 mg of cholesterol per kg in the various organs. This was 7-fold greater than the rate of accumulation in control mice. The rate of LDL clearance in the NPC mouse was normal (523 ml/day per kg) and accounted for the uptake of 78 mg/day per kg of cholesterol in LDL whereas 8 mg/day per kg was taken up from CMs. Deletion of the LDL receptor in NPC mice altered the concentration of unesterified cholesterol in every organ in a manner consistent with the changes also observed in the rate of LDL cholesterol uptake in those tissues. Similarly, altering the flow of cholesterol to the liver through the CM pathway changed the concentration of unesterified cholesterol in that organ. Together, these observations strongly support the conclusion that, in NPC disease, it is cholesterol carried in LDL and CMs that is sequestered in the tissues and not sterol that is newly synthesized and carried in high density lipoprotein.

Environmental controls on modern scleractinian coral and reef-scale calcification.

PubMed

Courtney, Travis A; Lebrato, Mario; Bates, Nicholas R; Collins, Andrew; de Putron, Samantha J; Garley, Rebecca; Johnson, Rod; Molinero, Juan-Carlos; Noyes, Timothy J; Sabine, Christopher L; Andersson, Andreas J

2017-11-01

Modern reef-building corals sustain a wide range of ecosystem services because of their ability to build calcium carbonate reef systems. The influence of environmental variables on coral calcification rates has been extensively studied, but our understanding of their relative importance is limited by the absence of in situ observations and the ability to decouple the interactions between different properties. We show that temperature is the primary driver of coral colony ( Porites astreoides and Diploria labyrinthiformis ) and reef-scale calcification rates over a 2-year monitoring period from the Bermuda coral reef. On the basis of multimodel climate simulations (Coupled Model Intercomparison Project Phase 5) and assuming sufficient coral nutrition, our results suggest that P. astreoides and D. labyrinthiformis coral calcification rates in Bermuda could increase throughout the 21st century as a result of gradual warming predicted under a minimum CO 2 emissions pathway [representative concentration pathway (RCP) 2.6] with positive 21st-century calcification rates potentially maintained under a reduced CO 2 emissions pathway (RCP 4.5). These results highlight the potential benefits of rapid reductions in global anthropogenic CO 2 emissions for 21st-century Bermuda coral reefs and the ecosystem services they provide.

SEEPLUS: A SIMPLE ONLINE CLIMATE MODEL

NASA Astrophysics Data System (ADS)

Tsutsui, Junichi

A web application for a simple climate model - SEEPLUS (a Simple climate model to Examine Emission Pathways Leading to Updated Scenarios) - has been developed. SEEPLUS consists of carbon-cycle and climate-change modules, through which it provides the information infrastructure required to perform climate-change experiments, even on a millennial-timescale. The main objective of this application is to share the latest scientific knowledge acquired from climate modeling studies among the different stakeholders involved in climate-change issues. Both the carbon-cycle and climate-change modules employ impulse response functions (IRFs) for their key processes, thereby enabling the model to integrate the outcome from an ensemble of complex climate models. The current IRF parameters and forcing manipulation are basically consistent with, or within an uncertainty range of, the understanding of certain key aspects such as the equivalent climate sensitivity and ocean CO2 uptake data documented in representative literature. The carbon-cycle module enables inverse calculation to determine the emission pathway required in order to attain a given concentration pathway, thereby providing a flexible way to compare the module with more advanced modeling studies. The module also enables analytical evaluation of its equilibrium states, thereby facilitating the long-term planning of global warming mitigation.

Environmental controls on modern scleractinian coral and reef-scale calcification

PubMed Central

Courtney, Travis A.; Lebrato, Mario; Bates, Nicholas R.; Collins, Andrew; de Putron, Samantha J.; Garley, Rebecca; Johnson, Rod; Molinero, Juan-Carlos; Noyes, Timothy J.; Sabine, Christopher L.; Andersson, Andreas J.

2017-01-01

Modern reef-building corals sustain a wide range of ecosystem services because of their ability to build calcium carbonate reef systems. The influence of environmental variables on coral calcification rates has been extensively studied, but our understanding of their relative importance is limited by the absence of in situ observations and the ability to decouple the interactions between different properties. We show that temperature is the primary driver of coral colony (Porites astreoides and Diploria labyrinthiformis) and reef-scale calcification rates over a 2-year monitoring period from the Bermuda coral reef. On the basis of multimodel climate simulations (Coupled Model Intercomparison Project Phase 5) and assuming sufficient coral nutrition, our results suggest that P. astreoides and D. labyrinthiformis coral calcification rates in Bermuda could increase throughout the 21st century as a result of gradual warming predicted under a minimum CO2 emissions pathway [representative concentration pathway (RCP) 2.6] with positive 21st-century calcification rates potentially maintained under a reduced CO2 emissions pathway (RCP 4.5). These results highlight the potential benefits of rapid reductions in global anthropogenic CO2 emissions for 21st-century Bermuda coral reefs and the ecosystem services they provide. PMID:29134196

On the deduction of chemical reaction pathways from measurements of time series of concentrations.

PubMed

Samoilov, Michael; Arkin, Adam; Ross, John

2001-03-01

We discuss the deduction of reaction pathways in complex chemical systems from measurements of time series of chemical concentrations of reacting species. First we review a technique called correlation metric construction (CMC) and show the construction of a reaction pathway from measurements on a part of glycolysis. Then we present two new improved methods for the analysis of time series of concentrations, entropy metric construction (EMC), and entropy reduction method (ERM), and illustrate (EMC) with calculations on a model reaction system. (c) 2001 American Institute of Physics.

Climate change impacts on human health over Europe through its effect on air quality.

PubMed

Doherty, Ruth M; Heal, Mathew R; O'Connor, Fiona M

2017-12-05

This review examines the current literature on the effects of future emissions and climate change on particulate matter (PM) and O 3 air quality and on the consequent health impacts, with a focus on Europe. There is considerable literature on the effects of climate change on O 3 but fewer studies on the effects of climate change on PM concentrations. Under the latest Intergovernmental Panel on Climate Change (IPCC) 5th assessment report (AR5) Representative Concentration Pathways (RCPs), background O 3 entering Europe is expected to decrease under most scenarios due to higher water vapour concentrations in a warmer climate. However, under the extreme pathway RCP8.5 higher (more than double) methane (CH 4 ) abundances lead to increases in background O 3 that offset the O 3 decrease due to climate change especially for the 2100 period. Regionally, in polluted areas with high levels of nitrogen oxides (NO x ), elevated surface temperatures and humidities yield increases in surface O 3 - termed the O 3 climate penalty - especially in southern Europe. The O 3 response is larger for metrics that represent the higher end of the O 3 distribution, such as daily maximum O 3 . Future changes in PM concentrations due to climate change are much less certain, although several recent studies also suggest a PM climate penalty due to high temperatures and humidity and reduced precipitation in northern mid-latitude land regions in 2100.A larger number of studies have examined both future climate and emissions changes under the RCP scenarios. Under these pathways the impact of emission changes on air quality out to the 2050s will be larger than that due to climate change, because of large reductions in emissions of O 3 and PM pollutant precursor emissions and the more limited climate change response itself. Climate change will also affect climate extreme events such as heatwaves. Air pollution episodes are associated with stagnation events and sometimes heat waves. Air quality during the 2003 heatwave over Europe has been examined in numerous studies and mechanisms for enhancing O 3 have been identified.There are few studies on health effects associated with climate change impacts alone on air quality, but these report higher O 3 -related health burdens in polluted populated regions and greater PM 2.5 health burdens in these emission regions. Studies that examine the combined impacts of climate change and anthropogenic emissions change under the RCP scenarios report reductions in global and European premature O 3 -respiratory related and PM mortalities arising from the large decreases in precursor emissions. Under RCP 8.5 the large increase in CH 4 leads to global and European excess O 3 -respiratory related mortalities in 2100. For future health effects, besides uncertainty in future O 3 and particularly PM concentrations, there is also uncertainty in risk estimates such as effect modification by temperature on pollutant-response relationships and potential future adaptation that would alter exposure risk.

Revealing common disease mechanisms shared by tumors of different tissues of origin through semantic representation of genomic alterations and topic modeling.

PubMed

Chen, Vicky; Paisley, John; Lu, Xinghua

2017-03-14

Cancer is a complex disease driven by somatic genomic alterations (SGAs) that perturb signaling pathways and consequently cellular function. Identifying patterns of pathway perturbations would provide insights into common disease mechanisms shared among tumors, which is important for guiding treatment and predicting outcome. However, identifying perturbed pathways is challenging, because different tumors can have the same perturbed pathways that are perturbed by different SGAs. Here, we designed novel semantic representations that capture the functional similarity of distinct SGAs perturbing a common pathway in different tumors. Combining this representation with topic modeling would allow us to identify patterns in altered signaling pathways. We represented each gene with a vector of words describing its function, and we represented the SGAs of a tumor as a text document by pooling the words representing individual SGAs. We applied the nested hierarchical Dirichlet process (nHDP) model to a collection of tumors of 5 cancer types from TCGA. We identified topics (consisting of co-occurring words) representing the common functional themes of different SGAs. Tumors were clustered based on their topic associations, such that each cluster consists of tumors sharing common functional themes. The resulting clusters contained mixtures of cancer types, which indicates that different cancer types can share disease mechanisms. Survival analysis based on the clusters revealed significant differences in survival among the tumors of the same cancer type that were assigned to different clusters. The results indicate that applying topic modeling to semantic representations of tumors identifies patterns in the combinations of altered functional pathways in cancer.

JS-K, a nitric oxide pro-drug, regulates growth and apoptosis through the ubiquitin-proteasome pathway in prostate cancer cells.

PubMed

Tan, Guobin; Qiu, Mingning; Chen, Lieqian; Zhang, Sai; Ke, Longzhi; Liu, Jianjun

2017-05-26

In view of the fact that JS-K might regulate ubiquitin E3 ligase and that ubiquitin E3 ligase plays an important role in the mechanism of CRPC formation, the goal was to investigate the probable mechanism by which JS-K regulates prostate cancer cells. Proliferation inhibition by JS-K on prostate cancer cells was examined usingCCK-8 assays. Caspase 3/7 activity assays and flow cytometry were performed to examine whether JS-K induced apoptosis in prostate cancer cells. Western blotting and co-immunoprecipitation analyses investigated JS-K's effects on the associated apoptosis mechanism. Real time-PCR and Western blotting were performed to assess JS-K's effect on transcription of specific AR target genes. Western blotting was also performed to detect Siah2 and AR protein concentrations and co-immunoprecipitation to detect interactions of Siah2 and AR, NCoR1 and AR, and p300 and AR. JS-K inhibited proliferation and induced apoptosis in prostate cancer cells. JS-K increased p53 and Mdm2 concentrations and regulated the caspase cascade reaction-associated protein concentrations. JS-K inhibited transcription of AR target genes and down-regulated PSA protein concentrations. JS-K inhibited Siah2 interactions and also inhibited the ubiquitination of AR. With further investigation, JS-K was found to stabilize AR and NCoR1 interactions and diminish AR and p300 interactions. The present results suggested that JS-K might have been able to inhibit proliferation and induce apoptosis via regulation of the ubiquitin-proteasome degradation pathway, which represented a promising platform for the development of new compounds for PCa treatments.

Multiple oxygen entry pathways in globin proteins revealed by intrinsic pathway identification method

NASA Astrophysics Data System (ADS)

Takayanagi, Masayoshi; Kurisaki, Ikuo; Nagaoka, Masataka

2015-12-01

Each subunit of human hemoglobin (HbA) stores an oxygen molecule (O2) in the binding site (BS) cavity near the heme group. The BS is buried in the interior of the subunit so that there is a debate over the O2 entry pathways from solvent to the BS; histidine gate or multiple pathways. To elucidate the O2 entry pathways, we executed ensemble molecular dynamics (MD) simulations of T-state tetramer HbA in high concentration O2 solvent to simulate spontaneous O2 entry from solvent into the BS. By analyzing 128 independent 8 ns MD trajectories by intrinsic pathway identification by clustering (IPIC) method, we found 141 and 425 O2 entry events into the BS of the α and β subunits, respectively. In both subunits, we found that multiple O2 entry pathways through inside cavities play a significant role for O2 entry process of HbA. The rate constants of O2 entry estimated from the MD trajectories correspond to the experimentally observed values. In addition, by analyzing monomer myoglobin, we verified that the high O2 concentration condition can reproduce the ratios of each multiple pathway in the one-tenth lower O2 concentration condition. These indicate the validity of the multiple pathways obtained in our MD simulations.

Synthesis, antiproliferative activity and mechanism of gallium(III)-thiosemicarbazone complexes as potential anti-breast cancer agents.

PubMed

Qi, Jinxu; Yao, Qian; Qian, Kun; Tian, Liang; Cheng, Zhen; Yang, Dongmei; Wang, Yihong

2018-05-14

Five thiosemicarbazone ligands were synthesized and characterized by condensation with different aldehydes or ketones by 4-phenylthiosemicarbazone. The representative dichlorido[2-(Di-2-pyridinylmethylene)-Nphenylhydrazinecarbothioamide-N,N,S]-gallium(III) (Ga4) was characterized by X-ray single crystal diffraction, which was 1:1 ligand/Ga(III) complexes. The structure-activity relationship of these ligands and Ga (III) complexes have been investigated, and the results demonstrate that the formation of Ga (III) complexes have significant antiproliferative activity over the corresponding ligands. The anticancer mechanism of gallium (III) complexes has been studied in detail, which is typical agents that effect on the mitochondrial apoptotic pathway. The ability of gallium (III) complexes to inhibit the cell cycle does not enhanced with the increasing concentrations, whereas the ability to promote apoptosis is concentration-dependent. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Physical Controls on Oxygen Distribution and Denitrification Potential in the North West Arabian Sea

NASA Astrophysics Data System (ADS)

Queste, Bastien Y.; Vic, Clément; Heywood, Karen J.; Piontkovski, Sergey A.

2018-05-01

At suboxic oxygen concentrations, key biogeochemical cycles change and denitrification becomes the dominant remineralization pathway. Earth system models predict oxygen loss across most ocean basins in the next century; oxygen minimum zones near suboxia may become suboxic and therefore denitrifying. Using an ocean glider survey and historical data, we show oxygen loss in the Gulf of Oman (from 6-12 to <2 μmol kg-1) not represented in climatologies. Because of the nonlinearity between denitrification and oxygen concentration, resolutions of current Earth system models are too coarse to accurately estimate denitrification. We develop a novel physical proxy for oxygen from the glider data and use a high-resolution physical model to show eddy stirring of oxygen across the Gulf of Oman. We use the model to investigate spatial and seasonal differences in the ratio of oxic and suboxic water across the Gulf of Oman and waters exported to the wider Arabian Sea.

Creating lenticular galaxies with mergers

NASA Astrophysics Data System (ADS)

Querejeta, Miguel; Eliche-Moral, M. Carmen; Tapia, Trinidad; Borlaff, Alejandro; van de Ven, Glenn; Lyubenova, Mariya; Martig, Marie; Falcón-Barroso, Jesús; Méndez-Abreu, Jairo; Zamorano, Jaime; Gallego, Jesús

2017-03-01

Lenticular galaxies (S0s) represent the majority of early-type galaxies in the local Universe, but their formation channels are still poorly understood. While galaxy mergers are obvious pathways to suppress star formation and increase bulge sizes, the marked parallelism between spiral and lenticular galaxies (e.g. photometric bulge-disc coupling) seemed to rule out a potential merger origin. Here, we summarise our recent work in which we have shown, through N-body numerical simulations, that disc-dominated lenticulars can emerge from major mergers of spiral galaxies, in good agreement with observational photometric scaling relations. Moreover, we show that mergers simultaneously increase the light concentration and reduce the angular momentum relative to their spiral progenitors. This explains the mismatch in angular momentum and concentration between spirals and lenticulars recently revealed by CALIFA observations, which is hard to reconcile with simple fading mechanisms (e.g. ram-pressure stripping).

Possible Roles of Fluoride and Carbonate in Biochemical Carbonated Apatite Formation

NASA Astrophysics Data System (ADS)

Meouch, Orysia; Omelon, Sidney

2016-04-01

Marine phosphorites are predominantly composed of carbonated fluorapatite (CFA = Ca10-a-b-cNaaMgb(PO4)6-x(CO3)x-y-z(CO3.F)y(SO4)zF2, where x=y+a+2c, and c represents the number of Ca vacancies, with a P2O5 content that ranges from 18-40 %. Sulphur-oxidizing bacteria of the Beggiatoa genus concentration phosphorous as intracellular polyphosphate ((PO3-)n) which is depolymerized into inorganic orthophosphate (Pi). Consequently, an increase in pore water Pi concentration favours carbonated apatite precipitation. The carbonate and fluoride that is characteristic of phosphorite CFA is also located in the vertebrate skeleton. This similarity suggests a biochemical pathway for CFA precipitation. Preliminary Raman spectroscopy and powder x-ray diffraction results that suggest a role for fluoride, and possibly carbonate, in the biochemical depolymerisation of polyphosphates with alkaline phosphatase will be presented.

Predicted Responses of Vegetation to Climate Change: A Global Analysis of Changes in Primary Productivity and Water Use Efficiency in the 21st Century

NASA Astrophysics Data System (ADS)

Bernardes, S.

2016-12-01

Global coupled carbon-climate simulations show considerable variability in outputs for atmospheric and land fields over the 21st century. This variability includes changes in temperature and in the quantity and spatiotemporal distribution of precipitation for large regions on the planet. Studies have considered that reductions in water availability due to decreased precipitation and increased water demand by the atmosphere may negatively affect plant metabolism and reduce carbon uptake. Future increases in carbon dioxide concentrations are expected to affect those interactions and potentially offset reductions in productivity. It is uncertain how plants will adjust their water use efficiency (WUE, plant production per water loss by evapotranspiration) in response to changing environmental conditions. This work investigates predicted changes in WUE in the 21st century by analyzing an ensemble of Earth System Models from the Coupled Model Intercomparison Project 5 (CMIP5), together with flux tower data and products derived from the Moderate Resolution Imaging Spectroradiometer (MODIS) sensor. Two representative concentration pathways were selected to describe possible climate futures (RCP4.5 and RCP8.5). Periods of analysis included 2006-2099 (predicted) and 1850-2005 (reference). Comparisons between modeled, flux and satellite data for IPCC SREX regions were used to address the significant intermodel variability observed for the CMIP5 ensemble (larger variability for RCP8.5, higher intermodel agreement in Southeast Asia, lower intermodel agreement in arid areas). Model skill was evaluated in support of model selection and the spatiotemporal analysis of changes in WUE. Global, regional and latitudinal distributions of departures of projected conditions in relation to historical values are presented for both concentration pathways. Results showed high model sensitivity to different concentration pathways and increase in GPP and WUE for most of the planet (increases consistently higher for RCP8.5). Higher increases in GPP and WUE are predicted to occur over higher latitudes in the northern hemisphere (boreal region), with WUE usually following GPP in changes. Decreases in productivity and WUE occur mostly in the tropics, affecting tropical forests in Central America and in the Amazon.

A Multimodel Ensemble Analysis of Global Changes in Plant Water Use Efficiency and Primary Productivity in the 21st Century

NASA Astrophysics Data System (ADS)

Bernardes, S.

2017-12-01

Outputs from coupled carbon-climate models show considerable variability in atmospheric and land fields over the 21st century, including changes in temperature and in the spatiotemporal distribution and quantity of precipitation over the planet. Reductions in water availability due to decreased precipitation and increased water demand by the atmosphere may reduce carbon uptake by critical ecosystems. Conversely, increases in atmospheric carbon dioxide have the potential to offset reductions in productivity. This work focuses on predicted responses of plants to environmental changes and on how plants will adjust their water use efficiency (WUE, plant production per water loss by evapotranspiration) in the 21st century. Predicted changes in WUE were investigated using an ensemble of Earth System Models from the Coupled Model Intercomparison Project 5 (CMIP5), flux tower data and products derived from the Moderate Resolution Imaging Spectroradiometer (MODIS) sensor. Scenarios for climate futures used two representative concentration pathways, including carbon concentration peak in 2040 (RCP4.5) and rising emissions throughout the 21st century (RCP8.5). Model results included the periods 2006-2009 (predicted) and 1850-2005 (reference). IPCC SREX regions were used to compare modeled, flux and satellite data and to address the significant intermodel variability observed for the CMIP5 ensemble (larger variability for RCP8.5, higher intermodel agreement in Southeast Asia, lower intermodel agreement in arid areas). An evaluation of model skill at the regional level supported model selection and the spatiotemporal analysis of changes in WUE. Departures of projected conditions in relation to historical values are presented for both concentration pathways at global, regional levels, including latitudinal distributions. High model sensitivity to different concentration pathways and increase in GPP and WUE was observed for most of the planet (increases consistently higher for RCP8.5). Higher latitudes in the northern hemisphere (boreal region) are predicted to experience higher increases in GPP and WUE, with WUE usually following GPP in changes. Models point to decreases in productivity and WUE mostly in the tropics, affecting tropical forests in the Amazon and in Central America.

Two factors of the lectin pathway of complement, l-ficolin and mannan-binding lectin, and their associations with prematurity, low birthweight and infections in a large cohort of Polish neonates.

PubMed

Swierzko, Anna St; Atkinson, Anne P M; Cedzynski, Maciej; Macdonald, Shirley L; Szala, Agnieszka; Domzalska-Popadiuk, Iwona; Borkowska-Klos, Monika; Jopek, Aleksandra; Szczapa, Jerzy; Matsushita, Misao; Szemraj, Janusz; Turner, Marc L; Kilpatrick, David C

2009-02-01

Ficolins and one collectin, mannan-binding lectin (MBL), are the only factors known to activate the lectin pathway (LP) of complement. There is considerable circumstantial evidence that MBL insufficiency can increase susceptibility to various infections and influence the course of several non-infectious diseases complicated by infections. Much less information is available concerning l-ficolin. We report the results of a prospective study to investigate any association between either MBL deficiency or l-ficolin deficiency with prematurity, low birthweight or perinatal infections in a large cohort of Polish neonates, representing an ethnically homogenous population (n=1832). Cord blood samples were analysed to determine mbl-2 gene variants, MBL concentrations and MBL-MASP-2 complex activities (MBL-dependent lectin pathway activity) as well as l-ficolin levels. Median concentrations of l-ficolin and MBL were 2500 and 1124 ng/ml, respectively, while median LP activity was 272 mU/ml. After genotyping, 60.6% of babies were mbl-2 A/A, 35.4% were A/O and 4% were O/O genotypes. We found relative l-ficolin deficiency to be associated with prematurity, low birthweight and infections. l-Ficolin concentration correlated with gestational age and with birthweight, independently of gestational age. Preterm deliveries (<38 weeks) occurred more frequently among neonates with low LP activity but not with those having low serum MBL levels. Similarly, no association of serum MBL deficiency with low birthweight was found, but there was a correlation between LP activity and birthweight. Genotypes conferring very low serum MBL concentrations were associated with perinatal infections, and high-MBL-conferring genotypes were associated with prematurity. Our findings suggest that l-ficolin participates in host defence during the perinatal period and constitute the first evidence that relative l-ficolin deficiency may contribute to the adverse consequences of prematurity. Some similar trends were found with facets of MBL deficiency, but the observed relationships were weaker and less consistent.

Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression.

PubMed

Bohacova, Viera; Seres, Mario; Pavlikova, Lucia; Kontar, Szilvia; Cagala, Martin; Bobal, Pavel; Otevrel, Jan; Brtko, Julius; Sulova, Zdena; Breier, Albert

2018-05-01

The acceleration of drug efflux activity realized by plasma membrane transporters in neoplastic cells, particularly by P-glycoprotein (P-gp, ABCB1 member of the ABC transporter family), represents a frequently observed molecular cause of multidrug resistance (MDR). This multiple resistance represents a real obstacle in the effective chemotherapy of neoplastic diseases. Therefore, identifying cytotoxic substances that are also effective in P-gp overexpressing cells may be useful for the rational design of substances for the treatment of malignancies with developed MDR. Here, we showed that triorganotin derivatives—tributyltin-chloride (TBT-Cl), tributyltin-bromide (TBT-Br), tributyltin-iodide (TBT-I) and tributyltin-isothiocyanate (TBT-NCS) or triphenyltin-chloride (TPT-Cl) and triphenyltin-isothiocyanate (TPT-NCS)—could induce the death of L1210 mice leukemia cells at a submicromolar concentration independently of P-gp overexpression. The median lethal concentration obtained for triorganotin derivatives did not exceed 0.5 µM in the induction of cell death of either P-gp negative or P-gp positive L1210 cells. Apoptosis related to regulatory pathway of Bcl-2 family proteins seems to be the predominant mode of cell death in either P-gp negative or P-gp positive L1210 cells. TBT-Cl and TBT-Br were more efficient with L1210 cells overexpressing P-gp than with their counterpart P-gp negative cells. In contrast, TBT-I and TPT-NCS induced a more pronounced cell death effect on P-gp negative cells than on P-gp positive cells. Triorganotin derivatives did not affect P-gp efflux in native cells measured by calcein retention within the cells. Taken together, we assumed that triorganotin derivatives represent substances suitable for suppressing the viability of P-gp positive malignant cells.

The Global Food System as a Transport Pathway for Hazardous Chemicals: The Missing Link between Emissions and Exposure

PubMed Central

Ng, Carla A.; von Goetz, Natalie

2016-01-01

Background: Food is a major pathway for human exposure to hazardous chemicals. The modern food system is becoming increasingly complex and globalized, but models for food-borne exposure typically assume locally derived diets or use concentrations directly measured in foods without accounting for food origin. Such approaches may not reflect actual chemical intakes because concentrations depend on food origin, and representative analysis is seldom available. Processing, packaging, storage, and transportation also impart different chemicals to food and are not yet adequately addressed. Thus, the link between environmental emissions and realistic human exposure is effectively broken. Objectives: We discuss the need for a fully integrated treatment of the modern industrialized food system, and we propose strategies for using existing models and relevant supporting data sources to track chemicals during production, processing, packaging, storage, and transport. Discussion: Fate and bioaccumulation models describe how chemicals distribute in the environment and accumulate through local food webs. Human exposure models can use concentrations in food to determine body burdens based on individual or population characteristics. New models now include the impacts of processing and packaging but are far from comprehensive. We propose to close the gap between emissions and exposure by utilizing a wider variety of models and data sources, including global food trade data, processing, and packaging models. Conclusions: A comprehensive approach that takes into account the complexity of the modern global food system is essential to enable better prediction of human exposure to chemicals in food, sound risk assessments, and more focused risk abatement strategies. Citation: Ng CA, von Goetz N. 2017. The global food system as a transport pathway for hazardous chemicals: the missing link between emissions and exposure. Environ Health Perspect 125:1–7; http://dx.doi.org/10.1289/EHP168 PMID:27384039

Normoxic Cyclic GMP-independent Oxidative Signaling by Nitrite Enhances Airway Epithelial Cell Proliferation and Wound Healing

PubMed Central

Wang, Ling; Frizzell, Sheila A.; Zhao, Xuejun; Gladwin, Mark T.

2013-01-01

The airway epithelium provides important barrier and host defense functions. Recent studies reveal that nitrite is an endocrine reservoir of nitric oxide (NO) bioactivity that is converted to NO by enzymatic reductases along the physiological oxygen gradient. Nitrite signaling has been described as NO dependent activation mediated by reactions with deoxygenated redox active hemoproteins, such as hemoglobin, myoglobin, neuroglobin, xanthine oxidoreductase (XO) and NO synthase at low pH and oxygen tension. However, nitrite can also be readily oxidized to nitrogen dioxide (NO2•) via heme peroxidase reactions, suggesting the existence of alternative oxidative signaling pathways for nitrite under normoxic conditions. In the present study we examined normoxic signaling effects of sodium nitrite on airway epithelial cell wound healing. In an in vitro scratch injury model under normoxia, we exposed cultured monolayers of human airway epithelial cells to various concentrations of sodium nitrite and compared responses to NO donor. We found sodium nitrite potently enhanced airway epithelium wound healing at physiological concentrations (from 1uM). The effect of nitrite was blocked by the NO and NO2• scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (c-PTIO). Interestingly, nitrite treatment did not increase cyclic guanosine monophosphate (cGMP) levels under these normoxic conditions, even in the presence of a phosphodiesterase 5 inhibitor, suggesting cGMP independent signaling. Consistent with an oxidative signaling pathway requiring hydrogen peroxide (H2O2)/heme peroxidase/NO2• signaling, the effects of nitrite were potentiated by superoxide dismutase (SOD) and low concentration H2O2, whereas inhibited completely by catalase, followed by downstream extracellular-signal-regulated kinase (ERK) 1/2 activation. Our data represent the first description of normoxic nitrite signaling on lung epithelial cell proliferation and wound healing and suggest novel oxidative signaling pathways involving nitrite-H2O2 reactions, possibly via the intermediary, NO2•. PMID:22425780

Metabolomic Profiling of Plasma Samples from Women with Recurrent Spontaneous Abortion.

PubMed

Li, XiaoCui; Yin, MingHong; Gu, JinPing; Hou, YanYan; Tian, FuJu; Sun, Feng

2018-06-13

BACKGROUND Gas chromatography coupled with mass spectrometry (GC-MS) and liquid chromatography coupled with mass spectrometry (LC-MS) metabolomics have been deployed to detect novel differential metabolites in cases with recurrent spontaneous abortion (RSA). MATERIAL AND METHODS Fifty patients who had recurrent spontaneous abortions (RSAs) and 51 control patients (age, gestational age, and body mass index (BMI) match) were enrolled in this study. Untargeted GC-MS and targeted LC-MS were combined to discover and validate the different metabolomic profiles between groups. Score plots of orthogonal partial least-squares discriminant analysis (OPLS-DA) clearly separated the RSA group from the control group. The variable importance in projection (VIP) generated in OPLS-DA processing represented the contribution to the discrimination of each metabolite ion between groups. Variables with a VIP >1 and P<0.05 were considered to be different variables. We also used MetaboAnalyst 3.0 to analyze the pathway impact of potential metabolite biomarkers. RESULTS Fifty-four metabolites were significantly different between the two groups, as indicated by a VIP >1 and P<0.05. The metabolic pathways involving glycine, serine, threonine (P=0.00529, impact=0.26), beta-alanine (P=0.0284, impact=0.27), and phenylalanine metabolism (P=0.0217, impact=0.17), along with the tricarboxylic acid (TCA) cycle (P=0.0113, impact=0.19) and the glycolysis pathway (P=0.037, impact=0.1) are obviously related to RSA. Verification by LC-MS showed that the concentration of lactic acid in RSA was higher than that in the control group (P<0.05), while the concentration of 5-methoxytryptamine was significantly lower in the RSA group (P<0.05). CONCLUSIONS In our study, untargeted GC-MS was used to detect disturbance of metabolism occurs in RSA and targeted LC-MS further was used to show that plasma concentrations of two metabolites (lactic acid and 5-methoxytryptamine) were different in the RSA compared to the control group.

RCP4.5: A Pathway for Stabilization of Radiative Forcing by 2100

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

Thomson, Allison M.; Calvin, Katherine V.; Smith, Steven J.

2011-07-29

Representative Concentration Pathway (RCP) 4.5 is a scenario that stabilizes radiative forcing at 4.5 W m{sup -2} in the year 2100 without ever exceeding that value. Simulated with the Global Change Assessment Model (GCAM), RCP4.5 includes long-term, global emissions of greenhouse gases, short-lived species, and land-use-land-cover in a global economic framework. RCP4.5 was updated from earlier GCAM scenarios to incorporate historical emissions and land cover information common to the RCP process and follows a cost-minimizing pathway to reach the target radiative forcing. The imperative to limit emissions in order to reach this target drives changes in the energy system, includingmore » shifts to electricity, to lower emissions energy technologies and to the deployment of carbon capture and geologic storage technology. In addition, the RCP4.5 emissions price also applies to land use emissions; as a result, forest lands expand from their present day extent. The simulated future emissions and land use were downscaled from the regional simulation to a grid to facilitate transfer to climate models. While there are many alternative pathways to achieve a radiative forcing level of 4.5 W m{sup -2}, the application of the RCP4.5 provides a common platform for climate models to explore the climate system response to stabilizing the anthropogenic components of radiative forcing.« less

Molecular Mechanisms for Regulation of Intestinal Calcium Absorption by Vitamin D and Other Factors

PubMed Central

Fleet, James C.; Schoch, Ryan D.

2011-01-01

Optimal intestinal calcium (Ca) absorption is necessary for the protection of bone and the prevention of osteoporosis. Ca absorption can be represented as the sum of a saturable pathway and a non-saturable pathway that is primarily dependent upon luminal Ca concentration. While models have been proposed to describe these transport components, significant gaps still exist in our understanding of these processes. Habitual low intake of Ca up-regulates the saturable transport pathway, a process mediated by increased renal production of 1,25 dihydroxyvitamin D (1,25(OH)2 D). Consistent with this, low vitamin D status as well as deletion/mutation of the vitamin D receptor (VDR) or 25 hydroxyvitamin D-1α hydroxylase (CYP27B1) genes limit Ca absorption by reducing the saturable pathway. There is some evidence that non-saturable Ca absorption in the ileum is also regulated by vitamin D status, but the mechanism is unclear. Treatment with a number of hormones can regulate Ca absorption in vivo [e.g. parathyroid hormone (PTH), thyroid hormone, growth hormone (GH)/insulin-like growth factor I (IGF-1), estrogen, testosterone]. However, some of these actions are indirect (i.e. mediated through the regulation of vitamin D metabolism or signaling), whereas only a few (e.g. estrogen, IGF-1) have been shown to persist in the absence of vitamin D signaling. PMID:21182397

Enhancing the relevance of new scenarios for climate change impacts, adaptation and vulnerability research

NASA Astrophysics Data System (ADS)

van Ruijven, B. J.

2013-12-01

Over the past three decades, scenario analyses have occupied a central role in assessments of the potential impacts of climate change on natural and human systems at different scales during the 21st century. Here, we discuss the role and relevance of new scenarios using shared socioeconomic pathways (SSPs) and representative concentration pathways (RCPs) for climate change impacts, adaptation, and vulnerability (IAV) research. It first provides an overview of uses of social-environmental scenarios in IAV studies and identifies the main shortcomings of earlier such scenarios. Second, the paper elaborates on two aspects of new scenarios needing to be improved in order to enhance their usefulness for IAV studies: the ability to work coherently across spatial scales and adding indicators of importance to projections of vulnerability and adaptive capacity in addition to standard indicators of population and gross domestic product. This paper presents a research agenda to add income distribution, spatial population, human health projections, and governance indicators to the new scenarios.

Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway.

PubMed

Thress, Kenneth; Macintyre, Terry; Wang, Haiyun; Whitston, Dave; Liu, Zhong-Ying; Hoffmann, Ethan; Wang, Tao; Brown, Jeffrey L; Webster, Kevin; Omer, Charles; Zage, Peter E; Zeng, Lizhi; Zweidler-McKay, Patrick A

2009-07-01

Tropomyosin-related kinases (TrkA, TrkB, and TrkC) are receptor tyrosine kinases that, along with their ligands, the neurotrophins, are involved in neuronal cell growth, development, and survival. The Trk-neurotrophin pathway may also play a role in tumorigenesis through oncogenic fusions, mutations, and autocrine signaling, prompting the development of novel Trk inhibitors as agents for cancer therapy. This report describes the identification of AZ-23, a novel, potent, and selective Trk kinase inhibitor. In vitro studies with AZ-23 showed improved selectivity over previous compounds and inhibition of Trk kinase activity in cells at low nanomolar concentrations. AZ-23 showed in vivo TrkA kinase inhibition and efficacy in mice following oral administration in a TrkA-driven allograft model and significant tumor growth inhibition in a Trk-expressing xenograft model of neuroblastoma. AZ-23 represents a potent and selective Trk kinase inhibitor from a novel series with the potential for use as a treatment for cancer.

Deciphering early events involved in hyperosmotic stress-induced programmed cell death in tobacco BY-2 cells.

PubMed

Monetti, Emanuela; Kadono, Takashi; Tran, Daniel; Azzarello, Elisa; Arbelet-Bonnin, Delphine; Biligui, Bernadette; Briand, Joël; Kawano, Tomonori; Mancuso, Stefano; Bouteau, François

2014-03-01

Hyperosmotic stresses represent one of the major constraints that adversely affect plants growth, development, and productivity. In this study, the focus was on early responses to hyperosmotic stress- (NaCl and sorbitol) induced reactive oxygen species (ROS) generation, cytosolic Ca(2+) concentration ([Ca(2+)]cyt) increase, ion fluxes, and mitochondrial potential variations, and on their links in pathways leading to programmed cell death (PCD). By using BY-2 tobacco cells, it was shown that both NaCl- and sorbitol-induced PCD seemed to be dependent on superoxide anion (O2·(-)) generation by NADPH-oxidase. In the case of NaCl, an early influx of sodium through non-selective cation channels participates in the development of PCD through mitochondrial dysfunction and NADPH-oxidase-dependent O2·(-) generation. This supports the hypothesis of different pathways in NaCl- and sorbitol-induced cell death. Surprisingly, other shared early responses, such as [Ca(2+)]cyt increase and singlet oxygen production, do not seem to be involved in PCD.

Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome

PubMed Central

Lanaspa, Miguel A; Ishimoto, Takuji; Li, Nanxing; Cicerchi, Christina; Orlicky, David J.; Ruzicky, Philip; Rivard, Christopher; Inaba, Shinichiro; Roncal-Jimenez, Carlos A.; Bales, Elise S.; Diggle, Christine P.; Asipu, Aruna; Petrash, J. Mark; Kosugi, Tomoki; Maruyama, Shoichi; Sanchez-Lozada, Laura G.; McManaman, James L.; Bonthron, David T; Sautin, Yuri Y.; Johnson, Richard J.

2013-01-01

Carbohydrates with high glycemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations glucose are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously-produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase deficient mice were protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism whereby glucose promotes the development of metabolic syndrome. PMID:24022321

System-based strategies for p53 recovery.

PubMed

Azam, Muhammad Rizwan; Fazal, Sahar; Ullah, Mukhtar; Bhatti, Aamer I

2018-06-01

The authors have proposed a systems theory-based novel drug design approach for the p53 pathway. The pathway is taken as a dynamic system represented by ordinary differential equations-based mathematical model. Using control engineering practices, the system analysis and subsequent controller design is performed for the re-activation of wild-type p53. p53 revival is discussed for both modes of operation, i.e. the sustained and oscillatory. To define the problem in control system paradigm, modification in the existing mathematical model is performed to incorporate the effect of Nutlin. Attractor point analysis is carried out to select the suitable domain of attraction. A two-loop negative feedback control strategy is devised to drag the system trajectories to the attractor point and to regulate cellular concentration of Nutlin, respectively. An integrated framework is constituted to incorporate the pharmacokinetic effects of Nutlin in the cancerous cells. Bifurcation analysis is also performed on the p53 model to see the conditions for p53 oscillation.

Global changes of extreme coastal wave energy fluxes triggered by intensified teleconnection patterns

NASA Astrophysics Data System (ADS)

Mentaschi, Lorenzo; Vousdoukas, Michalis I.; Voukouvalas, Evangelos; Dosio, Alessandro; Feyen, Luc

2017-03-01

In this study we conducted a comprehensive modeling analysis to identify global trends in extreme wave energy flux (WEF) along coastlines in the 21st century under a high emission pathway (Representative Concentration Pathways 8.5). For the end of the century, results show a significant increase up to 30% in 100 year return level WEF for the majority of the coastal areas of the southern temperate zone, while in the Northern Hemisphere large coastal areas are characterized by a significant negative trend. We show that the most significant long-term trends of extreme WEF can be explained by intensification of teleconnection patterns such as the Antarctic Oscillation, El Niño-Southern Oscillation, and North Atlantic Oscillation. The projected changes will have broad implications for ocean engineering applications and disaster risk management. Especially low-lying coastal countries in the Southern Hemisphere will be particularly vulnerable due to the combined effects of projected relative sea level rise and more extreme wave activities.

Climate and human intervention effects on future fire activity and consequences for air pollution across the 21st century

NASA Astrophysics Data System (ADS)

Val Martin, M.; Pierce, J. R.; Heald, C. L.; Li, F.; Lawrence, D. M.; Wiedinmyer, C.; Tilmes, S.; Vitt, F.

2016-12-01

Emissions of aerosols and gases from fires have been shown to adversely affect air quality across the world. Fire activity is strongly related to climate and anthropogenic activities. Current fire projections for the 21st century seem very uncertain, ranging from increasing to declining depending on the climate, land cover change and population growth scenarios used. Here we present an analysis of the changes in future wildfire activity and consequences on air quality, with focus on PM2.5 and surface O3 over regions vulnerable to fire. We use the global Community Earth System Model (CESM) with a process-based fire model to simulate emissions from agriculture, peatland, deforestation and landscape fires for present-day and throughout the current century. We consider two future Representative Concentration Pathways climate scenarios combined with population density changes predicted from Shared Socio-economic Pathways to project climate and demographic effects on fire activity and further consequences for future air quality.

Hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease by the Akt/eNOS/NO pathway.

PubMed

Jin, Sheng; Teng, Xu; Xiao, Lin; Xue, Hongmei; Guo, Qi; Duan, Xiaocui; Chen, Yuhong; Wu, Yuming

2017-12-01

Reductions in hydrogen sulfide (H 2 S) production have been implicated in the pathogenesis of hypertension; however, no studies have examined the functional role of hydrogen sulfide in hypertensive heart disease. We hypothesized that the endogenous production of hydrogen sulfide would be reduced and exogenous hydrogen sulfide would ameliorate cardiac dysfunction in N ω -nitro- L-arginine methyl ester ( L-NAME)-induced hypertensive rats. Therefore, this study investigated the cardioprotective effects of hydrogen sulfide on L-NAME-induced hypertensive heart disease and explored potential mechanisms. The rats were randomly divided into five groups: Control, Control + sodium hydrosulfide (NaHS), L-NAME, L-NAME + NaHS, and L-NAME + NaHS + glibenclamide (Gli) groups. Systolic blood pressure was monitored each week. In Langendorff-isolated rat heart, cardiac function represented by ±LV dP/dt max and left ventricular developing pressure was recorded after five weeks of treatment. Hematoxylin and Eosin and Masson's trichrome staining and myocardium ultrastructure under transmission electron microscopy were used to evaluate cardiac remodeling. The plasma nitric oxide and hydrogen sulfide concentrations, as well as nitric oxide synthases and cystathionine-γ-lyase activity in left ventricle tissue were determined. The protein expression of p-Akt, Akt, p-eNOS, and eNOS in left ventricle tissue was analyzed using Western blot. After five weeks of L-NAME treatment, there was a time-dependent hypertension, cardiac remodeling, and dysfunction accompanied by a decrease in eNOS phosphorylation, nitric oxide synthase activity, and nitric oxide concentration. Meanwhile, cystathionine-γ-lyase activity and hydrogen sulfide concentration were also decreased. NaHS treatment significantly increased plasma hydrogen sulfide concentration and subsequently promoted the Akt/eNOS/NO pathway which inhibited the development of hypertension and attenuated cardiac remodeling and dysfunction. The cardioprotective effects of NaHS were counteracted by Gli which inhibited the Akt/eNOS/NO pathway. This suggests that the effects of hydrogen sulfide were mediated by the activation of the K ATP channels. In conclusion, hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease via the activation of the Akt/eNOS/NO pathway, which was mediated by K ATP channels. Impact statement 1. We found that H 2 S ameliorated L-NAME-induced cardiac remodeling and dysfunction, and played a protective role in L-NAME-induced hypertensive heart disease, which the existing studies have not reported. 2. H 2 S activated the Akt/eNOS/NO pathway, thereby playing a cardioprotective role in L-NAME-induced hypertensive heart disease. 3. The cardioprotective effect of H 2 S was mediated by ATP-sensitive potassium channels.

Global atmospheric particle formation from CERN CLOUD measurements

NASA Astrophysics Data System (ADS)

Dunne, Eimear M.; Gordon, Hamish; Carslaw, Kenneth S.

2017-04-01

New particle formation (or nucleation) is acknowledged as a significant source of climate-relevant aerosol throughout the atmosphere. However, performing atmospherically relevant nucleation experiments in a laboratory setting is extremely challenging. As a result, until now, the parameterisations used to represent new particle formation in global aerosol models were largely based on in-situ observations or theoretical nucleation models, and usually only represented the binary H2SO4-H2O system. Several different chemicals can affect particle formation rates, even at extremely low trace concentrations, which are technically challenging to measure directly. Nucleation rates also respond to environmental changes in e.g. temperature in a highly non-linear fashion. The CERN CLOUD experiment was designed to provide the most controlled and accurate nucleation rate measurements to date, over the full range of free tropospheric temperatures and down to sulphuric acid concentrations of the order of 105 cm-3. We will present a parameterisation of inorganic nucleation rates for use in global models, based on these measurements, which includes four separate nucleation pathways: binary neutral, binary ion-induced, ternary neutral, and ternary ion-induced. Both inorganic and organic nucleation parameterisations derived from CLOUD measurements have been implemented in the GLOMAP global aerosol model. The parameterisations depend on temperature and on concentrations of sulphuric acid, ammonia, organic vapours, and ions. One of CLOUD's main original goals was to determine the sensitivity of atmospheric aerosol to changes in the nucleation rate over a solar cycle. We will show that, in a present-day atmosphere, the changes in climate-relevant aerosol (in the form of cloud-level cloud condensation nuclei) over a solar cycle are on average about 0.1%, with local changes of less than 1%. In contrast, anthropogenic changes in ammonia since pre-industrial times were estimated to have a much greater influence, resulting in a radiative forcing of between -0.62 and -0.66 W m-2. Including ternary inorganic pathways in GLOMAP improved the model's agreement with free tropospheric observations, especially aircraft measurements. The further inclusion of an organic parameterisation, which increased nucleation in the summertime boundary layer, brought our results more in line with observations made at surface stations. We therefore believe that, while the addition of other nucleation pathways (such as amine-induced nucleation) will doubtless improve agreement with local in-situ measurements, this model set-up provides a good representation of the global atmosphere as a whole. By presenting this novel parameterisation at EGU, we hope to encourage its uptake among the aerosol modelling community.

Pathway-Based Concentration Response Profiles from Toxicogenomics Data

EPA Science Inventory

Microarray analysis of gene expression of in vitro systems could be a powerful tool for assessing chemical hazard. Differentially expressed genes specific to cells, chemicals, and concentrations can be organized into molecular pathways that inform mode of action. An important par...

Modeling the optimal central carbon metabolic pathways under feedback inhibition using flux balance analysis.

PubMed

De, Rajat K; Tomar, Namrata

2012-12-01

Metabolism is a complex process for energy production for cellular activity. It consists of a cascade of reactions that form a highly branched network in which the product of one reaction is the reactant of the next reaction. Metabolic pathways efficiently produce maximal amount of biomass while maintaining a steady-state behavior. The steady-state activity of such biochemical pathways necessarily incorporates feedback inhibition of the enzymes. This observation motivates us to incorporate feedback inhibition for modeling the optimal activity of metabolic pathways using flux balance analysis (FBA). We demonstrate the effectiveness of the methodology on a synthetic pathway with and without feedback inhibition. Similarly, for the first time, the Central Carbon Metabolic (CCM) pathways of Saccharomyces cerevisiae and Homo sapiens have been modeled and compared based on the above understanding. The optimal pathway, which maximizes the amount of the target product(s), is selected from all those obtained by the proposed method. For this, we have observed the concentration of the product inhibited enzymes of CCM pathway and its influence on its corresponding metabolite/substrate. We have also studied the concentration of the enzymes which are responsible for the synthesis of target products. We further hypothesize that an optimal pathway would opt for higher flux rate reactions. In light of these observations, we can say that an optimal pathway should have lower enzyme concentration and higher flux rates. Finally, we demonstrate the superiority of the proposed method by comparing it with the extreme pathway analysis.

Projected changes of the southwest Australian wave climate under two atmospheric greenhouse gas concentration pathways

NASA Astrophysics Data System (ADS)

Wandres, Moritz; Pattiaratchi, Charitha; Hemer, Mark A.

2017-09-01

Incident wave energy flux is responsible for sediment transport and coastal erosion in wave-dominated regions such as the southwestern Australian (SWA) coastal zone. To evaluate future wave climates under increased greenhouse gas concentration scenarios, past studies have forced global wave simulations with wind data sourced from global climate model (GCM) simulations. However, due to the generally coarse spatial resolution of global climate and wave simulations, the effects of changing offshore wave conditions and sea level rise on the nearshore wave climate are still relatively unknown. To address this gap of knowledge, we investigated the projected SWA offshore, shelf, and nearshore wave climate under two potential future greenhouse gas concentration trajectories (representative concentration pathways RCP4.5 and RCP8.5). This was achieved by downscaling an ensemble of global wave simulations, forced with winds from GCMs participating in the Coupled Model Inter-comparison Project (CMIP5), into two regional domains, using the Simulating WAves Nearshore (SWAN) wave model. The wave climate is modeled for a historical 20-year time slice (1986-2005) and a projected future 20-year time-slice (2081-2100) for both scenarios. Furthermore, we compare these scenarios to the effects of considering sea-level rise (SLR) alone (stationary wave climate), and to the effects of combined SLR and projected wind-wave change. Results indicated that the SWA shelf and nearshore wave climate is more sensitive to changes in offshore mean wave direction than offshore wave heights. Nearshore, wave energy flux was projected to increase by ∼10% in exposed areas and decrease by ∼10% in sheltered areas under both climate scenarios due to a change in wave directions, compared to an overall increase of 2-4% in offshore wave heights. With SLR, the annual mean wave energy flux was projected to increase by up to 20% in shallow water (< 30 m) as a result of decreased wave dissipation. In winter months, the longshore wave energy flux, which is responsible for littoral drift, is expected to increase by up to 39% (62%) under the RCP4.5 (RCP8.5) greenhouse gas concentration pathway with SLR. The study highlights the importance of using high-resolution wave simulations to evaluate future regional wave climates, since the coastal wave climate is more responsive to changes in wave direction and sea level than offshore wave heights.

Modulation of xenobiotic biotransformation system and hormonal responses in Atlantic salmon (Salmo salar) after exposure to tributyltin (TBT).

PubMed

Mortensen, Anne Skjetne; Arukwe, Augustine

2007-04-01

Multiple biological effects of tributyltin (TBT) on juvenile salmon have been investigated. Fish were exposed for 7 days to waterborne TBT at nominal concentrations of 50 and 250 microg/L dissolved in dimethyl sulfoxide (DMSO). Hepatic samples were analyzed for gene expression patterns in the hormonal and xenobiotic biotransformation pathways using validated real-time PCR method. Immunochemical and several cytochrome P450 (CYP)-mediated enzyme activity (ethoxyresorufin: EROD, benzyloxyresorufin: BROD, methoxyresorufin: MROD and pentoxyresorufin: PROD) assays were analyzed. Our data show that TBT produced concentration-specific decrease of estrogen receptor-alpha (ERalpha), vitellogenin (Vtg), zona radiata protein (Zr-protein) and increase of estrogen receptor-beta (ERbeta) and androgen receptor-beta (ARbeta) in the hormonal pathway. In the xenobiotic biotransformation pathway, TBT produced apparent increase and decrease at respective low and high concentration, on aryl hydrocarbon receptor-alpha (AhRalpha), AhR nuclear translocator (ARNT) and AhR repressor (AhRR) mRNA. The expression of CYP1A1 and GST showed a TBT concentration-dependent decrease. The AhRbeta, CYP3A and uridine diphosphoglucuronosyl transferase (UGT) mRNA expressions were significantly induced after exposure to TBT. Immunochemical analysis of CYP3A and CYP1A1 protein levels confirmed the TBT effects observed at the transcriptional levels. The effect of TBT on the biotransformation enzyme gene expressions partially co-related but did not directly parallel enzyme activity levels for EROD, BROD, MROD and PROD. In general, these findings confirm previous reports on the endocrine effects of TBT, in addition to effects on hepatic CYP1A isoenzyme at the transcriptional level that transcends to protein and enzymatic levels. The induced expression patterns of CYP3A and UGT mRNA after TBT exposure, suggest the involvement of CYP3A and UGT in TBT metabolism in fish. The effect of TBT on CYP3A is proposed to represent another hormonal effect of TBT not previously reported in any fish or lower vertebrate. The proposed androgenic effect is supported by the observation that TBT also induced ARbeta mRNA expression in a concentration-specific manner. To our knowledge, this is the first study that has simultaneously studied multiple responses after exposure to TBT in fish.

Learning cellular sorting pathways using protein interactions and sequence motifs.

PubMed

Lin, Tien-Ho; Bar-Joseph, Ziv; Murphy, Robert F

2011-11-01

Proper subcellular localization is critical for proteins to perform their roles in cellular functions. Proteins are transported by different cellular sorting pathways, some of which take a protein through several intermediate locations until reaching its final destination. The pathway a protein is transported through is determined by carrier proteins that bind to specific sequence motifs. In this article, we present a new method that integrates protein interaction and sequence motif data to model how proteins are sorted through these sorting pathways. We use a hidden Markov model (HMM) to represent protein sorting pathways. The model is able to determine intermediate sorting states and to assign carrier proteins and motifs to the sorting pathways. In simulation studies, we show that the method can accurately recover an underlying sorting model. Using data for yeast, we show that our model leads to accurate prediction of subcellular localization. We also show that the pathways learned by our model recover many known sorting pathways and correctly assign proteins to the path they utilize. The learned model identified new pathways and their putative carriers and motifs and these may represent novel protein sorting mechanisms. Supplementary results and software implementation are available from http://murphylab.web.cmu.edu/software/2010_RECOMB_pathways/.

Estimating human exposure to PFOS isomers and PFCA homologues: the relative importance of direct and indirect (precursor) exposure.

PubMed

Gebbink, Wouter A; Berger, Urs; Cousins, Ian T

2015-01-01

Contributions of direct and indirect (via precursors) pathways of human exposure to perfluorooctane sulfonic acid (PFOS) isomers and perfluoroalkyl carboxylic acids (PFCAs) are estimated using a Scenario-Based Risk Assessment (SceBRA) modelling approach. Monitoring data published since 2008 (including samples from 2007) are used. The estimated daily exposures (resulting from both direct and precursor intake) for the general adult population are highest for PFOS and perfluorooctanoic acid (PFOA), followed by perfluorohexanoic acid (PFHxA) and perfluorodecanoic acid (PFDA), while lower daily exposures are estimated for perfluorobutanoic acid (PFBA) and perfluorododecanoic acid (PFDoDA). The precursor contributions to the individual perfluoroalkyl acid (PFAA) daily exposures are estimated to be 11-33% for PFOS, 0.1-2.5% for PFBA, 3.7-34% for PFHxA, 13-64% for PFOA, 5.2-66% for PFDA, and 0.7-25% for PFDoDA (ranges represent estimated precursor contributions in a low- and high-exposure scenario). For PFOS, direct intake via diet is the major exposure pathway regardless of exposure scenario. For PFCAs, the dominant exposure pathway is dependent on perfluoroalkyl chain length and exposure scenario. Modelled PFOS and PFOA concentrations in human serum using the estimated intakes from an intermediate-exposure scenario are in agreement with measured concentrations in different populations. The isomer pattern of PFOS resulting from total intakes (direct and via precursors) is estimated to be enriched with linear PFOS (84%) relative to technical PFOS (70% linear). This finding appears to be contradictory to the observed enrichment of branched PFOS isomers in recent human serum monitoring studies and suggests that either external exposure is not fully understood (e.g. there are unknown precursors, missing or poorly quantified exposure pathways) and/or that there is an incomplete understanding of the isomer-specific human pharmacokinetic processes of PFOS, its precursors and intermediates. Copyright © 2014. Published by Elsevier Ltd.

A Sense of Balance: Experimental Investigation and Modeling of a Malonyl-CoA Sensor in Escherichia coli.

PubMed

Fehér, Tamás; Libis, Vincent; Carbonell, Pablo; Faulon, Jean-Loup

2015-01-01

Production of value-added chemicals in microorganisms is regarded as a viable alternative to chemical synthesis. In the past decade, several engineered pathways producing such chemicals, including plant secondary metabolites in microorganisms have been reported; upscaling their production yields, however, was often challenging. Here, we analyze a modular device designed for sensing malonyl-CoA, a common precursor for both fatty acid and flavonoid biosynthesis. The sensor can be used either for high-throughput pathway screening in synthetic biology applications or for introducing a feedback circuit to regulate production of the desired chemical. Here, we used the sensor to compare the performance of several predicted malonyl-CoA-producing pathways, and validated the utility of malonyl-CoA reductase and malonate-CoA transferase for malonyl-CoA biosynthesis. We generated a second-order dynamic linear model describing the relation of the fluorescence generated by the sensor to the biomass of the host cell representing a filter/amplifier with a gain that correlates with the level of induction. We found the time constants describing filter dynamics to be independent of the level of induction but distinctively clustered for each of the production pathways, indicating the robustness of the sensor. Moreover, by monitoring the effect of the copy-number of the production plasmid on the dose-response curve of the sensor, we managed to coarse-tune the level of pathway expression to maximize malonyl-CoA synthesis. In addition, we provide an example of the sensor's use in analyzing the effect of inducer or substrate concentrations on production levels. The rational development of models describing sensors, supplemented with the power of high-throughput optimization provide a promising potential for engineering feedback loops regulating enzyme levels to maximize productivity yields of synthetic metabolic pathways.

Dynamic imaging of adaptive stress response pathway activation for prediction of drug induced liver injury.

PubMed

Wink, Steven; Hiemstra, Steven W; Huppelschoten, Suzanne; Klip, Janna E; van de Water, Bob

2018-05-01

Drug-induced liver injury remains a concern during drug treatment and development. There is an urgent need for improved mechanistic understanding and prediction of DILI liabilities using in vitro approaches. We have established and characterized a panel of liver cell models containing mechanism-based fluorescent protein toxicity pathway reporters to quantitatively assess the dynamics of cellular stress response pathway activation at the single cell level using automated live cell imaging. We have systematically evaluated the application of four key adaptive stress pathway reporters for the prediction of DILI liability: SRXN1-GFP (oxidative stress), CHOP-GFP (ER stress/UPR response), p21 (p53-mediated DNA damage-related response) and ICAM1 (NF-κB-mediated inflammatory signaling). 118 FDA-labeled drugs in five human exposure relevant concentrations were evaluated for reporter activation using live cell confocal imaging. Quantitative data analysis revealed activation of single or multiple reporters by most drugs in a concentration and time dependent manner. Hierarchical clustering of time course dynamics and refined single cell analysis allowed the allusion of key events in DILI liability. Concentration response modeling was performed to calculate benchmark concentrations (BMCs). Extracted temporal dynamic parameters and BMCs were used to assess the predictive power of sub-lethal adaptive stress pathway activation. Although cellular adaptive responses were activated by non-DILI and severe-DILI compounds alike, dynamic behavior and lower BMCs of pathway activation were sufficiently distinct between these compound classes. The high-level detailed temporal- and concentration-dependent evaluation of the dynamics of adaptive stress pathway activation adds to the overall understanding and prediction of drug-induced liver liabilities.

Concentrations and export of phosphorus during the cranberry harvest flood

NASA Astrophysics Data System (ADS)

Kennedy, C. D.; Kleinman, P. J. A.; DeMoranville, C. J.

2014-12-01

The cranberry industry occupies a unique place in the history of southeastern Massachusetts, where commercial production of cranberries has existed for nearly two centuries. Currently, water quality represents one of the greatest challenges facing the industry, with federal regulations limiting the use of phosphorus (P) fertilizer via total maximum daily load (TMDL) implementation. In response to environmental concerns, cranberry growers have decreased their annual P fertilizer application rates by a factor of four, from ~40 kg P ha-1 in the early 1970s to ~10 kg P ha-1 in 2013. Despite these industry-wide reductions, legacy P derived from periods of high P fertilizer application likely make cranberry farms non-point sources of P to surface water. In this study, concentrations and export of P were determined to characterize the sources and transport pathways of P in harvest floodwaters for four cranberry farms. Among the sites, a general pattern emerged of sharp increases in concentrations of total dissolved P (TDP) and total particulate P (TPP) during the later part of the flood release. Differences in the exact timing of increases in TDP and TPP were interpreted to represent distinct transport pathways: (1) near-surface transport of TDP derived from soils, and (2) subsurface transport of TPP resulting from resuspension and erosion of ditch sediments. Values of total P (TP = TDP + TPP) export were relatively low for three sites (0.3-0.8 kg P ha-1) and high for one site (5.3 kg P ha-1). Export of TP from the high-P site accounted for roughly half of the annual value allocated to cranberry farms in a recent TMDL. Historical P fertilizer records from 2005-2013 showed similar present-day application rates among the sites (~10 kg P ha-1), but higher rates between 2005 and 2007 for the high-P site (30 vs. 10 kg P ha-1). Although other factors likely contribute, legacy P derived from past fertilizer applications imparts an important control on P export in cranberry floodwaters.

Dependence of future mortality changes on global CO2 concentrations: A review.

PubMed

Lee, Jae Young; Choi, Hayoung; Kim, Ho

2018-05-01

The heterogeneity among previous studies of future mortality projections due to climate change has often hindered comparisons and syntheses of resulting impacts. To address this challenge, the present study introduced a novel method to normalize the results from projection studies according to different baseline and projection periods and climate scenarios, thereby facilitating comparison and synthesis. This study reviewed the 15 previous studies involving projected climate change-related mortality under Representative Concentration Pathways. To synthesize their results, we first reviewed the important study design elements that affected the reported results in previous studies. Then, we normalized the reported results by CO 2 concentration in order to eliminate the effects of the baseline period, projection period, and climate scenario choices. For twenty-five locations worldwide, the normalized percentage changes in temperature-attributable mortality per 100 ppm increase in global CO 2 concentrations ranged between 41.9% and 330%, whereas those of total mortality ranged between 0.3% and 4.8%. The normalization methods presented in this work will guide future studies to provide their results in a normalized format and facilitate research synthesis to reinforce our understanding on the risk of climate change. Copyright © 2018 Elsevier Ltd. All rights reserved.

New pathway of stratocumulus to cumulus transition via aerosol-cloud-precipitation interaction

NASA Astrophysics Data System (ADS)

Yamaguchi, T.; Feingold, G.; Kazil, J.

2017-12-01

The stratocumulus to cumulus transition (SCT) is typically considered to be a slow, multi-day process, caused primarily by dry air entrainment associated with overshooting cumulus rising under stratocumulus, with minor influence of precipitation. In this presentation, we show rapid SCT induced by a strong precipitation-induced modulation with Lagrangian SCT large eddy simulations. A large eddy model is coupled with a two-moment bulk microphysics scheme that predicts aerosol and droplet number concentrations. Moderate aerosol concentrations (100-250 cm-3) produce little to no drizzle from the stratocumulus deck. Large amounts of rain eventually form and wash out stratocumulus and much of the aerosol, and a cumulus state appears for approximately 10 hours. Initiation of strong rain formation is identified in penetrative cumulus clouds which are much deeper than stratocumulus, and they are able to condense large amounts of water. We show that prediction of cloud droplet number is necessary for this fast SCT since it is a result of a positive feedback of collision-coalescence induced aerosol depletion enhancing drizzle formation. Simulations with fixed droplet concentrations that bracket the time varying aerosol/drop concentrations are therefore not representative of the role of drizzle in the SCT.

Inorganic elements in green sea turtles (Chelonia mydas): relationships among external and internal tissues.

PubMed

Faust, Derek R; Hooper, Michael J; Cobb, George P; Barnes, Melanie; Shaver, Donna; Ertolacci, Shauna; Smith, Philip N

2014-09-01

Inorganic elements from anthropogenic sources have entered marine environments worldwide and are detectable in marine organisms, including sea turtles. Threatened and endangered classifications of sea turtles have heretofore made assessments of contaminant concentrations difficult because of regulatory restrictions on obtaining samples using nonlethal techniques. In the present study, claw and skin biopsy samples were examined as potential indicators of internal tissue burdens in green sea turtles (Chelonia mydas). Significant relationships were observed between claw and liver, and claw and muscle concentrations of mercury, nickel, arsenic, and selenium (p < 0.05). Similarly, significant relationships were observed between skin biopsy concentrations and those in liver, kidney, and muscle tissues for mercury, arsenic, selenium, and vanadium (p < 0.05). Concentrations of arsenic, barium, chromium, nickel, strontium, vanadium, and zinc in claws and skin biopsies were substantially elevated when compared with all other tissues, indicating that these highly keratinized tissues may represent sequestration or excretion pathways. Correlations between standard carapace length and cobalt, lead, and manganese concentrations were observed (p < 0.05), indicating that tissue concentrations of these elements may be related to age and size. Results suggest that claws may indeed be useful indicators of mercury and nickel concentrations in liver and muscle tissues, whereas skin biopsy inorganic element concentrations may be better suited as indicators of mercury, selenium, and vanadium concentrations in liver, kidney, and muscle tissues of green sea turtles. © 2014 SETAC.

Metabolism of Nitrogen Oxides in Ammonia-Oxidizing Bacteria

NASA Astrophysics Data System (ADS)

Kozlowski, J.; Stein, L. Y.

2014-12-01

Ammonia-oxidizing bacteria (AOB) are key microorganisms in the transformation of nitrogen intermediates in most all environments. Until recently there was very little work done to elucidate the physiology of ammonia-oxidizing bacteria cultivated from variable trophic state environments. With a greater variety of ammonia-oxidizers now in pure culture the importance of comparative physiological and genomic analysis is crucial. Nearly all known physiology of ammonia-oxidizing bacteria lies within the Nitrosomonas genus with Nitrosomonas europaea strain ATCC 19718 as the model. To more broadly characterize and understand the nature of obligate ammonia chemolithotrophy and the contribution of AOB to production of nitrogen oxides, Nitrosomonas spp. and Nitrosospira spp. isolated from variable trophic states and with sequenced genomes, were utilized. Instantaneous ammonia- and hydroxylamine-oxidation kinetics as a function of oxygen and substrate concentration were measured using an oxygen micro-sensor. The pathway intermediates nitric oxide and nitrous oxide were measured in real time using substrate-specific micro-sensors to elucidate whether production of these molecules is stoichiometric with rates of substrate oxidation. Genomic inventory was compared among the strains to identify specific pathways and modules to explain physiological differences in kinetic rates and production of N-oxide intermediates as a condition of their adaptation to different ammonium concentrations. This work provides knowledge of how nitrogen metabolism is differentially controlled in AOB that are adapted to different concentrations of ammonium. Overall, this work will provide further insight into the control of ammonia oxidizing chemolithotrophy across representatives of the Nitrosomonas and Nitrosospira genus, which can then be applied to examine additional genome-sequenced AOB isolates.

Parental genetic material and oxygen concentration affect hatch dynamics of mouse embryo in vitro.

PubMed

Zhan, Shaoquan; Cao, Shanbo; Du, Hongzi; Sun, Yuan; Li, Li; Ding, Chenhui; Zheng, Haiyan; Huang, Junjiu

2018-04-21

Hatching is crucial for mammalian embryo implantation, since difficulties during this process can lead to implantation failure, ectopic pregnancy and consequent infertility. Despite years of intensive researches, how internal and external factors affecting embryo hatch are still largely unclear. The effects of parental genetic material and oxygen concentration on hatch process were examined. Fertilized and parthenogenetic mouse preimplantation embryos were cultured in vitro under 5 and 20% oxygen for 120 h. Zona pellucida drilling by Peizo micromanipulation were performed to resemble the breach by sperm penetration. Firstly, parthenogenetic embryos had similarly high blastocyst developmental efficiency as fertilized embryos, but significantly higher hatch ratio than fertilized embryos in both O 2 concentrations. 5% O 2 reduced the hatch rate of fertilized embryos from 58.2 to 23.8%, but increased that of parthenogenetic embryos from 81.2 to 90.8% significantly. Analogously, 5% O 2 decreased the ratio of Oct4-positive cells in fertilized blastocysts, whereas increased that in parthenogenetic blastocysts. Additionally, 5% O 2 increased the total embryonic cell number in both fertilized and parthegenetic embryos, when compared to 20% O 2 , and the total cell number of fertilized embryos was also higher than that of parthegenetic embryos, despite O 2 concentration. Real-time PCR revealed that the expression of key genes involving in MAPK pathway and superoxide dismutase family might contribute to preimplantation development and consequent blastocyst hatch in vitro. Finally, we showed that fertilized and parthenogenetic embryos have diverse hatch dynamics in vitro, although the zona pellucida integrity is not the main reason for their mechanistic differences. Both parental genetic material and O 2 concentration, as the representative of intrinsic and extrinsic factors respectively, have significant impacts on mouse preimplantation development and subsequent hatch dynamics, probably by regulating the gene expression involving in MAPK pathway and superoxide dismutase family to control embryonic cell proliferation and allocation of ICM cells.

Temperature and precipitation drive temporal variability in aquatic carbon and GHG concentrations and fluxes in a peatland catchment.

PubMed

Dinsmore, K J; Billett, M F; Dyson, K E

2013-07-01

The aquatic pathway is increasingly being recognized as an important component of catchment carbon and greenhouse gas (GHG) budgets, particularly in peatland systems due to their large carbon store and strong hydrological connectivity. In this study, we present a complete 5-year data set of all aquatic carbon and GHG species from an ombrotrophic Scottish peatland. Measured species include particulate and dissolved forms of organic carbon (POC, DOC), dissolved inorganic carbon (DIC), CO2 , CH4 and N2 O. We show that short-term variability in concentrations exists across all species and this is strongly linked to discharge. Seasonal cyclicity was only evident in DOC, CO2 and CH4 concentration; however, temperature correlated with monthly means in all species except DIC. Although the temperature correlation with monthly DOC and POC concentrations appeared to be related to biological productivity in the terrestrial system, we suggest the temperature correlation with CO2 and CH4 was primarily due to in-stream temperature-dependent solubility. Interannual variability in total aquatic carbon concentration was strongly correlated with catchment gross primary productivity (GPP) indicating a strong potential terrestrial aquatic linkage. DOC represented the largest aquatic carbon flux term (19.3 ± 4.59 g C m(-2)  yr(-1) ), followed by CO2 evasion (10.0 g C m(-2)  yr(-1) ). Despite an estimated contribution to the total aquatic carbon flux of between 8 and 48%, evasion estimates had the greatest uncertainty. Interannual variability in total aquatic carbon export was low in comparison with variability in terrestrial biosphere-atmosphere exchange, and could be explained primarily by temperature and precipitation. Our results therefore suggest that climatic change is likely to have a significant impact on annual carbon losses through the aquatic pathway, and as such, aquatic exports are fundamental to the understanding of whole catchment responses to climate change. © 2013 Blackwell Publishing Ltd.

Analysis of nicotine-induced DNA damage in cells of the human respiratory tract.

PubMed

Ginzkey, Christian; Stueber, Thomas; Friehs, Gudrun; Koehler, Christian; Hackenberg, Stephan; Richter, Elmar; Hagen, Rudolf; Kleinsasser, Norbert H

2012-01-05

Epithelium of the upper and lower airways is a common origin of tobacco-related cancer. The main tobacco alkaloid nicotine may be associated with tumor progression. The potential of nicotine in inducing DNA mutations as a step towards cancer initiation is still controversially discussed. Different subtypes of nicotinic acetylcholine receptors (nAChR) are expressed in human nasal mucosa and a human bronchial cell line representing respiratory mucosa as a possible target for receptor-mediated pathways. In the present study, both cell systems were investigated with respect to DNA damage induced by nicotine and its mechanisms. Specimens of human nasal mucosa were harvested during surgery of the nasal air passage. After enzymatic digestion over night, single cells were exposed to an increasing nicotine concentration between 0.001 mM and 4.0mM. In a second step co-incubation was performed using the antioxidant N-acetylcysteine (NAC) and the nAChR antagonist mecamylamine. DNA damage was assessed using the alkali version of the comet assay. Dose finding experiments for mecamylamine to evaluate the maximal inhibitory effect were performed in the human bronchial cell line BEAS-2B with an increasing mecamylamine concentration and a constant nicotine concentration. The influence of nicotine in the apoptotic pathway was evaluated in BEAS-2B cells with the TUNEL assay combined with flow cytometry. After 1h of nicotine exposure with 0.001, 0.01, 0.1, 1.0 and 4.0mM, significant DNA damage was determined at 1.0mM. Further co-incubation experiments with mecamylamine and NAC were performed using 1.0mM of nicotine. The strongest inhibitory effect was measured at 1.0mM mecamylamine and this concentration was used for co-incubation. Both, the antioxidant NAC at a concentration of 1.0mM, based on the literature, as well as the receptor antagonist were capable of complete inhibition of the nicotine-induced DNA migration in the comet assay. A nicotine-induced increase or decrease in apoptosis as assessed by the TUNEL assay in BEAS-2B could not be detected. These results support the hypothesis that oxidative stress is responsible for nicotine-induced DNA damage. Similar results exist for other antioxidants in different cell systems. The decrease in DNA damage after co-incubation with a nAChR antagonist indicates a receptor-dependent pathway of induction for oxidative stress. Further investigations concerning pathways of receptor-mediated DNA damage via nAChR, the role of reactive oxygen species and apoptosis in this cell system will elucidate underlying mechanisms. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Exposure assessment of adult intake of bisphenol A (BPA) with emphasis on canned food dietary exposures.

PubMed

Lorber, Matthew; Schecter, Arnold; Paepke, Olaf; Shropshire, William; Christensen, Krista; Birnbaum, Linda

2015-04-01

Bisphenol A (BPA) is a high-volume, synthetic compound found in epoxy resins and plastics used in food packaging. Food is believed to be a major source of BPA intake. In this study, we measured the concentration of BPA in convenience samplings of foodstuffs purchased in Dallas, Texas. Sampling entailed collection of 204 samples of fresh, frozen, and canned foods in two rounds in 2010. BPA was positive in 73% of the canned food samples, while it was found in only 7% of non-canned foods at low concentrations. The results of this food sampling program were used to calculate adult dietary intakes of BPA. A pathway approach combined food intakes, a "canned fraction" parameter which described what portion of total intake of that food came from canned products, and measured food concentrations. Dietary intakes were calculated as 12.6 ng/kg-day, of which 12.4 ng/kg-day was from canned foods. Canned vegetable intakes alone were 11.9 ng/kg-day. This dietary intake was compared to total intakes of BPA estimated from urine measurements of the National Health and Nutrition Examination Survey (NHANES). Total adult central tendency intakes ranged from 30 to 70 ng/kg-day for NHANES cycles between 2005 and 2010. Three possibilities were explored to explain the difference between these two approaches for intake estimation. Not all foods which may have been canned, particularly canned beverages such as soft drinks, were sampled in our food sampling program. Second, non-food pathways of exposure may be important for adults, including thermal paper exposures, and dust and air exposures. Finally, our canned food concentrations may not be adequately representative of canned foods in the United States; they were found to be generally lower compared to canned food concentrations measured in six other worldwide food surveys including three in North America. Our finding that canned food concentrations greatly exceeded non-canned concentrations was consistent with other studies, and underscores the importance of canned foods in the overall exposure of adults of BPA. Copyright © 2015. Published by Elsevier Ltd.

Encoding of temporal signals by the TGF-β pathway and implications for embryonic patterning

PubMed Central

Sorre, Benoit; Warmflash, Aryeh; Brivanlou, Ali H.; Siggia, Eric D.

2014-01-01

Summary Genetics and biochemistry have defined the components and wiring of the signaling pathways that pattern the embryo. Among them, the TGF-β pathway has the potential to behave as a morphogen: invitro experiments have clearly established that it can dictate cell fate in a concentration dependent manner. How morphogens convey positional information in a developing embryo, where signal levels are changing with time, is less understood. Using integrated microfluidic cell culture and time-lapse microscopy, we demonstrate here that the speed of ligand presentation has a key and previously unexpected influence on TGF-β signaling outcomes. The response to a TGF-β concentration step is transient and adaptive, slowly increasing the ligand concentration diminishes the response and well-spaced pulses of ligand combine additively resulting in greater pathway output than with constant stimulation. Our results suggest that in an embryonic context, the speed of change of ligand concentration is an instructive signal for patterning. PMID:25065773

Pathways To Partnerships: Coalitions for Environmental Education. Selected Papers from the Annual Conference of the North American Association for Environmental Education (22nd, Big Sky, Montana, 1993).

ERIC Educational Resources Information Center

Mrazek, Rick, Ed.

The theme of the 1993 conference of the North American Association for Environmental Education was "Pathways to Partnerships: Coalitions for Environmental Education." Speakers on environmental issues represented government agencies and legislative houses, international institutions, businesses, and academia and included U.S. Representative Karan…

High environmental stress yields greater tocotrienol content while changing vitamin e profiles of wild emmer wheat seeds.

PubMed

Watts, Emily J; Shen, Yu; Lansky, Ephraim P; Nevo, Eviatar; Bobe, Gerd; Traber, Maret G

2015-02-01

Vitamin E is an essential human nutrient that was first isolated from wheat. Emmer wheat, the cereal of Old World agriculture and a precursor to durum wheat, grows wild in the Fertile Crescent. Evolution Canyon, Israel, provides a microsite that models effects of contrasting environments. The north-facing and south-facing slopes exhibit low and high stress environments, respectively. Wild emmer wheat seeds were collected from both slopes and seed tocochromanol contents measured to test the hypothesis that high stress alters emmer wheat seed tocol-omics. Seeds from high stress areas contained more total vitamin E (108±15 nmol/g) than seeds from low stress environments (80±17 nmol/g, P=.0004). Vitamin E profiles within samples from these different environments revealed significant differences in isoform concentrations. Within each region, β- plus γ-tocotrienols represented the highest concentration of wheat tocotrienols (high stress, P<.0001; low stress, P<.0001), while α-tocopherol represented the highest concentration of the tocopherols (high stress, P=.0002; low stress, P<.0001). Percentages of both δ-tocotrienol and δ-tocopherol increased in high stress conditions. Changes under higher stress apparently are due to increased pathway flux toward more tocotrienol production. The production of more δ-isoforms suggests increased flow through a divergent path controlled by the VTE1 gene. Hence, stress conditions alter plant responses such that vitamin E profiles are changed, likely an attempt to provide additional antioxidant activity to promote seed viability and longevity.

Long-term evolution of biodegradation and volatilization rates in a crude oil-contaminated aquifer

USGS Publications Warehouse

Chaplin, B.P.; Delin, G.N.; Baker, R.J.; Lahvis, M.A.

2002-01-01

Volatilization and subsequent biodegradation near the water Table make up a coupled natural attenuation pathway that results in significant mass loss of hydrocarbons. Rates of biodegradation and volatilization were documented twice 12 years apart at a crude-oil spill site near Bemidji, Minnesota. Biodegradation rates were determined by calibrating a gas transport model to O2, CO2, and CH4 gas-concentration data in the unsaturated zone. Reaction stoichiometry was assumed in converting O2 and CO2 gas-flux estimates to rates of aerobic biodegradation and CH4 gas-flux estimates to rates of methanogenesis. Model results indicate that the coupled pathway has resulted in significant hydrocarbon mass loss at the site, and it was estimated that approximately 10.52 kg/day were lost in 1985 and 1.99 kg/day in 1997. In 1985 3% of total volatile hydrocarbons diffusing from the floating oil were biodegraded in the lower 1 m of the unsaturated zone and increased to 52% by 1997. Rates of hydrocarbon biodegradation above the center of the floating oil were relatively stable from 1985 to 1997, as the primary metabolic pathway shifted from aerobic to methanogenic biodegradation. Model results indicate that in 1997 biodegradation under methanogenenic conditions represented approximately one-half of total hydrocarbon biodegradation in the lower 1 m of the unsaturated zone. Further downgradient, where substrate concentrations have greatly increased, total biodegradation rates increased by greater than an order of magnitude from 0.04 to 0.43 g/m2-day. It appears that volatilization is the primary mechanism for attenuation in early stages of plume evolution, while biodegradation dominates in later stages.

Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine.

PubMed

Bai, Qiufang; Song, Dan; Gu, Li; Verkhratsky, Alexei; Peng, Liang

2017-04-01

Here, we present the data indicating that chronic treatment with fluoxetine regulates Cav-1/PTEN/PI3K/AKT/GSK-3β signalling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At lower concentrations, fluoxetine downregulates gene expression of Cav-1, decreases membrane content of PTEN, increases activity of PI3K/AKT, and elevates GSK-3β phosphorylation thus suppressing its activity. At higher concentrations, fluoxetine acts in an inverse fashion. As expected, fluoxetine at lower concentrations increased while at higher concentrations decreased glycogen content in astrocytes. Our findings indicate that bi-phasic regulation of glycogen content via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine may be responsible for both therapeutic and side effects of the drug.

Assessing the present and future probability of Hurricane Harvey's rainfall

NASA Astrophysics Data System (ADS)

Emanuel, Kerry

2017-11-01

We estimate, for current and future climates, the annual probability of areally averaged hurricane rain of Hurricane Harvey's magnitude by downscaling large numbers of tropical cyclones from three climate reanalyses and six climate models. For the state of Texas, we estimate that the annual probability of 500 mm of area-integrated rainfall was about 1% in the period 1981–2000 and will increase to 18% over the period 2081–2100 under Intergovernmental Panel on Climate Change (IPCC) AR5 representative concentration pathway 8.5. If the frequency of such event is increasingly linearly between these two periods, then in 2017 the annual probability would be 6%, a sixfold increase since the late 20th century.

Large-scale stress factors affecting coral reefs: open ocean sea surface temperature and surface seawater aragonite saturation over the next 400 years

NASA Astrophysics Data System (ADS)

Meissner, K. J.; Lippmann, T.; Sen Gupta, A.

2012-06-01

One-third of the world's coral reefs have disappeared over the last 30 years, and a further third is under threat today from various stress factors. The main global stress factors on coral reefs have been identified as changes in sea surface temperature (SST) and changes in surface seawater aragonite saturation (Ωarag). Here, we use a climate model of intermediate complexity, which includes an ocean general circulation model and a fully coupled carbon cycle, in conjunction with present-day observations of inter-annual SST variability to investigate three IPCC representative concentration pathways (RCP 3PD, RCP 4.5, and RCP 8.5), and their impact on the environmental stressors of coral reefs related to open ocean SST and open ocean Ωarag over the next 400 years. Our simulations show that for the RCP 4.5 and 8.5 scenarios, the threshold of 3.3 for zonal and annual mean Ωarag would be crossed in the first half of this century. By year 2030, 66-85% of the reef locations considered in this study would experience severe bleaching events at least once every 10 years. Regardless of the concentration pathway, virtually every reef considered in this study (>97%) would experience severe thermal stress by year 2050. In all our simulations, changes in surface seawater aragonite saturation lead changes in temperatures.

Transcriptomic study of the toxic mechanism triggered by beauvericin in Jurkat cells.

PubMed

Escrivá, L; Jennen, D; Caiment, F; Manyes, L

2018-03-01

Beauvericin (BEA), an ionophoric cyclic hexadepsipeptide mycotoxin, is able to increase oxidative stress by altering membrane ion permeability and uncoupling oxidative phosphorylation. A toxicogenomic study was performed to investigate gene expression changes triggered by BEA exposure (1.5, 3 and 5 μM; 24 h) in Jurkat cells through RNA-sequencing and differential gene expression analysis. Perturbed gene expression was observed in a concentration dependent manner, with 43 differentially expressed genes (DEGs) overlapped in the three studied concentrations. Gene ontology (GO) analysis showed several biological processes related to electron transport chain, oxidative phosphorylation, and cellular respiration significantly altered. Molecular functions linked to mitochondrial respiratory chain and oxidoreductase activity were over-represented (q-value < 0.01). Pathway analysis revealed oxidative phosphorylation and electron transport chain as the most significantly altered pathways in all studied doses (z-score > 1.96; adj p-value < 0.05). 77 genes involved in the respiratory chain were significantly down-regulated at least at one dose. Moreover, 21 genes related to apoptosis and programmed cell death, and 12 genes related to caspase activity were significantly altered, mainly affecting initiator caspases 8, 9 and 10. The results demonstrated BEA-induced mitochondrial damage affecting the respiratory chain, and pointing to apoptosis through the caspase cascade in human lymphoblastic T cells. Copyright © 2017 Elsevier B.V. All rights reserved.

A density functional theory study of the decomposition mechanism of nitroglycerin.

PubMed

Pei, Liguan; Dong, Kehai; Tang, Yanhui; Zhang, Bo; Yu, Chang; Li, Wenzuo

2017-08-21

The detailed decomposition mechanism of nitroglycerin (NG) in the gas phase was studied by examining reaction pathways using density functional theory (DFT) and canonical variational transition state theory combined with a small-curvature tunneling correction (CVT/SCT). The mechanism of NG autocatalytic decomposition was investigated at the B3LYP/6-31G(d,p) level of theory. Five possible decomposition pathways involving NG were identified and the rate constants for the pathways at temperatures ranging from 200 to 1000 K were calculated using CVT/SCT. There was found to be a lower energy barrier to the β-H abstraction reaction than to the α-H abstraction reaction during the initial step in the autocatalytic decomposition of NG. The decomposition pathways for CHOCOCHONO 2 (a product obtained following the abstraction of three H atoms from NG by NO 2 ) include O-NO 2 cleavage or isomer production, meaning that the autocatalytic decomposition of NG has two reaction pathways, both of which are exothermic. The rate constants for these two reaction pathways are greater than the rate constants for the three pathways corresponding to unimolecular NG decomposition. The overall process of NG decomposition can be divided into two stages based on the NO 2 concentration, which affects the decomposition products and reactions. In the first stage, the reaction pathway corresponding to O-NO 2 cleavage is the main pathway, but the rates of the two autocatalytic decomposition pathways increase with increasing NO 2 concentration. However, when a threshold NO 2 concentration is reached, the NG decomposition process enters its second stage, with the two pathways for NG autocatalytic decomposition becoming the main and secondary reaction pathways.

Neural pathways for visual speech perception

PubMed Central

Bernstein, Lynne E.; Liebenthal, Einat

2014-01-01

This paper examines the questions, what levels of speech can be perceived visually, and how is visual speech represented by the brain? Review of the literature leads to the conclusions that every level of psycholinguistic speech structure (i.e., phonetic features, phonemes, syllables, words, and prosody) can be perceived visually, although individuals differ in their abilities to do so; and that there are visual modality-specific representations of speech qua speech in higher-level vision brain areas. That is, the visual system represents the modal patterns of visual speech. The suggestion that the auditory speech pathway receives and represents visual speech is examined in light of neuroimaging evidence on the auditory speech pathways. We outline the generally agreed-upon organization of the visual ventral and dorsal pathways and examine several types of visual processing that might be related to speech through those pathways, specifically, face and body, orthography, and sign language processing. In this context, we examine the visual speech processing literature, which reveals widespread diverse patterns of activity in posterior temporal cortices in response to visual speech stimuli. We outline a model of the visual and auditory speech pathways and make several suggestions: (1) The visual perception of speech relies on visual pathway representations of speech qua speech. (2) A proposed site of these representations, the temporal visual speech area (TVSA) has been demonstrated in posterior temporal cortex, ventral and posterior to multisensory posterior superior temporal sulcus (pSTS). (3) Given that visual speech has dynamic and configural features, its representations in feedforward visual pathways are expected to integrate these features, possibly in TVSA. PMID:25520611

Phenylalanine and tyrosine levels are rate-limiting factors in production of health promoting metabolites in Vitis vinifera cv. Gamay Red cell suspension

PubMed Central

Manela, Neta; Oliva, Moran; Ovadia, Rinat; Sikron-Persi, Noga; Ayenew, Biruk; Fait, Aaron; Galili, Gad; Perl, Avichai; Weiss, David; Oren-Shamir, Michal

2015-01-01

Environmental stresses such as high light intensity and temperature cause induction of the shikimate pathway, aromatic amino acids (AAA) pathways, and of pathways downstream from AAAs. The induction leads to production of specialized metabolites that protect the cells from oxidative damage. The regulation of the diverse AAA derived pathways is still not well understood. To gain insight on that regulation, we increased AAA production in red grape Vitis vinifera cv. Gamay Red cell suspension, without inducing external stress on the cells, and characterized the metabolic effect of this induction. Increased AAA production was achieved by expressing a feedback-insensitive bacterial form of 3-deoxy- D-arabino-heptulosonate 7-phosphate synthase enzyme (AroG*) of the shikimate pathway under a constitutive promoter. The presence of AroG* protein led to elevated levels of primary metabolites in the shikimate and AAA pathways including phenylalanine and tyrosine, and to a dramatic increase in phenylpropanoids. The AroG* transformed lines accumulated up to 20 and 150 fold higher levels of resveratrol and dihydroquercetin, respectively. Quercetin, formed from dihydroquercetin, and resveratrol, are health promoting metabolites that are induced due to environmental stresses. Testing the expression level of key genes along the stilbenoids, benzenoids, and phenylpropanoid pathways showed that transcription was not affected by AroG*. This suggests that concentrations of AAAs, and of phenylalanine in particular, are rate-limiting in production of these metabolites. In contrast, increased phenylalanine production did not lead to elevated concentrations of anthocyanins, even though they are also phenylpropanoid metabolites. This suggests a control mechanism of this pathway that is independent of AAA concentration. Interestingly, total anthocyanin concentrations were slightly lower in AroG* cells, and the relative frequencies of the different anthocyanins changed as well. PMID:26236327

Phenylalanine and tyrosine levels are rate-limiting factors in production of health promoting metabolites in Vitis vinifera cv. Gamay Red cell suspension.

PubMed

Manela, Neta; Oliva, Moran; Ovadia, Rinat; Sikron-Persi, Noga; Ayenew, Biruk; Fait, Aaron; Galili, Gad; Perl, Avichai; Weiss, David; Oren-Shamir, Michal

2015-01-01

Environmental stresses such as high light intensity and temperature cause induction of the shikimate pathway, aromatic amino acids (AAA) pathways, and of pathways downstream from AAAs. The induction leads to production of specialized metabolites that protect the cells from oxidative damage. The regulation of the diverse AAA derived pathways is still not well understood. To gain insight on that regulation, we increased AAA production in red grape Vitis vinifera cv. Gamay Red cell suspension, without inducing external stress on the cells, and characterized the metabolic effect of this induction. Increased AAA production was achieved by expressing a feedback-insensitive bacterial form of 3-deoxy- D-arabino-heptulosonate 7-phosphate synthase enzyme (AroG (*)) of the shikimate pathway under a constitutive promoter. The presence of AroG(*) protein led to elevated levels of primary metabolites in the shikimate and AAA pathways including phenylalanine and tyrosine, and to a dramatic increase in phenylpropanoids. The AroG (*) transformed lines accumulated up to 20 and 150 fold higher levels of resveratrol and dihydroquercetin, respectively. Quercetin, formed from dihydroquercetin, and resveratrol, are health promoting metabolites that are induced due to environmental stresses. Testing the expression level of key genes along the stilbenoids, benzenoids, and phenylpropanoid pathways showed that transcription was not affected by AroG (*). This suggests that concentrations of AAAs, and of phenylalanine in particular, are rate-limiting in production of these metabolites. In contrast, increased phenylalanine production did not lead to elevated concentrations of anthocyanins, even though they are also phenylpropanoid metabolites. This suggests a control mechanism of this pathway that is independent of AAA concentration. Interestingly, total anthocyanin concentrations were slightly lower in AroG(*) cells, and the relative frequencies of the different anthocyanins changed as well.

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data

EPA Science Inventory

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified rel...

Learning Cellular Sorting Pathways Using Protein Interactions and Sequence Motifs

PubMed Central

Lin, Tien-Ho; Bar-Joseph, Ziv

2011-01-01

Abstract Proper subcellular localization is critical for proteins to perform their roles in cellular functions. Proteins are transported by different cellular sorting pathways, some of which take a protein through several intermediate locations until reaching its final destination. The pathway a protein is transported through is determined by carrier proteins that bind to specific sequence motifs. In this article, we present a new method that integrates protein interaction and sequence motif data to model how proteins are sorted through these sorting pathways. We use a hidden Markov model (HMM) to represent protein sorting pathways. The model is able to determine intermediate sorting states and to assign carrier proteins and motifs to the sorting pathways. In simulation studies, we show that the method can accurately recover an underlying sorting model. Using data for yeast, we show that our model leads to accurate prediction of subcellular localization. We also show that the pathways learned by our model recover many known sorting pathways and correctly assign proteins to the path they utilize. The learned model identified new pathways and their putative carriers and motifs and these may represent novel protein sorting mechanisms. Supplementary results and software implementation are available from http://murphylab.web.cmu.edu/software/2010_RECOMB_pathways/. PMID:21999284

Bergenin Plays an Anti-Inflammatory Role via the Modulation of MAPK and NF-κB Signaling Pathways in a Mouse Model of LPS-Induced Mastitis.

PubMed

Gao, Xue-jiao; Guo, Meng-yao; Zhang, Ze-cai; Wang, Tian-cheng; Cao, Yong-guo; Zhang, Nai-sheng

2015-01-01

Mastitis is a major disease in humans and other animals and is characterized by mammary gland inflammation. It is a major disease of the dairy industry. Bergenin is an active constituent of the plants of genus Bergenia. Research indicates that bergenin has multiple biological activities, including anti-inflammatory and immunomodulatory properties. The objective of this study was to evaluate the protective effects and mechanism of bergenin on the mammary glands during lipopolysaccharide (LPS)-induced mastitis. In this study, mice were treated with LPS to induce mammary gland mastitis as a model for the disease. Bergenin treatment was initiated after LPS stimulation for 24 h. The results indicated that bergenin attenuated inflammatory cell infiltration and decreased the concentration of NO, TNF-α, IL-1β, and IL-6, which were increased in LPS-induced mouse mastitis. Furthermore, bergenin downregulated the phosphorylation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathway proteins in mammary glands with mastitis. In conclusion, bergenin reduced the expression of NO, TNF-α, IL-1β, and IL-6 proinflammatory cytokines by inhibiting the activation of the NF-κB and MAPKs signaling pathways, and it may represent a novel treatment strategy for mastitis.

The mechanism of zinc uptake by cultured rat liver cells.

PubMed Central

Taylor, J A; Simons, T J

1994-01-01

1. The initial rate of 65Zn uptake into cultured rat hepatocytes has been measured over a range of Zn2+ concentrations from 3 x 10(-10) M to 5 x 10(-6) M. Histidine and albumin were used to buffer Zn2+ ions at concentrations below 1 x 10(-6) M. 2. The results suggest there are two mechanisms for Zn2+ uptake; a high-affinity, saturable pathway, with a maximum velocity (Vmax) of 20-30 pmol (mg protein)-1 min-1 and a Michaelis-Menten constant (Km) of about 2 x 10(-9) M Zn2+ (with histidine), and a low-affinity, linear pathway, that only makes a significant contribution to Zn2+ uptake at Zn2+ concentrations above 1 x 10(-6) M. 3. Transport via the high-affinity pathway is dependent on the concentration of Zn2+ ions and not on the concentrations of Zn(2+)-ligand complexes, suggesting that Zn2+ is the transported species. 4. The affinity of the saturable pathway for Zn2+ is slightly lower in the presence of albumin, with a Km of about 1.3 x 10(-8) M. The reason for this is uncertain. PMID:8014898

Redirecting reproductive immunology research toward pregnancy as a period of temporary immune tolerance.

PubMed

Gleicher, Norbert; Kushnir, Vitaly A; Barad, David H

2017-04-01

Referring to two recent publications, we here propose that clinical reproductive immunology has for decades stagnated because reproductive medicine, including assisted reproduction (AR), has failed to accept embryo implantation as an immune system-driven process, dependent on establishment of maternal tolerance toward the implanting fetal semi-allograft (and complete allograft in cases of oocyte donation). Pregnancy represents a biologically unique period of temporary (to the period of gestation restricted) tolerance, otherwise only known in association with parasitic infections. Rather than investigating the immune pathways necessary to induce this rather unique state of tolerance toward the rapidly growing parasitic antigen load of the fetus, the field, instead, concentrated on irrelevant secondary immune phenomena (i.e., "immunological noise"). It, therefore, does not surprise that interesting recent research, offering new potential insights into maternal tolerance during pregnancy, was mostly published outside of the field of reproductive medicine. This research offers evidence for existence of inducible maternal tolerance pathways with the ability of improving maternal fecundity and, potentially, reducing such late pregnancy complications as premature labor and preeclampsia/eclampsia due to premature abatement of maternal tolerance. Increasing evidence also suggests that tolerance-inducing immune pathways are similar in successful pregnancy, successful organ transplantation and, likely also in the tolerance of "self" (i.e., prevention of autoimmunity). Identifying and isolating these pathways, therefore, may greatly benefit all three of these clinical areas, and research in reproductive immunology should be accordingly redirected.

Expression profiling analysis: Uncoupling protein 2 deficiency improves hepatic glucose, lipid profiles and insulin sensitivity in high-fat diet-fed mice by modulating expression of genes in peroxisome proliferator-activated receptor signaling pathway.

PubMed

Zhou, Mei-Cen; Yu, Ping; Sun, Qi; Li, Yu-Xiu

2016-03-01

Uncoupling protein 2 (UCP2), which was an important mitochondrial inner membrane protein associated with glucose and lipid metabolism, widely expresses in all kinds of tissues including hepatocytes. The present study aimed to explore the impact of UCP2 deficiency on glucose and lipid metabolism, insulin sensitivity and its effect on the liver-associated signaling pathway by expression profiling analysis. Four-week-old male UCP2-/- mice and UCP2+/+ mice were randomly assigned to four groups: UCP2-/- on a high-fat diet, UCP2-/- on a normal chow diet, UCP2+/+ on a high-fat diet and UCP2+/+ on a normal chow diet. The differentially expressed genes in the four groups on the 16th week were identified by Affymetrix gene array. The results of intraperitoneal glucose tolerance test and insulin tolerance showed that blood glucose and β-cell function were improved in the UCP2-/- group on high-fat diet. Enhanced insulin sensitivity was observed in the UCP2-/- group. The differentially expressed genes were mapped to 23 pathways (P < 0.05). We concentrated on the 'peroxisome proliferator-activated receptor (PPAR) signaling pathway' (P = 3.19 × 10(-11)), because it is closely associated with the regulation of glucose and lipid profiles. In the PPAR signaling pathway, seven genes (PPARγ, Dbi, Acsl3, Lpl, Me1, Scd1, Fads2) in the UCP2-/- mice were significantly upregulated. The present study used gene arrays to show that activity of the PPAR signaling pathway involved in the improvement of glucose and lipid metabolism in the liver of UCP2-deficient mice on a long-term high-fat diet. The upregulation of genes in the PPAR signaling pathway could explain our finding that UCP2 deficiency ameliorated insulin sensitivity. The manipulation of UCP2 protein expression could represent a new strategy for the prevention and treatment of diabetes.

Use of the adverse outcome pathway framework to represent cross-species consequences of specific pathway perturbations

EPA Science Inventory

The adverse outcome pathway (AOP) framework has been developed as a means for assembling scientifically defensible descriptions of how particular molecular perturbations, termed molecular initiating events (MIEs), can evoke a set of predictable responses at different levels of bi...

Integrating Aggregate Exposure Pathway (AEP) and Adverse ...

EPA Pesticide Factsheets

High throughput toxicity testing (HTT) holds the promise of providing data for tens of thousands of chemicals that currently have no data due to the cost and time required for animal testing. Interpretation of these results require information linking the perturbations seen in vitro with adverse outcomes in vivo and requires knowledge of how estimated exposure to the chemicals compare to the in vitro concentrations that show an effect. This abstract discusses how Adverse Outcome Pathways (AOPs) can be used to link HTT with adverse outcomes of regulatory significance and how Aggregate Exposure Pathways (AEPs) can connect concentrations of environment stressors at a source with an expected target site concentration designed to provide exposure estimates that are comparable to concentrations identified in HTT. Presentation at the ICCA-LRI and JRC Workshop: Fit-For-Purpose Exposure Assessment For Risk-Based Decision Making

How Unusual were Hurricane Harvey's Rains?

NASA Astrophysics Data System (ADS)

Emanuel, K.

2017-12-01

We apply an advanced technique for hurricane risk assessment to evaluate the probability of hurricane rainfall of Harvey's magnitude. The technique embeds a detailed computational hurricane model in the large-scale conditions represented by climate reanalyses and by climate models. We simulate 3700 hurricane events affecting the state of Texas, from each of three climate reanalyses spanning the period 1980-2016, and 2000 events from each of six climate models for each of two periods: the period 1981-2000 from historical simulations, and the period 2081-2100 from future simulations under Representative Concentration Pathway (RCP) 8.5. On the basis of these simulations, we estimate that hurricane rain of Harvey's magnitude in the state of Texas would have had an annual probability of 0.01 in the late twentieth century, and will have an annual probability of 0.18 by the end of this century, with remarkably small scatter among the six climate models downscaled. If the event frequency is changing linearly over time, this would yield an annual probability of 0.06 in 2017.

Comprehensive comparative analysis of volatile compounds in citrus fruits of different species.

PubMed

Zhang, Haipeng; Xie, Yunxia; Liu, Cuihua; Chen, Shilin; Hu, Shuangshuang; Xie, Zongzhou; Deng, Xiuxin; Xu, Juan

2017-09-01

The volatile profiles of fruit peels and juice sacs from 108 citrus accessions representing seven species were analyzed. Using GC-MS 162 and 107 compounds were determined in the peels and juice sacs, respectively. In the peels, monoterpene alcohols were accumulated in loose-skin mandarins; clementine tangerines and papedas were rich in sesquiterpene alcohols, sesquiterpenes, monoterpene alcohols and monoterpene aldehydes. β-pinene and sabinene were specifically accumulated in 4 of 5 lemon germplasms. Furthermore, concentrations of 34 distinctive compounds were selected to best represent the volatile profiles of seven species for HCA analysis, and the clustering results were in agreement with classic citrus taxonomy. Comparison of profiles from different growing seasons and production areas indicated that environmental factors play important roles in volatile metabolism. In addition, a few citrus germplasms that accumulated certain compounds were determined as promising breeding materials. Notably, volatile biosynthesis via MVA pathway in C. ichangensis 'Huaihua' was enhanced. Copyright © 2017. Published by Elsevier Ltd.

Ecosystem service impacts of future changes in CO2, climate, and land use as simulated by a coupled vegetation/land-use model system

NASA Astrophysics Data System (ADS)

Rabin, S. S.; Alexander, P.; Henry, R.; Anthoni, P.; Pugh, T.; Rounsevell, M.; Arneth, A.

2017-12-01

In a future of increasing atmospheric carbon dioxide (CO2) concentrations, changing climate, increasing human populations, and changing socioeconomic dynamics, the global agricultural system will need to adapt in order to feed the world. Global modeling can help to explore what these adaptations will look like, and their potential impacts on ecosystem services. To do so, however, the complex interconnections among the atmosphere, terrestrial ecosystems, and society mean that these various parts of the Earth system must be examined as an interconnected whole. With the goal of answering these questions, a model system has been developed that couples a biologically-representative global vegetation model, LPJ-GUESS, with the PLUMv2 land use model. LPJ-GUESS first simulates—at 0.5º resolution across the world—the potential yield of various crops and pasture under a range of management intensities for a time step given its atmospheric CO2 level and climatic forcings. These potential yield simulations are fed into PLUMv2, which uses them in conjunction with endogenous agricultural commodity demand and prices to produce land use and management inputs (fertilizer and irrigation water) at a sub-national level for the next time step. This process is performed through 2100 for a range of future climate and societal scenarios—the Representative Concentration Pathways (RCPs) and the Shared Socioeconomic Pathways (SSPs), respectively—providing a thorough exploration of possible trajectories of land use and land cover change. The land use projections produced by PLUMv2 are fed back into LPJ-GUESS to simulate the future impacts of land use change, along with increasing CO2 and climate change, on terrestrial ecosystems. This integrated analysis examines the resulting impacts on regulating and provisioning ecosystem services affecting biophysics (albedo); carbon, nitrogen, and water cycling; and the emission of biogenic volatile organic compounds (BVOCs).

Global wheat production potentials and management flexibility under the representative concentration pathways

NASA Astrophysics Data System (ADS)

Balkovic, Juraj; van der Velde, Marijn; Skalsky, Rastislav; Xiong, Wei; Folberth, Christian; Khabarov, Nikolay; Smirnov, Alexey

2014-05-01

Global wheat production is strongly linked with food security as wheat is one of the main sources of human nutrition. Increasing or stabilizing wheat yields in response to climate change is therefore imperative. To do so will require agricultural management interventions that have different levels of flexibility at regional level. Climate change is expected to worsen wheat growing conditions in many places and thus negatively impact on future management opportunities for sustainable intensification. We quantified, in a spatially explicit manner, global wheat yield developments under the envelope of Representative Concentration Pathways (RCP 2.6, 4.5, 6.0 and 8.5) under current and alternative fertilization and irrigation management to estimate future flexibility to cope with climate change impacts. A large-scale implementation of the EPIC model was integrated with the most recent information on global wheat cultivation currently available, and it was used to simulate regional and global wheat yields and production under historical climate and the RCP-driven and bias-corrected HadGEM2-ES climate projections. Fertilization and irrigation management scenarios were designed to project actual and exploitable (under current irrigation infrastructure) yields as well as the climate- and water-limited yield potentials. With current nutrient and water management, and across all RCPs, the global wheat production at the end of the century decreased from 50 to 100 Mt - with RCP2.6 having the lowest and RCP8.5 the highest impact. Despite the decrease in global wheat production potential on current cropland, the exploitable and climatic production gap of respectively 350 and 580 Mt indicates a considerable flexibility to counteract negative climate change impacts across all RCPs. Agricultural management could increase global wheat production by approximately 30% through intensified fertilization and 50% through improved fertilization and extended irrigation if nutrients or water were not limiting.

Response of a multi-stressed Mediterranean river to future climate and socio-economic scenarios.

PubMed

Stefanidis, Konstantinos; Panagopoulos, Yiannis; Mimikou, Maria

2018-06-15

Streams and rivers are among the most threatened ecosystems in Europe due to the combined effects of multiple pressures related to anthropogenic activities. Particularly in the Mediterranean region, changes in hydromorphology along with increased nutrient loadings are known to affect the ecological functions and ecosystem services of streams and rivers with the anticipated climate change being likely to further impair their functionality and structure. In this study, we investigated the combined effects of agricultural driven stressors on the ecology and delivered services of the Pinios river basin in Greece under three future world scenarios developed within the EU funded MARS project. Scenarios are based on combinations of Representative Concentration Pathways and Shared Socioeconomic Pathways and refer to early century (2030) and mid-century (2060) representing future climate worlds with particular socioeconomic characteristics. To assess the responses of ecological and ecosystem service indicators to the scenarios we first simulated hydrology and water quality in Pinios with a process-based model. Simulated abiotic stressor parameters (predictors) were linked to two biotic indicators, the macroinvertebrate indicators ASPT and EPT, with empirical modelling based on boosted regression trees and general linear models. Our results showed that the techno world scenario driven by fast economic growth and intensive exploitation of energy resources had the largest impact on both the abiotic status (nutrient loads and concentrations in water) and the biotic indicators. In contrast, the predicted changes under the other two future worlds, consensus and fragmented, were more diverse and were mostly dictated by the projected climate. This work showed that the future scenarios, especially the mid-century ones, had significant impact on both abiotic status and biotic responses underpinning the need for implementing catchment management practices able to mitigate the ecological threat on waters in the long-term. Copyright © 2018 Elsevier B.V. All rights reserved.

Agmatine potentiates neuroprotective effects of subthreshold concentrations of ketamine via mTOR/S6 kinase signaling pathway.

PubMed

Tavares, Mauren K; Dos Reis, Suellen; Platt, Nicolle; Heinrich, Isabella A; Wolin, Ingrid A V; Leal, Rodrigo B; Kaster, Manuella P; Rodrigues, Ana Lúcia S; Freitas, Andiara E

2018-05-12

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most robust neurobiological findings in the pathophysiology of major depressive disorder (MDD) over the last 40 years. The persistent increase in glucocorticoids levels induces morphological and anatomical changes in the brain, especially in the hippocampus. Ketamine represents a major advance for the treatment of MDD, however the psychotomimetic effects of this compound limit its widespread use. Agmatine is a neuromodulator that has been shown to be a putative novel and well-tolerated antidepressant/augmenter drug. In this study, the exposure of HT22 hippocampal neuronal cell line to corticosterone (50 μM) induced a significant neuronal cell death. Interestingly, the incubation of HT22 cells with the fast-acting antidepressant drug ketamine (1 μM) prevented the corticosterone-induced toxicity. Similarly, agmatine caused a significant cytoprotection at the concentration of 0.1 μM against corticosterone (50 μM) cell damage. Notably, the incubation with a subthreshold concentration of ketamine (0.01 μM) in combination with a subthreshold concentration of agmatine (0.001 μM) prevented the neuronal damage elicited by corticosterone (50 μM). A 24 h co-incubation with subthreshold concentrations of ketamine (0.01 μM) and agmatine (0.001 μM) was able to cause a significant increase in the phosphorylation levels of Akt (Ser 473 ) and p70S6 kinase (Thr 389 ) as well as PSD95 immunocontent. Neither glycogen synthase kinase-3β (Ser 9 ) phosphorylation nor β catenin immunocontent were altered by a 24 h co-incubation period. Finally, the co-incubation of cells for 30 min did not produce any effect in the phosphorylation or immunocontent of any protein investigated. Taken together, our results support the notion that the combination of subthreshold concentrations of ketamine and agmatine has cytoprotective effects against corticosterone-induced cell death. This effect is accompanied by its ability to activate Akt and mTOR/S6 kinase signaling pathway, and increase the expression of synaptic proteins. Copyright © 2018. Published by Elsevier Ltd.

Identifying pathways and processes affecting nitrate and orthophosphate inputs to streams in agricultural watersheds

USGS Publications Warehouse

Tesoriero, A.J.; Duff, J.H.; Wolock, D.M.; Spahr, N.E.; Almendinger, J.E.

2009-01-01

Understanding nutrient pathways to streams will improve nutrient management strategies and estimates of the time lag between when changes in land use practices occur and when water quality effects that result from these changes are observed. Nitrate and orthophosphate (OP) concentrations in several environmental compartments were examined in watersheds having a range of base flow index (BFI) values across the continental United States to determine the dominant pathways for water and nutrient inputs to streams. Estimates of the proportion of stream nitrate that was derived from groundwater increased as BFI increased. Nitrate concentration gradients between groundwater and surface water further supported the groundwater source of nitrate in these high BFI streams. However, nitrate concentrations in stream-bed pore water in all settings were typically lower than stream or upland groundwater concentrations, suggesting that nitrate discharge to streams was not uniform through the bed. Rather, preferential pathways (e.g., springs, seeps) may allow high nitrate groundwater to bypass sites of high biogeochemical transformation. Rapid pathway compartments (e.g., overland flow, tile drains) had OP concentrations that were typically higher than in streams and were important OP conveyers in most of these watersheds. In contrast to nitrate, the proportion of stream OP that is derived from ground water did not systematically increase as BFI increased. While typically not the dominant source of OP, groundwater discharge was an important pathway of OP transport to streams when BFI values were very high and when geochemical conditions favored OP mobility in groundwater. Copyright ?? 2009 by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America. All rights reserved.

Dynamics Sampling in Transition Pathway Space.

PubMed

Zhou, Hongyu; Tao, Peng

2018-01-09

The minimum energy pathway contains important information describing the transition between two states on a potential energy surface (PES). Chain-of-states methods were developed to efficiently calculate minimum energy pathways connecting two stable states. In the chain-of-states framework, a series of structures are generated and optimized to represent the minimum energy pathway connecting two states. However, multiple pathways may exist connecting two existing states and should be identified to obtain a full view of the transitions. Therefore, we developed an enhanced sampling method, named as the direct pathway dynamics sampling (DPDS) method, to facilitate exploration of a PES for multiple pathways connecting two stable states as well as addition minima and their associated transition pathways. In the DPDS method, molecular dynamics simulations are carried out on the targeting PES within a chain-of-states framework to directly sample the transition pathway space. The simulations of DPDS could be regulated by two parameters controlling distance among states along the pathway and smoothness of the pathway. One advantage of the chain-of-states framework is that no specific reaction coordinates are necessary to generate the reaction pathway, because such information is implicitly represented by the structures along the pathway. The chain-of-states setup in a DPDS method greatly enhances the sufficient sampling in high-energy space between two end states, such as transition states. By removing the constraint on the end states of the pathway, DPDS will also sample pathways connecting minima on a PES in addition to the end points of the starting pathway. This feature makes DPDS an ideal method to directly explore transition pathway space. Three examples demonstrate the efficiency of DPDS methods in sampling the high-energy area important for reactions on the PES.

Comparison of pathway and center of gravity of the calcaneus on non-involved and involved sides according to eccentric and concentric strengthening in patients with achilles tendinopathy.

PubMed

Yu, Jaeho; Lee, Gyuchang

2012-01-01

This study compares the changes in pathway and center of gravity (COG) on the calcaneus of non-involved and involved sides according to eccentric and concentric strengthening in patients with unilateral Achilles tendinopathy. The goal was to define the biomechanical changes according to eccentric strengthening for the development of clinical guidelines. Eighteen patients with Achilles tendinopathy were recruited at the K Rehabilitation Hospital in Seoul. The subjects were instructed to perform 5 sessions of concentric strengthening. The calcaneal pathway was measured using a three-dimensional (3D) motion analyzer, and COG was measured by a force plate. Subsequently, eccentric strengthening was implemented, and identical variables were measured. Concentric and eccentric strengthening was carried out on both the involved and non-involved sides. There was no significant difference in the calcaneal pathway in patients with Achilles tendinopathy during concentric and eccentric strengthening. However, during eccentric strengthening, the calcaneal pathway significantly increased on the involved side compared to the non-involved side for all variables excluding the z-axis. COG significantly decreased on the involved side when compared to the non-involved side in patients with Achilles tendinopathy during eccentric and concentric strengthening. During concentric strengthening, all variables of the COG significantly increased on the involved side compared to the non-involved side. Compared with eccentric strengthening, concentric strengthening decreased the stability of ankle joints and increased the movement distance of the calcaneus in patients with Achilles tendinopathy. Furthermore, eccentric strengthening was verified to be an effective exercise method for prevention of Achilles tendinopathy through the reduction of forward and backward path length of foot pressure. The regular application of eccentric strengthening was found to be effective in the secondary prevention of Achilles tendinopathy in a clinical setting.

Maximizing the efficiency of multienzyme process by stoichiometry optimization.

PubMed

Dvorak, Pavel; Kurumbang, Nagendra P; Bendl, Jaroslav; Brezovsky, Jan; Prokop, Zbynek; Damborsky, Jiri

2014-09-05

Multienzyme processes represent an important area of biocatalysis. Their efficiency can be enhanced by optimization of the stoichiometry of the biocatalysts. Here we present a workflow for maximizing the efficiency of a three-enzyme system catalyzing a five-step chemical conversion. Kinetic models of pathways with wild-type or engineered enzymes were built, and the enzyme stoichiometry of each pathway was optimized. Mathematical modeling and one-pot multienzyme experiments provided detailed insights into pathway dynamics, enabled the selection of a suitable engineered enzyme, and afforded high efficiency while minimizing biocatalyst loadings. Optimizing the stoichiometry in a pathway with an engineered enzyme reduced the total biocatalyst load by an impressive 56 %. Our new workflow represents a broadly applicable strategy for optimizing multienzyme processes. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A COMPACT CONCENTRATION OF LARGE GRAINS IN THE HD 142527 PROTOPLANETARY DUST TRAP

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

Casassus, Simon; Marino, Sebastian; Pérez, Sebastian

2015-10-20

A pathway to the formation of planetesimals, and eventually giant planets, may occur in concentrations of dust grains trapped in pressure maxima. Dramatic crescent-shaped dust concentrations have been seen in recent radio images at submillimeter wavelengths. These disk asymmetries could represent the initial phases of planet formation in the dust trap scenario, provided that grain sizes are spatially segregated. A testable prediction of azimuthal dust trapping is that progressively larger grains should be more sharply confined and should follow a distribution that is markedly different from the gas. However, gas tracers such as {sup 12}CO and the infrared emission frommore » small grains are both very optically thick where the submillimeter continuum originates, so previous observations have been unable to test the trapping predictions or to identify compact concentrations of larger grains required for planet formation by core accretion. Here we report multifrequency observations of HD 142527, from 34 to 700 GHz, that reveal a compact concentration of grains approaching centimeter sizes, with a few Earth masses, embedded in a large-scale crescent of smaller, submillimeter-sized particles. The emission peaks at wavelengths shorter than ∼1 mm are optically thick and trace the temperature structure resulting from shadows cast by the inner regions. Given this temperature structure, we infer that the largest dust grains are concentrated in the 34 GHz clump. We conclude that dust trapping is efficient enough for grains observable at centimeter wavelengths to lead to compact concentrations.« less

Transport of perfluoroalkyl substances (PFAS) from an arctic glacier to downstream locations: implications for sources.

PubMed

Kwok, Karen Y; Yamazaki, Eriko; Yamashita, Nobuyoshi; Taniyasu, Sachi; Murphy, Margaret B; Horii, Yuichi; Petrick, Gert; Kallerborn, Roland; Kannan, Kurunthachalam; Murano, Kentaro; Lam, Paul K S

2013-03-01

Perfluoroalkyl substances (PFAS) have been globally detected in various environmental matrices, yet their fate and transport to the Arctic is still unclear, especially for the European Arctic. In this study, concentrations of 17 PFAS were quantified in two ice cores (n=26), surface snow (n=9) and surface water samples (n=14) collected along a spatial gradient in Svalbard, Norway. Concentrations of selected ions (Na(+), SO4(2-), etc.) were also determined for tracing the origins and sources of PFAS. Perfluorobutanoate (PFBA), perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) were the dominant compounds found in ice core samples. Taking PFOA, PFNA and perfluorooctane-sulfonate (PFOS) as examples, higher concentrations were detected in the middle layers of the ice cores representing the period of 1997-2000. Lower concentrations of C8-C12 perfluorocarboxylates (PFCAs) were detected in comparison with concentrations measured previously in an ice core from the Canadian Arctic, indicating that contamination levels in the European Arctic are lower. Average PFAS concentrations were found to be lower in surface snow and melted glacier water samples, while increased concentrations were observed in river water downstream near the coastal area. Perfluorohexanesulfonate (PFHxS) was detected in the downstream locations, but not in the glacier, suggesting existence of local sources of this compound. Long-range atmospheric transport of PFAS was the major deposition pathway for the glaciers, while local sources (e.g., skiing activities) were identified in the downstream locations. Copyright © 2012 Elsevier B.V. All rights reserved.

The underlying pathway structure of biochemical reaction networks

PubMed Central

Schilling, Christophe H.; Palsson, Bernhard O.

1998-01-01

Bioinformatics is yielding extensive, and in some cases complete, genetic and biochemical information about individual cell types and cellular processes, providing the composition of living cells and the molecular structure of its components. These components together perform integrated cellular functions that now need to be analyzed. In particular, the functional definition of biochemical pathways and their role in the context of the whole cell is lacking. In this study, we show how the mass balance constraints that govern the function of biochemical reaction networks lead to the translation of this problem into the realm of linear algebra. The functional capabilities of biochemical reaction networks, and thus the choices that cells can make, are reflected in the null space of their stoichiometric matrix. The null space is spanned by a finite number of basis vectors. We present an algorithm for the synthesis of a set of basis vectors for spanning the null space of the stoichiometric matrix, in which these basis vectors represent the underlying biochemical pathways that are fundamental to the corresponding biochemical reaction network. In other words, all possible flux distributions achievable by a defined set of biochemical reactions are represented by a linear combination of these basis pathways. These basis pathways thus represent the underlying pathway structure of the defined biochemical reaction network. This development is significant from a fundamental and conceptual standpoint because it yields a holistic definition of biochemical pathways in contrast to definitions that have arisen from the historical development of our knowledge about biochemical processes. Additionally, this new conceptual framework will be important in defining, characterizing, and studying biochemical pathways from the rapidly growing information on cellular function. PMID:9539712

Scenario and modelling uncertainty in global mean temperature change derived from emission driven Global Climate Models

NASA Astrophysics Data System (ADS)

Booth, B. B. B.; Bernie, D.; McNeall, D.; Hawkins, E.; Caesar, J.; Boulton, C.; Friedlingstein, P.; Sexton, D.

2012-09-01

We compare future changes in global mean temperature in response to different future scenarios which, for the first time, arise from emission driven rather than concentration driven perturbed parameter ensemble of a Global Climate Model (GCM). These new GCM simulations sample uncertainties in atmospheric feedbacks, land carbon cycle, ocean physics and aerosol sulphur cycle processes. We find broader ranges of projected temperature responses arising when considering emission rather than concentration driven simulations (with 10-90 percentile ranges of 1.7 K for the aggressive mitigation scenario up to 3.9 K for the high end business as usual scenario). A small minority of simulations resulting from combinations of strong atmospheric feedbacks and carbon cycle responses show temperature increases in excess of 9 degrees (RCP8.5) and even under aggressive mitigation (RCP2.6) temperatures in excess of 4 K. While the simulations point to much larger temperature ranges for emission driven experiments, they do not change existing expectations (based on previous concentration driven experiments) on the timescale that different sources of uncertainty are important. The new simulations sample a range of future atmospheric concentrations for each emission scenario. Both in case of SRES A1B and the Representative Concentration Pathways (RCPs), the concentration pathways used to drive GCM ensembles lies towards the lower end of our simulated distribution. This design decision (a legecy of previous assessments) is likely to lead concentration driven experiments to under-sample strong feedback responses in concentration driven projections. Our ensemble of emission driven simulations span the global temperature response of other multi-model frameworks except at the low end, where combinations of low climate sensitivity and low carbon cycle feedbacks lead to responses outside our ensemble range. The ensemble simulates a number of high end responses which lie above the CMIP5 carbon cycle range. These high end simulations can be linked to sampling a number of stronger carbon cycle feedbacks and to sampling climate sensitivities above 4.5 K. This latter aspect highlights the priority in identifying real world climate sensitivity constraints which, if achieved, would lead to reductions on the uppper bound of projected global mean temperature change. The ensembles of simulations presented here provides a framework to explore relationships between present day observables and future changes while the large spread of future projected changes, highlights the ongoing need for such work.

Impact of rising greenhouse gas concentrations on future tropical ozone and UV exposure

NASA Astrophysics Data System (ADS)

Meul, Stefanie; Dameris, Martin; Langematz, Ulrike; Abalichin, Janna; Kerschbaumer, Andreas; Kubin, Anne; Oberländer-Hayn, Sophie

2016-03-01

Future projections of tropical total column ozone (TCO) are challenging, as its evolution is affected not only by the expected decline of ozone depleting substances but also by the uncertain increase of greenhouse gas (GHG) emissions. To assess the range of tropical TCO projections, we analyze simulations with a chemistry-climate model forced by three different GHG scenarios (Representative Concentration Pathway (RCP) 4.5, RCP6.0, and RCP8.5). We find that tropical TCO will be lower by the end of the 21st century compared to the 1960s in all scenarios with the largest decrease in the medium RCP6.0 scenario. Uncertainties of the projected TCO changes arise from the magnitude of stratospheric column decrease and tropospheric ozone increase which both strongly vary between the scenarios. In the three scenario simulations the stratospheric column decrease is not compensated by the increase in tropospheric ozone. The concomitant increase in harmful ultraviolet irradiance reaches up to 15% in specific regions in the RCP6.0 scenario.

Kinetic Model for the Radical Degradation of Tri-Halonitromethane Disinfection Byproducts in Water

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

Stephen P. Mezyk; Bruce J. Mincher; William J. Cooper

The halonitromethanes (HNMs) are byproducts of the ozonation and chlorine/chloramine treatment of drinking waters. Although typically occurring at low concentrations HNMs have high cytotoxicity and mutagenicity, and may therefore represent a significant human health hazard. In this study, we have investigated the radical based mineralization of fully-halogenated HNMs in water using the congeners bromodichloronitromethane and chlorodibromonitromethane. We have combined absolute reaction rate constants for their reactions with the hydroxyl radical and the hydrated electron as measured by electron pulse radiolysis and analytical measurements of stable product concentrations obtained by 60Co steady-state radiolysis with a kinetic computer model that includes watermore » radiolysis reactions and halide/nitrogen oxide radical chemistry to fully elucidate the reaction pathways of these HNMs. These results are compared to our previous similar study of the fully chlorinated HNM chloropicrin. The full optimized computer model, suitable for predicting the behavior of this class of compounds in irradiated drinking water is provided.« less

The projected demise of Barnes Ice Cap: Evidence of an unusually warm 21st century Arctic

NASA Astrophysics Data System (ADS)

Gilbert, A.; Flowers, G. E.; Miller, G. H.; Refsnider, K. A.; Young, N. E.; Radić, V.

2017-03-01

As a remnant of the Laurentide Ice Sheet, Barnes Ice Cap owes its existence and present form in part to the climate of the last glacial period. The ice cap has been sustained in the present interglacial climate by its own topography through the mass balance-elevation feedback. A coupled mass balance and ice-flow model, forced by Coupled Model Intercomparison Project Phase 5 climate model output, projects that the current ice cap will likely disappear in the next 300 years. For greenhouse gas Representative Concentration Pathways of +2.6 to +8.5 Wm-2, the projected ice-cap survival times range from 150 to 530 years. Measured concentrations of cosmogenic radionuclides 10Be, 26Al, and 14C at sites exposed near the ice-cap margin suggest the pending disappearance of Barnes Ice Cap is very unusual in the last million years. The data and models together point to an exceptionally warm 21st century Arctic climate.

Impact of Climate Change on Potential, Attainable, and Actual Wheat Yield in Oklahoma

NASA Astrophysics Data System (ADS)

Dhakal, K.; Linde, E.; Kakani, V. G.; Alderman, P. D.; Brunson, D.; Ochsner, T. E.; Carver, B.

2017-12-01

Gradually developing climatic and weather anomalies due to increasing atmospheric greenhouse gases concentration can pose threat to farmers and resource managers. This study was aimed at investigating the effects of climate change on winter wheat (Triticum aestivum L.) under the Representative Concentration Pathways 6.0 and 8.5 using downscaled climate projections from different models and their ensembles. Daily data of maximum and minimum air temperature, rainfall, and solar radiation for, four General Circulation Models (MRIOC5, MRI-CGCM3, HadGEM2-ES, CSRIO-Mk3.6.0), ensemble of four models and ensemble of 17 GCMs, at 800 m resolution, were developed for two RCPs using Marksim. We describe a methodology for rapid synthesis of GCM-based, spatially explicit, high resolution future weather data inputs for the DSSAT crop model, for cropland area across wheat growing regions of Oklahoma for the future period 2040-2060. The potential impacts of climate change and variability on potential, attainable, and actual winter wheat yield in Oklahoma is discussed.

Accumulation and transport of minerals by marine protozoa. Progress report, September 1, 1976--November 30, 1977. [Mineral concentration by Tintinnida in coastal waters

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

Gold, K.

Tintinnida are abundant microzooplankton found in all of the world's oceans, and important components of the marine food web as predators, prey, and as regenerators of nutrients. The agglutinated forms take on added importance in coastal waters. Representatives of this group have the unique ability among ciliates to pick up particles from the environment and incorporate them into the lorica. The ecological significance of the phenomenon lies in: it is a pathway whereby radionuclides, metals and other toxic substance can be biologically concentrated and transferred from sediments and the water column to the biota; from the viewpoint of microzooplankton asmore » indicators of environmental perturbations, pollution, or water mass movements, it is important to determine whether minerals accumulated on the lorica can serve as a guide to the site where they originate. Results are reported from studies in progress on the types of mineral matter accumulated by tintinnids.« less

Inferring sources of polycyclic aromatic hydrocarbons (PAHs) in sediments from the western Taiwan Strait through end-member mixing analysis.

PubMed

Li, Tao; Sun, Guihua; Ma, Shengzhong; Liang, Kai; Yang, Chupeng; Li, Bo; Luo, Weidong

2016-11-15

Concentration, spatial distribution, composition and sources of polycyclic aromatic hydrocarbons (PAHs) were investigated based on measurements of 16 PAH compounds in surface sediments of the western Taiwan Strait. Total PAH concentrations ranged from 2.41 to 218.54ngg -1 . Cluster analysis identified three site clusters representing the northern, central and southern regions. Sedimentary PAHs mainly originated from a mixture of pyrolytic and petrogenic in the north, from pyrolytic in the central, and from petrogenic in the south. An end-member mixing model was performed using PAH compound data to estimate mixing proportions for unknown end-members (i.e., extreme-value sample points) proposed by principal component analysis (PCA). The results showed that the analyzed samples can be expressed as mixtures of three end-members, and the mixing of different end-members was strongly related to the transport pathway controlled by two currents, which alternately prevail in the Taiwan Strait during different seasons. Copyright © 2016. Published by Elsevier Ltd.

Activity Dependent Signal Transduction in Skeletal Muscle

NASA Technical Reports Server (NTRS)

Hamilton, Susan L.

1999-01-01

The overall goals of this project are: 1) to define the initial signal transduction events whereby the removal of gravitational load from antigravity muscles, such as the soleus, triggers muscle atrophy, and 2) to develop countermeasures to prevent this from happening. Our rationale for this approach is that, if countermeasures can be developed to regulate these early events, we could avoid having to deal with the multiple cascades of events that occur downstream from the initial event. One of our major findings is that hind limb suspension causes an early and sustained increase in intracellular Ca(2+) concentration ([Ca (2+)](sub i)). In most cells the consequences of changes in ([Ca (2+)](sub i))depend on the amplitude, frequency and duration of the Ca(2+) signal and on other factors in the intracellular environment. We propose that muscle remodeling in microgravity represents a change in the balance among several CA(2+) regulated signal transduction pathways, in particular those involving the transcription factors NFAT and NFkB and the pro-apoptotic protein BAD. Other Ca(2+) sensitive pathways involving PKC, ras, rac, and CaM kinase II may also contribute to muscle remodeling.

Microbiome-host systems interactions: protective effects of propionate upon the blood-brain barrier.

PubMed

Hoyles, Lesley; Snelling, Tom; Umlai, Umm-Kulthum; Nicholson, Jeremy K; Carding, Simon R; Glen, Robert C; McArthur, Simon

2018-03-21

Gut microbiota composition and function are symbiotically linked with host health and altered in metabolic, inflammatory and neurodegenerative disorders. Three recognised mechanisms exist by which the microbiome influences the gut-brain axis: modification of autonomic/sensorimotor connections, immune activation, and neuroendocrine pathway regulation. We hypothesised interactions between circulating gut-derived microbial metabolites, and the blood-brain barrier (BBB) also contribute to the gut-brain axis. Propionate, produced from dietary substrates by colonic bacteria, stimulates intestinal gluconeogenesis and is associated with reduced stress behaviours, but its potential endocrine role has not been addressed. After demonstrating expression of the propionate receptor FFAR3 on human brain endothelium, we examined the impact of a physiologically relevant propionate concentration (1 μM) on BBB properties in vitro. Propionate inhibited pathways associated with non-specific microbial infections via a CD14-dependent mechanism, suppressed expression of LRP-1 and protected the BBB from oxidative stress via NRF2 (NFE2L2) signalling. Together, these results suggest gut-derived microbial metabolites interact with the BBB, representing a fourth facet of the gut-brain axis that warrants further attention.

Deciphering early events involved in hyperosmotic stress-induced programmed cell death in tobacco BY-2 cells

PubMed Central

Monetti, Emanuela; Kadono, Takashi; Bouteau, François

2014-01-01

Hyperosmotic stresses represent one of the major constraints that adversely affect plants growth, development, and productivity. In this study, the focus was on early responses to hyperosmotic stress- (NaCl and sorbitol) induced reactive oxygen species (ROS) generation, cytosolic Ca2+ concentration ([Ca2+]cyt) increase, ion fluxes, and mitochondrial potential variations, and on their links in pathways leading to programmed cell death (PCD). By using BY-2 tobacco cells, it was shown that both NaCl- and sorbitol-induced PCD seemed to be dependent on superoxide anion (O2·–) generation by NADPH-oxidase. In the case of NaCl, an early influx of sodium through non-selective cation channels participates in the development of PCD through mitochondrial dysfunction and NADPH-oxidase-dependent O2·– generation. This supports the hypothesis of different pathways in NaCl- and sorbitol-induced cell death. Surprisingly, other shared early responses, such as [Ca2+]cyt increase and singlet oxygen production, do not seem to be involved in PCD. PMID:24420571

Writing with ring currents: selectively hydrogenated polycyclic aromatics as finite models of graphene and graphane

PubMed Central

Fowler, Patrick W.; Gibson, Christopher M.; Bean, David E.

2014-01-01

Alternating partial hydrogenation of the interior region of a polycyclic aromatic hydrocarbon gives a finite model system representing systems on the pathway from graphene to the graphane modification of the graphene sheet. Calculations at the DFT and coupled Hartree–Fock levels confirm that sp2 cycles of bare carbon centres isolated by selective hydrogenation retain the essentially planar geometry and electron delocalization of the annulene that they mimic. Delocalization is diagnosed by the presence of ring currents, as detected by ipsocentric calculation and visualization of the current density induced in the π system by a perpendicular external magnetic field. These induced ‘ring’ currents have essentially the same sense, strength and orbital origin as in the free hydrocarbon. Subjected to the important experimental proviso of the need for atomic-scale control of hydrogenation, this finding predicts the possibility of writing single, multiple and concentric diatropic and/or paratropic ring currents on the graphene/graphane sheet. The implication is that pathways for free flow of ballistic current can be modelled in the same way. PMID:24611026

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data.

PubMed

Deziel, Nicole C; Freeman, Laura E Beane; Graubard, Barry I; Jones, Rena R; Hoppin, Jane A; Thomas, Kent; Hines, Cynthia J; Blair, Aaron; Sandler, Dale P; Chen, Honglei; Lubin, Jay H; Andreotti, Gabriella; Alavanja, Michael C R; Friesen, Melissa C

2017-03-01

Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1-19% and ≥ 20%, respectively (88 statistics, five studies). Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta-regression of published data. Environ Health Perspect 125:296-305; http://dx.doi.org/10.1289/EHP426.

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data

PubMed Central

Deziel, Nicole C.; Freeman, Laura E. Beane; Graubard, Barry I.; Jones, Rena R.; Hoppin, Jane A.; Thomas, Kent; Hines, Cynthia J.; Blair, Aaron; Sandler, Dale P.; Chen, Honglei; Lubin, Jay H.; Andreotti, Gabriella; Alavanja, Michael C. R.; Friesen, Melissa C.

2016-01-01

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. Methods: From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). Results: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1–19% and ≥ 20%, respectively (88 statistics, five studies). Conclusion: Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta-regression of published data. Environ Health Perspect 125:296–305; http://dx.doi.org/10.1289/EHP426 PMID:27458779

Inhibition of class IA PI3K enzymes in non-small cell lung cancer cells uncovers functional compensation among isoforms.

PubMed

Stamatkin, Christopher; Ratermann, Kelley L; Overley, Colleen W; Black, Esther P

2015-01-01

Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies while normal cell proliferation requires pathway functionality. Although inhibitors of the PI3K pathway are in clinical trials or approved for therapy, an understanding of the functional activities of pathway members in specific malignancies is needed. In lung cancers, the PI3K pathway is often aberrantly activated by mutation of genes encoding EGFR, KRAS, and PIK3CA proteins. We sought to understand whether class IA PI3K enzymes represent rational therapeutic targets in cells of non-squamous lung cancers by exploring pharmacological and genetic inhibitors of PI3K enzymes in a non-small cell lung cancer (NSCLC) cell line system. We found that class IA PI3K enzymes were expressed in all cell lines tested, but treatment of NSCLC lines with isoform-selective inhibitors (A66, TGX-221, CAL-101 and IC488743) had little effect on cell proliferation or prolonged inhibition of AKT activity. Inhibitory pharmacokinetic and pharmacodynamic responses were observed using these agents at non-isoform selective concentrations and with the pan-class I (ZSTK474) agent. Response to pharmacological inhibition suggested that PI3K isoforms may functionally compensate for one another thus limiting efficacy of single agent treatment. However, combination of ZSTK474 and an EGFR inhibitor (erlotinib) in NSCLC resistant to each single agent reduced cellular proliferation. These studies uncovered unanticipated cellular responses to PI3K isoform inhibition in NSCLC that does not correlate with PI3K mutations, suggesting that patients bearing tumors with wildtype EGFR and KRAS are unlikely to benefit from inhibitors of single isoforms but may respond to pan-isoform inhibition.

Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway.

PubMed

Jo, Guk Heui; Kim, Gi-Young; Kim, Wun-Jae; Park, Kun Young; Choi, Yung Hyun

2014-10-01

Sulforaphane, a naturally occurring isothiocyanate found in cruciferous vegetables, has received a great deal of attention because of its ability to inhibit cell proliferation and induce apoptosis in cancer cells. In this study, we investigated the anticancer activity of sulforaphane in the T24 human bladder cancer line, and explored its molecular mechanism of action. Our results showed that treatment with sulforaphane inhibited cell viability and induced apoptosis in T24 cells in a concentration-dependent manner. Sulforaphane-induced apoptosis was associated with mitochondria dysfunction, cytochrome c release and Bcl-2/Bax dysregulation. Furthermore, the increased activity of caspase-9 and -3, but not caspase-8, was accompanied by the cleavage of poly ADP-ribose polymerase, indicating the involvement of the mitochondria-mediated intrinsic apoptotic pathway. Concomitant with these changes, sulforaphane triggered reactive oxygen species (ROS) generation, which, along with the blockage of sulforaphane-induced loss of mitochondrial membrane potential and apoptosis, was strongly attenuated by the ROS scavenger N-acetyl-L-cysteine. Furthermore, sulforaphane was observed to activate endoplasmic reticulum (ER) stress and the nuclear factor-E2-related factor-2 (Nrf2) signaling pathway, as demonstrated by the upregulation of ER stress‑related proteins, including glucose-regulated protein 78 and C/EBP-homologous protein, and the accumulation of phosphorylated Nrf2 proteins in the nucleus and induction of heme oxygenase-1 expression, respectively. Taken together, these results demonstrate that sulforaphane has antitumor effects against bladder cancer cells through an ROS-mediated intrinsic apoptotic pathway, and suggest that ER stress and Nrf2 may represent strategic targets for sulforaphane-induced apoptosis.

Future possible crop yield scenarios under multiple SSP and RCP scenarios.

NASA Astrophysics Data System (ADS)

Sakurai, G.; Yokozawa, M.; Nishimori, M.; Okada, M.

2016-12-01

Understanding the effect of future climate change on global crop yields is one of the most important tasks for global food security. Future crop yields would be influenced by climatic factors such as the changes of temperature, precipitation and atmospheric carbon dioxide concentration. On the other hand, the effect of the changes of agricultural technologies such as crop varieties, pesticide and fertilizer input on crop yields have large uncertainty. However, not much is available on the contribution ratio of each factor under the future climate change scenario. We estimated the future global yields of four major crops (maize, soybean, rice and wheat) under three Shared Socio Economic Pathways (SSPs) and four Representative Concentration Pathways (RCPs). For this purpose, firstly, we estimated a parameter of a process based model (PRYSBI2) using a Bayesian method for each 1.125 degree spatial grid. The model parameter is relevant to the agricultural technology (we call "technological parameter" here after). Then, we analyzed the relationship between the values of technological parameter and GDP values. We found that the estimated values of the technological parameter were positively correlated with the GDP. Using the estimated relationship, we predicted future crop yield during 2020 and 2100 under SSP1, SSP2 and SSP3 scenarios and RCP 2.6, 4.5, 6.0 and 8.5. The estimated crop yields were different among SSP scenarios. However, we found that the yield difference attributable to SSPs were smaller than those attributable to CO2 fertilization effects and climate change. Particularly, the estimated effect of the change of atmospheric carbon dioxide concentration on global yields was more than four times larger than that of GDP for C3 crops.

Stable isotope probing of acetate fed anaerobic batch incubations shows a partial resistance of acetoclastic methanogenesis catalyzed by Methanosarcina to sudden increase of ammonia level.

PubMed

Hao, Liping; Lü, Fan; Mazéas, Laurent; Desmond-Le Quéméner, Elie; Madigou, Céline; Guenne, Angéline; Shao, Liming; Bouchez, Théodore; He, Pinjing

2015-02-01

Ammonia inhibition represents a major operational issue for anaerobic digestion. In order to refine our understanding of the terminal catabolic steps in thermophilic anaerobic digestion under ammonia stress, we studied batch thermophilic acetate fed experiments at low (0.26 g L(-1)) and high (7.00 g L(-1)) Total Ammonia Nitrogen concentrations (TAN). Although methane production started immediately for all incubations and resulted in methane yields close to stoichiometric expectations, a 62-72% decrease of methanogenic rate was observed throughout the incubation at 7.00 g L(-1) of TAN compared to 0.26 g L(-1). Stable Isotope Probing analysis of active microbial communities in (13)C-acetate fed experiments coupled to automated ribosomal intergenic spacer analysis and 16S rDNA pyrotag sequencing confirmed that microbial communities were similar for both TAN conditions. At both TAN levels, the (13)C-labeled bacterial community was mainly affiliated to Clostridia-relatives, with OPB54 bacteria being the most abundant sequence in the heavy DNA 16S rDNA pyrotag library. Sequences closely related to Methanosarcina thermophila were also abundantly retrieved in the heavy DNA fractions, showing that this methanogen was still actively assimilating labeled carbon from acetate at free ammonia nitrogen concentrations up to 916 mg L(-1). Stable isotopic signature analysis of biogas, measured in unlabeled acetate fed experiments that were conducted in parallel, confirmed that acetoclastic methanogenic pathway was dominant at both ammonia concentrations. Our work demonstrates that, besides the syntrophic acetate oxidation pathway, acetoclastic methanogenesis catalyzed by Methanosarcina can also play a major role in methane production at high ammonia levels. Copyright © 2014 Elsevier Ltd. All rights reserved.

Wnt/β-Catenin Expression Does Not Correlate with Serum Alkaline Phosphatase Concentration in Canine Osteosarcoma Patients

PubMed Central

Piskun, Caroline M.; Muthuswamy, Anantharaman; Huelsmeyer, Michael K.; Thompson, Victoria; Stein, Timothy J.

2011-01-01

Osteosarcoma is an aggressive malignancy of the bone and an increase in serum alkaline phosphatase concentration has clinical prognostic value in both humans and canines. Increased serum alkaline phosphatase concentration at the time of diagnosis has been associated with poorer outcomes for osteosarcoma patients. The biology underlying this negative prognostic factor is poorly understood. Given that activation of the Wnt signaling pathway has been associated with alkaline phosphatase expression in osteoblasts, we hypothesized that the Wnt/β-catenin signaling pathway would be differentially activated in osteosarcoma tissue based on serum ALP status. Archived canine osteosarcoma samples and primary canine osteosarcoma cell lines were used to evaluate the status of Wnt/β-catenin signaling pathway activity through immunohistochemical staining, western immunoblot analyses, quantitative reverse-transcription polymerase chain reaction, and a Wnt-responsive promoter activity assay. We found no significant difference in β-catenin expression or activation between OSA populations differing in serum ALP concentration. Pathway activity was mildly increased in the primary OSA cell line generated from a patient with increased serum ALP compared to the normal serum ALP OSA cell line. Further investigation into the mechanisms underlying differences in serum ALP concentration is necessary to improve our understanding of the biological implications of this negative prognostic indicator. PMID:22022527

Differential reconstructed gene interaction networks for deriving toxicity threshold in chemical risk assessment.

PubMed

Yang, Yi; Maxwell, Andrew; Zhang, Xiaowei; Wang, Nan; Perkins, Edward J; Zhang, Chaoyang; Gong, Ping

2013-01-01

Pathway alterations reflected as changes in gene expression regulation and gene interaction can result from cellular exposure to toxicants. Such information is often used to elucidate toxicological modes of action. From a risk assessment perspective, alterations in biological pathways are a rich resource for setting toxicant thresholds, which may be more sensitive and mechanism-informed than traditional toxicity endpoints. Here we developed a novel differential networks (DNs) approach to connect pathway perturbation with toxicity threshold setting. Our DNs approach consists of 6 steps: time-series gene expression data collection, identification of altered genes, gene interaction network reconstruction, differential edge inference, mapping of genes with differential edges to pathways, and establishment of causal relationships between chemical concentration and perturbed pathways. A one-sample Gaussian process model and a linear regression model were used to identify genes that exhibited significant profile changes across an entire time course and between treatments, respectively. Interaction networks of differentially expressed (DE) genes were reconstructed for different treatments using a state space model and then compared to infer differential edges/interactions. DE genes possessing differential edges were mapped to biological pathways in databases such as KEGG pathways. Using the DNs approach, we analyzed a time-series Escherichia coli live cell gene expression dataset consisting of 4 treatments (control, 10, 100, 1000 mg/L naphthenic acids, NAs) and 18 time points. Through comparison of reconstructed networks and construction of differential networks, 80 genes were identified as DE genes with a significant number of differential edges, and 22 KEGG pathways were altered in a concentration-dependent manner. Some of these pathways were perturbed to a degree as high as 70% even at the lowest exposure concentration, implying a high sensitivity of our DNs approach. Findings from this proof-of-concept study suggest that our approach has a great potential in providing a novel and sensitive tool for threshold setting in chemical risk assessment. In future work, we plan to analyze more time-series datasets with a full spectrum of concentrations and sufficient replications per treatment. The pathway alteration-derived thresholds will also be compared with those derived from apical endpoints such as cell growth rate.

Occurrence of organophosphate flame retardants in drinking water from China.

PubMed

Li, Jun; Yu, Nanyang; Zhang, Beibei; Jin, Ling; Li, Meiying; Hu, Mengyang; Zhang, Xiaowei; Wei, Si; Yu, Hongxia

2014-05-01

Several organophosphate flame retardants (OPFRs) have been identified as known or suspected carcinogens or neurotoxic substances. Given the potential health risks of these compounds, we conducted a comprehensive survey of nine OPFRs in drinking water in China. We found total concentrations of OPFRs in tap water ranging from 85.1 ng/L to 325 ng/L, and tris(2-butoxyethyl) phosphate (TBEP), triphenyl phosphate (TPP), and tris(2-chloroisopropyl) phosphate (TCPP) were the most common components. Similar OPFR concentrations and profiles were observed in water samples processed through six different waterworks in Nanjing, China. However, boiling affected OPFR levels in drinking water by either increasing (e.g., TBEP) or decreasing (e.g., tributyl phosphate, TBP) concentrations depending on the particular compound and the state of the indoor environment. We also found that bottled water contained many of the same major OPFR compounds with concentrations 10-25% lower than those in tap water, although TBEP contamination in bottled water remained a concern. Finally, we concluded that the risk of ingesting OPFRs through drinking water was not a major health concern for either adults or children in China. Nevertheless, drinking water ingestion represents an important exposure pathway for OPFRs. Copyright © 2014. Published by Elsevier Ltd.

Disentangling the multigenic and pleiotropic nature of molecular function

PubMed Central

2015-01-01

Background Biological processes at the molecular level are usually represented by molecular interaction networks. Function is organised and modularity identified based on network topology, however, this approach often fails to account for the dynamic and multifunctional nature of molecular components. For example, a molecule engaging in spatially or temporally independent functions may be inappropriately clustered into a single functional module. To capture biologically meaningful sets of interacting molecules, we use experimentally defined pathways as spatial/temporal units of molecular activity. Results We defined functional profiles of Saccharomyces cerevisiae based on a minimal set of Gene Ontology terms sufficient to represent each pathway's genes. The Gene Ontology terms were used to annotate 271 pathways, accounting for pathway multi-functionality and gene pleiotropy. Pathways were then arranged into a network, linked by shared functionality. Of the genes in our data set, 44% appeared in multiple pathways performing a diverse set of functions. Linking pathways by overlapping functionality revealed a modular network with energy metabolism forming a sparse centre, surrounded by several denser clusters comprised of regulatory and metabolic pathways. Signalling pathways formed a relatively discrete cluster connected to the centre of the network. Genetic interactions were enriched within the clusters of pathways by a factor of 5.5, confirming the organisation of our pathway network is biologically significant. Conclusions Our representation of molecular function according to pathway relationships enables analysis of gene/protein activity in the context of specific functional roles, as an alternative to typical molecule-centric graph-based methods. The pathway network demonstrates the cooperation of multiple pathways to perform biological processes and organises pathways into functionally related clusters with interdependent outcomes. PMID:26678917

Future efficiency of run of the river hydropower schemes based on climate change scenarios: case study in UK catchments

NASA Astrophysics Data System (ADS)

Pasten Zapata, Ernesto; Moggridge, Helen; Jones, Julie; Widmann, Martin

2017-04-01

Run-of-the-River (ROR) hydropower schemes are expected to be importantly affected by climate change as they rely in the availability of river flow to generate energy. As temperature and precipitation are expected to vary in the future, the hydrological cycle will also undergo changes. Therefore, climate models based on complex physical atmospheric interactions have been developed to simulate future climate scenarios considering the atmosphere's greenhouse gas concentrations. These scenarios are classified according to the Representative Concentration Pathways (RCP) that are generated according to the concentration of greenhouse gases. This study evaluates possible scenarios for selected ROR hydropower schemes within the UK, considering three different RCPs: 2.6, 4.5 and 8.5 W/m2 for 2100 relative to pre-industrial values. The study sites cover different climate, land cover, topographic and hydropower scheme characteristics representative of the UK's heterogeneity. Precipitation and temperature outputs from state-of-the-art Regional Climate Models (RCMs) from the Euro-CORDEX project are used as input for a HEC-HMS hydrological model to simulate the future river flow available. Both uncorrected and bias-corrected RCM simulations are analyzed. The results of this project provide an insight of the possible effects of climate change towards the generation of power from the ROR hydropower schemes according to the different RCP scenarios and contrasts the results obtained from uncorrected and bias-corrected RCMs. This analysis can aid on the adaptation to climate change as well as the planning of future ROR schemes in the region.

A zonal evaluation of intrinsic susceptibility in selected principal aquifers of the United States

USGS Publications Warehouse

Wellman, Tristan P.; Kauffman, Leon; Clark, Brian

2012-01-01

A method was developed to evaluate intrinsic groundwater susceptibility in 11 study areas across the United States. Calibrated groundwater-flow models and a variable-advection particle-tracking scheme that accounts for uncertainty were used to derive ranges of conservative solute concentration and groundwater age within spatially defined zones from solute loading to the water table. Aquifers were partitioned into six zones; four relative depth zones and two zones to represent pumping wells and surface water. Five years after solute was introduced in simulated recharge and stream leakage, normalized zone concentrations were detected at values above 10-4 in the shallowest aquifer zone, well zone, and surface-water zone for 10 of the 11 study areas. At the 125-year time scale, 9 out of the 11 study areas exhibited detectable concentrations in all zones and the majority of zones possess concentrations that are substantial relative to the source concentration (ClCo > 10-1). Thresholds defined by the time representing the earliest 1% of groundwater-transit times were used to identify fast transport pathways within the groundwater. The 1% thresholds occurred in a period of days to years for the shallow zone, days to decades for the well and surface-water zones, and years to millennia for the deeper zones. Thresholds defined by the 99th percentile of groundwater travel times were used to reflect late-time response and ranged considerably between study area (~102 to ~106 years), which highlights the potential for chemical constituents to persist in groundwater for long periods under a conservative state. The results of this investigation provide an instructive example of the intricate relations between climate and aquifer characteristics and their role on solute transport in groundwater. The proposed method accounts for dynamical processes in the aquifer and complements more traditional assessments of susceptibility using (apparent) mean water age.

Glycolytic intermediates and adenosine phosphates in rat liver at high altitude /3,800 m/.

NASA Technical Reports Server (NTRS)

Cipriano, L. F.; Pace, N.

1973-01-01

Liver tissue obtained from adult rats exposed to 3800 m altitude for intervals ranging from 1.5 hr to 63 days was examined by enzymatic analysis. During the first 3 hr of exposure, an immediate decrease in rephosphorylation of high-energy phosphates led to reduced glycogenesis and eventual pileup of AMP, pyruvate, fructose 1,6-diphosphate, glucose 6-phosphate, and glucose. This was accompanied by a reduction of pentose phosphate pathway activity. After 3 to 6 hr, a secondary adjustment of substrate concentrations occurred along with the apparent facilitation of phosphofructokinase. This secondary adjustment appears to increase anaerobic production of ATP and represents a significant intracellular contribution to the acclimatization process at high altitude.

Assessing the present and future probability of Hurricane Harvey's rainfall.

PubMed

Emanuel, Kerry

2017-11-28

We estimate, for current and future climates, the annual probability of areally averaged hurricane rain of Hurricane Harvey's magnitude by downscaling large numbers of tropical cyclones from three climate reanalyses and six climate models. For the state of Texas, we estimate that the annual probability of 500 mm of area-integrated rainfall was about 1% in the period 1981-2000 and will increase to 18% over the period 2081-2100 under Intergovernmental Panel on Climate Change (IPCC) AR5 representative concentration pathway 8.5. If the frequency of such event is increasingly linearly between these two periods, then in 2017 the annual probability would be 6%, a sixfold increase since the late 20th century. Copyright © 2017 the Author(s). Published by PNAS.

Drug induced rhabdomyolysis

PubMed Central

Hohenegger, Martin

2012-01-01

Rhabdomyolysis is a clinical condition of potential life threatening destruction of skeletal muscle caused by diverse mechanisms including drugs and toxins. Given the fact that structurally not related compounds cause an identical phenotype pinpoints to common targets or pathways, responsible for executing rhabdomyolysis. A drop in myoplasmic ATP paralleled with sustained elevations in cytosolic Ca2+ concentration represents a common signature of rhabdomyolysis. Interestingly, cardiac tissue is hardly affected or only secondary, as a consequence of imbalance in electrolytes or acid–base equilibrium. This dogma is now impaired by compounds, which show up with combined toxicity in heart and skeletal muscle. In this review, cases of rhabdomyolysis with novel recently approved drugs will be explored for new target mechanisms in the light of previously described pathomechanisms. PMID:22560920

A hydrothermal seep on the Costa Rica margin: middle ground in a continuum of reducing ecosystems

PubMed Central

Levin, Lisa A.; Orphan, Victoria J.; Rouse, Greg W.; Rathburn, Anthony E.; Ussler, William; Cook, Geoffrey S.; Goffredi, Shana K.; Perez, Elena M.; Waren, Anders; Grupe, Benjamin M.; Chadwick, Grayson; Strickrott, Bruce

2012-01-01

Upon their initial discovery, hydrothermal vents and methane seeps were considered to be related but distinct ecosystems, with different distributions, geomorphology, temperatures, geochemical properties and mostly different species. However, subsequently discovered vents and seep systems have blurred this distinction. Here, we report on a composite, hydrothermal seep ecosystem at a subducting seamount on the convergent Costa Rica margin that represents an intermediate between vent and seep ecosystems. Diffuse flow of shimmering, warm fluids with high methane concentrations supports a mixture of microbes, animal species, assemblages and trophic pathways with vent and seep affinities. Their coexistence reinforces the continuity of reducing environments and exemplifies a setting conducive to interactive evolution of vent and seep biota. PMID:22398162

Neuronal growth promoting sesquiterpene-neolignans; syntheses and biological studies.

PubMed

Cheng, Xu; Harzdorf, Nicole; Khaing, Zin; Kang, Danby; Camelio, Andrew M; Shaw, Travis; Schmidt, Christine E; Siegel, Dionicio

2012-01-14

The use of small molecules that can promote neuronal growth represents a promising approach to regenerative science. Along these lines we have developed separate short or modular syntheses of the natural products caryolanemagnolol and clovanemagnolol, small molecules previously shown to promote neuronal growth and induce choline acetyltransferase activity. The postulated biosynthetic pathways, potentially leading to the assembly of these molecules in nature, have guided the laboratory syntheses, allowing the preparation of both natural products in as few as two steps. With synthetic access to the compounds as single enantiomers we have examined clovanemagnolol's ability to promote the growth of embryonic hippocampal and cortical neurons. Clovanemagnolol has been shown to be a potent neurotrophic agent, promoting neuronal growth at concentrations of 10 nM.

Pathways to Performance: An Examination of Entry Pathway and First-Year University Results

ERIC Educational Resources Information Center

Diamond, Mark R.; O'Brien-Malone, Angela

2018-01-01

Although diversity at universities has increased dramatically over the past 150 years, many groups are still under-represented relative to their proportion in the general population. Initiatives to improve diversity have included the increased use of entry pathways other than direct admission from secondary school. As admissions via these…

Pathways to Sexual Risk Taking among Female Adolescent Detainees

ERIC Educational Resources Information Center

Lopez, Vera; Kopak, Albert; Robillard, Alyssa; Gillmore, Mary Rogers; Holliday, Rhonda C.; Braithwaite, Ronald L.

2011-01-01

Sexual risk taking among female delinquents represents a significant public health problem. Research is needed to understand the pathways leading to sexual risk taking among this population. This study sought to address this issue by identifying and testing two pathways from child maltreatment to non-condom use among 329 White and 484 African…

A System-Level Pathway-Phenotype Association Analysis Using Synthetic Feature Random Forest

PubMed Central

Pan, Qinxin; Hu, Ting; Malley, James D.; Andrew, Angeline S.; Karagas, Margaret R.; Moore, Jason H.

2015-01-01

As the cost of genome-wide genotyping decreases, the number of genome-wide association studies (GWAS) has increased considerably. However, the transition from GWAS findings to the underlying biology of various phenotypes remains challenging. As a result, due to its system-level interpretability, pathway analysis has become a popular tool for gaining insights on the underlying biology from high-throughput genetic association data. In pathway analyses, gene sets representing particular biological processes are tested for significant associations with a given phenotype. Most existing pathway analysis approaches rely on single-marker statistics and assume that pathways are independent of each other. As biological systems are driven by complex biomolecular interactions, embracing the complex relationships between single-nucleotide polymorphisms (SNPs) and pathways needs to be addressed. To incorporate the complexity of gene-gene interactions and pathway-pathway relationships, we propose a system-level pathway analysis approach, synthetic feature random forest (SF-RF), which is designed to detect pathway-phenotype associations without making assumptions about the relationships among SNPs or pathways. In our approach, the genotypes of SNPs in a particular pathway are aggregated into a synthetic feature representing that pathway via Random Forest (RF). Multiple synthetic features are analyzed using RF simultaneously and the significance of a synthetic feature indicates the significance of the corresponding pathway. We further complement SF-RF with pathway-based Statistical Epistasis Network (SEN) analysis that evaluates interactions among pathways. By investigating the pathway SEN, we hope to gain additional insights into the genetic mechanisms contributing to the pathway-phenotype association. We apply SF-RF to a population-based genetic study of bladder cancer and further investigate the mechanisms that help explain the pathway-phenotype associations using SEN. The bladder cancer associated pathways we found are both consistent with existing biological knowledge and reveal novel and plausible hypotheses for future biological validations. PMID:24535726

Interactions between ethylene and auxin are crucial to the control of grape (Vitis vinifera L.) berry ripening.

PubMed

Böttcher, Christine; Burbidge, Crista A; Boss, Paul K; Davies, Christopher

2013-12-23

Fruit development is controlled by plant hormones, but the role of hormone interactions during fruit ripening is poorly understood. Interactions between ethylene and the auxin indole-3-acetic acid (IAA) are likely to be crucial during the ripening process, since both hormones have been shown to be implicated in the control of ripening in a range of different fruit species. Grapevine (Vitis vinifera L.) homologues of the TRYPTOPHAN AMINOTRANSFERASE RELATED (TAR) and YUCCA families, functioning in the only characterized pathway of auxin biosynthesis, were identified and the expression of several TAR genes was shown to be induced by the pre-ripening application of the ethylene-releasing compound Ethrel. The induction of TAR expression was accompanied by increased IAA and IAA-Asp concentrations, indicative of an upregulation of auxin biosynthesis and conjugation. Exposure of ex planta, pre-ripening berries to the ethylene biosynthesis inhibitor aminoethoxyvinylglycine resulted in decreased IAA and IAA-Asp concentrations. The delayed initiation of ripening observed in Ethrel-treated berries might therefore represent an indirect ethylene effect mediated by increased auxin concentrations. During berry development, the expression of three TAR genes and one YUCCA gene was upregulated at the time of ripening initiation and/or during ripening. This increase in auxin biosynthesis gene expression was preceded by high expression levels of the ethylene biosynthesis genes 1-aminocyclopropane-1-carboxylate synthase and 1-aminocyclopropane-1-carboxylate oxidase. In grape berries, members of both gene families involved in the two-step pathway of auxin biosynthesis are expressed, suggesting that IAA is produced through the combined action of TAR and YUCCA proteins in developing berries. The induction of TAR expression by Ethrel applications and the developmental expression patterns of auxin and ethylene biosynthesis genes indicate that elevated concentrations of ethylene prior to the initiation of ripening might lead to an increased production of IAA, suggesting a complex involvement of this auxin and its conjugates in grape berry ripening.

Interactions between ethylene and auxin are crucial to the control of grape (Vitis vinifera L.) berry ripening

PubMed Central

2013-01-01

Background Fruit development is controlled by plant hormones, but the role of hormone interactions during fruit ripening is poorly understood. Interactions between ethylene and the auxin indole-3-acetic acid (IAA) are likely to be crucial during the ripening process, since both hormones have been shown to be implicated in the control of ripening in a range of different fruit species. Results Grapevine (Vitis vinifera L.) homologues of the TRYPTOPHAN AMINOTRANSFERASE RELATED (TAR) and YUCCA families, functioning in the only characterized pathway of auxin biosynthesis, were identified and the expression of several TAR genes was shown to be induced by the pre-ripening application of the ethylene-releasing compound Ethrel. The induction of TAR expression was accompanied by increased IAA and IAA-Asp concentrations, indicative of an upregulation of auxin biosynthesis and conjugation. Exposure of ex planta, pre-ripening berries to the ethylene biosynthesis inhibitor aminoethoxyvinylglycine resulted in decreased IAA and IAA-Asp concentrations. The delayed initiation of ripening observed in Ethrel-treated berries might therefore represent an indirect ethylene effect mediated by increased auxin concentrations. During berry development, the expression of three TAR genes and one YUCCA gene was upregulated at the time of ripening initiation and/or during ripening. This increase in auxin biosynthesis gene expression was preceded by high expression levels of the ethylene biosynthesis genes 1-aminocyclopropane-1-carboxylate synthase and 1-aminocyclopropane-1-carboxylate oxidase. Conclusions In grape berries, members of both gene families involved in the two-step pathway of auxin biosynthesis are expressed, suggesting that IAA is produced through the combined action of TAR and YUCCA proteins in developing berries. The induction of TAR expression by Ethrel applications and the developmental expression patterns of auxin and ethylene biosynthesis genes indicate that elevated concentrations of ethylene prior to the initiation of ripening might lead to an increased production of IAA, suggesting a complex involvement of this auxin and its conjugates in grape berry ripening. PMID:24364881

Bisphenol A at a low concentration boosts mouse spermatogonial cell proliferation by inducing the G protein-coupled receptor 30 expression

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

Sheng, Zhi-Guo; Huang, Wei; Liu, Yu-Xiang

Bisphenol A (BPA) is one of the most prevalent chemicals in daily-use materials, therefore, human exposure to BPA is ubiquitous. We found that low concentrations of BPA stimulate the spermatogonial GC-1 cells proliferation by G protein-coupled receptor 30 (GPR30)-mediated epidermal growth factor receptor (EGFR)-extracellular regulated kinase (ERK)-c-Fos pathway. However, through the same pathway GPR30 expression has been shown to be induced by EGF, an EGFR ligand. Thus, we want to know if low concentrations of BPA are able to induce the GPR30 expression and the possible mechanism(s) in GC-1 cells. By transient transfection with expression plasmids, 10{sup −9} M BPAmore » significantly transactivates the Gpr30-5′-flanking region through activating the GPR30, cGMP-dependent protein kinase (PKG), estrogen receptor-α (ER-α), and EFGR-ERK pathways. Furthermore, an activator protein-1 (AP-1) site located within this region is found to be responsible for the transactivation of BPA. Expectedly, through the same pathways, BPA significantly induces the gene and protein expression of GPR30. c-Fos is further observed to be strongly recruited to the AP-1 site in a chromatin immunoprecipitation assay and its dysfunction on the AP-1 site markedly suppresses the expression of GPR30, p-ERK1/2, p-Ser118-ER-α and cell proliferation by BPA. Our results demonstrate that a low-concentration BPA induces GPR30 expression through the GPR30-EFGR-ERK-c-Fos, ER-α, and PKG pathways, presumably boosting the cells proliferation via a regulatory loop. The present study provides a novel insight into the potential role of GPR30 in the initiation and progression of male germ cell cancer induced by environmentally relevant BPA. - Highlights: ► Low concentrations of BPA activate the PKG and GPR30-EFGR-ERK-ER-α pathways. ► Low concentrations of BPA activate the AP-1 site of Gpr30-5′-flanking region. ► Low concentrations of BPA induce the expression of GPR30 gene and protein. ► Low concentrations of BPA boost GC-1 cells proliferation via a regulatory loop.« less

An Overview of Pathways of Regulated Necrosis in Acute Kidney Injury.

PubMed

Kers, Jesper; Leemans, Jaklien C; Linkermann, Andreas

2016-05-01

Necrosis is the predominant form of regulated cell death in acute kidney injury (AKI) and represents results in the formation of casts that appear in the urine sedimentation, referred to as muddy brown casts, which are part of the diagnosis of AKI. Pathologists referred to this typical feature as acute tubular necrosis. We are only beginning to understand the dynamics and the molecular pathways that underlie such typical necrotic morphology. In this review, we provide an overview of candidate pathways and summarize the emerging evidence for the relative contribution of these pathways of regulated necrosis, such as necroptosis, ferroptosis, mitochondrial permeability transition-mediated regulated necrosis, parthanatos, and pyroptosis. Inhibitors of each of these pathways are available, and clinical trials may be started after the detection of the most promising drug targets, which will be discussed here. With the global burden of AKI in mind, inhibitiors of regulated necrosis represent promising means to prevent this disease. Copyright © 2016 Elsevier Inc. All rights reserved.

TNFα-induced IKKβ complex activation influences epithelial, but not stromal cell survival in endometriosis.

PubMed

Kocbek, Vida; Grandi, Giovanni; Blank, Fabian; Wotzkow, Carlos; Bersinger, Nick A; Mueller, Michael D; Kyo, Satoru; McKinnon, Brett D

2016-11-01

Can the activity of the IκB kinase (IKKβ) complex in endometriotic cells contribute to endometriotic lesion survival? There is a constitutive activity of the IKKβ catalytic complex in peritoneal and deeply infiltrating lesions that can influence epithelial, but not stromal cell viability. Endometriotic lesions exist in an inflammatory microenvironment with higher local concentrations of cytokines, such as tumour necrosis factor α (TNFα). TNFα stimulates the activation of the IKKβ complex, an important nodal point in multiple signalling pathways that influence gene transcription, proliferation and apoptosis. However, few data on the regulation of IKKβ in endometriotic tissue are currently available. A retrospective analysis of endometriotic tissue from peritoneal, ovarian and deeply infiltrating lesions from 37 women. Basal and activated (phosphorylated) IKKβ concentrations were analysed by western blotting and immunohistochemistry. The relationship between the expression and activation of these proteins and peritoneal fluid (TNFα) concentrations, measured via ELISA, was examined. A subsequent in vitro analysis of TNFα treatment on the activation of IKKβ and the effect on epithelial and stromal cell viability by its inhibition with PS1145 was also performed. Levels of the phosphorylated IKKβ complex in endometriotic lesions had a significant positive correlation with peritoneal fluid TNFα concentrations. Phosphorylated IKKβ complex was more prevalent in peritoneal and deeply infiltrating endometriosis lesions compared with ovarian lesions. IKKβ was present in both epithelial and stromal cells in all lesions but active IKKβ was limited to epithelial cells. TNFα stimulated an increased expression of phosphorylated IKKβ and the inhibition of this kinase with PS1145 significantly influenced ectopic epithelial cells viability but not eutopic epithelial cells, or endometrial stromal cells. In vitro analysis on epithelial cells was performed with immortalized cell lines and not primary cell cultures and only low sample numbers were available for the study. The regulation of aberrant signalling pathways represents a promising yet relatively unexplored area of endometriosis progression. The IKKβ complex is activated by inflammation and is critical nodal point of numerous downstream kinase-signalling pathways, including NFκB (nuclear factor κB), mTOR (mammalian target of rapamycin) and BAD (Bcl2-antagonist of cell death). This study shows a significant relationship between peritoneal fluid TNFα and IKKβ activation in epithelial cells that will have significant consequences for the continued survival of these cells at ectopic locations through the regulation of downstream pathways. None. The study was funded by the Swiss National Science Foundation (Grant Number 320030_140774). The authors have no conflict of interest to declare. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Aqueous-Phase Mechanism for Secondary Organic Aerosol Formation from Isoprene: Application to the Southeast United States and Co-Benefit of SO2 Emission Controls

NASA Technical Reports Server (NTRS)

Marais, E. A.; Jacob, D. J.; Jimenez, J. L.; Campuzano-Jost, P.; Day, D. A.; Hu, W.; Krechmer, J.; Zhu, L.; Kim, P. S.; Miller, C. C.;

The influence of fluorides on mouse sperm capacitation.

PubMed

Dvoráková-Hortová, K; Sandera, M; Jursová, M; Vasinová, J; Peknicová, J

2008-10-01

Increasing infertility, due to pathological changes on sperm, has become a serious issue. Eco-toxicological effect of rising concentration of fluorides can be enhanced in the presence of aluminium ions by forming fluorometallic complexes, analogues of phosphate groups that interfere with the activity of G-proteins and P-type ATPases, which are part of several signalling pathways during sperm maturation. In order for sperm to gain fertilizing ability, they must undergo in the female reproductive tract, capacitation that includes tyrosine phosphorylation and consequent actin polymerization. The present paper reports the findings of 3-month oral toxicity in mice of fluorides at the concentrations 0, 1, 10, and 100ppm and their synergic action with aluminium at dose of 10ppm. There were no mortalities, clinical signs of discomfort or body weight loss during the experiment. The analysis revealed, for the concentrations of 10 and 100ppm, abnormalities of spermatogenesis and ability of epididymal spermatozoa to capacitate in vitro, as the result of decreased sperm head tyrosine phosphorylation and actin polymerization. The enhancing overload caused by fluorides represents a potential factor, having an impact on function of sperm, hence contributing to a growing infertility in the human population.

Distribution and size fractionation of elemental sulfur in aqueous environments: The Chesapeake Bay and Mid-Atlantic Ridge

NASA Astrophysics Data System (ADS)

Findlay, Alyssa J.; Gartman, Amy; MacDonald, Daniel J.; Hanson, Thomas E.; Shaw, Timothy J.; Luther, George W.

2014-10-01

Elemental sulfur is an important intermediate of sulfide oxidation and may be produced via abiotic and biotic pathways. In this study the concentration and size fractionation of elemental sulfur were measured in two different sulfidic marine environments: the Chesapeake Bay and buoyant hydrothermal vent plumes along the Mid-Atlantic Ridge. Nanoparticulate sulfur (<0.2 μm) was found to comprise up to 90% of the total elemental sulfur in anoxic deep waters of the Chesapeake Bay. These data were compared with previous studies of elemental sulfur, and represent one of the few reports of nanoparticulate elemental sulfur in the environment. Additionally, a strain of phototrophic sulfide oxidizing bacteria isolated from the Chesapeake Bay was shown to produce elemental sulfur as a product of sulfide oxidation. Elemental sulfur concentrations are also presented from buoyant hydrothermal vent plumes located along the Mid-Atlantic Ridge. In the Mid-Atlantic Ridge plume, S0 concentrations up to 33 μM were measured in the first meter of rising plumes at three different vent sites, and nanoparticulate S0 was up to 44% of total elemental sulfur present.

Proteomic analysis of Populus × euramericana (clone I-214) roots to identify key factors involved in zinc stress response.

PubMed

Romeo, Stefania; Trupiano, Dalila; Ariani, Andrea; Renzone, Giovanni; Scippa, Gabriella S; Scaloni, Andrea; Sebastiani, Luca

2014-07-15

Contamination of soil and water by heavy metals has become a widespread problem; environmental pollution by high zinc (Zn) concentration occurs frequently. Although poplar (Populus spp.) has been identified as suitable for phytoremediation approaches, its response to high Zn concentrations are still not clearly understood. For this reason, we investigated the effects of Zn in Populus×euramericana clone I-214 roots by proteomic analysis. Comparative experiments were conducted on rooted woody cuttings grown in nutrient solutions containing 1mM (treatment) or 1μM (control) Zn concentrations. A gel-based proteomic approach coupled with morphological and chemical analysis was used to identify differentially represented proteins in treated roots and to investigate the effect of Zn treatment on the poplar root system. Data shows that Zn was accumulated preferentially in roots, that the antioxidant system, the carbohydrate/energy and amino acid metabolisms were the main pathways modulated by Zn excess, and that mitochondria and vacuoles were the cellular organelles predominately affected by Zn stress. A coordination between cell death and proliferation/growth seems to occur under this condition to counteract the Zn-induced damage. Copyright © 2014 Elsevier GmbH. All rights reserved.

Indole-3-acetic acid biosynthesis in Fusarium delphinoides strain GPK, a causal agent of Wilt in Chickpea.

PubMed

Kulkarni, Guruprasad B; Sanjeevkumar, S; Kirankumar, B; Santoshkumar, M; Karegoudar, T B

2013-02-01

Fusarium delphinoides (Ascomycota; Nectriaceae) is an indole-3-acetic acid (IAA) producing plant pathogen and a causal agent of wilt in chickpea. The IAA biosynthetic pathway in F. delphinoides strain GPK (FDG) was examined by analyzing metabolic intermediates and by feeding experiments. Gas chromatograph (GC) analysis of FDG culture filtrates showed the presence of metabolic intermediates of indole-3-pyruvic acid (IPyA), indole-3-acetamide (IAM), and tryptamine (TRA) pathways. The different IAA biosynthetic pathways were further confirmed by identifying the presence of different enzymes of these pathways. Substrate specificity study of aromatic amino acid aminotransferase revealed that the enzyme is highly specific for tryptophan (Trp) and α-ketoglutarate (α-kg) as amino group donor and acceptor, respectively. Furthermore, the concentration-dependent effect of exogenous IAA on fungal growth was established. Low concentration of exogenous IAA increases the fungal growth and at high concentration it decreases the growth of FDG.

Downregulation of Adipose Tissue Fatty Acid Trafficking in Obesity

PubMed Central

McQuaid, Siobhán E.; Hodson, Leanne; Neville, Matthew J.; Dennis, A. Louise; Cheeseman, Jane; Humphreys, Sandy M.; Ruge, Toralph; Gilbert, Marjorie; Fielding, Barbara A.; Frayn, Keith N.; Karpe, Fredrik

2011-01-01

OBJECTIVE Lipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat. RESEARCH DESIGN AND METHODS To investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10). RESULTS Abdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function. CONCLUSIONS Enlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity. PMID:20943748

Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells

PubMed Central

2011-01-01

Background Xenobiotics represent an environmental stress and as such are a source for antibiotics, including the isoquinoline (IQ) compound IQ-143. Here, we demonstrate the utility of complementary analysis of both host and pathogen datasets in assessing bacterial adaptation to IQ-143, a synthetic analog of the novel type N,C-coupled naphthyl-isoquinoline alkaloid ancisheynine. Results Metabolite measurements, gene expression data and functional assays were combined with metabolic modeling to assess the effects of IQ-143 on Staphylococcus aureus, Staphylococcus epidermidis and human cell lines, as a potential paradigm for novel antibiotics. Genome annotation and PCR validation identified novel enzymes in the primary metabolism of staphylococci. Gene expression response analysis and metabolic modeling demonstrated the adaptation of enzymes to IQ-143, including those not affected by significant gene expression changes. At lower concentrations, IQ-143 was bacteriostatic, and at higher concentrations bactericidal, while the analysis suggested that the mode of action was a direct interference in nucleotide and energy metabolism. Experiments in human cell lines supported the conclusions from pathway modeling and found that IQ-143 had low cytotoxicity. Conclusions The data suggest that IQ-143 is a promising lead compound for antibiotic therapy against staphylococci. The combination of gene expression and metabolite analyses with in silico modeling of metabolite pathways allowed us to study metabolic adaptations in detail and can be used for the evaluation of metabolic effects of other xenobiotics. PMID:21418624

Assessing carbon dioxide removal through global and regional ocean alkalinization under high and low emission pathways

NASA Astrophysics Data System (ADS)

Lenton, Andrew; Matear, Richard J.; Keller, David P.; Scott, Vivian; Vaughan, Naomi E.

2018-04-01

Atmospheric carbon dioxide (CO2) levels continue to rise, increasing the risk of severe impacts on the Earth system, and on the ecosystem services that it provides. Artificial ocean alkalinization (AOA) is capable of reducing atmospheric CO2 concentrations and surface warming and addressing ocean acidification. Here, we simulate global and regional responses to alkalinity (ALK) addition (0.25 PmolALK yr-1) over the period 2020-2100 using the CSIRO-Mk3L-COAL Earth System Model, under high (Representative Concentration Pathway 8.5; RCP8.5) and low (RCP2.6) emissions. While regionally there are large changes in alkalinity associated with locations of AOA, globally we see only a very weak dependence on where and when AOA is applied. On a global scale, while we see that under RCP2.6 the carbon uptake associated with AOA is only ˜ 60 % of the total, under RCP8.5 the relative changes in temperature are larger, as are the changes in pH (140 %) and aragonite saturation state (170 %). The simulations reveal AOA is more effective under lower emissions, therefore the higher the emissions the more AOA is required to achieve the same reduction in global warming and ocean acidification. Finally, our simulated AOA for 2020-2100 in the RCP2.6 scenario is capable of offsetting warming and ameliorating ocean acidification increases at the global scale, but with highly variable regional responses.

Analysis of leukotrienes in cerebrospinal fluid of a reference population and patients with inborn errors of metabolism: further evidence for a pathognomonic profile in LTC(4)-synthesis deficiency.

PubMed

Mayatepek, E; Zelezny, R; Hoffmann, G F

2000-02-25

Cysteinyl leukotrienes (LTC(4), LTD(4), LTE(4)) are potent lipid mediators derived from arachidonate in the 5-lipoxygenase pathway. Recently, the first inborn error of leukotriene synthesis, LTC(4)-synthesis deficiency, has been identified in association with a fatal developmental syndrome. The absence of leukotrienes in cerebrospinal fluid was one of the most striking biochemical findings in this disorder. We analysed leukotrienes in cerebrospinal fluid of patients with a broad spectrum of other well-defined inborn errors of metabolism, including glutathione synthetase deficiency (n=2), Zellweger syndrome (n=3), mitochondrial disorders (n=8), fatty acid oxidation defects (n=7), organic acidurias (n=7), neurotransmitter defects (n=5) and patients with non-specific neurological symptoms, as a reference population (n=120). The concentrations of leukotrienes were not related to age. Representative percentiles were calculated as reference intervals of each leukotriene. In all patients with an inborn error of metabolism concentration of cysteinyl leukotrienes and LTB(4) did not differ from the reference group. Our results indicate that absence of cysteinyl leukotrienes (<5 pg/ml) in association with normal or increased LTB(4) (50.0-67.3 pg/ml) is pathognomonic for LTC(4)-synthesis deficiency. The unique profile of leukotrienes in cerebrospinal fluid in this new disorder is primarily related to the defect and represents a new diagnostic approach.

A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways.

PubMed

Gan, Fei-Fei; Ling, Hui; Ang, Xiaohui; Reddy, Shridhivya A; Lee, Stephanie S-H; Yang, Hong; Tan, Sock-Hoon; Hayes, John D; Chui, Wai-Keung; Chew, Eng-Hui

2013-11-01

Natural compounds containing vanilloid and Michael acceptor moieties appear to possess anti-cancer and chemopreventive properties. The ginger constituent shogaol represents one such compound. In this study, the anti-cancer potential of a synthetic novel shogaol analog 3-phenyl-3-shogaol (3-Ph-3-SG) was assessed by evaluating its effects on signaling pathways. At non-toxic concentrations, 3-Ph-3-SG suppressed cancer cell invasion in MDA-MB-231 and MCF-7 breast carcinoma cells through inhibition of PMA-activated MMP-9 expression. At similar concentrations, 3-Ph-3-SG reduced expression of the inflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostanglandin-E2 (PGE2) in RAW 264.7 macrophage-like cells. Inhibition of cancer cell invasion and inflammation by 3-Ph-3-SG were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway. The 3-Ph-3-SG also demonstrated cytoprotective effects by inducing the antioxidant response element (ARE)-driven genes NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1). Cytoprotection by 3-Ph-3-SG was achieved at least partly through modification of cysteine residues in the E3 ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein 1 (Keap1), which resulted in accumulation of transcription factor NF-E2 p45-related factor 2 (Nrf2). The activities of 3-Ph-3-SG were comparable to those of 6-shogaol, the most abundant naturally-occurring shogaol, and stronger than those of 4-hydroxyl-null deshydroxy-3-phenyl-3-shogaol, which attested the importance of the 4-hydroxy substituent in the vanilloid moiety for bioactivity. In summary, 3-Ph-3-SG is shown to possess activities that modulate stress-associated pathways relevant to multiple steps in carcinogenesis. Therefore, it warrants further investigation of this compound as a promising candidate for use in chemotherapeutic and chemopreventive strategies. © 2013.

Single nucleotide variants and InDels identified from whole-genome re-sequencing of Guzerat, Gyr, Girolando and Holstein cattle breeds.

PubMed

Stafuzza, Nedenia Bonvino; Zerlotini, Adhemar; Lobo, Francisco Pereira; Yamagishi, Michel Eduardo Beleza; Chud, Tatiane Cristina Seleguim; Caetano, Alexandre Rodrigues; Munari, Danísio Prado; Garrick, Dorian J; Machado, Marco Antonio; Martins, Marta Fonseca; Carvalho, Maria Raquel; Cole, John Bruce; Barbosa da Silva, Marcos Vinicius Gualberto

2017-01-01

Whole-genome re-sequencing, alignment and annotation analyses were undertaken for 12 sires representing four important cattle breeds in Brazil: Guzerat (multi-purpose), Gyr, Girolando and Holstein (dairy production). A total of approximately 4.3 billion reads from an Illumina HiSeq 2000 sequencer generated for each animal 10.7 to 16.4-fold genome coverage. A total of 27,441,279 single nucleotide variations (SNVs) and 3,828,041 insertions/deletions (InDels) were detected in the samples, of which 2,557,670 SNVs and 883,219 InDels were novel. The submission of these genetic variants to the dbSNP database significantly increased the number of known variants, particularly for the indicine genome. The concordance rate between genotypes obtained using the Bovine HD BeadChip array and the same variants identified by sequencing was about 99.05%. The annotation of variants identified numerous non-synonymous SNVs and frameshift InDels which could affect phenotypic variation. Functional enrichment analysis was performed and revealed that variants in the olfactory transduction pathway was over represented in all four cattle breeds, while the ECM-receptor interaction pathway was over represented in Girolando and Guzerat breeds, the ABC transporters pathway was over represented only in Holstein breed, and the metabolic pathways was over represented only in Gyr breed. The genetic variants discovered here provide a rich resource to help identify potential genomic markers and their associated molecular mechanisms that impact economically important traits for Gyr, Girolando, Guzerat and Holstein breeding programs.

Single nucleotide variants and InDels identified from whole-genome re-sequencing of Guzerat, Gyr, Girolando and Holstein cattle breeds

PubMed Central

Lobo, Francisco Pereira; Yamagishi, Michel Eduardo Beleza; Chud, Tatiane Cristina Seleguim; Caetano, Alexandre Rodrigues; Munari, Danísio Prado; Garrick, Dorian J.; Machado, Marco Antonio; Martins, Marta Fonseca; Carvalho, Maria Raquel; Cole, John Bruce; Barbosa da Silva, Marcos Vinicius Gualberto

2017-01-01

Whole-genome re-sequencing, alignment and annotation analyses were undertaken for 12 sires representing four important cattle breeds in Brazil: Guzerat (multi-purpose), Gyr, Girolando and Holstein (dairy production). A total of approximately 4.3 billion reads from an Illumina HiSeq 2000 sequencer generated for each animal 10.7 to 16.4-fold genome coverage. A total of 27,441,279 single nucleotide variations (SNVs) and 3,828,041 insertions/deletions (InDels) were detected in the samples, of which 2,557,670 SNVs and 883,219 InDels were novel. The submission of these genetic variants to the dbSNP database significantly increased the number of known variants, particularly for the indicine genome. The concordance rate between genotypes obtained using the Bovine HD BeadChip array and the same variants identified by sequencing was about 99.05%. The annotation of variants identified numerous non-synonymous SNVs and frameshift InDels which could affect phenotypic variation. Functional enrichment analysis was performed and revealed that variants in the olfactory transduction pathway was over represented in all four cattle breeds, while the ECM-receptor interaction pathway was over represented in Girolando and Guzerat breeds, the ABC transporters pathway was over represented only in Holstein breed, and the metabolic pathways was over represented only in Gyr breed. The genetic variants discovered here provide a rich resource to help identify potential genomic markers and their associated molecular mechanisms that impact economically important traits for Gyr, Girolando, Guzerat and Holstein breeding programs. PMID:28323836

Metagenomic analysis of rapid gravity sand filter microbial communities suggests novel physiology of Nitrospira spp.

PubMed

Palomo, Alejandro; Jane Fowler, S; Gülay, Arda; Rasmussen, Simon; Sicheritz-Ponten, Thomas; Smets, Barth F

2016-11-01

Rapid gravity sand filtration is a drinking water production technology widely used around the world. Microbially catalyzed processes dominate the oxidative transformation of ammonia, reduced manganese and iron, methane and hydrogen sulfide, which may all be present at millimolar concentrations when groundwater is the source water. In this study, six metagenomes from various locations within a groundwater-fed rapid sand filter (RSF) were analyzed. The community gene catalog contained most genes of the nitrogen cycle, with particular abundance in genes of the nitrification pathway. Genes involved in different carbon fixation pathways were also abundant, with the reverse tricarboxylic acid cycle pathway most abundant, consistent with an observed Nitrospira dominance. From the metagenomic data set, 14 near-complete genomes were reconstructed and functionally characterized. On the basis of their genetic content, a metabolic and geochemical model was proposed. The organisms represented by draft genomes had the capability to oxidize ammonium, nitrite, hydrogen sulfide, methane, potentially iron and manganese as well as to assimilate organic compounds. A composite Nitrospira genome was recovered, and amo-containing Nitrospira genome contigs were identified. This finding, together with the high Nitrospira abundance, and the abundance of atypical amo and hao genes, suggests the potential for complete ammonium oxidation by Nitrospira, and a major role of Nitrospira in the investigated RSFs and potentially other nitrifying environments.

Corticotropin-Releasing Factor Critical for Zebrafish Camouflage Behavior Is Regulated by Light and Sensitive to Ethanol

PubMed Central

Wagle, Mahendra; Mathur, Priya; Guo, Su

2011-01-01

The zebrafish camouflage response is an innate “hard-wired” behavior that offers an excellent opportunity to explore neural circuit assembly and function. Moreover, the camouflage response is sensitive to ethanol, making it a tractable system for understanding how ethanol influences neural circuit development and function. Here we report the identification of corticotropin releasing factor (CRF) as a critical component of the camouflage response pathway. We further show that ethanol, having no direct effect on the visual sensory system or the melanocytes, acts downstream of retinal ganglion cells and requires the CRF-proopiomelanocortin (POMC) pathway to exert its effect on camouflage. Treatment with ethanol, as well as alteration of light exposure that changes sensory input into the camouflage circuit, robustly modifies CRF expression in subsets of neurons. Activity of both Adenylyl Cyclase 5 and Extracellular signal Regulated Kinase (ERK) is required for such ethanol- or light- induced plasticity of crf expression. These results reveal an essential role of a peptidergic pathway in camouflage that is regulated by light and influenced by ethanol at concentrations relevant to abuse and anxiolysis, in a cAMP- and ERK- dependent manner. We conclude that this ethanol-modulated camouflage response represents a novel and relevant system for molecular genetic dissection of a neural circuit that is regulated by light and sensitive to ethanol. PMID:21209207

Corticotropin-releasing factor critical for zebrafish camouflage behavior is regulated by light and sensitive to ethanol.

PubMed

Wagle, Mahendra; Mathur, Priya; Guo, Su

2011-01-05

The zebrafish camouflage response is an innate "hard-wired" behavior that offers an excellent opportunity to explore neural circuit assembly and function. Moreover, the camouflage response is sensitive to ethanol, making it a tractable system for understanding how ethanol influences neural circuit development and function. Here we report the identification of corticotropin-releasing factor (CRF) as a critical component of the camouflage response pathway. We further show that ethanol, having no direct effect on the visual sensory system or the melanocytes, acts downstream of retinal ganglion cells and requires the CRF-proopiomelanocortin pathway to exert its effect on camouflage. Treatment with ethanol, as well as alteration of light exposure that changes sensory input into the camouflage circuit, robustly modifies CRF expression in subsets of neurons. Activity of both adenylyl cyclase 5 and extracellular signal-regulated kinase (ERK) is required for such ethanol-induced or light-induced plasticity of crf expression. These results reveal an essential role of a peptidergic pathway in camouflage that is regulated by light and influenced by ethanol at concentrations relevant to abuse and anxiolysis, in a cAMP-dependent and ERK-dependent manner. We conclude that this ethanol-modulated camouflage response represents a novel and relevant system for molecular genetic dissection of a neural circuit that is regulated by light and sensitive to ethanol.

Preliminary observations on high energy phosphates and metabolic pathway and transporter potentials in extensor carpi radialis brevis and trapezius muscles of women with work-related myalgia.

PubMed

Green, Howard J; Ranney, Don; Burnett, Margaret; Galvin, Patti; Kyle, Natasha; Lounsbury, David; Ouyang, Jing; Smith, Ian C; Stewart, Riley; Tick, Heather; Tupling, A Russell

2014-11-01

This study compared both the extensor carpi radialis brevis (ECRB) and the trapezius (TRAP) muscles of women with work-related myalgia (WRM) with healthy controls (CON) to determine whether abnormalities existed in cellular energy status and the potentials of the various metabolic pathways and segments involved in energy production and substrate transport. For both the ECRB (CON, n = 6-9; WRM, n = 13) and the TRAP (CON, n = 6-7; WRM, n = 10), no differences (P > 0.05) were found for the concentrations (in millimoles per kilogram of dry mass) of ATP, PCr, lactate, and glycogen. Similarly, with one exception, the maximal activities (in moles per milligram of protein per hour) of mitochondrial enzymes representative of the citric acid cycle (CAC), the electron transport chain (ETC), and β-oxidation, as well as the cytosolic enzymes involved in high energy phosphate transfer, glycogenolysis, glycolysis, lactate oxidation, and glucose phosphorylation were not different (P > 0.05). The glucose transporters GLUT1 and GLUT4, and the monocarboxylate transporters MCT1 and MCT4, were also normal in WRM. It is concluded that, in general, abnormalities in the resting energy and substrate state, the potential of the different metabolic pathways and segments, as well as the glucose and monocarboxylate transporters do not appear to be involved in the cellular pathophysiology of WRM.

De novo pyrimidine nucleotide synthesis mainly occurs outside of plastids, but a previously undiscovered nucleobase importer provides substrates for the essential salvage pathway in Arabidopsis.

PubMed

Witz, Sandra; Jung, Benjamin; Fürst, Sarah; Möhlmann, Torsten

2012-04-01

Nucleotide de novo synthesis is highly conserved among organisms and represents an essential biochemical pathway. In plants, the two initial enzymatic reactions of de novo pyrimidine synthesis occur in the plastids. By use of green fluorescent protein fusions, clear support is provided for a localization of the remaining reactions in the cytosol and mitochondria. This implies that carbamoyl aspartate, an intermediate of this pathway, must be exported and precursors of pyrimidine salvage (i.e., nucleobases or nucleosides) are imported into plastids. A corresponding uracil transport activity could be measured in intact plastids isolated from cauliflower (Brassica oleracea) buds. PLUTO (for plastidic nucleobase transporter) was identified as a member of the Nucleobase:Cation-Symporter1 protein family from Arabidopsis thaliana, capable of transporting purine and pyrimidine nucleobases. A PLUTO green fluorescent protein fusion was shown to reside in the plastid envelope after expression in Arabidopsis protoplasts. Heterologous expression of PLUTO in an Escherichia coli mutant lacking the bacterial uracil permease uraA allowed a detailed biochemical characterization. PLUTO transports uracil, adenine, and guanine with apparent affinities of 16.4, 0.4, and 6.3 μM, respectively. Transport was markedly inhibited by low concentrations of a proton uncoupler, indicating that PLUTO functions as a proton-substrate symporter. Thus, a protein for the absolutely required import of pyrimidine nucleobases into plastids was identified.

Fanconi anemia proteins FANCD2 and FANCI exhibit different DNA damage responses during S-phase

PubMed Central

Sareen, Archana; Chaudhury, Indrajit; Adams, Nicole; Sobeck, Alexandra

2012-01-01

Fanconi anemia (FA) pathway members, FANCD2 and FANCI, contribute to the repair of replication-stalling DNA lesions. FA pathway activation relies on phosphorylation of FANCI by the ataxia telangiectasia and Rad3-related (ATR) kinase, followed by monoubiquitination of FANCD2 and FANCI by the FA core complex. FANCD2 and FANCI are thought to form a functional heterodimer during DNA repair, but it is unclear how dimer formation is regulated or what the functions of the FANCD2–FANCI complex versus the monomeric proteins are. We show that the FANCD2–FANCI complex forms independently of ATR and FA core complex, and represents the inactive form of both proteins. DNA damage-induced FA pathway activation triggers dissociation of FANCD2 from FANCI. Dissociation coincides with FANCD2 monoubiquitination, which significantly precedes monoubiquitination of FANCI; moreover, monoubiquitination responses of FANCD2 and FANCI exhibit distinct DNA substrate specificities. A phosphodead FANCI mutant fails to dissociate from FANCD2, whereas phosphomimetic FANCI cannot interact with FANCD2, indicating that FANCI phosphorylation is the molecular trigger for FANCD2–FANCI dissociation. Following dissociation, FANCD2 binds replicating chromatin prior to—and independently of—FANCI. Moreover, the concentration of chromatin-bound FANCD2 exceeds that of FANCI throughout replication. Our results suggest that FANCD2 and FANCI function separately at consecutive steps during DNA repair in S-phase. PMID:22753026

Water scarcity under various socio-economic pathways and its potential effects on food production in the Yellow River basin

NASA Astrophysics Data System (ADS)

Yin, Yuanyuan; Tang, Qiuhong; Liu, Xingcai; Zhang, Xuejun

2017-02-01

Increasing population and socio-economic development have put great pressure on water resources of the Yellow River (YR) basin. The anticipated climate and socio-economic changes may further increase water stress. Many studies have investigated the changes in renewable water resources under various climate change scenarios, but few have considered the joint pressure from both climate change and socio-economic development. In this study, we assess water scarcity under various socio-economic pathways with emphasis on the impact of water scarcity on food production. The water demands in the 21st century are estimated based on the newly developed shared socio-economic pathways (SSPs) and renewable water supply is estimated using the climate projections under the Representative Concentration Pathway (RCP) 8.5 scenario. The assessment predicts that the renewable water resources would decrease slightly then increase. The domestic and industrial water withdrawals are projected to increase in the next a few decades and then remain at the high level or decrease slightly during the 21st century. The increase in water withdrawals will put the middle and lower reaches in a condition of severe water scarcity beginning in the next a few decades. If 40 % of the renewable water resources were used to sustain ecosystems, a portion of irrigated land would have to be converted to rain-fed agriculture, which would lead to a 2-11 % reduction in food production. This study highlights the links between water, food and ecosystems in a changing environment and suggests that trade-offs should be considered when developing regional adaptation strategies.

Understanding the Transport of Patagonian Dust and Its Influence on Marine Biological Activity in the South Atlantic Ocean

NASA Technical Reports Server (NTRS)

Johnson, Matthew; Meskhidze, Nicholas; Kiliyanpilakkil, Praju; Gasso, Santiago

2010-01-01

Modeling and remote sensing techniques were applied to examine the horizontal and vertical transport pathways of Patagonian dust and quantify the effect of soluble-iron- laden mineral dust deposition on marine primary productivity in the South Atlantic Ocean (SAO) surface waters. The global chemistry transport model GEOS-Chem, implemented with an iron dissolution scheme, was applied to evaluate the atmospheric transport and deposition of mineral dust and bioavailable iron during two dust outbreaks originating in the source regions of Patagonia. In addition to this "rapidly released" iron, offline calculations were also carried out to estimate the amount of bioavailable iron leached during the residence time of dust in the ocean mixed layer. Model simulations showed that the horizontal and vertical transport pathways of Patagonian dust plumes were largely influenced by the synoptic meteorological patterns of high and low pressure systems. Model-predicted horizontal and vertical transport pathways of Patagonian dust over the SAO were in reasonable agreement with remotely-sensed data. Comparison between remotely-sensed and offline calculated ocean surface chlorophyll-a concentrations indicated that, for the two dust outbreaks examined in this study, the deposition of bioavailable iron in the SAO through atmospheric pathways was insignificant. As the two dust transport episodes examined here represent typical outflows of mineral dust from South American sources, our study suggests that the atmospheric deposition of mineral dust is unlikely to induce large scale marine primary productivity and carbon sequestration in the South Atlantic sector of the Southern Ocean.

Age-related changes in ATP-producing pathways in human skeletal muscle in vivo.

PubMed

Lanza, Ian R; Befroy, Douglas E; Kent-Braun, Jane A

2005-11-01

Energy for muscle contractions is supplied by ATP generated from 1) the net hydrolysis of phosphocreatine (PCr) through the creatine kinase reaction, 2) oxidative phosphorylation, and 3) anaerobic glycolysis. The effect of old age on these pathways is unclear. The purpose of this study was to examine whether age may affect ATP synthesis rates from these pathways during maximal voluntary isometric contractions (MVIC). Phosphorus magnetic resonance spectroscopy was used to assess high-energy phosphate metabolite concentrations in skeletal muscle of eight young (20-35 yr) and eight older (65-80 yr) men. Oxidative capacity was assessed from PCr recovery after a 16-s MVIC. We determined the contribution of each pathway to total ATP synthesis during a 60-s MVIC. Oxidative capacity was similar across age groups. Similar rates of ATP synthesis from PCr hydrolysis and oxidative phosphorylation were observed in young and older men during the 60-s MVIC. Glycolytic flux was higher in young than older men during the 60-s contraction (P < 0.001). When expressed relative to the overall ATP synthesis rate, older men relied on oxidative phosphorylation more than young men (P = 0.014) and derived a smaller proportion of ATP from anaerobic glycolysis (P < 0.001). These data demonstrate that although oxidative capacity was unaltered with age, peak glycolytic flux and overall ATP production from anaerobic glycolysis were lower in older men during a high-intensity contraction. Whether this represents an age-related limitation in glycolytic metabolism or a preferential reliance on oxidative ATP production remains to be determined.

Estimating changes in urban ozone concentrations due to life cycle emissions from hydrogen transportation systems

NASA Astrophysics Data System (ADS)

Wang, Guihua; Ogden, Joan M.; Chang, Daniel P. Y.

Hydrogen has been proposed as a low polluting alternative transportation fuel that could help improve urban air quality. This paper examines the potential impact of introducing a hydrogen-based transportation system on urban ambient ozone concentrations. This paper considers two scenarios, where significant numbers of new hydrogen vehicles are added to a constant number of gasoline vehicles. In our scenarios hydrogen fuel cell vehicles (HFCVs) are introduced in Sacramento, California at market penetrations of 9% and 20%. From a life cycle analysis (LCA) perspective, considering all the emissions involved in producing, transporting, and using hydrogen, this research compares three hypothetical natural gas to hydrogen pathways: (1) on-site hydrogen production; (2) central hydrogen production with pipeline delivery; and (3) central hydrogen production with liquid hydrogen truck delivery. Using a regression model, this research shows that the daily maximum temperature correlates well with atmospheric ozone formation. However, increases in initial VOC and NO x concentrations do not necessarily increase the peak ozone concentration, and may even cause it to decrease. It is found that ozone formation is generally limited by NO x in the summer and is mostly limited by VOC in the fall in Sacramento. Of the three hydrogen pathways, the truck delivery pathway contributes the most to ozone precursor emissions. Ozone precursor emissions from the truck pathway at 9% market penetration can cause additional 3-h average VOC (or NO x) concentrations up to approximately 0.05% (or 1%) of current pollution levels, and at 20% market penetration up to approximately 0.1% (or 2%) of current pollution levels. However, all of the hydrogen pathways would result in very small (either negative or positive) changes in ozone air quality. In some cases they will result in worse ozone air quality (mostly in July, August, and September), and in some cases they will result in better ozone air quality (mostly in October). The truck pathway tends to cause a much wider fluctuation in degradation or improvement of ozone air quality: percentage changes in peak ozone concentrations are approximately -0.01% to 0.04% for the assumed 9% market penetration, and approximately -0.03% to 0.1% for the 20% market penetration. Moreover, the 20% on-site pathway occasionally results in a decrease of about -0.1% of baseline ozone pollution. Compared to the current ambient pollution level, all three hydrogen pathways are unlikely to cause a serious ozone problem for market penetration levels of HFCVs in the 9-20% range.

Pathway Distiller - multisource biological pathway consolidation

PubMed Central

2012-01-01

Background One method to understand and evaluate an experiment that produces a large set of genes, such as a gene expression microarray analysis, is to identify overrepresentation or enrichment for biological pathways. Because pathways are able to functionally describe the set of genes, much effort has been made to collect curated biological pathways into publicly accessible databases. When combining disparate databases, highly related or redundant pathways exist, making their consolidation into pathway concepts essential. This will facilitate unbiased, comprehensive yet streamlined analysis of experiments that result in large gene sets. Methods After gene set enrichment finds representative pathways for large gene sets, pathways are consolidated into representative pathway concepts. Three complementary, but different methods of pathway consolidation are explored. Enrichment Consolidation combines the set of the pathways enriched for the signature gene list through iterative combining of enriched pathways with other pathways with similar signature gene sets; Weighted Consolidation utilizes a Protein-Protein Interaction network based gene-weighting approach that finds clusters of both enriched and non-enriched pathways limited to the experiments' resultant gene list; and finally the de novo Consolidation method uses several measurements of pathway similarity, that finds static pathway clusters independent of any given experiment. Results We demonstrate that the three consolidation methods provide unified yet different functional insights of a resultant gene set derived from a genome-wide profiling experiment. Results from the methods are presented, demonstrating their applications in biological studies and comparing with a pathway web-based framework that also combines several pathway databases. Additionally a web-based consolidation framework that encompasses all three methods discussed in this paper, Pathway Distiller (http://cbbiweb.uthscsa.edu/PathwayDistiller), is established to allow researchers access to the methods and example microarray data described in this manuscript, and the ability to analyze their own gene list by using our unique consolidation methods. Conclusions By combining several pathway systems, implementing different, but complementary pathway consolidation methods, and providing a user-friendly web-accessible tool, we have enabled users the ability to extract functional explanations of their genome wide experiments. PMID:23134636

Pathway Distiller - multisource biological pathway consolidation.

PubMed

Doderer, Mark S; Anguiano, Zachry; Suresh, Uthra; Dashnamoorthy, Ravi; Bishop, Alexander J R; Chen, Yidong

2012-01-01

One method to understand and evaluate an experiment that produces a large set of genes, such as a gene expression microarray analysis, is to identify overrepresentation or enrichment for biological pathways. Because pathways are able to functionally describe the set of genes, much effort has been made to collect curated biological pathways into publicly accessible databases. When combining disparate databases, highly related or redundant pathways exist, making their consolidation into pathway concepts essential. This will facilitate unbiased, comprehensive yet streamlined analysis of experiments that result in large gene sets. After gene set enrichment finds representative pathways for large gene sets, pathways are consolidated into representative pathway concepts. Three complementary, but different methods of pathway consolidation are explored. Enrichment Consolidation combines the set of the pathways enriched for the signature gene list through iterative combining of enriched pathways with other pathways with similar signature gene sets; Weighted Consolidation utilizes a Protein-Protein Interaction network based gene-weighting approach that finds clusters of both enriched and non-enriched pathways limited to the experiments' resultant gene list; and finally the de novo Consolidation method uses several measurements of pathway similarity, that finds static pathway clusters independent of any given experiment. We demonstrate that the three consolidation methods provide unified yet different functional insights of a resultant gene set derived from a genome-wide profiling experiment. Results from the methods are presented, demonstrating their applications in biological studies and comparing with a pathway web-based framework that also combines several pathway databases. Additionally a web-based consolidation framework that encompasses all three methods discussed in this paper, Pathway Distiller (http://cbbiweb.uthscsa.edu/PathwayDistiller), is established to allow researchers access to the methods and example microarray data described in this manuscript, and the ability to analyze their own gene list by using our unique consolidation methods. By combining several pathway systems, implementing different, but complementary pathway consolidation methods, and providing a user-friendly web-accessible tool, we have enabled users the ability to extract functional explanations of their genome wide experiments.

Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla.

PubMed

Pannabecker, Thomas L

2013-04-01

Comparative studies of renal structure and function have potential to provide insights into the urine-concentrating mechanism of the mammalian kidney. This review focuses on the tubular transport pathways for water and urea that play key roles in fluid and solute movements between various compartments of the rodent renal inner medulla. Information on aquaporin water channel and urea transporter expression has increased our understanding of functional segmentation of medullary thin limbs of Henle's loops, collecting ducts, and vasa recta. A more complete understanding of membrane transporters and medullary architecture has identified new and potentially significant interactions between these structures and the interstitium. These interactions are now being introduced into our concept of how the inner medullary urine-concentrating mechanism works. A variety of regulatory pathways lead directly or indirectly to variable patterns of fluid and solute movements among the interstitial and tissue compartments. Animals with the ability to produce highly concentrated urine, such as desert species, are considered to exemplify tubular structure and function that optimize urine concentration. These species may provide unique insights into the urine-concentrating process.(1)

Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla

PubMed Central

2013-01-01

Comparative studies of renal structure and function have potential to provide insights into the urine-concentrating mechanism of the mammalian kidney. This review focuses on the tubular transport pathways for water and urea that play key roles in fluid and solute movements between various compartments of the rodent renal inner medulla. Information on aquaporin water channel and urea transporter expression has increased our understanding of functional segmentation of medullary thin limbs of Henle's loops, collecting ducts, and vasa recta. A more complete understanding of membrane transporters and medullary architecture has identified new and potentially significant interactions between these structures and the interstitium. These interactions are now being introduced into our concept of how the inner medullary urine-concentrating mechanism works. A variety of regulatory pathways lead directly or indirectly to variable patterns of fluid and solute movements among the interstitial and tissue compartments. Animals with the ability to produce highly concentrated urine, such as desert species, are considered to exemplify tubular structure and function that optimize urine concentration. These species may provide unique insights into the urine-concentrating process.1 PMID:23364530

Genetic variants in two pathways influence serum urate levels and gout risk: a systematic pathway analysis.

PubMed

Dong, Zheng; Zhou, Jingru; Xu, Xia; Jiang, Shuai; Li, Yuan; Zhao, Dongbao; Yang, Chengde; Ma, Yanyun; Wang, Yi; He, Hongjun; Ji, Hengdong; Zhang, Juan; Yuan, Ziyu; Yang, Yajun; Wang, Xiaofeng; Pang, Yafei; Jin, Li; Zou, Hejian; Wang, Jiucun

2018-03-01

The aims of this study were to identify candidate pathways associated with serum urate and to explore the genetic effect of those pathways on the risk of gout. Pathway analysis of the loci identified in genome-wide association studies (GWASs) showed that the ion transmembrane transporter activity pathway (GO: 0015075) and the secondary active transmembrane transporter activity pathway (GO: 0015291) were both associated with serum urate concentrations, with P FDR values of 0.004 and 0.007, respectively. In a Chinese population of 4,332 individuals, the two pathways were also found to be associated with serum urate (P FDR  = 1.88E-05 and 3.44E-04, separately). In addition, these two pathways were further associated with the pathogenesis of gout (P FDR  = 1.08E-08 and 2.66E-03, respectively) in the Chinese population and a novel gout-associated gene, SLC17A2, was identified (OR = 0.83, P FDR  = 0.017). The mRNA expression of candidate genes also showed significant differences among different groups at pathway level. The present study identified two transmembrane transporter activity pathways (GO: 0015075 and GO: 0015291) were associations with serum urate concentrations and the risk of gout. SLC17A2 was identified as a novel gene that influenced the risk of gout.

The consumption of canned food and beverages and urinary Bisphenol A concentrations in NHANES 2003-2008.

PubMed

Hartle, Jennifer C; Navas-Acien, Ana; Lawrence, Robert S

2016-10-01

Exposure to Bisphenol A (BPA) is ubiquitous and includes dietary and environmental pathways. BPA is rapidly glucuronidated in the body, and both BPA and its conjugates can be readily measured in urine. To investigate the contribution of canned food and beverages, known sources of BPA contamination, to BPA biomarkers of exposure using dietary and urinary BPA concentration information in a representative sample of the U.S. We evaluated 7669 NHANES 2003-2008 participants 6 years and older with 24-h dietary recall information and urinary BPA concentrations available. Using linear regression models, we evaluated the associations between recent canned food and beverage consumption and urinary BPA concentrations, adjusting for potential confounders. We found 9% of our participants consumed one canned food in the past 24h and 2% consumed two or more canned foods. The consumption of one canned food vs. none was associated with 24% (95% CI 1.11, 1.38) higher urinary BPA concentrations. The consumption of two or more canned foods vs. none was associated with 54% (95% CI 1.27, 1.88) higher urinary BPA concentrations. The consumption of one or more of some specific types of canned foods vs. none were associated with higher urinary BPA concentrations: 41% (95% CI 1.23, 1.63) higher BPA for vegetable and fruit, 70% (95% CI 1.18, 2.44) higher for canned pasta, and 229% (95% CI 1.22, 4.30) higher for canned soup. Canned beverages were not associated with urinary BPA concentrations. Canned food, including some specific types such as canned vegetable and fruit, canned pasta, and canned soup were associated with higher levels of urinary BPA concentrations. Copyright © 2016 Elsevier Inc. All rights reserved.

The consumption of canned food and beverages and urinary Bisphenol A concentrations in NHANES 2003–2008

PubMed Central

Hartle, Jennifer C.; Navas-Acien; Lawrence, Robert S.

2016-01-01

Background Exposure to Bisphenol A (BPA) is ubiquitous and includes dietary and environmental pathways. BPA is rapidly glucuronidated in the body, and both BPA and its conjugates can be readily measured in urine. Objectives To investigate the contribution of canned food and beverages, known sources of BPA contamination, to BPA biomarkers of exposure using dietary and urinary BPA concentration information in a representative sample of the U.S. population. Methods We evaluated 7,669 NHANES 2003–2008 participants 6 years and older with 24-hour dietary recall information and urinary BPA concentrations available. Using linear regression models, we evaluated the associations between recent canned food and beverage consumption and urinary BPA concentrations, adjusting for potential confounders. Results We found 9% of our participants consumed one canned food in the past 24 hours and 2% consumed two or more canned foods. The consumption of one canned food vs. none was associated with 24% (95% CI 1.11, 1.38) higher urinary BPA concentrations. The consumption of two or more canned foods vs. none was associated with 54% (95% CI 1.27, 1.88) higher urinary BPA concentrations. The consumption of one or more of some specific types of canned foods vs. none were associated with higher urinary BPA concentrations: 41% (95% CI 1.23, 1.63) higher BPA for vegetable and fruit, 70% (95% CI 1.18, 2.44) higher for canned pasta, and 229% (95% CI 1.22, 4.30) higher for canned soup. Canned beverages were not associated with urinary BPA concentrations. Conclusions Canned food, including some specific types such as canned vegetable and fruit, canned pasta, and canned soup were associated with higher levels of urinary BPA concentrations. PMID:27362993

Scale appropriate modelling to represent dominant pollution processes in agricultural catchments, to underpin management and policy decisions

NASA Astrophysics Data System (ADS)

Adams, Russell; Quinn, Paul

2014-05-01

We present the development of scale appropriate modelling techniques to represent dominant pollution processes in agricultural catchments to underpin catchment management and its implications on policy. A quasi-physically based, spatially lumped macro-model (CRAFT), has been developed to assess mitigation options for nitrogen and phosphorus. CRAFT has been developed to use daily time series data of rainfall, stream flow and nutrient concentration data, and can be applied to catchments varying in size from a few hectares to 100s of square kilometres. If stream flow routing is added to the model then potentially larger catchments and sub-daily time steps could be represented. There are two key issues addressed here. Firstly, the model can be used to assess the usefulness of monitoring data collected at a high temporal resolution at considerable expense compared to routine grab sampling. An earlier study in the Frome catchment in southern England collected sub-daily water quality data for more than 12 months at the catchment outlet, comprising: total oxidised nitrogen (TON); soluble reactive phosphorus (SRP) and total phosphorus (TP) concentrations. The three data sets have quite different temporal signals relating to flow pathways with different residence times and the importance of runoff events in generating acute pollution. The flexible model structure was therefore developed to include different sources of runoff including overland flow from impervious areas in the catchment, where pollution hotspots will be located (e.g. farmyards). The model has been used to assess the value of collecting high resolution monitoring data, in this case by resampling the Frome sub-daily data to a daily timestep, and comparing these model simulations against those calibrated using all the samples. The usefulness of the high resolution data can be assessed on whether a daily model would undepredict (for example) high nutrient concentrations that can be identified in the sub-daily monitoring data. Secondly, the study aims to investigate the mitigation measures that can be used to address the catchment scale sources of N and P, under EU or other governmental legislation designed to reduce their loads. In a complex catchment like the Frome, the mitigation measures are likely to target both point and non-point sources, particularly of SRP (e.g. wastewater treatment plant discharges and soluble fertilizer applications respectively). For a modelling tool to be useful to land holders and policy makers, it is imperative that these stakeholders can investigate different scenarios by easily manipulating the model input parameters, e.g. by reducing the diffuse sources of SRP and TON (by parameter adjustment), or modifying flow pathways through runoff attenuation (e.g. reducing runoff from farmyards), and the model structure reflects this functionality allowing it to be used as a runoff attenuation tool.

Polybrominated diphenyl ethers in indoor dust in Ottawa, Canada: implications for sources and exposure.

PubMed

Wilford, Bryony H; Shoeib, Mahiba; Harner, Tom; Zhu, Jiping; Jones, Kevin C

2005-09-15

Polybrominated diphenyl ethers (PBDEs) are widely used as additive flame retardants in plastics, soft furnishings, electrical and electronic equipment, and insulation in the indoor environment, and may be released indoors via volatilization or as dusts. The penta-and octa-brominated mixes are now banned in most parts of Europe, and phasing out of their use has recently begun in North America. This study follows a previous investigation into indoor air levels of PBDEs. House dust was analyzed from the family vacuum cleaners of 68 of the same 74 randomly selected homes, in Ottawa, Canada during the winter of 2002-2003. PBDEs, comprising on average 42% BDE-209, were found in all samples. The levels were log-normally distributed with a geometric mean sigmaPBDE of 2000 ng g(-1), and a median of 1800 ng g(-1) dust. The levels in dust did not correlate with questionnaire information on house characteristics. Correlations were found between pentamix congener levels in dust and in air from the same homes, but not for congeners of the more highly brominated mixes. Exposure scenarios are presented for mean and high dust ingestion rates, and compared against exposures from other pathways, for both adults and toddlers (6 months-2 years). Assuming a mean dust ingestion rate and median dust and air concentrations, adults would be exposed to ca. 7.5 ng sigmaPBDE d(-1) via the dust ingestion pathway, which represents approximately 14% of total daily exposure when compared to diet (82%) and inhalation (4%). However, for toddlers the equivalent intakes would be 99 ng d(-1), representing 80% of their daily PBDE exposure. At high dust ingestion rates these values increase to 180 ng d(-1) (80% daily intake) for adults and 360 ng d(-1) (89% daily intake) for toddlers. The data give a clearer picture of sources of PBDE exposure in the home environment and suggest that dust could be a significant exposure pathway for some individuals, particularly children.

Water deficit alters differentially metabolic pathways affecting important flavor and quality traits in grape berries of Cabernet Sauvignon and Chardonnay

PubMed Central

Deluc, Laurent G; Quilici, David R; Decendit, Alain; Grimplet, Jérôme; Wheatley, Matthew D; Schlauch, Karen A; Mérillon, Jean-Michel; Cushman, John C; Cramer, Grant R

2009-01-01

Background Water deficit has significant effects on grape berry composition resulting in improved wine quality by the enhancement of color, flavors, or aromas. While some pathways or enzymes affected by water deficit have been identified, little is known about the global effects of water deficit on grape berry metabolism. Results The effects of long-term, seasonal water deficit on berries of Cabernet Sauvignon, a red-wine grape, and Chardonnay, a white-wine grape were analyzed by integrated transcript and metabolite profiling. Over the course of berry development, the steady-state transcript abundance of approximately 6,000 Unigenes differed significantly between the cultivars and the irrigation treatments. Water deficit most affected the phenylpropanoid, ABA, isoprenoid, carotenoid, amino acid and fatty acid metabolic pathways. Targeted metabolites were profiled to confirm putative changes in specific metabolic pathways. Water deficit activated the expression of numerous transcripts associated with glutamate and proline biosynthesis and some committed steps of the phenylpropanoid pathway that increased anthocyanin concentrations in Cabernet Sauvignon. In Chardonnay, water deficit activated parts of the phenylpropanoid, energy, carotenoid and isoprenoid metabolic pathways that contribute to increased concentrations of antheraxanthin, flavonols and aroma volatiles. Water deficit affected the ABA metabolic pathway in both cultivars. Berry ABA concentrations were highly correlated with 9-cis-epoxycarotenoid dioxygenase (NCED1) transcript abundance, whereas the mRNA expression of other NCED genes and ABA catabolic and glycosylation processes were largely unaffected. Water deficit nearly doubled ABA concentrations within berries of Cabernet Sauvignon, whereas it decreased ABA in Chardonnay at véraison and shortly thereafter. Conclusion The metabolic responses of grapes to water deficit varied with the cultivar and fruit pigmentation. Chardonnay berries, which lack any significant anthocyanin content, exhibited increased photoprotection mechanisms under water deficit conditions. Water deficit increased ABA, proline, sugar and anthocyanin concentrations in Cabernet Sauvignon, but not Chardonnay berries, consistent with the hypothesis that ABA enhanced accumulation of these compounds. Water deficit increased the transcript abundance of lipoxygenase and hydroperoxide lyase in fatty metabolism, a pathway known to affect berry and wine aromas. These changes in metabolism have important impacts on berry flavor and quality characteristics. Several of these metabolites are known to contribute to increased human-health benefits. PMID:19426499

Implementing Toxicity Testing in the 21st Century (TT21C): Making safety decisions using toxicity pathways, and progress in a prototype risk assessment.

PubMed

Adeleye, Yeyejide; Andersen, Melvin; Clewell, Rebecca; Davies, Michael; Dent, Matthew; Edwards, Sue; Fowler, Paul; Malcomber, Sophie; Nicol, Beate; Scott, Andrew; Scott, Sharon; Sun, Bin; Westmoreland, Carl; White, Andrew; Zhang, Qiang; Carmichael, Paul L

2015-06-05

Risk assessment methodologies in toxicology have remained largely unchanged for decades. The default approach uses high dose animal studies, together with human exposure estimates, and conservative assessment (uncertainty) factors or linear extrapolations to determine whether a specific chemical exposure is 'safe' or 'unsafe'. Although some incremental changes have appeared over the years, results from all new approaches are still judged against this process of extrapolating high-dose effects in animals to low-dose exposures in humans. The US National Research Council blueprint for change, entitled Toxicity Testing in the 21st Century: A Vision and Strategy called for a transformation of toxicity testing from a system based on high-dose studies in laboratory animals to one founded primarily on in vitro methods that evaluate changes in normal cellular signalling pathways using human-relevant cells or tissues. More recently, this concept of pathways-based approaches to risk assessment has been expanded by the description of 'Adverse Outcome Pathways' (AOPs). The question, however, has been how to translate this AOP/TT21C vision into the practical tools that will be useful to those expected to make safety decisions. We have sought to provide a practical example of how the TT21C vision can be implemented to facilitate a safety assessment for a commercial chemical without the use of animal testing. To this end, the key elements of the TT21C vision have been broken down to a set of actions that can be brought together to achieve such a safety assessment. Such components of a pathways-based risk assessment have been widely discussed, however to-date, no worked examples of the entire risk assessment process exist. In order to begin to test the process, we have taken the approach of examining a prototype toxicity pathway (DNA damage responses mediated by the p53 network) and constructing a strategy for the development of a pathway based risk assessment for a specific chemical in a case study mode. This contribution represents a 'work-in-progress' and is meant to both highlight concepts that are well-developed and identify aspects of the overall process which require additional development. To guide our understanding of what a pathways-based risk assessment could look like in practice, we chose to work on a case study chemical (quercetin) with a defined human exposure and to bring a multidisciplinary team of chemists, biologists, modellers and risk assessors to work together towards a safety assessment. Our goal was to see if the in vitro dose response for quercetin could be sufficiently understood to construct a TT21C risk assessment without recourse to rodent carcinogenicity study data. The data presented include high throughput pathway biomarkers (p-H2AX, p-ATM, p-ATR, p-Chk2, p53, p-p53, MDM2 and Wip1) and markers of cell-cycle, apoptosis and micronuclei formation, plus gene transcription in HT1080 cells. Eighteen point dose response curves were generated using flow cytometry and imaging to determine the concentrations that resulted in significant perturbation. NOELs and BMDs were compared to the output from biokinetic modelling and the potential for in vitro to in vivo extrapolation explored. A first tier risk assessment was performed comparing the total quercetin concentration in the in vitro systems with the predicted total quercetin concentration in plasma and tissues. The shortcomings of this approach and recommendations for improvement are described. This paper therefore describes the current progress in an ongoing research effort aimed at providing a pathways-based, proof-of-concept in vitro-only safety assessment for a consumer use product. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Theoretical Analysis of Fas Ligand-Induced Apoptosis with an Ordinary Differential Equation Model.

PubMed

Shi, Zhimin; Li, Yan; Liu, Zhihai; Mi, Jun; Wang, Renxiao

2012-12-01

Upon the treatment of Fas ligand, different types of cells exhibit different apoptotic mechanisms, which are determined by a complex network of biological pathways. In order to derive a quantitative interpretation of the cell sensitivity and apoptosis pathways, we have developed an ordinary differential equation model. Our model is intended to include all of the known major components in apoptosis pathways mediated by Fas receptor. It is composed of 29 equations using a total of 49 rate constants and 13 protein concentrations. All parameters used in our model were derived through nonlinear fitting to experimentally measured concentrations of four selected proteins in Jurkat T-cells, including caspase-3, caspase-8, caspase-9, and Bid. Our model is able to correctly interpret the role of kinetic parameters and protein concentrations in cell sensitivity to FasL. It reveals the possible reasons for the transition between type-I and type-II pathways and also provides some interesting predictions, such as the more decisive role of Fas over Bax in apoptosis pathway and a possible feedback mechanism between type-I and type-II pathways. But our model failed in predicting FasL-induced apoptotic mechanism of NCI-60 cells from their gene-expression levels. Limitations in our model are also discussed. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

(Na+ + K+)-ATPase Is a Target for Phosphoinositide 3-Kinase/Protein Kinase B and Protein Kinase C Pathways Triggered by Albumin*

PubMed Central

Peruchetti, Diogo B.; Pinheiro, Ana Acacia S.; Landgraf, Sharon S.; Wengert, Mira; Takiya, Christina M.; Guggino, William B.; Caruso-Neves, Celso

2011-01-01

In recent decades, evidence has confirmed the crucial role of albumin in the progression of renal disease. However, the possible role of signaling pathways triggered by physiologic concentrations of albumin in the modulation of proximal tubule (PT) sodium reabsorption has not been considered. In the present work, we have shown that a physiologic concentration of albumin increases the expression of the α1 subunit of (Na+ + K+)-ATPase in LLC-PK1 cells leading to an increase in enzyme activity. This process involves the sequential activation of PI3K/protein kinase B and protein kinase C pathways promoting inhibition of protein kinase A. This integrative network is inhibited when albumin concentration is increased, similar to renal disease, leading to a decrease in the α1 subunit of (Na+ + K+)-ATPase expression. Together, the results indicate that variation in albumin concentration in PT cells has an important effect on PT sodium reabsorption and, consequently, on renal sodium excretion. PMID:22057272

Mercury speciation and exchanges at the air-water interface of a tropical artificial reservoir, French Guiana.

PubMed

Muresan, B; Cossa, D; Richard, S; Burban, B

2007-10-15

The distribution and speciation of mercury (Hg) in air, rain, and surface waters from the artificial tropical lake of Petit-Saut in French Guiana were investigated during the 2003/04 period. In the air, total gaseous mercury (TGM) at the dam station averaged 12+/-2 pmol m(-3) of which >98% was gaseous elemental mercury (GEM). GEM distribution depicted a day-night cycling with high concentrations (up to 15 pmol m(-3)) at dawn and low concentrations (down to 5 pmol m(-3)) at nightfall. Reactive gaseous mercury (RGM) represented <1% of the GEM with a mean concentration of 4+/-3 fmol m(-3). Diel RGM variations were negatively related to GEM. In the rain, the sum of all Hg species in the unfiltered (HgT(UNF)) averaged 16+/-12 pmol L(-1). Temporal distribution of HgT(UNF) exhibited a pattern of high concentrations during the late dry seasons (up to 57.5 pmol L(-1)) and low concentrations (down to 2.7 pmol L(-1)) in the course of the wet seasons. Unfiltered reactive (HgR(UNF)), dissolved gaseous (DGM) and monomethyl (MMHg(UNF)) Hg constituted 20, 5 and 5% of HgT(UNF), respectively. All measured Hg species were positively related and displayed negative relationships with the pH of the rain. In the reservoir surface waters, dissolved total mercury (HgT(D)) averaged 3.4+/-1.2 pmol L(-1) of which 10% consisted of DGM. DGM showed a trend of high concentrations during the dry seasons (480+/-270 fmol L(-1)) and lower (230+/-130 fmol L(-1)) in the course of the wet seasons. Diel variations included diurnal photo-induced DGM production (of about 60 fmol L(-1) h(-1)) coupled to minute to hour oxidation/reduction cycles (of >100 fmol L(-1) amplitude). Finally, calculated atmospheric Hg inputs to the Petit-Saut reservoir represented 14 mol yr(-1) whereas DGM evasion reached 23 mol yr(-1). Apportionment among forms of Hg deposition indicated that up to 75% of the total Hg invasive flux follows the rainfall pathway.

The effect of long-range air mass transport pathways on PM10 and NO2 concentrations at urban and rural background sites in Ireland: Quantification using clustering techniques.

PubMed

Donnelly, Aoife A; Broderick, Brian M; Misstear, Bruce D

2015-01-01

The specific aims of this paper are to: (i) quantify the effects of various long range transport pathways nitrogen dioxide (NO2) and particulate matter with diameter less than 10μm (PM10) concentrations in Ireland and identify air mass movement corridors which may lead to incidences poor air quality for application in forecasting; (ii) compare the effects of such pathways at various sites; (iii) assess pathways associated with a period of decreased air quality in Ireland. The origin of and the regions traversed by an air mass 96h prior to reaching a receptor is modelled and k-means clustering is applied to create air-mass groups. Significant differences in air pollution levels were found between air mass cluster types at urban and rural sites. It was found that easterly or recirculated air masses lead to higher NO2 and PM10 levels with average NO2 levels varying between 124% and 239% of the seasonal mean and average PM10 levels varying between 103% and 199% of the seasonal mean at urban and rural sites. Easterly air masses are more frequent during winter months leading to higher overall concentrations. The span in relative concentrations between air mass clusters is highest at the rural site indicating that regional factors are controlling concentration levels. The methods used in this paper could be applied to assist in modelling and forecasting air quality based on long range transport pathways and forecast meteorology without the requirement for detailed emissions data over a large regional domain or the use of computationally demanding modelling techniques.

Microfluidic device generating stable concentration gradients for long term cell culture: application to Wnt3a regulation of β-catenin signaling.

PubMed

Cimetta, Elisa; Cannizzaro, Christopher; James, Richard; Biechele, Travis; Moon, Randall T; Elvassore, Nicola; Vunjak-Novakovic, Gordana

2010-12-07

In developing tissues, proteins and signaling molecules present themselves in the form of concentration gradients, which determine the fate specification and behavior of the sensing cells. To mimic these conditions in vitro, we developed a microfluidic device designed to generate stable concentration gradients at low hydrodynamic shear and allowing long term culture of adhering cells. The gradient forms in a culture space between two parallel laminar flow streams of culture medium at two different concentrations of a given morphogen. The exact algorithm for defining the concentration gradients was established with the aid of mathematical modeling of flow and mass transport. Wnt3a regulation of β-catenin signaling was chosen as a case study. The highly conserved Wnt-activated β-catenin pathway plays major roles in embryonic development, stem cell proliferation and differentiation. Wnt3a stimulates the activity of β-catenin pathway, leading to translocation of β-catenin to the nucleus where it activates a series of target genes. We cultured A375 cells stably expressing a Wnt/β-catenin reporter driving the expression of Venus, pBARVS, inside the microfluidic device. The extent to which the β-catenin pathway was activated in response to a gradient of Wnt3a was assessed in real time using the BARVS reporter gene. On a single cell level, the β-catenin signaling was proportionate to the concentration gradient of Wnt3a; we thus propose that the modulation of Wnt3a gradients in real time can provide new insights into the dynamics of β-catenin pathway, under conditions that replicate some aspects of the actual cell-tissue milieu. Our device thus offers a highly controllable platform for exploring the effects of concentration gradients on cultured cells.

Alterations in receptor expression or agonist concentration change the pathways gastrin-releasing peptide receptor uses to regulate extracellular signal-regulated kinase.

PubMed

Chen, Pei-Wen; Kroog, Glenn S

2004-12-01

G protein-coupled receptors activate extracellular signal-regulated kinases (ERKs) via different pathways in different cell types. In this study, we demonstrate that gastrin-releasing peptide receptor (GRPr) regulates ERK through multiple pathways in a single cell type depending upon receptor expression and agonist concentration. We examined stably transfected BALB/c 3T3 fibroblasts expressing GRPr constructs at different levels and treated the cells with several concentrations of bombesin (BN, a GRPr agonist) to activate a variable number of GRPr per cell. GRPr induced two waves of ERK activation and one wave of ERK inhibition. One wave of activation required an intact GRPr carboxyl-terminal domain (CTD). It peaked 6 min after addition of high BN concentration ([BN]) in cells with high GRPr expression. Another wave of activation was CTD-independent. It peaked 2 to 4 min after BN addition in cells when [BN] and/or GRPr expression were lower. The early wave of ERK activation was more sensitive than the later one to pretreatment with Bisindolylmaleimide I (GF 109203X) (a protein kinase C inhibitor) or hypertonic sucrose. Because these two waves of activation differ in time course, dose-response curve, requirement for GRPr CTD, and sensitivity to inhibitors, they result from different signaling pathways. A third pathway in these cells inhibited ERK phosphorylation 2 min after addition of high [BN] in cells with high GRPr expression. Furthermore, a GRPr-expressing human duodenal cancer cell line showed differential sensitivity to GF 109203X throughout BN-induced ERK activation, indicating that GRPr may activate ERK via multiple pathways in cells expressing endogenous GRPr.

Adverse Outcome Pathways – Tailoring Development to Support Use

EPA Science Inventory

Adverse Outcome Pathways (AOPs) represent an ideal framework for connecting high-throughput screening (HTS) data and other toxicity testing results to adverse outcomes of regulatory importance. The AOP Knowledgebase (AOP-KB) captures AOP information to facilitate the development,...

Adverse outcome pathway (AOP) development: Guiding principles and best practices

EPA Science Inventory

Adverse outcome pathways (AOPs) represent a conceptual framework that can support greater application of mechanistic data in regulatory decision-making. However, in order for the scientific community to collectively address the daunting challenge of describing relevant toxicologi...

Experiences of women with a diagnosis of breast cancer: a clinical pathway approach.

PubMed

Lindop, E; Cannon, S

2001-06-01

The study presented in this paper formed the first part of a large survey of breast cancer patients in one health authority in England, UK looking at individual needs expressed by women with a diagnosis of breast cancer. The paper provides an account of the experiences of 12 women with a diagnosis of breast cancer. The women represent a wide age range and different stages of illness. The transcribed accounts of the women were analysed by means of Qualitative Solutions and Research, Non-Numerical Unstructured Data Indexing Searching and Theorising (QSR*NUDIST). The study examined the individual experiences of women with a diagnosis of breast cancer and its aftermath as they passed through different stages related to it. The women's experiences are presented within the conceptual framework of the clinical pathway and their accounts represent their journey along the pathway. Various significant points in this journey are portrayed representing the women's reactions to diagnosis, treatment, femininity and body image, support, family and friends, information and after care.

Regulation of expression, activity and localization of fungal chitin synthases

PubMed Central

Rogg, Luise E.; Fortwendel, Jarrod R.; Juvvadi, Praveen R.; Steinbach, William J.

2013-01-01

The fungal cell wall represents an attractive target for pharmacologic inhibition, as many of the components are fungal-specific. Though targeted inhibition of β-glucan synthesis is effective treatment for certain fungal infections, the ability of the cell wall to dynamically compensate via the cell wall integrity pathway may limit overall efficacy. To date, chitin synthesis inhibitors have not been successfully deployed in the clinical setting. Fungal chitin synthesis is a complex and highly regulated process. Regulation of chitin synthesis occurs on multiple levels, thus targeting of these regulatory pathways may represent an exciting alternative approach. A variety of signaling pathways have been implicated in chitin synthase regulation, at both transcriptional and post-transcriptional levels. Recent research suggests that localization of chitin synthases likely represents a major regulatory mechanism. However, much of the regulatory machinery is not necessarily shared among different chitin synthases. Thus, an in depth understanding of the precise roles of each protein in cell wall maintenance and repair will be essential to identifying the most likely therapeutic targets. PMID:21526913

Hanford Environmental Dose Reconstruction Project monthly report, November 1992

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

Cannon, S.D.; Finch, S.M.

1992-12-31

The objective of the Hanford Environmental Dose Reconstruction (HEDR) Project is to estimate the radiation doses that individuals and populations could have received from nuclear operations at Hanford since 1944. The TSP consists of experts in environmental pathways, epidemiology, surface-water transport, ground-water transport, statistics, demography, agriculture, meteorology, nuclear engineering, radiation dosimetry, and cultural anthropology. Included are appointed members representing the states of Oregon, Washington. and Idaho, a representative of Native American tribes, and an individual representing the public. The project is divided into the following technical tasks: Source terms; environmental transport; environmental monitoring data; demography, food consumption and agriculture; environmentalmore » pathways and dose estimates.« less

Hanford Environmental Dose Reconstruction Project monthly report, November 1992

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

Cannon, S.D.; Finch, S.M.

1992-01-01

The objective of the Hanford Environmental Dose Reconstruction (HEDR) Project is to estimate the radiation doses that individuals and populations could have received from nuclear operations at Hanford since 1944. The TSP consists of experts in environmental pathways, epidemiology, surface-water transport, ground-water transport, statistics, demography, agriculture, meteorology, nuclear engineering, radiation dosimetry, and cultural anthropology. Included are appointed members representing the states of Oregon, Washington. and Idaho, a representative of Native American tribes, and an individual representing the public. The project is divided into the following technical tasks: Source terms; environmental transport; environmental monitoring data; demography, food consumption and agriculture; environmentalmore » pathways and dose estimates.« less

Living with death: The evolution of the mitochondrial pathway of apoptosis in animals

PubMed Central

Oberst, Andrew; Bender, Cheryl; Green, Douglas R.

2008-01-01

The mitochondrial pathway of cell death, in which apoptosis proceeds following mitochondrial outer membrane permeablization (MOMP), release of cytochrome c, and APAF-1 apoptosome-mediated caspase activation, represents the major pathway of physiological apoptosis in vertebrates. However, the well-characterized apoptotic pathways of the invertebrates C. elegans and D. melanogaster indicate that this apoptotic pathway is not universally conserved among animals. This review will compare the role of the mitochondria in the apoptotic programs of mammals, nematodes, and flies, and will survey our knowledge of the apoptotic pathways of other, less familiar model organisms in an effort to explore the evolutionary origins of the mitochondrial pathway of apoptosis. PMID:18451868

Comparison of Pathway and Center of Gravity of the Calcaneus on Non-Involved and Involved Sides According to Eccentric and Concentric Strengthening in Patients With Achilles Tendinopathy

PubMed Central

Yu, JaeHo; Lee, GyuChang

2012-01-01

This study compares the changes in pathway and center of gravity (COG) on the calcaneus of non-involved and involved sides according to eccentric and concentric strengthening in patients with unilateral Achilles tendinopathy. The goal was to define the biomechanical changes according to eccentric strengthening for the development of clinical guidelines. Eighteen patients with Achilles tendinopathy were recruited at the K Rehabilitation Hospital in Seoul. The subjects were instructed to perform 5 sessions of concentric strengthening. The calcaneal pathway was measured using a three-dimensional (3D) motion analyzer, and COG was measured by a force plate. Subsequently, eccentric strengthening was implemented, and identical variables were measured. Concentric and eccentric strengthening was carried out on both the involved and non-involved sides. There was no significant difference in the calcaneal pathway in patients with Achilles tendinopathy during concentric and eccentric strengthening. However, during eccentric strengthening, the calcaneal pathway significantly increased on the involved side compared to the non-involved side for all variables excluding the z-axis. COG significantly decreased on the involved side when compared to the non-involved side in patients with Achilles tendinopathy during eccentric and concentric strengthening. During concentric strengthening, all variables of the COG significantly increased on the involved side compared to the non-involved side. Compared with eccentric strengthening, concentric strengthening decreased the stability of ankle joints and increased the movement distance of the calcaneus in patients with Achilles tendinopathy. Furthermore, eccentric strengthening was verified to be an effective exercise method for prevention of Achilles tendinopathy through the reduction of forward and backward path length of foot pressure. The regular application of eccentric strengthening was found to be effective in the secondary prevention of Achilles tendinopathy in a clinical setting. Key point Compared with eccentric strengthening, concentric strengthening decreased the stability of ankle joints, increasing movement of the calcaneus in patients with Achilles tendinopathy. Eccentric strengthening was shown to be an effective exercise method for preventing Achilles tendinopathy through the reduction of forward and backward path length of foot pressure. It was verified that regular application of eccentric strengthening is effective in secondary prevention of Achilles tendinopathy in the clinical setting. PMID:24149129

In vitro study on reversal of ovarian cancer cell resistance to cisplatin by naringin via the nuclear factor-κB signaling pathway.

PubMed

Zhu, Hong; Gao, Jun; Wang, Lei; Qian, Ke-Jian; Cai, Li-Ping

2018-03-01

The aim of the present study was to investigate the mechanism of action by which naringin reverses the resistance of ovarian cancer cells to cisplatin. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blotting assays were used to detect the effects of different concentrations of naringin on the expressions of nuclear factor (NF)-κB and P-glycoprotein (P-gp) in the SKOV3/CDDP cell line. Small interfering RNA (siRNA) targeting NF-κB was designed and synthesized to silence NF-κB, and recombinant plasmid vectors overexpressing NF-κB were constructed to transfect cells. RT-qPCR and western blotting assays were subsequently performed to detect the effects of NF-κB on the expression of P-gp at the mRNA and protein levels. Naringin was added to the NF-κB-overexpressing SKOV3/CDDP cells and cultured for 48 h, followed by the detection of the expression of P-gp. RT-PCR and western blotting results demonstrated that the gene and protein expressions of NF-κB and P-gp were significantly decreased in a dose-dependent manner by naringin treatment (P<0.05). In cells overexpressing NF-κB, P-gp expression was significantly elevated (P<0.05), and the expression of P-gp was significantly decreased when NF-κB was silenced (P<0.05). Treatment with naringin was able to significantly ameliorate the NF-κB-induced overexpression of P-gp (P<0.05). These results indicate that naringin is able to inhibit the expression of NF-κB and P-gp in SKOV3/CDDP cells. Such an inhibitory effect may increase gradually with concentration, and is associated with blockade of the NF-κB signaling pathway. This pathway may represent one of the mechanisms of action by which Naringin reverses resistance to platinum-based agents in ovarian cancer cells.

Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks.

PubMed

Ramanan, Vijay K; Kim, Sungeun; Holohan, Kelly; Shen, Li; Nho, Kwangsik; Risacher, Shannon L; Foroud, Tatiana M; Mukherjee, Shubhabrata; Crane, Paul K; Aisen, Paul S; Petersen, Ronald C; Weiner, Michael W; Saykin, Andrew J

2012-12-01

Memory deficits are prominent features of mild cognitive impairment (MCI) and Alzheimer's disease (AD). The genetic architecture underlying these memory deficits likely involves the combined effects of multiple genetic variants operative within numerous biological pathways. In order to identify functional pathways associated with memory impairment, we performed a pathway enrichment analysis on genome-wide association data from 742 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. A composite measure of memory was generated as the phenotype for this analysis by applying modern psychometric theory to item-level data from the ADNI neuropsychological test battery. Using the GSA-SNP software tool, we identified 27 canonical, expertly-curated pathways with enrichment (FDR-corrected p-value < 0.05) against this composite memory score. Processes classically understood to be involved in memory consolidation, such as neurotransmitter receptor-mediated calcium signaling and long-term potentiation, were highly represented among the enriched pathways. In addition, pathways related to cell adhesion, neuronal differentiation and guided outgrowth, and glucose- and inflammation-related signaling were also enriched. Among genes that were highly-represented in these enriched pathways, we found indications of coordinated relationships, including one large gene set that is subject to regulation by the SP1 transcription factor, and another set that displays co-localized expression in normal brain tissue along with known AD risk genes. These results 1) demonstrate that psychometrically-derived composite memory scores are an effective phenotype for genetic investigations of memory impairment and 2) highlight the promise of pathway analysis in elucidating key mechanistic targets for future studies and for therapeutic interventions.

Modeling functional neuroanatomy for an anatomy information system.

PubMed

Niggemann, Jörg M; Gebert, Andreas; Schulz, Stefan

2008-01-01

Existing neuroanatomical ontologies, databases and information systems, such as the Foundational Model of Anatomy (FMA), represent outgoing connections from brain structures, but cannot represent the "internal wiring" of structures and as such, cannot distinguish between different independent connections from the same structure. Thus, a fundamental aspect of Neuroanatomy, the functional pathways and functional systems of the brain such as the pupillary light reflex system, is not adequately represented. This article identifies underlying anatomical objects which are the source of independent connections (collections of neurons) and uses these as basic building blocks to construct a model of functional neuroanatomy and its functional pathways. The basic representational elements of the model are unnamed groups of neurons or groups of neuron segments. These groups, their relations to each other, and the relations to the objects of macroscopic anatomy are defined. The resulting model can be incorporated into the FMA. The capabilities of the presented model are compared to the FMA and the Brain Architecture Management System (BAMS). Internal wiring as well as functional pathways can correctly be represented and tracked. This model bridges the gap between representations of single neurons and their parts on the one hand and representations of spatial brain structures and areas on the other hand. It is capable of drawing correct inferences on pathways in a nervous system. The object and relation definitions are related to the Open Biomedical Ontology effort and its relation ontology, so that this model can be further developed into an ontology of neuronal functional systems.

Differentiating high priority pathway-based toxicity from non ...

EPA Pesticide Factsheets

The ToxCast chemical screening approach enables the rapid assessment of large numbers of chemicals for biological effects, primarily at the molecular level. Adverse outcome pathways (AOPs) offer a means to link biomolecular effects with potential adverse outcomes at the level of the individual or population, thus enhancing the utility of the ToxCast effort for hazard assessment. Thus, efforts are underway to develop AOPs relevant to the pathway perturbations detected in ToxCast assays. However, activity (?‘hits’) determined for chemical-assay pairs may reflect target-specific activity relevant to a molecular initiating event of an AOP, or more generalized cell stress and cytotoxicity-mediated effects. Previous work identified a ?‘cytotoxic burst’ phenomenon wherein large numbers of assays begin to respond at or near concentrations that elicit cytotoxicity. The concentration range at which the “burst” occurs is definable, statistically. Consequently, in order to focus AOP development on the ToxCast assay targetswhich are most sensitive and relevant to pathway-specific effects, we conducted a meta-analysis to identify which assays were frequently responding at concentrations well below the cytotoxic burst. Assays were ranked by the fraction of chemical hits below the burst concentration range compared to the number of chemicals tested, resulting in a preliminary list of potentially important, target-specific assays. After eliminating cytotoxicity a

Communicating uncertainty in circulation aspects of climate change

NASA Astrophysics Data System (ADS)

Shepherd, Ted

2017-04-01

The usual way of representing uncertainty in climate change is to define a likelihood range of possible futures, conditioned on a particular pathway of greenhouse gas concentrations (RCPs). Typically these likelihood ranges are derived from multi-model ensembles. However, there is no obvious basis for treating such ensembles as probability distributions. Moreover, for aspects of climate related to atmospheric circulation, such an approach generally leads to large uncertainty and low confidence in projections. Yet this does not mean that the associated climate risks are small. We therefore need to develop suitable ways of communicating climate risk whilst acknowledging the uncertainties. This talk will outline an approach based on conditioning the purely thermodynamic aspects of climate change, concerning which there is comparatively high confidence, on circulation-related aspects, and treating the latter through non-probabilistic storylines.

Implications of alternative assumptions regarding future air pollution control in RCP-like scenarios

NASA Astrophysics Data System (ADS)

Chuwah, Clifford; van Noije, Twan; van Vuuren, Detlef; Hazeleger, Wilco; Strunk, Achim; Deetman, Sebastiaan; Mendoza Beltran, Angelica; van Vliet, Jasper

2013-04-01

Estimation of future emissions of short-lived trace gases and aerosols from human activities is a main source of uncertainty in projections of future air quality and climate forcing. The Representative Concentration Pathways (RCPs), however, all assume that worldwide ambitious air pollution control policies will be implemented in the coming decades. In this study, we therefore explore the consequences of four alternative emission scenarios generated using the IMAGE integrated assessment model following the methods used to generate the RCPs. These scenarios combine low and high air pollution variants of the scenarios with radiative forcing targets in 2100 of 2.6 W/m2 and 6.0 W/m2 (the high air pollution variants assume no improvement in emission factors, representing a hypothetical upper end of emission levels). Analysis using the global atmospheric chemistry and transport model TM5 shows that climate mitigation and air pollution control policy variants studied here have similar large-scale effects on the concentrations of ozone and black carbon; the impact of climate policy, however, has a stronger impact on sulphate concentrations. Air pollution control measures could significantly reduce the warming by tropospheric ozone and black carbon and the cooling by sulphate already in 2020, and on the longer term contribute to enhanced warming by methane. These effects tend to cancel each other at the global scale. According to our estimates the effect of the worldwide implementation of air pollution control measures on the total global mean direct radiative forcing in 2050 is +0.09 W/m2 in the 6.0 W/m2 scenario and -0.16 W/m2 in the 2.6 W/m2 scenario.

Global trends in peatland methane production

NASA Astrophysics Data System (ADS)

Hoyt, A.; Corbett, J. E.; Gandois, L.; Cobb, A.; Pangala, S. R.; Gauci, V.; Harvey, C. F.

2017-12-01

Peatland methane production rates and fluxes to the atmosphere vary globally. Here we present a systematic comparison of peatland CH4 production across latitudes. We developed and applied an isotope-based mass transport model to characterize rates of methanogenesis and recharge rates across ten ombrotrophic peatlands from around the world. We validated our model against peat incubations and surface fluxes where data was available. We found striking similarities in the DIC and CH4 concentrations and δ13C isotope profiles across northern bogs, despite highly variable precipitation, recharge rates, and peat characteristics. Profiles from northern sites were similar because increased recharge rates were always compensated by increased CH4 production rates. This could represent a feedback mechanism between recharge rates and methanogenesis in northern bogs or could represent a shared dependence of these two properties on the degree of peat decomposition. We also found strong differences between northern and tropical sites, both in the rate of CH4 production, the recharge rate, and in the transport pathways and fluxes to the atmosphere. Our findings have important implications for methane transport and release to the atmosphere. In northern bogs, low flow rates allow CH4 concentrations to build up, and CH4 escapes by surface diffusion, ebullition, and plant-mediated transport. Thus, the majority of CH4 produced escapes through the peat surface. In tropical peatlands, high flow rates suppress CH4 concentrations, which do not build up above the threshold for ebullition. Instead, CH4 leaves the peat by lateral transport and surface fluxes are small. This work provides evidence that peat properties and hydrology are fundamental controls on decomposition, CH4 production, and peat formation across latitudes.

Analyzing the Impacts of a Biogas-to-Electricity Purchase Incentive on Electric Vehicle Deployment with the MA 3T Vehicle Choice Model

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

Podkaminer, Kara; Xie, Fei; Lin, Zhenhong

In 2014, the EPA approved a biogas-to-electricity pathway under the Renewable Fuel Standard (RFS). However, no specific applications for this pathway have been approved to date. This analysis helps understand the impact of the pathway by representing the biogas-to-electricity pathway as a point of purchase incentive and tests the impact of this incentive on EV deployment using a vehicle consumer choice model.

A headlight on liquid biopsies: a challenging tool for breast cancer management.

PubMed

Massihnia, Daniela; Perez, Alessandro; Bazan, Viviana; Bronte, Giuseppe; Castiglia, Marta; Fanale, Daniele; Barraco, Nadia; Cangemi, Antonina; Di Piazza, Florinda; Calò, Valentina; Rizzo, Sergio; Cicero, Giuseppe; Pantuso, Gianni; Russo, Antonio

2016-04-01

Breast cancer is the most frequent carcinoma and second most common cause of cancer-related mortality in postmenopausal women. The acquisition of somatic mutations represents the main mechanism through which cancer cells overcome physiological cellular signaling pathways (e.g., PI3K/Akt/mTOR, PTEN, TP53). To date, diagnosis and metastasis monitoring is mainly carried out through tissue biopsy and/or re-biopsy, a very invasive procedure limited only to certain locations and not always feasible in clinical practice. In order to improve disease monitoring over time and to avoid painful procedure such as tissue biopsy, liquid biopsy may represent a new precious tool. Indeed, it represents a basin of "new generation" biomarkers that are spread into the bloodstream from both primary and metastatic sites. Moreover, elevated concentrations of circulating tumor DNA (ctDNA) as well as circulating tumor cells (CTCs) have been found in blood plasma of patients with various tumor types. Nowadays, several new approaches have been introduced for the detection and characterization of CTCs and ctDNA, allowing a real-time monitoring of tumor evolution. This review is focused on the clinical relevance of liquid biopsy in breast cancer and will provide an update concerning CTCs and ctDNA utility as a tool for breast cancer patient monitoring during the course of disease.

Approximating dose and risk for contaminants in groundwater from the underground nuclear test areas of the Nevada National Security Site (NNSS)

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

Daniels, Jeffrey I.; Chapman, Jenny; Pohlmann, Karl F.

As part of the Environmental Management Program at the Nevada National Security Site (NNSS), the Underground Test Area (UGTA) Activity investigates the potential impacts of radionuclides that were introduced into groundwater from the underground nuclear tests conducted near or below the NNSS water table between 1951 and 1992. Groundwater models are being used to simulate contaminant transport and forecast contaminant boundaries that encompass areas where the groundwater has a five percent or greater probability of containing contaminants above the Safe Drinking Water Act Maximum Contaminant Levels (SDWA MCLs) at any time during the next 1,000 years. Transport modeling conducted formore » the Frenchman Flat Corrective Action Unit (CAU) at the NNSS identified the beta/photon-emitting radionuclides tritium (3H), carbon-14 (14C), chlorine-36 (36Cl), technetium-99 (99Tc), and iodine-129 (129I) as having the greatest influence in defining the farthest extent of the modeled CAU contaminant boundary. These same radionuclides are assumed here as the contaminants of concern (COCs) for all underground nuclear tests at the NNSS because models are not yet complete for the other CAUs.Potential public exposure to the COCs will only occur and be of concern if the COCs migrate into the groundwater beneath public or private lands at levels that exceed either individual SDWA MCLs or dose and risk limits. Groundwater flow directions strongly suggest that any contaminant boundary predicted by contaminant fate and transport modeling to overlap public or private lands is more likely to occur to the west and/or southwest of the NNSS and the adjacent Nevada Test and Training Range (NTTR). Well-established, rural communities exist in these directions. Estimates of representative activity concentrations at the applicable SDWA MCL were developed for the five COCs. It is assumed that these COC concentrations may collectively occur at some public or private location in the future, but that situation does not exist today. These representative activity concentrations are evaluated with respect to conforming collectively to a modern annual committed effective dose (CED) and lifetime excess cancer morbidity risk for a hypothetical reasonably maximally exposed individual (RMEI). This approach goes beyond the SDWA MCL focus of the contaminant boundary because individual COC concentrations may comply with the SDWA MCL but not collectively meet the modern health-protection metrics and the SDWA language, especially if future modeling studies or monitoring activities show multiple radionuclides from different SDWA MCL categories to be COCs. For the drinking water exposure pathway alone, the annual committed effective dose (CED) for the RMEI from all five COCs that are collectively at estimated activity concentrations equal to their SDWA MCL is well below the U.S. Department of Energy health-protective CED limit of 100 millirem (mrem)/yr. This is consistent using both the NNSS unclassified, 1992 decay-corrected radionuclide atom inventory and the atom inventory based on radionuclides measured in groundwater obtained from the ALMENDRO cavity in 2009 to calculate the SDWA MCL activity concentrations in groundwater. The RMEI’s total lifetime excess cancer risk from the drinking water exposure pathway for both atom inventories is within the range of 1 × 10 -4 to ≤ 1 × 10 -6, which is considered health protective according to modern SDWA MCL regulatory language. The biosphere exposure pathways are drinking water, garden produce, animal products, inadvertent soil ingestion, and indoor and outdoor air inhalation. The exposure parameters for communities west and southwest of the NNSS were developed when the Yucca Mountain high-level, nuclear-waste disposal facility was under consideration. For all biosphere exposure pathways, calculations of the annual CED and lifetime excess cancer morbidity risk for the RMEI revealed that: 1) The annual CED is well within health-protective guidance (<< 100 mrem CED/yr) for the COC activity concentrations at the SDWA MCL, regardless of the atom inventory used. 2) The calculated 70-year lifetime excess cancer morbidity risk (6 x 10 -5) is within the health-protective range when the five COC activity concentrations are derived using the NNSS 1992 atom inventory, but it is at the upper limit of the acceptable range (1 x 10 -4) using the ALMENDRO 2009 atom inventory. 3) Tritium (3H) is the principal COC for producing annual dose and lifetime excess cancer risk, regardless of the atom inventory used. 4) Overall, the drinking water ingestion pathway is the dominant exposure pathway contributing to the total annual CED and lifetime excess cancer risk, followed by eating locally grown produce and animal products. 5) When tritium completely decays (after about 100 years), the RMEI’s lifetime risk will fall well within the health-protective range (i.e., 1 × 10-4 to ≤ 1 × 10 -6) and 36Cl will then become the most important contributor to the RMEI’s total annual CED and lifetime excess cancer morbidity risk from eating local produce and animal products. In the event that radionuclide concentrations begin to approach SDWA MCLs, a reasonable risk-management strategy for keeping lifetime risk more in compliance with regulatory guidance would be to use local sources of groundwater that are below SDWA MCLs or to limit the consumption of local produce and animal products that have ingested COC-contaminated groundwater. The viability of the latter strategy increases where the annual CED due to 36Cl approaches that of 3H.The dose and risk values calculated here for an RMEI are specific to the assumption that the five COCs occur in groundwater beneath public or private lands at concentrations that are collectively at the SDWA MCL. Currently, these COCs are essentially absent from groundwater beneath public or private lands beyond the boundaries of the NNSS and NTTR other than at very low, naturally occurring concentrations. The analyses presented here can be readily applied to determine dose and risk for COC concentrations actually measured in future monitoring samples.« less

Water Footprint and Land Requirement of Solar Thermochemical Jet-Fuel Production.

PubMed

Falter, Christoph; Pitz-Paal, Robert

2017-11-07

The production of alternative fuels via the solar thermochemical pathway has the potential to provide supply security and to significantly reduce greenhouse gas emissions. H 2 O and CO 2 are converted to liquid hydrocarbon fuels using concentrated solar energy mediated by redox reactions of a metal oxide. Because attractive production locations are in arid regions, the water footprint and the land requirement of this fuel production pathway are analyzed. The water footprint consists of 7.4 liters per liter of jet fuel of direct demand on-site and 42.4 liters per liter of jet fuel of indirect demand, where the dominant contributions are the mining of the rare earth oxide ceria, the manufacturing of the solar concentration infrastructure, and the cleaning of the mirrors. The area-specific productivity is found to be 33 362 liters per hectare per year of jet fuel equivalents, where the land coverage is mainly due to the concentration of solar energy for heat and electricity. The water footprint and the land requirement of the solar thermochemical fuel pathway are larger than the best power-to-liquid pathways but an order of magnitude lower than the best biomass-to-liquid pathways. For the production of solar thermochemical fuels arid regions are best-suited, and for biofuels regions of a moderate and humid climate.

Transport pathway and source area for Artemisia pollen in Beijing, China

NASA Astrophysics Data System (ADS)

Qin, Xiaoxin; Li, Yiyin; Sun, Xu; Meng, Ling; Wang, Xiaoke

2017-12-01

Artemisia pollen is an important allergen responsible for allergic rhinitis in Beijing, China. To explore the transport pathways and source areas of Artemisia pollen, we used Burkard 7-day traps to monitor daily pollen concentrations in 2016 in an urban and suburban locality. Backward trajectories of 24- and 96-h and their cluster analysis were performed to identify transport pathways of Artemisia pollen using the HYSPLIT model on 0.5° × 0.5° GADS meteorological data. The potential source contribution function (PSCF) and concentration weighted trajectory (CWT) were calculated to further identify the major potential source areas at local, regional, and long-range scales. Our results showed significant differences in Artemisia pollen concentration between urban and suburban areas, attributed to differences in plant distribution and altitude of the sampling locality. Such differences arisen from both pollen emission and air mass movements, hence pollen dispersal. At local or regional scales, source area of northwestern parts of Beijing City, Hebei Province and northern and northwestern parts of Inner Mongolia influenced the major transport pathways of Artemisia pollen. Transport pathway at a long-range scale and its corresponding source area extended to northwestern parts of Mongolia. The regional-scale transport affected by wind and altitude is more profound for Artemisia pollen at the suburban than at the urban station.

Ability of Mn2+ to Permeate the Eye and Availability of Manganese-enhanced Magnetic Resonance Imaging for Visual Pathway Imaging via Topical Administration

PubMed Central

Chen, Yao; Shi, Chun-Yan; Li, Ying; Hu, Yun-Tao; Han, Hong-Bin; Sun, Xiao-Dong; Salvi, Satyajeet S; Ma, Zhi-Zhong

2016-01-01

Background: Manganese-enhanced magnetic resonance imaging (MEMRI) for visual pathway imaging via topical administration requires further research. This study investigated the permeability of the corneal epithelium and corneal toxicity after topical administration of Mn2+ to understand the applicability of MEMRI. Methods: Forty New Zealand rabbits were divided into 0.05 mol/L, 0.10 mol/L, and 0.20 mol/L groups as well as a control group (n = 10 in each group). Each group was further subdivided into epithelium-removed and epithelium-intact subgroups (n = 5 in each subgroup). Rabbits were given 8 drops of MnCl2 in 5 min intervals. The Mn2+ concentrations in the aqueous and vitreous humors were analyzed using inductively coupled plasma-mass spectrometry at different time points. MEMRI scanning was carried out to image the visual pathway after 24 h. The corneal toxicity of Mn2+ was evaluated with corneal imaging and pathology slices. Results: Between the aqueous and vitreous humors, there was a 10 h lag for the peak Mn2+ concentration times. The intraocular Mn2+ concentration increased with the concentration gradients of Mn2+ and was higher in the epithelium-removed subgroup than that in the epithelium-intact subgroup. The enhancement of the visual pathway was achieved in the 0.10 mol/L and 0.20 mol/L epithelium-removed subgroups. The corresponding peak concentrations of Mn2+ were 5087 ± 666 ng/ml, 22920 ± 1188 ng/ml in the aqueous humor and 884 ± 78 ng/ml, 2556 ± 492 ng/ml in the vitreous body, respectively. Corneal injury was evident in the epithelium-removed and 0.20 mol/L epithelium-intact subgroups. Conclusions: The corneal epithelium is a barrier to Mn2+, and the iris and lens septum might be another intraocular barrier to the permeation of Mn2+. An elevated Mn2+ concentration contributes to the increased permeation of Mn2+, higher MEMRI signal, and corneal toxicity. The enhancement of the visual pathway requires an effective Mn2+ concentration in the vitreous body. PMID:27453232

High-throughput screening of chemical effects on ...

EPA Pesticide Factsheets

Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2,060 chemical samples on steroidogenesis via HPLC-MS/MS quantification of 10 steroid hormones, including progestagens, glucocorticoids, androgens, and estrogens. The study employed a three stage screening strategy. The first stage established the maximum tolerated concentration (MTC; >70% viability) per sample. The second stage quantified changes in hormone levels at the MTC while the third stage performed concentration-response (CR) on a subset of samples. At all stages, cells were pre-stimulated with 10 µM forskolin for 48 h to induce steroidogenesis followed by chemical treatment for 48 h. Of the 2,060 chemical samples evaluated, 524 samples were selected for six-point CR screening, based in part on significantly altering at least 4 hormones at the MTC. CR screening identified 232 chemical samples with concentration-dependent effects on 17β-estradiol and/or testosterone, with 411 chemical samples showing an effect on at least one hormone across the steroidogenesis pathway. Clustering of the concentration-dependent chemical-mediated steroid hormone effects grouped chemical samples into five distinct profiles generally representing putative mechanisms of action, including CYP17A1 and HSD3B inhibition. A d

High-throughput screening of chemical effects on steroidogenesis using H295R human adrenocortical carcinoma cells

EPA Pesticide Factsheets

Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2060 chemical samples on steroidogenesis via high-performance liquid chromatography followed by tandem mass spectrometry quantification of 10 steroid hormones, including progestagens, glucocorticoids, androgens, and estrogens. The study employed a 3 stage screening strategy. The first stage established the maximum tolerated concentration (MTC; ? 70% viability) per sample. The second stage quantified changes in hormone levels at the MTC whereas the third stage performed concentration-response (CR) on a subset of samples. At all stages, cells were prestimulated with 10 00b5M forskolin for 48??h to induce steroidogenesis followed by chemical treatment for 48??h. Of the 2060 chemical samples evaluated, 524 samples were selected for 6-point CR screening, based in part on significantly altering at least 4 hormones at the MTC. CR screening identified 232 chemical samples with concentration-dependent effects on 1703b2-estradiol and/or testosterone, with 411 chemical samples showing an effect on at least one hormone across the steroidogenesis pathway. Clustering of the concentration-dependent chemical-mediated steroid hormone effects grouped chemical samples into 5 distinct profiles generally representing putative mec

The impact of climate change and emissions control on future ozone levels: Implications for human health.

PubMed

Stowell, Jennifer D; Kim, Young-Min; Gao, Yang; Fu, Joshua S; Chang, Howard H; Liu, Yang

2017-11-01

Overwhelming evidence has shown that, from the Industrial Revolution to the present, human activities influence ground-level ozone (O 3 ) concentrations. Past studies demonstrate links between O 3 exposure and health. However, knowledge gaps remain in our understanding concerning the impacts of climate change mitigation policies on O 3 concentrations and health. Using a hybrid downscaling approach, we evaluated the separate impact of climate change and emission control policies on O 3 levels and associated excess mortality in the US in the 2050s under two Representative Concentration Pathways (RCPs). We show that, by the 2050s, under RCP4.5, increased O 3 levels due to combined climate change and emission control policies, could contribute to an increase of approximately 50 premature deaths annually nationwide in the US. The biggest impact, however, is seen under RCP8.5, where rises in O 3 concentrations are expected to result in over 2,200 additional premature deaths annually. The largest increases in O 3 are seen in RCP8.5 in the Northeast, the Southeast, the Central, and the West regions of the US. Additionally, when O 3 increases are examined by climate change and emissions contributions separately, the benefits of emissions mitigation efforts may significantly outweigh the effects of climate change mitigation policies on O 3 -related mortality. Copyright © 2017 Elsevier Ltd. All rights reserved.

Microarray characterization of gene expression changes in blood during acute ethanol exposure

PubMed Central

2013-01-01

Background As part of the civil aviation safety program to define the adverse effects of ethanol on flying performance, we performed a DNA microarray analysis of human whole blood samples from a five-time point study of subjects administered ethanol orally, followed by breathalyzer analysis, to monitor blood alcohol concentration (BAC) to discover significant gene expression changes in response to the ethanol exposure. Methods Subjects were administered either orange juice or orange juice with ethanol. Blood samples were taken based on BAC and total RNA was isolated from PaxGene™ blood tubes. The amplified cDNA was used in microarray and quantitative real-time polymerase chain reaction (RT-qPCR) analyses to evaluate differential gene expression. Microarray data was analyzed in a pipeline fashion to summarize and normalize and the results evaluated for relative expression across time points with multiple methods. Candidate genes showing distinctive expression patterns in response to ethanol were clustered by pattern and further analyzed for related function, pathway membership and common transcription factor binding within and across clusters. RT-qPCR was used with representative genes to confirm relative transcript levels across time to those detected in microarrays. Results Microarray analysis of samples representing 0%, 0.04%, 0.08%, return to 0.04%, and 0.02% wt/vol BAC showed that changes in gene expression could be detected across the time course. The expression changes were verified by qRT-PCR. The candidate genes of interest (GOI) identified from the microarray analysis and clustered by expression pattern across the five BAC points showed seven coordinately expressed groups. Analysis showed function-based networks, shared transcription factor binding sites and signaling pathways for members of the clusters. These include hematological functions, innate immunity and inflammation functions, metabolic functions expected of ethanol metabolism, and pancreatic and hepatic function. Five of the seven clusters showed links to the p38 MAPK pathway. Conclusions The results of this study provide a first look at changing gene expression patterns in human blood during an acute rise in blood ethanol concentration and its depletion because of metabolism and excretion, and demonstrate that it is possible to detect changes in gene expression using total RNA isolated from whole blood. The analysis approach for this study serves as a workflow to investigate the biology linked to expression changes across a time course and from these changes, to identify target genes that could serve as biomarkers linked to pilot performance. PMID:23883607

What would it take to achieve the Paris temperature targets?

NASA Astrophysics Data System (ADS)

Sanderson, Benjamin M.; O'Neill, Brian C.; Tebaldi, Claudia

2016-07-01

The 2015 Paris Agreement aims to limit warming to 2 or 1.5°C above preindustrial level, although combined Intended Nationally Determined Contributions (INDCs) are likely insufficient to achieve these targets. We propose a set of idealized emission pathways consistent with the targets. If countries reduce emissions in line with their INDCs, the 2°C threshold could be avoided only if net zero greenhouse gas emissions (GHGEs) are achieved by 2085 and late century negative emissions are considerably in excess of those assumed in Representative Concentration Pathway (RCP) 2.6 (net -5 Gt CO2/yr, compared with -1.5 Gt CO2/yr in RCP2.6). More aggressive near-term reductions would allow 2°C to be avoided with less end-of-century carbon removal capacity. A 10% cut in GHGEs by 2030 (relative to 2015) could likely achieve 2°C with RCP2.6 level negative emissions. The 1.5°C target requires GHGEs to be reduced by almost a third by 2030 and net zero by 2050, while a 50 year overshoot of 1.5°C allows net zero GHGEs by 2060.

Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline

PubMed Central

Pulvino, Mary; Chen, Luojing; Oleksyn, David; Li, Jing; Compitello, George; Rossi, Randy; Spence, Stephen; Balakrishnan, Vijaya; Jordan, Craig; Poligone, Brian; Casulo, Carla; Burack, Richard; Shapiro, Joel L.; Bernstein, Steven; Friedberg, Jonathan W.; Deshaies, Raymond J.; Land, Hartmut; Zhao, Jiyong

2015-01-01

In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes. PMID:26142707

What would it take to achieve the Paris temperature targets?

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

Sanderson, Benjamin M.; O'Neill, Brian C.; Tebaldi, Claudia

Here, the 2015 Paris Agreement aims to limit warming to 2 or 1.5°C above preindustrial level, although combined Intended Nationally Determined Contributions (INDCs) are likely insufficient to achieve these targets. We propose a set of idealized emission pathways consistent with the targets. If countries reduce emissions in line with their INDCs, the 2°C threshold could be avoided only if net zero greenhouse gas emissions (GHGEs) are achieved by 2085 and late century negative emissions are considerably in excess of those assumed in Representative Concentration Pathway (RCP) 2.6 (net –5 Gt CO 2/yr, compared with –1.5 Gt CO 2/yr in RCP2.6).more » More aggressive near-term reductions would allow 2°C to be avoided with less end-of-century carbon removal capacity. A 10% cut in GHGEs by 2030 (relative to 2015) could likely achieve 2°C with RCP2.6 level negative emissions. The 1.5°C target requires GHGEs to be reduced by almost a third by 2030 and net zero by 2050, while a 50 year overshoot of 1.5°C allows net zero GHGEs by 2060.« less

What would it take to achieve the Paris temperature targets?

DOE PAGES

Sanderson, Benjamin M.; O'Neill, Brian C.; Tebaldi, Claudia

2016-06-27

Here, the 2015 Paris Agreement aims to limit warming to 2 or 1.5°C above preindustrial level, although combined Intended Nationally Determined Contributions (INDCs) are likely insufficient to achieve these targets. We propose a set of idealized emission pathways consistent with the targets. If countries reduce emissions in line with their INDCs, the 2°C threshold could be avoided only if net zero greenhouse gas emissions (GHGEs) are achieved by 2085 and late century negative emissions are considerably in excess of those assumed in Representative Concentration Pathway (RCP) 2.6 (net –5 Gt CO 2/yr, compared with –1.5 Gt CO 2/yr in RCP2.6).more » More aggressive near-term reductions would allow 2°C to be avoided with less end-of-century carbon removal capacity. A 10% cut in GHGEs by 2030 (relative to 2015) could likely achieve 2°C with RCP2.6 level negative emissions. The 1.5°C target requires GHGEs to be reduced by almost a third by 2030 and net zero by 2050, while a 50 year overshoot of 1.5°C allows net zero GHGEs by 2060.« less

Lyapunov exponents and phase diagrams reveal multi-factorial control over TRAIL-induced apoptosis

PubMed Central

Aldridge, Bree B; Gaudet, Suzanne; Lauffenburger, Douglas A; Sorger, Peter K

2011-01-01

Receptor-mediated apoptosis proceeds via two pathways: one requiring only a cascade of initiator and effector caspases (type I behavior) and the second requiring an initiator–effector caspase cascade and mitochondrial outer membrane permeabilization (type II behavior). Here, we investigate factors controlling type I versus II phenotypes by performing Lyapunov exponent analysis of an ODE-based model of cell death. The resulting phase diagrams predict that the ratio of XIAP to pro-caspase-3 concentrations plays a key regulatory role: type I behavior predominates when the ratio is low and type II behavior when the ratio is high. Cell-to-cell variability in phenotype is observed when the ratio is close to the type I versus II boundary. By positioning multiple tumor cell lines on the phase diagram we confirm these predictions. We also extend phase space analysis to mutations affecting the rate of caspase-3 ubiquitylation by XIAP, predicting and showing that such mutations abolish all-or-none control over activation of effector caspases. Thus, phase diagrams derived from Lyapunov exponent analysis represent a means to study multi-factorial control over a complex biochemical pathway. PMID:22108795

Ascorbate degradation in tomato leads to accumulation of oxalate, threonate and oxalyl threonate.

PubMed

Truffault, Vincent; Fry, Stephen C; Stevens, Rebecca G; Gautier, Hélène

2017-03-01

Ascorbate content in plants is controlled by its synthesis from carbohydrates, recycling of the oxidized forms and degradation. Of these pathways, ascorbate degradation is the least studied and represents a lack of knowledge that could impair improvement of ascorbate content in fruits and vegetables as degradation is non-reversible and leads to a depletion of the ascorbate pool. The present study revealed the nature of degradation products using [ 14 C]ascorbate labelling in tomato, a model plant for fleshy fruits; oxalate and threonate are accumulated in leaves, as is oxalyl threonate. Carboxypentonates coming from diketogulonate degradation were detected in relatively insoluble (cell wall-rich) leaf material. No [ 14 C]tartaric acid was found in tomato leaves. Ascorbate degradation was stimulated by darkness, and the degradation rate was evaluated at 63% of the ascorbate pool per day, a percentage that was constant and independent of the initial ascorbate or dehydroascorbic acid concentration over periods of 24 h or more. Furthermore, degradation could be partially affected by the ascorbate recycling pathway, as lines under-expressing monodehydroascorbate reductase showed a slight decrease in degradation product accumulation. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

The impact of drought on ozone dry deposition over eastern Texas

NASA Astrophysics Data System (ADS)

Huang, Ling; McDonald-Buller, Elena C.; McGaughey, Gary; Kimura, Yosuke; Allen, David T.

2016-02-01

Dry deposition represents a critical pathway through which ground-level ozone is removed from the atmosphere. Understanding the effects of drought on ozone dry deposition is essential for air quality modeling and management in regions of the world with recurring droughts. This work applied the widely used Zhang dry deposition algorithm to examine seasonal and interannual changes in estimated ozone dry deposition velocities and component resistances/conductances over eastern Texas during years with drought (2006 and 2011) as well as a year with slightly cooler temperatures and above average rainfall (2007). Simulated area-averaged daytime ozone dry deposition velocities ranged between 0.26 and 0.47 cm/s. Seasonal patterns reflected the combined seasonal variations in non-stomatal and stomatal deposition pathways. Daytime ozone dry deposition velocities during the growing season were consistently larger during 2007 compared to 2006 and 2011. These differences were associated with differences in stomatal conductances and were most pronounced in forested areas. Reductions in stomatal conductances under drought conditions were highly sensitive to increases in vapor pressure deficit and warmer temperatures in Zhang's algorithm. Reductions in daytime ozone deposition velocities and deposition mass during drought years were associated with estimates of higher surface ozone concentrations.

Investigation of Future Thermal Comforts in a Tropical Megacity Using Coupling of Energy Balance Model and Large Eddy Simulation

NASA Astrophysics Data System (ADS)

Sueishi, T.; Yucel, M.; Ashie, Y.; Varquez, A. C. G.; Inagaki, A.; Darmanto, N. S.; Nakayoshi, M.; Kanda, M.

2017-12-01

Recently, temperature in urban areas continue to rise as an effect of climate change and urbanization. Specifically, Asian megacities are projected to expand rapidly resulting to serious in the future atmospheric environment. Thus, detailed analysis of urban meteorology for Asian megacities is needed to prescribe optimum against these negative climate modifications. A building-resolving large eddy simulation (LES) coupled with an energy balance model is conducted for a highly urbanized district in central Jakarta on typical daytime hours. Five cases were considered; case 1 utilizes present urban scenario and four cases representing different urban configurations in 2050. The future configurations were based on representative concentration pathways (RCP) and shared socio-economic pathways (SSP). Building height maps and land use maps of simulation domains are shown in the attached figure (top). Case 1 3 focuses on the difference of future scenarios. Case 1 represents current climatic and urban conditions, case 2 and 3 was an idealized future represented by RCP2.6/SSP1 and RCP8.5/SSP3, respectively. More complex urban morphology was applied in case 4, vegetation and building area were changed in case 5. Meteorological inputs and anthropogenic heat emission (AHE) were calculated using Weather Research and Forecasting (WRF) model (Varquez et al [2017]). Sensible and latent heat flux from surfaces were calculated using an energy balance model (Ashie et al [2011]), with considers multi-reflection, evapotranspiration and evaporation. The results of energy balance model (shown in the middle line of figure), in addition to WRF outputs, were used as input into the PArallelized LES Model (PALM) (Raasch et al [2001]). From standard new effective temperature (SET*) which included the effects of temperature, wind speed, humidity and radiation, thermal comfort in urban area was evaluated. SET* contours at 1 m height are shown in the bottom line of the figure. Extreme climate change increase average SET* as expected; however, construction of dense high-rise buildings (case 2) can minimize this effect due to increased shading throughout the district. Acknowledgement: This research was supported by the Environment Research and Technology Development Fund (S-14) of the Ministry of the Environment, Japan.

Detergent sclerosants at sub-lytic concentrations induce endothelial cell apoptosis through a caspase dependent pathway.

PubMed

Cooley-Andrade, Osvaldo; Cheung, Kelvin; Chew, An-Ning; Connor, David Ewan; Parsi, Kurosh

2016-07-01

To investigate the apoptotic effects of detergent sclerosants sodium tetradecylsulphate (STS) and polidocanol (POL) on endothelial cells at sub-lytic concentrations. Human umbilical vein endothelial cells (HUVECs) were isolated and labelled with antibodies to assess for apoptosis and examined with confocal microscopy and flow cytometry. Isolated HUVECs viability was assessed using propidium iodide staining. Early apoptosis was determined by increased phosphatidylserine exposure by lactadherin binding. Caspase 3, 8, 9 and Bax activation as well as inhibitory assays with Pan Caspase (Z-VAD-FMK) and Bax (BI-6C9) were assessed to identify apoptotic pathways. Porimin activation was used to assess cell membrane permeability. Cell lysis reached almost 100 % with STS at 0.3 % and with POL at 0.6 %. Apoptosis was seen with both STS and POL at concentrations ranging from 0.075 to 0.15 %. PS exposure increased with both STS and POL and exhibited a dose-dependent trend. Active Caspase 3, 8 and 9 but not Bax were increased in HUVECs stimulated with low concentrations of both STS and POL. Inhibitory assays demonstrated Caspase 3, 8, 9 inhibition at low concentrations (0.075 to 0.6 %) with both STS and POL. Both agents increased the activation of porimin at all concentrations. Both sclerosants induced endothelial cell (EC) apoptosis at sub-lytic concentrations through a caspase-dependant pathway. Both agents induced EC oncosis.

Monitoring well utility in a heterogeneous DNAPL source zone area: Insights from proximal multilevel sampler wells and sampling capture-zone modelling

NASA Astrophysics Data System (ADS)

McMillan, Lindsay A.; Rivett, Michael O.; Wealthall, Gary P.; Zeeb, Peter; Dumble, Peter

2018-03-01

Groundwater-quality assessment at contaminated sites often involves the use of short-screen (1.5 to 3 m) monitoring wells. However, even over these intervals considerable variation may occur in contaminant concentrations in groundwater adjacent to the well screen. This is especially true in heterogeneous dense non-aqueous phase liquid (DNAPL) source zones, where cm-scale contamination variability may call into question the effectiveness of monitoring wells to deliver representative data. The utility of monitoring wells in such settings is evaluated by reference to high-resolution multilevel sampler (MLS) wells located proximally to short-screen wells, together with sampling capture-zone modelling to explore controls upon well sample provenance and sensitivity to monitoring protocols. Field data are analysed from the highly instrumented SABRE research site that contained an old trichloroethene source zone within a shallow alluvial aquifer at a UK industrial facility. With increased purging, monitoring-well samples tend to a flow-weighted average concentration but may exhibit sensitivity to the implemented protocol and degree of purging. Formation heterogeneity adjacent to the well-screen particularly, alongside pump-intake position and water level, influence this sensitivity. Purging of low volumes is vulnerable to poor reproducibility arising from concentration variability predicted over the initial 1 to 2 screen volumes purged. Marked heterogeneity may also result in limited long-term sample concentration stabilization. Development of bespoke monitoring protocols, that consider screen volumes purged, alongside water-quality indicator parameter stabilization, is recommended to validate and reduce uncertainty when interpreting monitoring-well data within source zone areas. Generalised recommendations on monitoring well based protocols are also developed. A key monitoring well utility is their proportionately greater sample draw from permeable horizons constituting a significant contaminant flux pathway and hence representative fraction of source mass flux. Acquisition of complementary, high-resolution, site monitoring data, however, vitally underpins optimal interpretation of monitoring-well datasets and appropriate advancement of a site conceptual model and remedial implementation.

A mathematical modelling approach to assessing the reliability of biomarkers of glutathione metabolism.

PubMed

Geenen, Suzanne; du Preez, Franco B; Reed, Michael; Nijhout, H Frederik; Kenna, J Gerry; Wilson, Ian D; Westerhoff, Hans V; Snoep, Jacky L

2012-07-16

One of the main pathways for the detoxification of reactive metabolites in the liver involves glutathione conjugation. Metabolic profiling studies have shown paradoxical responses in glutathione-related biochemical pathways. One of these is the increase in 5-oxoproline and ophthalmic acid concentrations with increased dosage of paracetamol. Experimental studies have thus far failed to resolve these paradoxes and the robustness of how these proposed biomarkers correlate with liver glutathione levels has been questioned. To better understand how these biomarkers behave in the glutathione system a kinetic model of this pathway was made. By using metabolic control analysis and by simulating biomarker levels under a variety of conditions, we found that 5-oxoproline and ophthalmic acid concentrations may not only depend on the glutathione but also on the methionine status of the cell. We show that neither of the two potential biomarkers are reliable on their own since they need additional information about the methionine status of the system to relate them uniquely to intracellular glutathione concentration. However, when both biomarkers are measured simultaneously a direct inference of the glutathione concentration can be made, irrespective of the methionine concentration in the system. Copyright © 2011 Elsevier B.V. All rights reserved.

Density functional theory studies on the solvent effects in Al(H2O)63+ water-exchange reactions: the number and arrangement of outer-sphere water molecules.

PubMed

Liu, Li; Zhang, Jing; Dong, Shaonan; Zhang, Fuping; Wang, Ye; Bi, Shuping

2018-03-07

Density functional theory (DFT) calculations combined with cluster models are performed at the B3LYP/6-311+G(d,p) level for investigating the solvent effects in Al(H 2 O) 6 3+ water-exchange reactions. A "One-by-one" method is proposed to obtain the most representative number and arrangement of explicit H 2 Os in the second hydration sphere. First, all the possible ways to locate one explicit H 2 O in second sphere (N m ' = 1) based on the gas phase structure (N m ' = 0) are examined, and the optimal pathway (with the lowest energy barrier) for N m ' = 1 is determined. Next, more explicit H 2 Os are added one by one until the inner-sphere is fully hydrogen bonded. Finally, the optimal pathways with N m ' = 0-7 are obtained. The structural and energetic parameters as well as the lifetimes of the transition states are compared with the results obtained with the "Independent-minimum" method and the "Independent-average" method, and all three methods show that the pathway with N m ' = 6 may be representative. Our results give a new idea for finding the representative pathway for water-exchange reactions in other hydrated metal ion systems.

Teaching resources. Model of the TIR1 pathway for auxin-mediated gene expression.

PubMed

Laskowski, Marta

2006-02-14

Auxin mediates numerous plant responses, some of which have been shown to require transcriptional regulation. One auxin response pathway, which depends on the relief of transcriptional repression, is mediated by TIR1 (transport inhibitor response protein 1). TIR1 is an auxin receptor and also a subunit of an SCF-type ubiquitin ligase. In the presence of a low concentration of auxin in the nucleus, members of the Aux/IAA family of transcriptional repressors bind to ARF proteins and inhibit the transcription of specific auxin response genes. Increased nuclear concentrations of auxin promote auxin binding to TIR1, causing the Aux/IAA proteins to associate with TIR1 and leading to their degradation by a proteasome-mediated pathway. This decreases the concentration of Aux/IAA proteins in the nucleus and thereby enables the expression of certain auxin response genes.

Controlling the Maillard reaction by reactant encapsulation: sodium chloride in cookies.

PubMed

Fiore, Alberto; Troise, Antonio Dario; Ataç Mogol, Burçe; Roullier, Victor; Gourdon, Anthony; El Mafadi Jian, Samira; Hamzalioğlu, Berat Aytül; Gökmen, Vural; Fogliano, Vincenzo

2012-10-31

Formation of Maillard reaction products (MRPs) including 5-hydroxymethylfurfural (HMF) and acrylamide has been an intensive area of research in recent decades. The presence of reactants such as sodium chloride may influence the Maillard reaction (MR) pathways through the dehydration of various key intermediates. The aim of this work was to test the potential of ingredient encapsulation to mitigate the MR by investigating the case of sodium chloride encapsulation on the HMF formation in cookies. Thirteen cookies were prepared with recipes containing free or encapsulated NaCl. Increasing NaCl concentration from 0 to 0.65% increases HMF concentration up to 75%, whereas in the presence of encapsulated NaCl the reduction of HMF varied from 18 to 61% due to the inhibition of sucrose pyrolytic decomposition and the fructofuranosyl cation formation. Data demonstrated that the more heat-resistant the lipid-based coating was, the more pronounced the reduction of HMF formation. The results showed that encapsulation represents a useful approach to prevent the formation of potentially harmful compounds in thermally processed foods.

Exploration of reaction mechanisms of anthocyanin degradation in a roselle extract through kinetic studies on formulated model media.

PubMed

Sinela, André Mundombe; Mertz, Christian; Achir, Nawel; Rawat, Nadirah; Vidot, Kevin; Fulcrand, Hélène; Dornier, Manuel

2017-11-15

Effect of oxygen, polyphenols and metals was studied on degradation of delphinidin and cyanidin 3-O-sambubioside of Hibiscus sabdariffa L. Experiments were conducted on aqueous extracts degassed or not, an isolated polyphenolic fraction and extract-like model media, allowing the impact of the different constituents to be decoupled. All solutions were stored for 2months at 37°C. Anthocyanin and their degradation compounds were regularly HPLC-DAD-analyzed. Oxygen concentration did not impact the anthocyanin degradation rate. Degradation rate of delphinidin 3-O-sambubioside increased 6-fold when mixed with iron from 1 to 13mg.kg -1 but decreased with chlorogenic and gallic acids. Degradation rate of cyanidin 3-O-sambubioside was not affected by polyphenols but increased by 3-fold with increasing iron concentration with a concomitant yield decrease of scission product, protocatechuic acid. Two pathways of degradation of anthocyanins were identified: a major metal-catalyzed oxidation followed by condensation and a minor scission which represents about 10% of degraded anthocyanins. Copyright © 2017 Elsevier Ltd. All rights reserved.

Free Radical Chemistry of Disinfection Byproducts. 3. Degradation Mechanisms of Chloronitromethane, Bromonitromethane and Dichloronitromethane

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

Bruce J. Mincher; Stephen P. Mezyk; William J. Cooper

2010-01-01

Halonitromethanes (HNMs) are byproducts formed through ozonation and chlorine/ chloramine disinfection processes in drinking waters that contain dissolved organic matter and bromide ions. These species occur at low concentration, but have been determined to have high cytotoxicity and mutagenicity and therefore may represent a human health hazard. In this study, we have investigated the chemistry involved in the mineralization of HNMs to non-hazardous inorganic products through the application of advanced oxidation and reduction processes. We have combined measured absolute reaction rate constants for the reactions of chloronitromethane, bromonitromethane and dichloronitromethane with the hydroxyl radical and the hydrated electron with amore » kinetic computer model in an attempt to elucidate the reaction pathways of these HNMs. The results are compared to measurements of stable products resulting from steady-state 60Co y-irradiations of the same compounds. The model predicted the decomposition of the parent compounds and ingrowth of chloride and bromide ions with excellent accuracy, but the prediction of the total nitrate ion concentration was slightly in error, reflecting the complexity of nitrogen oxide species reactions in irradiated solution.« less

Lake Michigan offshore ecosystem structure and food web changes from 1987 to 2008

USGS Publications Warehouse

Rogers, Mark W.; Bunnell, David B.; Madenjian, Charles P.; Warner, David M.

2014-01-01

Ecosystems undergo dynamic changes owing to species invasions, fisheries management decisions, landscape modifications, and nutrient inputs. At Lake Michigan, new invaders (e.g., dreissenid mussels (Dreissena spp.), spiny water flea (Bythotrephes longimanus), round goby (Neogobius melanostomus)) have proliferated and altered energy transfer pathways, while nutrient concentrations and stocking rates to support fisheries have changed. We developed an ecosystem model to describe food web structure in 1987 and ran simulations through 2008 to evaluate changes in biomass of functional groups, predator consumption, and effects of recently invading species. Keystone functional groups from 1987 were identified as Mysis, burbot (Lota lota), phytoplankton, alewife (Alosa pseudoharengus), nonpredatory cladocerans, and Chinook salmon (Oncorhynchus tshawytscha). Simulations predicted biomass reductions across all trophic levels and predicted biomasses fit observed trends for most functional groups. The effects of invasive species (e.g., dreissenid grazing) increased across simulation years, but were difficult to disentangle from other changes (e.g., declining offshore nutrient concentrations). In total, our model effectively represented recent changes to the Lake Michigan ecosystem and provides an ecosystem-based tool for exploring future resource management scenarios.

Lipidomics Biomarkers of Diet-Induced Hyperlipidemia and Its Treatment with Poria cocos.

PubMed

Miao, Hua; Zhao, Yu-Hui; Vaziri, Nosratola D; Tang, Dan-Dan; Chen, Hua; Chen, Han; Khazaeli, Mahyar; Tarbiat-Boldaji, Mehrdokht; Hatami, Leili; Zhao, Ying-Yong

2016-02-03

Hyperlipidemia is a major cause of atherosclerotic cardiovascular disease. Poria cocos (PC) is a medicinal product widely used in Asia. This study was undertaken to define the alterations of lipid metabolites in rats fed a high-fat diet to induce hyperlipidemia and to explore efficacy and mechanism of action of PC in the treatment of diet-induced hyperlipidemia. Plasma samples were then analyzed using UPLC-HDMS. The untreated rats fed a high-fat diet exhibited significant elevation of plasma triglyceride and total and low-density lipoprotein (LDL) cholesterol concentrations. This was associated with marked changes in plasma concentrations of seven fatty acids (palmitic acid, hexadecenoic acid, hexanoylcarnitine, tetracosahexaenoic acid, cervonoyl ethanolamide, 3-hydroxytetradecanoic acid, and 5,6-DHET) and five sterols [cholesterol ester (18:2), cholesterol, hydroxytestosterone, 19-hydroxydeoxycorticosterone, and cholic acid]. These changes represented disorders of biosynthesis and metabolism of the primary bile acids, steroids, and fatty acids and mitochondrial fatty acid elongation pathways in diet-induced hyperlipidemia. Treatment with PC resulted in significant improvements of hyperlipidemia and the associated abnormalities of the lipid metabolites.

Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent.

PubMed

Ogunniyi, Abiodun D; Khazandi, Manouchehr; Stevens, Andrew J; Sims, Sarah K; Page, Stephen W; Garg, Sanjay; Venter, Henrietta; Powell, Andrew; White, Karen; Petrovski, Kiro R; Laven-Law, Geraldine; Tótoli, Eliane G; Salgado, Hérida R; Pi, Hongfei; Coombs, Geoffrey W; Shinabarger, Dean L; Turnidge, John D; Paton, James C; McCluskey, Adam; Trott, Darren J

2017-01-01

The spread of multidrug resistance among bacterial pathogens poses a serious threat to public health worldwide. Recent approaches towards combating antimicrobial resistance include repurposing old compounds with known safety and development pathways as new antibacterial classes with novel mechanisms of action. Here we show that an analog of the anticoccidial drug robenidine (4,6-bis(2-((E)-4-methylbenzylidene)hydrazinyl)pyrimidin-2-amine; NCL195) displays potent bactericidal activity against Streptococcus pneumoniae and Staphylococcus aureus by disrupting the cell membrane potential. NCL195 was less cytotoxic to mammalian cell lines than the parent compound, showed low metabolic degradation rates by human and mouse liver microsomes, and exhibited high plasma concentration and low plasma clearance rates in mice. NCL195 was bactericidal against Acinetobacter spp and Neisseria meningitidis and also demonstrated potent activity against A. baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. in the presence of sub-inhibitory concentrations of ethylenediaminetetraacetic acid (EDTA) and polymyxin B. These findings demonstrate that NCL195 represents a new chemical lead for further medicinal chemistry and pharmaceutical development to enhance potency, solubility and selectivity against serious bacterial pathogens.

Modeling of the U1 snRNP assembly pathway in alternative splicing in human cells using Petri nets.

PubMed

Kielbassa, J; Bortfeldt, R; Schuster, S; Koch, I

2009-02-01

The investigation of spliceosomal processes is currently a topic of intense research in molecular biology. In the molecular mechanism of alternative splicing, a multi-protein-RNA complex - the spliceosome - plays a crucial role. To understand the biological processes of alternative splicing, it is essential to comprehend the biogenesis of the spliceosome. In this paper, we propose the first abstract model of the regulatory assembly pathway of the human spliceosomal subunit U1. Using Petri nets, we describe its highly ordered assembly that takes place in a stepwise manner. Petri net theory represents a mathematical formalism to model and analyze systems with concurrent processes at different abstraction levels with the possibility to combine them into a uniform description language. There exist many approaches to determine static and dynamic properties of Petri nets, which can be applied to analyze biochemical systems. In addition, Petri net tools usually provide intuitively understandable graphical network representations, which facilitate the dialog between experimentalists and theoreticians. Our Petri net model covers binding, transport, signaling, and covalent modification processes. Through the computation of structural and behavioral Petri net properties and their interpretation in biological terms, we validate our model and use it to get a better understanding of the complex processes of the assembly pathway. We can explain the basic network behavior, using minimal T-invariants which represent special pathways through the network. We find linear as well as cyclic pathways. We determine the P-invariants that represent conserved moieties in a network. The simulation of the net demonstrates the importance of the stability of complexes during the maturation pathway. We can show that complexes that dissociate too fast, hinder the formation of the complete U1 snRNP.

Methane seepage along the Hikurangi Margin offshore New Zealand: 6 years of multidisciplinary studies

NASA Astrophysics Data System (ADS)

Greinert, J.; Bialas, J.; Klaucke, I.; Crutchley, G.; Dale, A.; Linke, P.; Sommer, S.; Bowden, D.; Rowden, A.; de Haas, H.; de Stigter, H.; Faure, K.

2012-12-01

Detailed studies in 2006, 2007 and 2011 along the east coast of New Zealand's North Island highlighted the close link of sub-bottom fluid pathways and seafloor expressions of methane seepage such as clam fields, carbonate build-ups, tubeworms, bacterial mats and methane release (Marine Geology 272). Prior to our studies, only accidental observations of hydroacoustic anomalies, recoveries of calyptogena shells and methane-derived carbonate chimneys indicated active seepage. Wide areas of the sub-seafloor show BSR structures, gas migration pathways, gas chimneys and blanking zones, which are closely linked to actual seep sites. Sidescan surveys showed four prominent seep areas at Omakere Ridge in 1120m water depth, three of them perfectly matching the shapes and locations of faults seen in high resolution 3D-seismic surveys. The fourth seep, Bear's Paw, on its western side represents an old seep which developed into a cold water coral habitat. At the actively seeping eastern part, gas hydrates could be retrieved and bubble release was observed hydroacoustically and confirmed by high dissolved methane values (380nM). No strong microbial oxidation effects could be found in δ13C values plotting along a mixing curve between pure seep (-70 ‰PDB) and atmospheric methane (-47 ‰PDB). Lander deployments show a tide-influenced gas discharge with sometimes eruptive bubble release with possible plume development transporting methane-charged water higher up into the water column. Rock Garden, with just above 600m water depth at its top outside the gas hydrate stability zone, hosts two main seep areas. ROV observations at Faure Site document eruptive releases of free gas from decimeter-wide craters at the seafloor. Flux estimates show peak releases of 420ml/min with bubbles up to 9mm in diameter. Concentrations of dissolved methane reach up to 3500nM close to the bottom, but higher concentrations are limited to below 400m of water depth; here, methane is transported towards the sea surface or even into the mixed layer. Faure site is just at the limit of the gas hydrate phase boundary, where relatively high-permeable sediment layers act as preferred pathway for fluids from below a shallow BSR. Seismic studies at the seep site LM-3 show gas chimneys as main fluid migration pathways in the sub-seafloor. Opouawe Bank has the densest occurrence of seeps. In water depths between 800 and 1200m, seeps of different ages and appearances exist in close proximity. North and South Tower resemble old structures with massive aragonitic carbonate blocks paving the seafloor, tube worms, bacterial mats, clams and beds of ampharetid polychaetes. These patchy polychaetes habitats have a very high total oxygen uptake of up to 83.7 mmol m^-2 day^-1) feeding from organic carbon generated via aerobic methane oxidation. Hydroacoustic flares at the 1200m deep Towers rise more than 600m into the water column above, which the dissolved gas concentrations quickly drop to background. In contrast, the isolated Takahe seep only 2 miles away shows no carbonates at the seafloor surface despite a well developed acoustic gas chimney and surface-near gas hydrates. This seep represents a much younger seep which highlights the great spatial and temporal variability in seep occurrences and activity, which can also be found in fossil seeps on land.

Sum over Histories Representation for Kinetic Sensitivity Analysis: How Chemical Pathways Change When Reaction Rate Coefficients Are Varied

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

Bai, Shirong; Davis, Michael J.; Skodje, Rex T.

2015-11-12

The sensitivity of kinetic observables is analyzed using a newly developed sum over histories representation of chemical kinetics. In the sum over histories representation, the concentrations of the chemical species are decomposed into the sum of probabilities for chemical pathways that follow molecules from reactants to products or intermediates. Unlike static flux methods for reaction path analysis, the sum over histories approach includes the explicit time dependence of the pathway probabilities. Using the sum over histories representation, the sensitivity of an observable with respect to a kinetic parameter such as a rate coefficient is then analyzed in terms of howmore » that parameter affects the chemical pathway probabilities. The method is illustrated for species concentration target functions in H-2 combustion where the rate coefficients are allowed to vary over their associated uncertainty ranges. It is found that large sensitivities are often associated with rate limiting steps along important chemical pathways or by reactions that control the branching of reactive flux« less

Arginine deiminase pathway enzymes: evolutionary history in metamonads and other eukaryotes.

PubMed

Novák, Lukáš; Zubáčová, Zuzana; Karnkowska, Anna; Kolisko, Martin; Hroudová, Miluše; Stairs, Courtney W; Simpson, Alastair G B; Keeling, Patrick J; Roger, Andrew J; Čepička, Ivan; Hampl, Vladimír

2016-10-06

Multiple prokaryotic lineages use the arginine deiminase (ADI) pathway for anaerobic energy production by arginine degradation. The distribution of this pathway among eukaryotes has been thought to be very limited, with only two specialized groups living in low oxygen environments (Parabasalia and Diplomonadida) known to possess the complete set of all three enzymes. We have performed an extensive survey of available sequence data in order to map the distribution of these enzymes among eukaryotes and to reconstruct their phylogenies. We have found genes for the complete pathway in almost all examined representatives of Metamonada, the anaerobic protist group that includes parabasalids and diplomonads. Phylogenetic analyses indicate the presence of the complete pathway in the last common ancestor of metamonads and heterologous transformation experiments suggest its cytosolic localization in the metamonad ancestor. Outside Metamonada, the complete pathway occurs rarely, nevertheless, it was found in representatives of most major eukaryotic clades. Phylogenetic relationships of complete pathways are consistent with the presence of the Archaea-derived ADI pathway in the last common ancestor of all eukaryotes, although other evolutionary scenarios remain possible. The presence of the incomplete set of enzymes is relatively common among eukaryotes and it may be related to the fact that these enzymes are involved in other cellular processes, such as the ornithine-urea cycle. Single protein phylogenies suggest that the evolutionary history of all three enzymes has been shaped by frequent gene losses and horizontal transfers, which may sometimes be connected with their diverse roles in cellular metabolism.

Involvement of S100A8/A9-TLR4-NLRP3 Inflammasome Pathway in Contrast-Induced Acute Kidney Injury.

PubMed

Tan, Xuexian; Zheng, Xiaohe; Huang, Zena; Lin, Jiaqiong; Xie, Chuli; Lin, Yan

2017-01-01

Contrast-induced acute kidney injury (CIAKI) is a common cause of hospital-acquired acute kidney injury (AKI). S100A8/A9-TLR4-NLRP3 inflammasome pathway triggers inflammation, apoptosis and tissue injury in several AKI models. Nevertheless, the underlying mechanism of S100A8/A9-TLR4-NLRP3 inflammasome pathway in CIKAI is not clear. We aimed to investigate the possible role of S100A8/A9-TLR4-NLRP3 inflammasome in the pathophysiology of CIAKI. We treated male rats and NRK-52E cells by iopromide to establish in vivo and in vitro models of CIAKI. We collected serum and urine samples to detect renal function. We obtained kidney tissue for histological analysis and detection of protein concentration. We used inhibitor of TLR4 and NLRP3-siRNA to further testify their role in CIAKI in NRK-52E cells. Iopromide caused elevation of SCr, BUN and NGAL level, decrease of endogenous creatinine clearance, morphological injury and tubular apoptosis, enhanced IL-1β and IL-18 expression, and increased expression of S100A8/A9, TLR4 and NLRP3 inflammsome. In NRK-52E cells, iopromide caused enhanced apoptotic rates and ROS generation, which could be ameliorated by inhibitor of TLR4 and NLRP3-siRNA. Moreover, inhibition of TLR4 dampened NLRP3 expression. S100A8/A9-TLR4-NLRP3 inflammasome pathway represented a key mechanism of CI-AKI, which provided a potential therapeutic target. © 2017 The Author(s). Published by S. Karger AG, Basel.

WNT Inhibitory Activity of Malus Pumila miller cv Annurca and Malus domestica cv Limoncella Apple Extracts on Human Colon-Rectal Cells Carrying Familial Adenomatous Polyposis Mutations.

PubMed

Riccio, Gennaro; Maisto, Maria; Bottone, Sara; Badolati, Nadia; Rossi, Giovanni Battista; Tenore, Gian Carlo; Stornaiuolo, Mariano; Novellino, Ettore

2017-11-18

Inhibitors of the Wingless-related Integration site (WNT)/β-catenin pathway have recently been under consideration as potential chemopreventive agents against Familial Adenomatous Polyposis (FAP). This autosomal-dominant syndrome is caused by germline mutations in the gene coding for the protein APC and leads to hyperactivation of the WNT/β-catenin signaling pathway, uncontrolled intestinal cell proliferation and formation of adenocarcinomas. The aim of the present work was to: (i) test, on in vitro cultures of cells carrying FAP mutations and on ex vivo biopsies of FAP patients, the WNT inhibitory activity of extracts from two common southern Italian apples, Malus pumila Miller cv. 'Annurca' and Malus domestica cv 'Limoncella'; (ii) identify the mechanisms underpinning their activities and; (iii) evaluate their potency upon gastrointestinal digestion. We here show that both Annurca and Limoncella apple extracts act as WNT inhibitors, mostly thanks to their polyphenolic contents. They inhibit the pathway in colon cells carrying FAP mutations with active dilutions falling in ranges close to consumer-relevant concentrations. Food-grade manufacturing of apple extracts increases their WNT inhibitory activity as result of the conversion of quercetin glycosides into the aglycone quercetin, a potent WNT inhibitor absent in the fresh fruit extract. However, in vitro simulated gastrointestinal digestion severely affected WNT inhibitory activity of apple extracts, as result of a loss of polyphenols. In conclusion, our results show that apple extracts inhibit the WNT pathway in colon cells carrying FAP mutations and represent a potential nutraceutical alternative for the treatment of this pathology. Enteric coating is advisable to preserve the activity of the extracts in the colon-rectal section of the digestive tract.

Imaging Preferential Flow Pathways of Contaminants from Passive Acid Mine Drainage Mitigation Sites Using Electrical Resistivity

NASA Astrophysics Data System (ADS)

Kelley, N.; Mount, G.; Terry, N.; Herndon, E.; Singer, D. M.

2017-12-01

The Critical Zone represents the surficial and shallow layer of rock, air, water, and soil where most interactions between living organisms and the Earth occur. Acid mine drainage (AMD) resulting from coal extraction can influence both biological and geochemical processes across this zone. Conservative estimates suggest that more than 300 million gallons of AMD are released daily, making this acidic solution of water and contaminants a common issue in areas with legacy or current coal extraction. Electrical resistivity imaging (ERI) provides a rapid and minimally invasive method to identify and monitor contaminant pathways from AMD remediation systems in the subsurface of the Critical Zone. The technique yields spatially continuous data of subsurface resistivity that can be inverted to determine electrical conductivity as a function of depth. Since elevated concentrations of heavy metals can directly influence soil conductivity, ERI data can be used to trace the flow pathways or perhaps unknown mine conduits and transport of heavy metals through the subsurface near acid mine drainage sources. This study aims to examine preferential contaminant migration from those sources through substrate pores, fractures, and shallow mine workings in the near subsurface surrounding AMD sites in eastern Ohio and western Pennsylvania. We utilize time lapse ERI measures during different hydrologic conditions to better understand the variability of preferential flow pathways in relation to changes in stage and discharge within the remediation systems. To confirm ERI findings, and provide constraint to geochemical reactions occurring in the shallow subsurface, we conducted Inductively Coupled Plasma (ICP) spectrometry analysis of groundwater samples from boreholes along the survey transects. Through these combined methods, we can provide insight into the ability of engineered systems to contain and isolate metals in passive acid mine drainage treatment systems.

WNT Inhibitory Activity of Malus Pumila miller cv Annurca and Malus domestica cv Limoncella Apple Extracts on Human Colon-Rectal Cells Carrying Familial Adenomatous Polyposis Mutations

PubMed Central

Maisto, Maria; Bottone, Sara; Badolati, Nadia; Rossi, Giovanni Battista; Novellino, Ettore

2017-01-01

Inhibitors of the Wingless-related Integration site (WNT)/β-catenin pathway have recently been under consideration as potential chemopreventive agents against Familial Adenomatous Polyposis (FAP). This autosomal-dominant syndrome is caused by germline mutations in the gene coding for the protein APC and leads to hyperactivation of the WNT/β-catenin signaling pathway, uncontrolled intestinal cell proliferation and formation of adenocarcinomas. The aim of the present work was to: (i) test, on in vitro cultures of cells carrying FAP mutations and on ex vivo biopsies of FAP patients, the WNT inhibitory activity of extracts from two common southern Italian apples, Malus pumila Miller cv. ‘Annurca’ and Malus domestica cv ‘Limoncella’; (ii) identify the mechanisms underpinning their activities and; (iii) evaluate their potency upon gastrointestinal digestion. We here show that both Annurca and Limoncella apple extracts act as WNT inhibitors, mostly thanks to their polyphenolic contents. They inhibit the pathway in colon cells carrying FAP mutations with active dilutions falling in ranges close to consumer-relevant concentrations. Food-grade manufacturing of apple extracts increases their WNT inhibitory activity as result of the conversion of quercetin glycosides into the aglycone quercetin, a potent WNT inhibitor absent in the fresh fruit extract. However, in vitro simulated gastrointestinal digestion severely affected WNT inhibitory activity of apple extracts, as result of a loss of polyphenols. In conclusion, our results show that apple extracts inhibit the WNT pathway in colon cells carrying FAP mutations and represent a potential nutraceutical alternative for the treatment of this pathology. Enteric coating is advisable to preserve the activity of the extracts in the colon-rectal section of the digestive tract. PMID:29156563

Genome Sequence Analysis of the Naphthenic Acid Degrading and Metal Resistant Bacterium Cupriavidus gilardii CR3

PubMed Central

Xiao, Jingfa; Hao, Lirui; Crowley, David E.; Zhang, Zhewen; Yu, Jun; Huang, Ning; Huo, Mingxin; Wu, Jiayan

2015-01-01

Cupriavidus sp. are generally heavy metal tolerant bacteria with the ability to degrade a variety of aromatic hydrocarbon compounds, although the degradation pathways and substrate versatilities remain largely unknown. Here we studied the bacterium Cupriavidus gilardii strain CR3, which was isolated from a natural asphalt deposit, and which was shown to utilize naphthenic acids as a sole carbon source. Genome sequencing of C. gilardii CR3 was carried out to elucidate possible mechanisms for the naphthenic acid biodegradation. The genome of C. gilardii CR3 was composed of two circular chromosomes chr1 and chr2 of respectively 3,539,530 bp and 2,039,213 bp in size. The genome for strain CR3 encoded 4,502 putative protein-coding genes, 59 tRNA genes, and many other non-coding genes. Many genes were associated with xenobiotic biodegradation and metal resistance functions. Pathway prediction for degradation of cyclohexanecarboxylic acid, a representative naphthenic acid, suggested that naphthenic acid undergoes initial ring-cleavage, after which the ring fission products can be degraded via several plausible degradation pathways including a mechanism similar to that used for fatty acid oxidation. The final metabolic products of these pathways are unstable or volatile compounds that were not toxic to CR3. Strain CR3 was also shown to have tolerance to at least 10 heavy metals, which was mainly achieved by self-detoxification through ion efflux, metal-complexation and metal-reduction, and a powerful DNA self-repair mechanism. Our genomic analysis suggests that CR3 is well adapted to survive the harsh environment in natural asphalts containing naphthenic acids and high concentrations of heavy metals. PMID:26301592

Dose–response analysis of phthalate effects on gene expression in rat whole embryo culture

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

Robinson, Joshua F.; Department of Toxicogenomics, Maastricht University, Maastricht; Verhoef, Aart

2012-10-01

The rat postimplantation whole embryo culture (WEC) model serves as a potential screening tool for developmental toxicity. In this model, cultured rat embryos are exposed during early embryogenesis and evaluated for morphological effects. The integration of molecular-based markers may lead to improved objectivity, sensitivity and predictability of WEC in assessing developmental toxic properties of compounds. In this study, we investigated the concentration-dependent effects of two phthalates differing in potency, mono(2-ethylhexyl) phthalate (MEHP) and monomethyl phthalate (MMP, less toxic), on the transcriptome in WEC to examine gene expression in relation with dysmorphogenesis. MEHP was more potent than MMP in inducing genemore » expression changes as well as changes on morphology. MEHP induced significant enrichment of cholesterol/lipid/steroid (CLS) metabolism and apoptosis pathways which was associated with developmental toxicity. Regulation of genes within CLS metabolism pathways represented the most sensitive markers of MEHP exposure, more sensitive than classical morphological endpoints. As shown in direct comparisons with toxicogenomic in vivo studies, alterations in the regulation of CLS metabolism pathways has been previously identified to be associated with developmental toxicity due to phthalate exposure in utero. Our results support the application of WEC as a model to examine relative phthalate potency through gene expression and morphological responses. Additionally, our results further define the applicability domain of the WEC model for developmental toxicological investigations. -- Highlights: ► We examine the effect of two phthalates on gene expression and morphology in WEC. ► MEHP is more potent than MMP in inducing gene expression changes and dysmorphogenesis. ► MEHP significantly disrupts cholesterol metabolism pathways in a dose-dependent manner. ► Specific phthalate-related mechanisms in WEC are relevant to mechanisms in vivo.« less

Upregulated Transcription of Plasmid and Chromosomal Ribulose Monophosphate Pathway Genes Is Critical for Methanol Assimilation Rate and Methanol Tolerance in the Methylotrophic Bacterium Bacillus methanolicus

PubMed Central

Jakobsen, Øyvind M.; Benichou, Aline; Flickinger, Michael C.; Valla, Svein; Ellingsen, Trond E.; Brautaset, Trygve

2006-01-01

The natural plasmid pBM19 carries the key mdh gene needed for the oxidation of methanol into formaldehyde by Bacillus methanolicus. Five more genes, glpX, fba, tkt, pfk, and rpe, with deduced roles in the cell primary metabolism, are also located on this plasmid. By using real-time PCR, we show that they are transcriptionally upregulated (6- to 40-fold) in cells utilizing methanol; a similar induction was shown for two chromosomal genes, hps and phi. These seven genes are involved in the fructose bisphosphate aldolase/sedoheptulose bisphosphatase variant of the ribulose monophosphate (RuMP) pathway for formaldehyde assimilation. Curing of pBM19 causes higher methanol tolerance and reduced formaldehyde tolerance, and the methanol tolerance is reversed to wild-type levels by reintroducing mdh. Thus, the RuMP pathway is needed to detoxify the formaldehyde produced by the methanol dehydrogenase-mediated conversion of methanol, and the in vivo transcription levels of mdh and the RuMP pathway genes reflect the methanol tolerance level of the cells. The transcriptional inducer of hps and phi genes is formaldehyde, and not methanol, and introduction of multiple copies of these two genes into B. methanolicus made the cells more tolerant of growth on high methanol concentrations. The recombinant strain also had a significantly higher specific growth rate on methanol than the wild type. While pBM19 is critical for growth on methanol and important for formaldehyde detoxification, the maintenance of this plasmid represents a burden for B. methanolicus when growing on mannitol. Our data contribute to a new and fundamental understanding of the regulation of B. methanolicus methylotrophy. PMID:16585766

Biosynthesis of rare ketoses through constructing a recombination pathway in an engineered Corynebacterium glutamicum.

PubMed

Yang, Jiangang; Zhu, Yueming; Li, Jitao; Men, Yan; Sun, Yuanxia; Ma, Yanhe

2015-01-01

Rare sugars have various known biological functions and potential for applications in pharmaceutical, cosmetics, and food industries. Here we designed and constructed a recombination pathway in Corynebacterium glutamicum, in which dihydroxyacetone phosphate (DHAP), an intermediate of the glycolytic pathway, and a variety of aldehydes were condensed to synthesize rare ketoses sequentially by rhamnulose-1-phosphate aldolase (RhaD) and fructose-1-phosphatase (YqaB) obtained from Escherichia coli. A wild-type strain harboring this artificial pathway had the ability to produce D-sorbose and D-psicose using D-glyceraldehyde and glucose as the substrates. The tpi gene, encoding triose phosphate isomerase was further deleted, and the concentration of DHAP increased to nearly 20-fold relative to that of the wild-type. After additional optimization of expression levels from rhaD and yqaB genes and of the fermentation conditions, the engineered strain SY6(pVRTY) exhibited preferable performance for rare ketoses production. Its yield increased to 0.59 mol/mol D-glyceraldehyde from 0.33 mol/mol D-glyceraldehyde and productivity to 2.35 g/L h from 0.58 g/L h. Moreover, this strain accumulated 19.5 g/L of D-sorbose and 13.4 g/L of D-psicose using a fed-batch culture mode under the optimal conditions. In addition, it was verified that the strain SY6(pVRTY) meanwhile had the ability to synthesize C4, C5, C6, and C7 rare ketoses when a range of representative achiral and homochiral aldehydes were applied as the substrates. Therefore, the platform strain exhibited the potential for microbial production of rare ketoses and deoxysugars. © 2014 Wiley Periodicals, Inc.

The NRF2-KEAP1 Pathway Is an Early Responsive Gene Network in Arsenic Exposed Lymphoblastoid Cells

PubMed Central

Córdova, Emilio J.; Martínez-Hernández, Angélica; Uribe-Figueroa, Laura; Centeno, Federico; Morales-Marín, Mirna; Koneru, Harsha; Coleman, Matthew A.; Orozco, Lorena

2014-01-01

Inorganic arsenic (iAs), a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 µM), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs. PMID:24516582

Upregulated transcription of plasmid and chromosomal ribulose monophosphate pathway genes is critical for methanol assimilation rate and methanol tolerance in the methylotrophic bacterium Bacillus methanolicus.

PubMed

Jakobsen, Øyvind M; Benichou, Aline; Flickinger, Michael C; Valla, Svein; Ellingsen, Trond E; Brautaset, Trygve

2006-04-01

The natural plasmid pBM19 carries the key mdh gene needed for the oxidation of methanol into formaldehyde by Bacillus methanolicus. Five more genes, glpX, fba, tkt, pfk, and rpe, with deduced roles in the cell primary metabolism, are also located on this plasmid. By using real-time PCR, we show that they are transcriptionally upregulated (6- to 40-fold) in cells utilizing methanol; a similar induction was shown for two chromosomal genes, hps and phi. These seven genes are involved in the fructose bisphosphate aldolase/sedoheptulose bisphosphatase variant of the ribulose monophosphate (RuMP) pathway for formaldehyde assimilation. Curing of pBM19 causes higher methanol tolerance and reduced formaldehyde tolerance, and the methanol tolerance is reversed to wild-type levels by reintroducing mdh. Thus, the RuMP pathway is needed to detoxify the formaldehyde produced by the methanol dehydrogenase-mediated conversion of methanol, and the in vivo transcription levels of mdh and the RuMP pathway genes reflect the methanol tolerance level of the cells. The transcriptional inducer of hps and phi genes is formaldehyde, and not methanol, and introduction of multiple copies of these two genes into B. methanolicus made the cells more tolerant of growth on high methanol concentrations. The recombinant strain also had a significantly higher specific growth rate on methanol than the wild type. While pBM19 is critical for growth on methanol and important for formaldehyde detoxification, the maintenance of this plasmid represents a burden for B. methanolicus when growing on mannitol. Our data contribute to a new and fundamental understanding of the regulation of B. methanolicus methylotrophy.

Electromagnetic radiation at 900 MHz induces sperm apoptosis through bcl-2, bax and caspase-3 signaling pathways in rats.

PubMed

Liu, Qi; Si, Tianlei; Xu, Xiaoyun; Liang, Fuqiang; Wang, Lufeng; Pan, Siyi

2015-08-04

The decreased reproductive capacity of men is an important factor contributing to infertility. Accumulating evidence has shown that Electromagnetic radiation potentially has negative effects on human health. However, whether radio frequency electromagnetic radiation (RF-EMR) affects the human reproductive system still requires further investigation. Therefore, The present study investigates whether RF-EMR at a frequency of 900 MHz can trigger sperm cell apoptosis and affect semen morphology, concentration, and microstructure. Twenty four rats were exposed to 900 MHz electromagnetic radiation with a special absorption rate of 0.66 ± 0.01 W/kg for 2 h/d. After 50d, the sperm count, morphology, apoptosis, reactive oxygen species (ROS), and total antioxidant capacity (TAC), representing the sum of enzymatic and nonenzymatic antioxidants, were investigated. Western blotting and reverse transcriptase PCR were used to determine the expression levels of apoptosis-related proteins and genes, including bcl-2, bax, cytochrome c, and capase-3. In the present study, the percentage of apoptotic sperm cells in the exposure group was significantly increased by 91.42% compared with the control group. Moreover, the ROS concentration in exposure group was increased by 46.21%, while the TAC was decreased by 28.01%. Radiation also dramatically decreased the protein and mRNA expression of bcl-2 and increased that of bax, cytochrome c, and capase-3. RF-EMR increases the ROS level and decreases TAC in rat sperm. Excessive oxidative stress alters the expression levels of apoptosis-related genes and triggers sperm apoptosis through bcl-2, bax, cytochrome c and caspase-3 signaling pathways.

Tissue Regeneration and Biomineralization in Sea Urchins: Role of Notch Signaling and Presence of Stem Cell Markers

PubMed Central

Reinardy, Helena C.; Emerson, Chloe E.; Manley, Jason M.; Bodnar, Andrea G.

2015-01-01

Echinoderms represent a phylum with exceptional regenerative capabilities that can reconstruct both external appendages and internal organs. Mechanistic understanding of the cellular pathways involved in regeneration in these animals has been hampered by the limited genomic tools and limited ability to manipulate regenerative processes. We present a functional assay to investigate mechanisms of tissue regeneration and biomineralization by measuring the regrowth of amputated tube feet (sensory and motor appendages) and spines in the sea urchin, Lytechinus variegatus. The ability to manipulate regeneration was demonstrated by concentration-dependent inhibition of regrowth of spines and tube feet by treatment with the mitotic inhibitor, vincristine. Treatment with the gamma-secretase inhibitor DAPT resulted in a concentration-dependent inhibition of regrowth, indicating that both tube feet and spine regeneration require functional Notch signaling. Stem cell markers (Piwi and Vasa) were expressed in tube feet and spine tissue, and Vasa-positive cells were localized throughout the epidermis of tube feet by immunohistochemistry, suggesting the existence of multipotent progenitor cells in these highly regenerative appendages. The presence of Vasa protein in other somatic tissues (e.g. esophagus, radial nerve, and a sub-population of coelomocytes) suggests that multipotent cells are present throughout adult sea urchins and may contribute to normal homeostasis in addition to regeneration. Mechanistic insight into the cellular pathways governing the tremendous regenerative capacity of echinoderms may reveal processes that can be modulated for regenerative therapies, shed light on the evolution of regeneration, and enable the ability to predict how these processes will respond to changing environmental conditions. PMID:26267358

Extreme sea levels on the rise along Europe's coasts

NASA Astrophysics Data System (ADS)

Vousdoukas, Michalis I.; Mentaschi, Lorenzo; Voukouvalas, Evangelos; Verlaan, Martin; Feyen, Luc

2017-03-01

Future extreme sea levels (ESLs) and flood risk along European coasts will be strongly impacted by global warming. Yet, comprehensive projections of ESL that include mean sea level (MSL), tides, waves, and storm surges do not exist. Here, we show changes in all components of ESLs until 2100 in view of climate change. We find that by the end of this century, the 100-year ESL along Europe's coastlines is on average projected to increase by 57 cm for Representative Concentration Pathways (RCP)4.5 and 81 cm for RCP8.5. The North Sea region is projected to face the highest increase in ESLs, amounting to nearly 1 m under RCP8.5 by 2100, followed by the Baltic Sea and Atlantic coasts of the UK and Ireland. Relative sea level rise (RSLR) is shown to be the main driver of the projected rise in ESL, with increasing dominance toward the end of the century and for the high-concentration pathway. Changes in storm surges and waves enhance the effects of RSLR along the majority of northern European coasts, locally with contributions up to 40%. In southern Europe, episodic extreme events tend to stay stable, except along the Portuguese coast and the Gulf of Cadiz where reductions in surge and wave extremes offset RSLR by 20-30%. By the end of this century, 5 million Europeans currently under threat of a 100-year ESL could be annually at risk from coastal flooding under high-end warming. The presented dataset is available through this link: http://data.jrc.ec.europa.eu/collection/LISCOAST.

Fructose Alters Intermediary Metabolism of Glucose in Human Adipocytes and Diverts Glucose to Serine Oxidation in the One–Carbon Cycle Energy Producing Pathway

PubMed Central

Varma, Vijayalakshmi; Boros, László G.; Nolen, Greg T.; Chang, Ching-Wei; Wabitsch, Martin; Beger, Richard D.; Kaput, Jim

2015-01-01

Increased consumption of sugar and fructose as sweeteners has resulted in the utilization of fructose as an alternative metabolic fuel that may compete with glucose and alter its metabolism. To explore this, human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes were differentiated to adipocytes in the presence of 0, 1, 2.5, 5 or 10 mM of fructose added to a medium containing 5 mM of glucose representing the normal blood glucose concentration. Targeted tracer [1,2-13C2]-d-glucose fate association approach was employed to examine the influence of fructose on the intermediary metabolism of glucose. Increasing concentrations of fructose robustly increased the oxidation of [1,2-13C2]-d-glucose to 13CO2 (p < 0.000001). However, glucose-derived 13CO2 negatively correlated with 13C labeled glutamate, 13C palmitate, and M+1 labeled lactate. These are strong markers of limited tricarboxylic acid (TCA) cycle, fatty acid synthesis, pentose cycle fluxes, substrate turnover and NAD+/NADP+ or ATP production from glucose via complete oxidation, indicating diminished mitochondrial energy metabolism. Contrarily, a positive correlation was observed between glucose-derived 13CO2 formed and 13C oleate and doses of fructose which indicate the elongation and desaturation of palmitate to oleate for storage. Collectively, these results suggest that fructose preferentially drives glucose through serine oxidation glycine cleavage (SOGC pathway) one-carbon cycle for NAD+/NADP+ production that is utilized in fructose-induced lipogenesis and storage in adipocytes. PMID:26087138

Delayed detection of climate mitigation benefits due to climate inertia and variability.

PubMed

Tebaldi, Claudia; Friedlingstein, Pierre

2013-10-22

Climate change mitigation acts by reducing greenhouse gas emissions, and thus curbing, or even reversing, the increase in their atmospheric concentration. This reduces the associated anthropogenic radiative forcing, and hence the size of the warming. Because of the inertia and internal variability affecting the climate system and the global carbon cycle, it is unlikely that a reduction in warming would be immediately discernible. Here we use 21st century simulations from the latest ensemble of Earth System Model experiments to investigate and quantify when mitigation becomes clearly discernible. We use one of the scenarios as a reference for a strong mitigation strategy, Representative Concentration Pathway (RCP) 2.6 and compare its outcome with either RCP4.5 or RCP8.5, both of which are less severe mitigation pathways. We analyze global mean atmospheric CO2, and changes in annually and seasonally averaged surface temperature at global and regional scales. For global mean surface temperature, the median detection time of mitigation is about 25-30 y after RCP2.6 emissions depart from the higher emission trajectories. This translates into detection of a mitigation signal by 2035 or 2045, depending on whether the comparison is with RCP8.5 or RCP4.5, respectively. The detection of climate benefits of emission mitigation occurs later at regional scales, with a median detection time between 30 and 45 y after emission paths separate. Requiring a 95% confidence level induces a delay of several decades, bringing detection time toward the end of the 21st century.

Hanford Environmental Dose Reconstruction Project monthly report

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

McMakin, A.H., Cannon, S.D.; Finch, S.M.

1992-09-01

The objective of the Hanford Environmental Dose Reconstruction MDR) Project is to estimate the radiation doses that individuals and populations could have received from nuclear operations at Hanford since 1944. The TSP consists of experts in envirorunental pathways. epidemiology, surface-water transport, ground-water transport, statistics, demography, agriculture, meteorology, nuclear engineering. radiation dosimetry. and cultural anthropology. Included are appointed members representing the states of Oregon, Washington, and Idaho, a representative of Native American tribes, and an individual representing the public. The project is divided into the following technical tasks. These tasks correspond to the path radionuclides followed from release to impact onmore » humans (dose estimates): Source Terms; Environmental Transport; Environmental Monitoring Data Demography, Food Consumption, and Agriculture; and Environmental Pathways and Dose Estimates.« less

Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake.

PubMed

Teng, Ya-Wen; Cerdena, Ignacio; Zeisel, Steven H

2012-11-01

Elevated homocysteine (Hcy) concentrations are associated with increased risk of several chronic diseases. Hcy can be removed by methylating it to form methionine via either the betaine homocysteine S-methyltransferase (BHMT) or the methionine synthase (MS) pathway. BHMT uses betaine as the methyl donor, whereas MS uses 5-methyltetrahydrofolate. We previously found that mice with the gene encoding Bhmt deleted (Bhmt(-/-)) had altered Hcy metabolites in tissues. This study aimed to determine whether folate supplementation of Bhmt(-/-) mice reverses, and folate deficiency exacerbates, these metabolic changes. Bhmt(-/-) mice and their littermates (Bhmt(+/+) mice) were fed a folate-deficient (FD; 0 mg/kg diet), a folate control (FC; 2 mg/kg diet), or a folate-supplemented (FS; 20 mg/kg diet) diet for 4 wk. Bhmt(-/-) mice had higher plasma Hcy and hepatic S-adenosylhomocysteine (AdoHcy) concentrations and had lower hepatic S-adenosylmethionine (AdoMet) concentrations compared with Bhmt(+/+) mice for all diets. Although the FD diet increased plasma Hcy (P < 0.05) and hepatic AdoHcy (P < 0.001) concentrations in Bhmt(+/+) mice compared with FC and FS mice, the FD diet had no effect on the metabolites measured in Bhmt(-/-) mice. The FS diet did not ameliorate elevated plasma Hcy and elevated hepatic AdoHcy concentrations but did increase hepatic AdoMet concentrations in Bhmt(-/-) mice (P < 0.001) compared with FD and FC mice. We conclude that the BHMT pathway is a major route for the elimination of Hcy in mice and that the MS pathway has little excess capacity to methylate the Hcy that accumulates when the BHMT pathway is blocked.

Potential impacts of agricultural drought on crop yield variability under a changing climate in Texas

NASA Astrophysics Data System (ADS)

Lee, K.; Leng, G.; Huang, M.; Sheffield, J.; Zhao, G.; Gao, H.

2017-12-01

Texas has the largest farm area in the U.S, and its revenue from crop production ranks third overall. With the changing climate, hydrological extremes such as droughts are becoming more frequent and intensified, causing significant yield reduction in rainfed agricultural systems. The objective of this study is to investigate the potential impacts of agricultural drought on crop yields (corn, sorghum, and wheat) under a changing climate in Texas. The Variable Infiltration Capacity (VIC) model, which is calibrated and validated over 10 major Texas river basins during the historical period, is employed in this study.The model is forced by a set of statistically downscaled climate projections from Coupled Model Intercomparison Project Phase 5 (CMIP5) model ensembles at a spatial resolution of 1/8°. The CMIP5 projections contain four Representative Concentration Pathways (RCP) that represent different greenhouse gas concentration (4.5 and 8.5 w/m2 are selected in this study). To carry out the analysis, VIC simulations from 1950 to 2099 are first analyzed to investigate how the frequency and severity of agricultural droughts will be altered in Texas (under a changing climate). Second, future crop yields are projected using a statistical crop model. Third, the effects of agricultural drought on crop yields are quantitatively analyzed. The results are expected to contribute to future water resources planning, with a goal of mitigating the negative impacts of future droughts on agricultural production in Texas.

The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns.

PubMed

Noguchi, Rei; Kubota, Hiroyuki; Yugi, Katsuyuki; Toyoshima, Yu; Komori, Yasunori; Soga, Tomoyoshi; Kuroda, Shinya

2013-05-14

Insulin governs systemic glucose metabolism, including glycolysis, gluconeogenesis and glycogenesis, through temporal change and absolute concentration. However, how insulin-signalling pathway selectively regulates glycolysis, gluconeogenesis and glycogenesis remains to be elucidated. To address this issue, we experimentally measured metabolites in glucose metabolism in response to insulin. Step stimulation of insulin induced transient response of glycolysis and glycogenesis, and sustained response of gluconeogenesis and extracellular glucose concentration (GLC(ex)). Based on the experimental results, we constructed a simple computational model that characterises response of insulin-signalling-dependent glucose metabolism. The model revealed that the network motifs of glycolysis and glycogenesis pathways constitute a feedforward (FF) with substrate depletion and incoherent feedforward loop (iFFL), respectively, enabling glycolysis and glycogenesis responsive to temporal changes of insulin rather than its absolute concentration. In contrast, the network motifs of gluconeogenesis pathway constituted a FF inhibition, enabling gluconeogenesis responsive to absolute concentration of insulin regardless of its temporal patterns. GLC(ex) was regulated by gluconeogenesis and glycolysis. These results demonstrate the selective control mechanism of glucose metabolism by temporal patterns of insulin.

The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns

PubMed Central

Noguchi, Rei; Kubota, Hiroyuki; Yugi, Katsuyuki; Toyoshima, Yu; Komori, Yasunori; Soga, Tomoyoshi; Kuroda, Shinya

2013-01-01

Insulin governs systemic glucose metabolism, including glycolysis, gluconeogenesis and glycogenesis, through temporal change and absolute concentration. However, how insulin-signalling pathway selectively regulates glycolysis, gluconeogenesis and glycogenesis remains to be elucidated. To address this issue, we experimentally measured metabolites in glucose metabolism in response to insulin. Step stimulation of insulin induced transient response of glycolysis and glycogenesis, and sustained response of gluconeogenesis and extracellular glucose concentration (GLCex). Based on the experimental results, we constructed a simple computational model that characterises response of insulin-signalling-dependent glucose metabolism. The model revealed that the network motifs of glycolysis and glycogenesis pathways constitute a feedforward (FF) with substrate depletion and incoherent feedforward loop (iFFL), respectively, enabling glycolysis and glycogenesis responsive to temporal changes of insulin rather than its absolute concentration. In contrast, the network motifs of gluconeogenesis pathway constituted a FF inhibition, enabling gluconeogenesis responsive to absolute concentration of insulin regardless of its temporal patterns. GLCex was regulated by gluconeogenesis and glycolysis. These results demonstrate the selective control mechanism of glucose metabolism by temporal patterns of insulin. PMID:23670537

The effect of ventilation on indoor exposure to semivolatile organic compounds.

PubMed

Liu, C; Zhang, Y; Benning, J L; Little, J C

2015-06-01

A mechanistic model was developed to examine how natural ventilation influences residential indoor exposure to semivolatile organic compounds (SVOCs) via inhalation, dermal sorption, and dust ingestion. The effect of ventilation on indoor particle mass concentration and mass transfer at source/sink surfaces, and the enhancing effect of particles on mass transfer at source/sink surfaces are included. When air exchange rate increases from 0.6/h to 1.8/h, the steady-state SVOC (gas-phase plus particle phase with log KOA varying from 9 to 13) concentration in the idealized model decreases by about 60%. In contrast, for the same change in ventilation, the simulated indoor formaldehyde (representing volatile organic compounds) gas-phase concentration decreases by about 70%. The effect of ventilation on exposure via each pathway has a relatively insignificant association with the KOA of the SVOCs: a change of KOA from 10(9) to 10(13) results in a change of only 2-30%. Sensitivity analysis identifies the deposition rate of PM2.5 as a primary factor influencing the relationship between ventilation and exposure for SVOCs with log KOA = 13. The relationship between ventilation rate and air speed near surfaces needs to be further substantiated. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The effects of urbanization on the hydrochemistry of base flow within the Chattahoochee River Basin (Georgia, USA)

NASA Astrophysics Data System (ADS)

Rose, Seth

2007-07-01

SummaryA comprehensive network of stream data ( n = 50) was used to assess the effects of urbanization upon the hydrochemical variation within base flow in the Chattahoochee River Basin (CRB), Georgia (USA). Base flow solute concentrations (particularly sulfate, chloride, bicarbonate alkalinity, and sodium) increase with the degree of urbanization and any degree of urbanization within the Atlanta Metropolitan Region (AMR) results in elevated base flow solute concentrations. This suggests that there are pervasive low-level non-point sources of contamination such as septic tanks systems and leaky sewer lines affecting the chemistry of shallow groundwater throughout much of the AMR and CRB. Six groups or subsets representing the "rural-to-urban gradient" were defined, characterized by the following order of increasing solute concentrations: rural basins < Chattahoochee River. semi-urbanized basins < urbanized basins < urban basins with main sewer trunk lines < urbanized basins directly receiving treated effluent and combined sewer overflow (CSO) basins. There is a strong and unusual basin-wide correlation ( r2 values >0.79) between Na-K-Cl within the CRB that likely reflects the widespread input of electrolytes present in human wastes and wastewater. The most likely source and pathway for contaminant input involves the mobilization of salts, originally present in waste water, within the riparian or hypoheric zone.

Alamethicin for using in bioavailability studies? - Re-evaluation of its effect.

PubMed

Vollmer, Maren; Klingebiel, Mirko; Rohn, Sascha; Maul, Ronald

2017-03-01

A major pathway for the elimination of drugs is the biliary and renal excretion following the formation of more hydrophilic secondary metabolites such as glucuronides. For in vitro investigations of the phase II metabolism, hepatic microsomes are commonly used in the combination with the pore-forming peptide alamethicin, also to give estimates for the in vivo situation. Thus, alamethicin may represent a neglected parameter in the characterization of microsomal in vitro assays. In the present study, the influence of varying alamethicin concentrations on glucuronide formation of selected phenolic compounds was investigated systematically. A correlation between the alamethicin impact and the lipophilicity of the investigated substrates was analyzed as well. Lipophilicity was determined by the logarithm of the octanol-water partition coefficient. For every substrate, a distinct alamethicin concentration could be detected leading to a maximal glucuronidation activity. Further increase of the alamethicin application led to negative effects. The differences between the maximum depletion rates with and without alamethicin addition varied between 2.7% and 18.2% depending on the substrate. A dependence on the lipophilicity could not be confirmed. Calculation of the apparent intrinsic clearance led to a more than 2-fold increase using the most effective alamethicin concentration compared to the alamethicin free control. Copyright © 2016 Elsevier Ltd. All rights reserved.

Juvenile-onset distal myopathy in Rottweiler dogs.

PubMed

Hanson, S M; Smith, M O; Walker, T L; Shelton, G D

1998-01-01

Two juvenile Rottweiler siblings were presented with the complaint of decreased activity and various postural abnormalities, including plantigrade and palmigrade stance and splayed forepaw digits. The neurologic examinations were otherwise normal. Electromyography revealed rare fibrillation potentials and positive sharp waves. Motor nerve conduction velocities were normal, whereas compound muscle action potentials from the interosseous muscles were decreased. These findings were consistent with a primary myopathy. A 3rd pup from a different litter and a 4th pup from a litter with 3 of 8 affected dogs had similar clinical presentations. Histopathologic changes in fresh-frozen muscle biopsy samples were similar in all pups and consisted of myofiber atrophy with mild myonecrosis, endomysial fibrosis and replacement of muscle with fatty tissue. These changes were more severe in distal muscles than in proximal muscles. Plasma carnitine concentrations (total and free) were decreased in all pups. Muscle carnitine concentrations (total and free) were decreased in 3 of 4 pups and the least affected pup had a borderline low free muscle carnitine concentration. Abnormalities involving major metabolic pathways were not found on quantification of organic and amino acids. Dystrophin immunocytochemistry was normal in 2 dogs tested. Distal myopathies in humans are classified under the dystrophic group of muscle disorders. These 4 cases represent a form of muscular dystrophy apparently not previously reported in dogs.

Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR.

PubMed Central

Kitareewan, S; Burka, L T; Tomer, K B; Parker, C E; Deterding, L J; Stevens, R D; Forman, B M; Mais, D E; Heyman, R A; McMorris, T; Weinberger, C

1996-01-01

RXR is a nuclear receptor that plays a central role in cell signaling by pairing with a host of other receptors. Previously, 9-cis-retinoic acid (9cRA) was defined as a potent RXR activator. Here we describe a unique RXR effector identified from organic extracts of bovine serum by following RXR-dependent transcriptional activity. Structural analyses of material in active fractions pointed to the saturated diterpenoid phytanic acid, which induced RXR-dependent transcription at concentrations between 4 and 64 microM. Although 200 times more potent than phytanic acid, 9cRA was undetectable in equivalent amounts of extract and cannot be present at a concentration that could account for the activity. Phytanic acid, another phytol metabolite, was synthesized and stimulated RXR with a potency and efficacy similar to phytanic acid. These metabolites specifically displaced [3H]-9cRA from RXR with Ki values of 4 microM, indicating that their transcriptional effects are mediated by direct receptor interactions. Phytol metabolites are compelling candidates for physiological effectors, because their RXR binding affinities and activation potencies match their micromolar circulating concentrations. Given their exclusive dietary origin, these chlorophyll metabolites may represent essential nutrients that coordinate cellular metabolism through RXR-dependent signaling pathways. PMID:8856661

Conversations at the Threshold: Collaboratively Navigating Post-High School Pathways with Local and Bureaucratic Literacies

ERIC Educational Resources Information Center

Weissman, Kabeera M.

2012-01-01

This study focused on exploring and creating life pathways with a group of twelfth graders at West Philadelphia High School. I invited students to inquire into "life pathways," broadly construed; participants chose to concentrate on transitions to college. Although scholars have investigated many elements of college access, there is…

Effects of Hybridization and Evolutionary Constraints on Secondary Metabolites: The Genetic Architecture of Phenylpropanoids in European Populus Species

PubMed Central

Caseys, Celine; Stritt, Christoph; Glauser, Gaetan; Blanchard, Thierry; Lexer, Christian

2015-01-01

The mechanisms responsible for the origin, maintenance and evolution of plant secondary metabolite diversity remain largely unknown. Decades of phenotypic studies suggest hybridization as a key player in generating chemical diversity in plants. Knowledge of the genetic architecture and selective constraints of phytochemical traits is key to understanding the effects of hybridization on plant chemical diversity and ecological interactions. Using the European Populus species P. alba (White poplar) and P. tremula (European aspen) and their hybrids as a model, we examined levels of inter- and intraspecific variation, heritabilities, phenotypic correlations, and the genetic architecture of 38 compounds of the phenylpropanoid pathway measured by liquid chromatography and mass spectrometry (UHPLC-MS). We detected 41 quantitative trait loci (QTL) for chlorogenic acids, salicinoids and flavonoids by genetic mapping in natural hybrid crosses. We show that these three branches of the phenylpropanoid pathway exhibit different geographic patterns of variation, heritabilities, and genetic architectures, and that they are affected differently by hybridization and evolutionary constraints. Flavonoid abundances present high species specificity, clear geographic structure, and strong genetic determination, contrary to salicinoids and chlorogenic acids. Salicinoids, which represent important defence compounds in Salicaceae, exhibited pronounced genetic correlations on the QTL map. Our results suggest that interspecific phytochemical differentiation is concentrated in downstream sections of the phenylpropanoid pathway. In particular, our data point to glycosyltransferase enzymes as likely targets of rapid evolution and interspecific differentiation in the ‘model forest tree’ Populus. PMID:26010156

Effects of hybridization and evolutionary constraints on secondary metabolites: the genetic architecture of phenylpropanoids in European populus species.

PubMed

Caseys, Celine; Stritt, Christoph; Glauser, Gaetan; Blanchard, Thierry; Lexer, Christian

2015-01-01

The mechanisms responsible for the origin, maintenance and evolution of plant secondary metabolite diversity remain largely unknown. Decades of phenotypic studies suggest hybridization as a key player in generating chemical diversity in plants. Knowledge of the genetic architecture and selective constraints of phytochemical traits is key to understanding the effects of hybridization on plant chemical diversity and ecological interactions. Using the European Populus species P. alba (White poplar) and P. tremula (European aspen) and their hybrids as a model, we examined levels of inter- and intraspecific variation, heritabilities, phenotypic correlations, and the genetic architecture of 38 compounds of the phenylpropanoid pathway measured by liquid chromatography and mass spectrometry (UHPLC-MS). We detected 41 quantitative trait loci (QTL) for chlorogenic acids, salicinoids and flavonoids by genetic mapping in natural hybrid crosses. We show that these three branches of the phenylpropanoid pathway exhibit different geographic patterns of variation, heritabilities, and genetic architectures, and that they are affected differently by hybridization and evolutionary constraints. Flavonoid abundances present high species specificity, clear geographic structure, and strong genetic determination, contrary to salicinoids and chlorogenic acids. Salicinoids, which represent important defence compounds in Salicaceae, exhibited pronounced genetic correlations on the QTL map. Our results suggest that interspecific phytochemical differentiation is concentrated in downstream sections of the phenylpropanoid pathway. In particular, our data point to glycosyltransferase enzymes as likely targets of rapid evolution and interspecific differentiation in the 'model forest tree' Populus.

De Novo Pyrimidine Nucleotide Synthesis Mainly Occurs outside of Plastids, but a Previously Undiscovered Nucleobase Importer Provides Substrates for the Essential Salvage Pathway in Arabidopsis[W

PubMed Central

Witz, Sandra; Jung, Benjamin; Fürst, Sarah; Möhlmann, Torsten

2012-01-01

Nucleotide de novo synthesis is highly conserved among organisms and represents an essential biochemical pathway. In plants, the two initial enzymatic reactions of de novo pyrimidine synthesis occur in the plastids. By use of green fluorescent protein fusions, clear support is provided for a localization of the remaining reactions in the cytosol and mitochondria. This implies that carbamoyl aspartate, an intermediate of this pathway, must be exported and precursors of pyrimidine salvage (i.e., nucleobases or nucleosides) are imported into plastids. A corresponding uracil transport activity could be measured in intact plastids isolated from cauliflower (Brassica oleracea) buds. PLUTO (for plastidic nucleobase transporter) was identified as a member of the Nucleobase:Cation-Symporter1 protein family from Arabidopsis thaliana, capable of transporting purine and pyrimidine nucleobases. A PLUTO green fluorescent protein fusion was shown to reside in the plastid envelope after expression in Arabidopsis protoplasts. Heterologous expression of PLUTO in an Escherichia coli mutant lacking the bacterial uracil permease uraA allowed a detailed biochemical characterization. PLUTO transports uracil, adenine, and guanine with apparent affinities of 16.4, 0.4, and 6.3 μM, respectively. Transport was markedly inhibited by low concentrations of a proton uncoupler, indicating that PLUTO functions as a proton-substrate symporter. Thus, a protein for the absolutely required import of pyrimidine nucleobases into plastids was identified. PMID:22474184

Effects of acute dieldrin exposure on neurotransmitters and global gene transcription in largemouth bass (Micropterus salmoides) hypothalamus

PubMed Central

Martyniuk, Christopher J.; Feswick, April; Spade, Daniel J.; Kroll, Kevin J.; Barber, David S.; Denslow, Nancy D.

2010-01-01

Exposure to dieldrin induces neurotoxic effects in the vertebrate CNS and disrupts reproductive processes in teleost fish. Reproductive impairment observed in fish by dieldrin is likely the result of multiple effects along the hypothalamic-pituitary-gonadal axis but the molecular signaling cascades are not well characterized. To better elucidate the mode of action of dieldrin in the hypothalamus, this study measured neurotransmitter levels and examined the transcriptomic response in female largemouth bass (LMB) to an acute treatment of dieldrin. Male and female LMB were injected with either vehicle or 10 mg dieldrin/kg and sacrificed after seven days. There were no significant changes in dopamine or DOPAC concentrations in the neuroendocrine brain of males and females after treatment but GABA levels in females were moderately increased 20–30% in the hypothalamus and cerebellum. In the female hypothalamus, there were 227 transcripts (p<0.001) identified as being differentially regulated by dieldrin. Functional enrichment analysis revealed transcription, DNA repair, ubiquitin-proteasome pathway, and cell communication, as biological processes over-represented in the microarray analysis. Pathway analysis identified DNA damage, inflammation, regeneration, and Alzheimer’s disease as major cell processes and diseases affected by dieldrin. Using multiple bioinformatics approaches, this study demonstrates that the teleostean hypothalamus is a target for dieldrin-induced neurotoxicity and provides mechanistic evidence that dieldrin activates similar cell pathways and biological processes that are also associated with the etiology of human neurological disorders. PMID:20438755

Methanotrophic bacteria.

PubMed Central

Hanson, R S; Hanson, T E

1996-01-01

Methane-utilizing bacteria (methanotrophs) are a diverse group of gram-negative bacteria that are related to other members of the Proteobacteria. These bacteria are classified into three groups based on the pathways used for assimilation of formaldehyde, the major source of cell carbon, and other physiological and morphological features. The type I and type X methanotrophs are found within the gamma subdivision of the Proteobacteria and employ the ribulose monophosphate pathway for formaldehyde assimilation, whereas type II methanotrophs, which employ the serine pathway for formaldehyde assimilation, form a coherent cluster within the beta subdivision of the Proteobacteria. Methanotrophic bacteria are ubiquitous. The growth of type II bacteria appears to be favored in environments that contain relatively high levels of methane, low levels of dissolved oxygen, and limiting concentrations of combined nitrogen and/or copper. Type I methanotrophs appear to be dominant in environments in which methane is limiting and combined nitrogen and copper levels are relatively high. These bacteria serve as biofilters for the oxidation of methane produced in anaerobic environments, and when oxygen is present in soils, atmospheric methane is oxidized. Their activities in nature are greatly influenced by agricultural practices and other human activities. Recent evidence indicates that naturally occurring, uncultured methanotrophs represent new genera. Methanotrophs that are capable of oxidizing methane at atmospheric levels exhibit methane oxidation kinetics different from those of methanotrophs available in pure cultures. A limited number of methanotrophs have the genetic capacity to synthesize a soluble methane monooxygenase which catalyzes the rapid oxidation of environmental pollutants including trichloroethylene. PMID:8801441

Study of ocular transport of drugs released from an intravitreal implant using magnetic resonance imaging.

PubMed

Kim, Hyuncheol; Lizak, Martin J; Tansey, Ginger; Csaky, Karl G; Robinson, Michael R; Yuan, Peng; Wang, Nam Sun; Lutz, Robert J

2005-02-01

Ensuring optimum delivery of therapeutic agents in the eye requires detailed information about the transport mechanisms and elimination pathways available. This knowledge can guide the development of new drug delivery devices. In this study, we investigated the movement of a drug surrogate, Gd-DTPA (Magnevist) released from a polymer-based implant in rabbit vitreous using T1-weighted magnetic resonance imaging (MRI). Intensity values in the MRI data were converted to concentration by comparison with calibration samples. Concentration profiles approaching pseudosteady state showed gradients from the implant toward the retinal surface, suggesting that diffusion was occurring into the retinal-choroidal-scleral (RCS) membrane. Gd-DTPA concentration varied from high values near the implant to lower values distal to the implant. Such regional concentration differences throughout the vitreous may have clinical significance when attempting to treat ubiquitous eye diseases using a single positional implant. We developed a finite element mathematical model of the rabbit eye and compared the MRI experimental concentration data with simulation concentration profiles. The model utilized a diffusion coefficient of Gd-DTPA in the vitreous of 2.8 x 10(-6) cm2 s(-1) and yielded a diffusion coefficient for Gd-DTPA through the simulated composite posterior membrane (representing the retina-choroidsclera membrane) of 6.0 x 10(-8) cm2 s(-1). Since the model membrane was 0.03-cm thick, this resulted in an effective membrane permeability of 2.0 x 10(-6) cm s(-1). Convective movement of Gd-DTPA was shown to have minimal effect on the concentration profiles since the Peclet number was 0.09 for this system.

The genes and enzymes of the carotenoid metabolic pathway in Vitis vinifera L.

PubMed Central

2012-01-01

Background Carotenoids are a heterogeneous group of plant isoprenoids primarily involved in photosynthesis. In plants the cleavage of carotenoids leads to the formation of the phytohormones abscisic acid and strigolactone, and C13-norisoprenoids involved in the characteristic flavour and aroma compounds in flowers and fruits and are of specific importance in the varietal character of grapes and wine. This work extends the previous reports of carotenoid gene expression and photosynthetic pigment analysis by providing an up-to-date pathway analysis and an important framework for the analysis of carotenoid metabolic pathways in grapevine. Results Comparative genomics was used to identify 42 genes putatively involved in carotenoid biosynthesis/catabolism in grapevine. The genes are distributed on 16 of the 19 chromosomes and have been localised to the physical map of the heterozygous ENTAV115 grapevine sequence. Nine of the genes occur as single copies whereas the rest of the carotenoid metabolic genes have more than one paralogue. The cDNA copies of eleven corresponding genes from Vitis vinifera L. cv. Pinotage were characterised, and four where shown to be functional. Microarrays provided expression profiles of 39 accessions in the metabolic pathway during three berry developmental stages in Sauvignon blanc, whereas an optimised HPLC analysis provided the concentrations of individual carotenoids. This provides evidence of the functioning of the lutein epoxide cycle and the respective genes in grapevine. Similarly, orthologues of genes leading to the formation of strigolactone involved in shoot branching inhibition were identified: CCD7, CCD8 and MAX1. Moreover, the isoforms typically have different expression patterns, confirming the complex regulation of the pathway. Of particular interest is the expression pattern of the three VvNCEDs: Our results support previous findings that VvNCED3 is likely the isoform linked to ABA content in berries. Conclusions The carotenoid metabolic pathway is well characterised, and the genes and enzymes have been studied in a number of plants. The study of the 42 carotenoid pathway genes of grapevine showed that they share a high degree of similarity with other eudicots. Expression and pigment profiling of developing berries provided insights into the most complete grapevine carotenoid pathway representation. This study represents an important reference study for further characterisation of carotenoid biosynthesis and catabolism in grapevine. PMID:22702718

Inhibition of Aurora A Kinase by Alisertib Induces Autophagy and Cell Cycle Arrest and Increases Chemosensitivity in Human Hepatocellular Carcinoma HepG2 Cells.

PubMed

Zhu, Qiaohua; Yu, Xinfa; Zhou, Zhi-Wei; Zhou, Chengyu; Chen, Xiao-Wu; Zhou, Shu-Feng

2017-01-01

Aurora A kinase represent a feasible target in cancer therapy. To evaluate the proteomic response of human liver carcinoma cells to alisertib (ALS) and identify the molecular targets of ALS, we examined the effects of ALS on the proliferation, cell cycle, autophagy, apoptosis, and chemosensitivity in HepG2 cells. The stable-isotope labeling by amino acids in cell culture (SILAC) based quantitative proteomic study was performed to evaluate the proteomic response to ALS. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy. Our SILAC proteomic study showed that ALS regulated the expression of 914 proteins, with 407 molecules being up-regulated and 507 molecules being down-regulated in HepG2 cells. Ingenuity pathway analysis (IPA) and KEGG pathway analysis identified 146 and 32 signaling pathways were regulated by ALS, respectively, which were associated with cell survival, programmed cell death, and nutrition-energy metabolism. Subsequently, the verification experiments showed that ALS remarkably arrested HepG2 cells in G2/M phase and led to an accumulation of aneuploidy via regulating the expression of key cell cycle regulators. ALS induced a marked autophagy in a concentration- and time-dependent manner via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Autophagy inhibition promoted the pro-apoptotic effect of ALS, indicating a cyto-protective role of ALS-induced autophagy. ALS increased the chemosensitivity of HepG2 cells to cisplatin and doxorubicin. Taken together, ALS induces autophagy and cell cycle arrest in HepG2 cells via PI3K/Akt/mTOR-mediated pathway. Autophagy inhibition may promote the anticancer effect of ALS and sensitize the chemotherapy in HepG2 cells. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Development and Performance of Alternative Electricity Sector Pathways Subject to Multiple Climate and Water Projections

NASA Astrophysics Data System (ADS)

Newmark, R. L.; Vorosmarty, C. J.; Miara, A.; Cohen, S.; Macknick, J.; Sun, Y.; Corsi, F.; Fekete, B. M.; Tidwell, V. C.

2017-12-01

Climate change impacts on air temperatures and water availability have the potential to alter future electricity sector investment decisions as well as the reliability and performance of the power sector. Different electricity sector configurations are more or less vulnerable to climate-induced changes. For example, once-through cooled thermal facilities are the most cost-effective and efficient technologies under cooler and wetter conditions, but can be substantially affected by and vulnerable to warmer and drier conditions. Non-thermal renewable technologies, such as PV and wind, are essentially "drought-proof" but have other integration and reliability challenges. Prior efforts have explored the impacts of climate change on electric sector development for a limited set of climate and electricity scenarios. Here, we provide a comprehensive suite of scenarios that evaluate how different electricity sector pathways could be affected by a range of climate and water resource conditions. We use four representative concentration pathway (RCP) scenarios under five global circulation models (GCM) as climate drivers to a Water Balance Model (WBM), to provide twenty separate future climate-water conditions. These climate-water conditions influence electricity sector development from present day to 2050 as determined using the Regional Energy Deployment Systems (ReEDS) model. Four unique electricity sector pathways will be considered, including business-as-usual, carbon cap, high renewable energy technology costs, and coal reliance scenarios. The combination of climate-water and electricity sector pathway scenarios leads to 80 potential future cases resulting in different national and regional electricity infrastructure configurations. The vulnerability of these configurations in relation to climate change (including in-stream thermal pollution impacts and environmental regulations) is evaluated using the Thermoelectric Power and Thermal Pollution (TP2M) model, providing quantitative estimates of the power sector's ability to meet loads, given changes in air temperature, water temperature, and water availability.

Low-dose occupational exposure to benzene and signal transduction pathways involved in the regulation of cellular response to oxidative stress.

PubMed

Fenga, Concettina; Gangemi, Silvia; Giambò, Federica; Tsitsimpikou, Christina; Golokhvast, Kirill; Tsatsakis, Aristidis; Costa, Chiara

2016-02-15

Benzene metabolism seems to modulate NF-κB, p38-MAPK (mitogen-activated protein kinase) and signal transducer and activator of transcription 3 (STAT3) signalling pathways via the production of reactive oxygen species. This study aims to evaluate the effects of low-dose, long-term exposure on NF-κB, STAT3, p38-MAPK and stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK) signal transduction pathways in peripheral blood mononuclear cells in gasoline station attendants. The influence of consumption of vegetables and fruits on these pathways has also been evaluated. A total of 91 men, employed in gasoline stations located in eastern Sicily, were enrolled for this study and compared with a control group of 63 male office workers with no history of exposure to benzene. The exposure was assessed by measuring urinary trans,trans-muconic acid (t,t-MA) concentration. Quantitative analyses were performed for proteins NF-κB p65, phospho-NF-κB p65, phospho-IκB-α, phospho-SAPK/JNK, phospho-p38 MAPK and phospho-STAT3 using an immunoenzymatic assay. The results of this study indicate significantly higher t,t-MA levels in gasoline station attendants. With regard to NF-κB, phospho-IκB-α and phospho-STAT3 proteins, statistically significant differences were observed in workers exposed to benzene. However, no differences were observed in SAPK/JNK and p38-MAPK activation. These changes were positively correlated with t,t-MA levels, but only phospho-NF-κB p65 was associated with the intake of food rich in antioxidant active principles. Chronic exposure to low-dose benzene can modulate signal transduction pathways activated by oxidative stress and involved in cell proliferation and apoptosis. This could represent a possible mechanism of carcinogenic action of chronic benzene exposure. Copyright © 2016 Elsevier Inc. All rights reserved.

Modeling Functional Neuroanatomy for an Anatomy Information System

PubMed Central

Niggemann, Jörg M.; Gebert, Andreas; Schulz, Stefan

2008-01-01

Objective Existing neuroanatomical ontologies, databases and information systems, such as the Foundational Model of Anatomy (FMA), represent outgoing connections from brain structures, but cannot represent the “internal wiring” of structures and as such, cannot distinguish between different independent connections from the same structure. Thus, a fundamental aspect of Neuroanatomy, the functional pathways and functional systems of the brain such as the pupillary light reflex system, is not adequately represented. This article identifies underlying anatomical objects which are the source of independent connections (collections of neurons) and uses these as basic building blocks to construct a model of functional neuroanatomy and its functional pathways. Design The basic representational elements of the model are unnamed groups of neurons or groups of neuron segments. These groups, their relations to each other, and the relations to the objects of macroscopic anatomy are defined. The resulting model can be incorporated into the FMA. Measurements The capabilities of the presented model are compared to the FMA and the Brain Architecture Management System (BAMS). Results Internal wiring as well as functional pathways can correctly be represented and tracked. Conclusion This model bridges the gap between representations of single neurons and their parts on the one hand and representations of spatial brain structures and areas on the other hand. It is capable of drawing correct inferences on pathways in a nervous system. The object and relation definitions are related to the Open Biomedical Ontology effort and its relation ontology, so that this model can be further developed into an ontology of neuronal functional systems. PMID:18579841

Precipitation pulse dynamics of carbon sequestration and efflux in highly weatherable soils

NASA Astrophysics Data System (ADS)

Barron-Gafford, G.; Minor, R.; Van Haren, J. L.; Dontsova, K.; Troch, P. A.

2013-12-01

Soils are the primary pool for terrestrial carbon on Earth, and loss of that carbon to the atmosphere or hydrosphere represents a significant efflux that can impact a host of other downstream processes. Soil respiration (Rsoil), the efflux of CO2 to the atmosphere, represents the major pathway by which carbon is lost from the soil system in more weathered soils. However, in newly formed soils, chemical weathering can significantly deplete soil CO2 concentrations. As vegetation colonizes these soils, multiple interacting and contradictory pathways evolve such that soil CO2 concentrations increase in response to plant inputs but are decreased through chemical reactions. Furthermore, abiotic drivers of soil temperature and moisture likely differentially affect these processes. Understanding the bio-geo-chemical drivers and feedbacks associated with soil CO2 production and efflux in the critical zone necessitates an integrated science approach, drawing on input from plant physiologists, bio- and geochemists, and hydrologists. Here, we created a series of 1-meter deep mesocosms filled with granular basalt that supported either a woody mesquite shrub, a bunchgrass, or was left as bare soil. Use of multiple plant functional types allowed us to explore the impacts of plant structure (primarily rooting profiles) on critical zone function in terms of water and carbon exchange surrounding precipitation pulse dynamics. Each mesocosm was outfitted with an array of soil moisture, temperature, water potential, and CO2 concentration sensors at the near-surface, 30, 55, and 80cm depths to quantify patterns of soil moisture and respiratory CO2 efflux in response to rainfall events of varying magnitude and intervening periods of drought. Five replicates of each were maintained under current ambient or projected (+4oC) air temperatures. In addition, we used minirhizotrons to quantify the response of roots to episodic rainfall and confirm differences among plant types and collected soils solution samples to quantify dissolved inorganic carbon (DIC), pH, and other solute concentrations. Importantly, we found Rsoil dynamics to be nearly in direct contrast to our classic understanding of patterns of soil CO2 efflux after rain events. Rsoil rates declined immediately upon wetting and gradually increased to pre-rain rates as the soils dried. Investigation into soil CO2 profile data showed that CO2 concentrations just below the surface declined significantly from near-ambient levels to near ~50ppm, which would directly impact rates of Rsoil. We detected differences among plant functional types in terms of rooting depth, water use, photosynthetic uptake, base rates of Rsoil, the time required to return to pre-rain rates of Rsoil, and the rates of soil weathering. Combining aboveground measurements of carbon uptake with these belowground estimates of carbon pools and efflux will allow us to make much more informed projections of carbon dynamics within highly weatherable soils across a range of global climate change projections and plant functional types.

Combining a nontargeted and targeted metabolomics approach to identify metabolic pathways significantly altered in polycystic ovary syndrome.

PubMed

Chang, Alice Y; Lalia, Antigoni Z; Jenkins, Gregory D; Dutta, Tumpa; Carter, Rickey E; Singh, Ravinder J; Nair, K Sreekumaran

2017-06-01

Polycystic ovary syndrome (PCOS) is a condition of androgen excess and chronic anovulation frequently associated with insulin resistance. We combined a nontargeted and targeted metabolomics approach to identify pathways and metabolites that distinguished PCOS from metabolic syndrome (MetS). Twenty obese women with PCOS were compared with 18 obese women without PCOS. Both groups met criteria for MetS but could not have diabetes mellitus or take medications that treat PCOS or affect lipids or insulin sensitivity. Insulin sensitivity was derived from the frequently sampled intravenous glucose tolerance test. A nontargeted metabolomics approach was performed on fasting plasma samples to identify differentially expressed metabolites, which were further evaluated by principal component and pathway enrichment analysis. Quantitative targeted metabolomics was then applied on candidate metabolites. Measured metabolites were tested for associations with PCOS and clinical variables by logistic and linear regression analyses. This multiethnic, obese sample was matched by age (PCOS, 37±6; MetS, 40±6years) and body mass index (BMI) (PCOS, 34.6±5.1; MetS, 33.7±5.2kg/m 2 ). Principal component analysis of the nontargeted metabolomics data showed distinct group separation of PCOS from MetS controls. From the subset of 385 differentially expressed metabolites, 22% were identified by accurate mass, resulting in 19 canonical pathways significantly altered in PCOS, including amino acid, lipid, steroid, carbohydrate, and vitamin D metabolism. Targeted metabolomics identified many essential amino acids, including branched-chain amino acids (BCAA) that were elevated in PCOS compared with MetS. PCOS was most associated with BCAA (P=.02), essential amino acids (P=.03), the essential amino acid lysine (P=.02), and the lysine metabolite α-aminoadipic acid (P=.02) in models adjusted for surrogate variables representing technical variation in metabolites. No significant differences between groups were observed in concentrations of free fatty acids or vitamin D metabolites. Evaluation of the relationship of metabolites with clinical characteristics showed 1) negative associations of essential and BCAA with insulin sensitivity and sex hormone-binding globulin and 2) positive associations with homeostasis model of insulin resistance and free testosterone; metabolites were not associated with BMI or percent body fat. PCOS was associated with significant metabolic alterations not attributed exclusively to androgen-related pathways, obesity, or MetS. Concentrations of essential amino acids and BCAA are increased in PCOS, which might result from or contribute to their insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Combining a Nontargeted and Targeted Metabolomics Approach to Identify Metabolic Pathways Significantly Altered in Polycystic Ovary Syndrome

PubMed Central

Chang, Alice Y.; Lalia, Antigoni Z.; Jenkins, Gregory D.; Dutta, Tumpa; Carter, Rickey E.; Singh, Ravinder J.; Sreekumaran Nair, K.

2017-01-01

Objective Polycystic ovary syndrome (PCOS) is a condition of androgen excess and chronic anovulation frequently associated with insulin resistance. We combined a nontargeted and targeted metabolomics approach to identify pathways and metabolites that distinguished PCOS from metabolic syndrome (MetS). Methods Twenty obese women with PCOS were compared with 18 obese women without PCOS. Both groups met criteria for MetS but could not have diabetes mellitus or take medications that treat PCOS or affect lipids or insulin sensitivity. Insulin sensitivity was derived from the frequently sampled intravenous glucose tolerance test. A nontargeted metabolomics approach was performed on fasting plasma samples to identify differentially expressed metabolites, which were further evaluated by principal component and pathway enrichment analysis. Quantitative targeted metabolomics was then applied on candidate metabolites. Measured metabolites were tested for associations with PCOS and clinical variables by logistic and linear regression analyses. Results This multiethnic, obese sample was matched by age (PCOS, 37 ± 6; MetS, 40 ± 6 years) and body mass index (BMI) (PCOS, 34.6 ± 5.1; MetS, 33.7 ± 5.2 kg/m2). Principal component analysis of the nontargeted metabolomics data showed distinct group separation of PCOS from MetS controls. From the subset of 385 differentially expressed metabolites, 22% were identified by accurate mass, resulting in 19 canonical pathways significantly altered in PCOS, including amino acid, lipid, steroid, carbohydrate, and vitamin D metabolism. Targeted metabolomics identified many essential amino acids, including branched-chain amino acids (BCAA) that were elevated in PCOS compared with MetS. PCOS was most associated with BCAA (P = .02), essential amino acids (P = .03), the essential amino acid lysine (P = .02), and the lysine metabolite α-aminoadipic acid (P = .02) in models adjusted for surrogate variables representing technical variation in metabolites. No significant differences between groups were observed in concentrations of free fatty acids or vitamin D metabolites. Evaluation of the relationship of metabolites with clinical characteristics showed 1) negative associations of essential and BCAA with insulin sensitivity and sex hormone–binding globulin and 2) positive associations with homeostasis model of insulin resistance and free testosterone; metabolites were not associated with BMI or percent body fat. Conclusions PCOS was associated with significant metabolic alterations not attributed exclusively to androgen-related pathways, obesity, or MetS. Concentrations of essential amino acids and BCAA are increased in PCOS, which might result from or contribute to their insulin resistance. PMID:28521878

Projections of atmospheric nitrous oxide under scenarios of improved agriculture and industrial efficiencies, diet modification, and representative concentration pathways (RCPs)

NASA Astrophysics Data System (ADS)

Davidson, E. A.

2011-12-01

Atmospheric concentrations of nitrous oxide (N2O), now at about 325ppb, have been increasing since the Industrial Revolution, as livestock herds increased globally and as use of synthetic-N fertilizers increased after WWII. The agricultural sector produces 70-80% of anthropogenic N2O. Significantly reducing those emissions while also improving the diets of the growing global human population will be very challenging. Increases in atmospheric N2O since 1860 are consistent with emissions factors of 2.5% of annual fertilizer-N usage and 2.0% of annual manure-N production being converted to N2O. These factors include both direct and indirect emissions attributable to these sources. Here I present projections of N2O emissions for a variety of scenarios including: (1) FAO population/diet scenarios with no changes in emission factors; (2) per-capita protein consumption in the developed world declines to 1980 levels by 2030 and only half of that is obtained from animal products, thus cutting global manure production by about 20%; (3) improvements in N-use efficiency and manure management reduce the emission factors by 50% by 2050; (4) same as 3 but industrial and transportation emissions are similarly reduced by 50% by 2050; and (5) all mitigations together. These projections are then compared to the four representative concentration pathways (RCPs) developed for the IPCC-AR5. With no further mitigation, the projections are consistent with RCP8.5, with atmospheric N2O at 368 ppb in 2050. RCP8.5 is a reasonable representation of N2O concentrations with growing agricultural production to feed a growing and better-nourished population, without improvements in agricultural efficiencies or changes in developed world diets. Major reductions in per-capita meat consumption in the developed world reduce projected 2050 N2O to 256 ppb, which is in line with RCP6.0. Cutting emission factors in half but without diet change would also lower projected 2050 N2O to 252ppb. Adding 50% improvements in other sectors reduces the 2050 N2O to 350ppm, which is in line with RCP4.5. Combining these improved efficiencies with reduced meat consumption results in leveling off of atmospheric N2O at 341 ppb in 2050, which achieves the most optimistic scenario of RCP3PD. All of these scenarios involve rather optimistic assumptions. Only the combination of technological and management improvements that increase N-use efficiencies by crops and decrease losses from manure management and significant reduction in meat consumption in the developed world can achieve stabilization of atmospheric N2O by 2050.

Socioeconomic Status, Schooling, and the Developmental Trajectories of Adolescents

ERIC Educational Resources Information Center

Crosnoe, Robert; Huston, Aletha C.

2007-01-01

The socioeconomic stratification of American society profoundly influences how the life course unfolds by shaping various developmental pathways as well as the connections among these pathways. Drawing on a nationally representative sample of American adolescents, this study charted trajectories of personal control and parental consultation from…

High concentrations of atmospheric ammonia induce alterations of gene expression in the breast muscle of broilers (Gallus gallus) based on RNA-Seq.

PubMed

Yi, Bao; Chen, Liang; Sa, Renna; Zhong, Ruqing; Xing, Huan; Zhang, Hongfu

2016-08-11

High concentrations of atmospheric ammonia are one of the key environmental stressors affecting broiler production performance, which causes remarkable economic losses as well as potential welfare problems of the broiler industry. Previous reports demonstrated that high levels of ammonia altered body fat distribution and meat quality of broilers. However, the molecular mechanisms and metabolic pathways in breast muscle altered by high concentrations of ambient ammonia exposure on broilers are still unknown. This study utilized RNA-Seq to compare the transcriptomes of breast muscles to identify differentially enriched genes in broilers exposed to high and low concentrations of atmospheric ammonia. A total of 267 promising candidate genes were identified by differential expression analysis, among which 67 genes were up-regulated and 189 genes were down-regulated. Bioinformatics analysis suggested that the up and down-regulation of these genes were involved in the following two categories of cellular pathways and metabolisms: Steroid biosynthesis (gga00100) and peroxisome proliferator-activated receptor (PPAR) signaling pathway (gga03320), which both participated in the lipid metabolism processes. This study suggests that longtime exposure to high concentrations of aerial ammonia can change fat content in breast muscle, meat quality and palatability via altering expression level of genes participating in important lipid metabolism pathways. These findings have provided novel insights into our understanding of molecular mechanisms of breast muscles exposed to ammonia in broilers. This study provides new information that could be used for genetic breeding and nutritional intervention in production practice of broilers industry in the future.

Simulating Chemical Kinetics Without Differential Equations: A Quantitative Theory Based on Chemical Pathways.

PubMed

Bai, Shirong; Skodje, Rex T

2017-08-17

A new approach is presented for simulating the time-evolution of chemically reactive systems. This method provides an alternative to conventional modeling of mass-action kinetics that involves solving differential equations for the species concentrations. The method presented here avoids the need to solve the rate equations by switching to a representation based on chemical pathways. In the Sum Over Histories Representation (or SOHR) method, any time-dependent kinetic observable, such as concentration, is written as a linear combination of probabilities for chemical pathways leading to a desired outcome. In this work, an iterative method is introduced that allows the time-dependent pathway probabilities to be generated from a knowledge of the elementary rate coefficients, thus avoiding the pitfalls involved in solving the differential equations of kinetics. The method is successfully applied to the model Lotka-Volterra system and to a realistic H 2 combustion model.

Relative Contributions of Agricultural Drift, Para-Occupational ...

EPA Pesticide Factsheets

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. Methods: From studies in North American agricultural areas published from 1995-2015, we abstracted dust pesticide concentrations reported as summary statistics (e.g., geometric means (GM)). We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). Results: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (inter-quartile range of published data) based on 52 statistics from 7 studies. For the para-occupational pathway, GMs were 2.3 times higher (95% confidence interval [CI]: 1.5-3.3; 15 statistics, 5 studies) in homes of farmers who applied pesticides more versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95%CI: 1.1-1.4) and 1.5 (95%CI: 1.2-1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for

Incorporating Topic Assignment Constraint and Topic Correlation Limitation into Clinical Goal Discovering for Clinical Pathway Mining.

PubMed

Xu, Xiao; Jin, Tao; Wei, Zhijie; Wang, Jianmin

2017-01-01

Clinical pathways are widely used around the world for providing quality medical treatment and controlling healthcare cost. However, the expert-designed clinical pathways can hardly deal with the variances among hospitals and patients. It calls for more dynamic and adaptive process, which is derived from various clinical data. Topic-based clinical pathway mining is an effective approach to discover a concise process model. Through this approach, the latent topics found by latent Dirichlet allocation (LDA) represent the clinical goals. And process mining methods are used to extract the temporal relations between these topics. However, the topic quality is usually not desirable due to the low performance of the LDA in clinical data. In this paper, we incorporate topic assignment constraint and topic correlation limitation into the LDA to enhance the ability of discovering high-quality topics. Two real-world datasets are used to evaluate the proposed method. The results show that the topics discovered by our method are with higher coherence, informativeness, and coverage than the original LDA. These quality topics are suitable to represent the clinical goals. Also, we illustrate that our method is effective in generating a comprehensive topic-based clinical pathway model.

Incorporating Topic Assignment Constraint and Topic Correlation Limitation into Clinical Goal Discovering for Clinical Pathway Mining

PubMed Central

Xu, Xiao; Wei, Zhijie

2017-01-01

Clinical pathways are widely used around the world for providing quality medical treatment and controlling healthcare cost. However, the expert-designed clinical pathways can hardly deal with the variances among hospitals and patients. It calls for more dynamic and adaptive process, which is derived from various clinical data. Topic-based clinical pathway mining is an effective approach to discover a concise process model. Through this approach, the latent topics found by latent Dirichlet allocation (LDA) represent the clinical goals. And process mining methods are used to extract the temporal relations between these topics. However, the topic quality is usually not desirable due to the low performance of the LDA in clinical data. In this paper, we incorporate topic assignment constraint and topic correlation limitation into the LDA to enhance the ability of discovering high-quality topics. Two real-world datasets are used to evaluate the proposed method. The results show that the topics discovered by our method are with higher coherence, informativeness, and coverage than the original LDA. These quality topics are suitable to represent the clinical goals. Also, we illustrate that our method is effective in generating a comprehensive topic-based clinical pathway model. PMID:29065617

New Insights into the Compositional Dependence of Li-Ion Transport in Polymer-Ceramic Composite Electrolytes.

PubMed

Zheng, Jin; Hu, Yan-Yan

2018-01-31

Composite electrolytes are widely studied for their potential in realizing improved ionic conductivity and electrochemical stability. Understanding the complex mechanisms of ion transport within composites is critical for effectively designing high-performance solid electrolytes. This study examines the compositional dependence of the three determining factors for ionic conductivity, including ion mobility, ion transport pathways, and active ion concentration. The results show that with increase in the fraction of ceramic Li 7 La 3 Zr 2 O 12 (LLZO) phase in the LLZO-poly(ethylene oxide) composites, ion mobility decreases, ion transport pathways transit from polymer to ceramic routes, and the active ion concentration increases. These changes in ion mobility, transport pathways, and concentration collectively explain the observed trend of ionic conductivity in composite electrolytes. Liquid additives alter ion transport pathways and increase ion mobility, thus enhancing ionic conductivity significantly. It is also found that a higher content of LLZO leads to improved electrochemical stability of composite electrolytes. This study provides insight into the recurring observations of compositional dependence of ionic conductivity in current composite electrolytes and pinpoints the intrinsic limitations of composite electrolytes in achieving fast ion conduction.

The in vitro metabolism of irinotecan (CPT-11) by carboxylesterase and β-glucuronidase in human colorectal tumours

PubMed Central

Tobin, Peter; Clarke, Stephen; Seale, J Paul; Lee, Soon; Solomon, Michael; Aulds, Sally; Crawford, Michael; Gallagher, James; Eyers, Tony; Rivory, Laurent

2006-01-01

Aims Irinotecan (CPT-11) is a prodrug that is used to treat metastatic colorectal cancer. It is activated to the topoisomerase poison SN-38 by carboxylesterases. SN-38 is metabolized to its inactive glucuronide, SN-38 glucuronide. The aim of this study was to determine, the reactivation of SN-38 from SN-38 glucuronide by β-glucuronidase may represent a significant pathway of SN-38 formation. Methods The production of SN-38 from irinotecan and SN-38 glucuronide (2.4, 9.6 and 19.2 µm) was measured in homogenates of human colorectal tumour, and matched normal colon mucosa from 21 patients). Results The rate of conversion of irinotecan (9.6 µM) was lower in tumour tissue than matched normal colon mucosa samples (0.30 ± 0.14 pmol min−1 mg−1 protein and 0.77 ± 0.59 pmol min−1 mg−1 protein, respectively; P < 0.005). In contrast, no significant difference was observed in β-glucuronidase activity between tumour and matched normal colon samples (4.56 ± 6.9 pmol min−1 mg−1 protein and 3.62 ± 2.95 pmol min−1 mg−1 protein, respectively, using 9.6 µM SN-38 glucuronide; P > 0.05). β-Glucuronidase activity in tumour correlated to that observed in matched normal tissue (r2 > 0.23, P < 0.05), whereas this was not the case for carboxylesterase activity. At equal concentrations of irinotecan and SN-38 glucuronide, the rate of β-glucuronidase-mediated SN-38 production was higher than that formed from irinotecan in both tumour and normal tissue (P < 0.05). However, at concentrations that reflect the relative plasma concentrations observed in patients, the rate of SN-38 production via these two pathways was comparable. Conclusions Tumour β-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo. PMID:16842384

Dynamics of Phosphorus export from small forested catchments in low mountain ranges in Germany

NASA Astrophysics Data System (ADS)

Julich, Stefan; Julich, Dorit; Benning, Raphael; Feger, Karl-Heinz

2017-04-01

Phosphorus (P) plays an important role in the nutrition of forest ecosystem. The transport of P in forest soils predominantly occurs along preferential water flow pathways bypassing large parts of the soil matrix. Therefore, rapid flow processes by preferential flow and/or during storm events may lead to significant P losses from forest soils. However only little knowledge about the dynamics, magnitude and driving processes of P exports into surface water exist. In this contribution, we present the results of two studies where two small forested catchments have been monitored for a period around 3 years. Both catchments are situated in low mountain ranges in Saxony (catchment size 21 ha) and Thuringia (catchment size 5 ha) representing medium P contents in the topsoil of 1142 mg kg-1 and 834 mg kg-1 respectively. During the regular sampling (monthly to weekly sampling frequency), the mean Total-P concentrations of 23 μg L-1(Thuringian Site) and 8 μg L-1(Saxonian Site) have been measured. However, during single storm events Total-P concentrations increased considerably with maximum concentrations of 134 μg L-1(Thuringian Site) and 203 μg L-1(Saxonian Site). Our findings indicate that during storm events, especially after longer dry periods, significant amounts of phosphorus can be exported from forest ecosystems. Comparison of discharge-concentration patterns of Total-P, Nitrogen and DOC, as well as dye tracer experiments, suggest that preferential flow along biopores and stone surfaces, and the interface between mineral soil and litter layer are main pathways of export from forests. For the site in Saxony we calculated mean annual export rates of 32.8 to 33.5 g ha-1 a-1 based on the weekly sampling with different load calculation methods (flow weighted methods up to linear regression models). If the events are included into the annual load calculation the mean annual export fluxes increase from 47.8 to 58.6 g ha-1 a-1 based on the different load calculation methods. This implies that the estimation of P-exports from forested catchments need to be based on appropriate monitoring schemes and load estimation methods.

Advanced glycation end products and sorbitol in blood from differently compensated diabetic dogs.

PubMed

Comazzi, S; Bertazzolo, W; Bonfanti, U; Spagnolo, V; Sartorelli, P

2008-06-01

Canine diabetes mellitus (DM) is a common metabolic disorder with long term complications, most of which are caused by glycosylation of structural proteins, decreases in antioxidant concentrations, altered osmotic balance and hypoxia due to impaired oxygen transport. Previous studies have demonstrated that under hyperglycemic conditions canine erythrocytes undergo swelling, probably due to activation of the polyol pathway. The present work aimed to assess the plasma concentration of advanced glycation end (AGE) products, stable Amadori-products generated by non-enzymatic glycosylation of proteins and the intracellular concentration of sorbitol, produced by the activation of polyol pathway in 34 blood samples from diabetic dogs and in 14 controls. AGE products were significantly higher (p<0.01) in plasma from diabetic dogs compared with control animals. The sorbitol concentration in erythrocytes was also significantly higher in diabetic dogs and, in particular, in poorly compensated animals and in dogs with ketonuria. In five cases that were analysed before and after clinical improvement, sorbitol concentration was found to correlate with improvement. These results suggest that non-specific glycosylation is increased and that the polyol pathway is activated in diabetic dogs in a manner that is proportionate to the severity of disease. Moreover, the concentration of AGE products and sorbitol may be useful for monitoring the onset of diabetic complications and assessing the most appropriate therapeutic approaches for management of canine DM.

The ERK/CREB pathway is involved in the c-Ski expression induced by low TGF-β1 concentrations during primary fibroblast proliferation.

PubMed

Li, Ping; Liu, Ping; Peng, Yan; Zhang, Zhuo-Hang; Li, Xiao-Ming; Xiong, Ren-Ping; Chen, Xing; Zhao, Yan; Ning, Ya-Lei; Yang, Nan; Zhang, Bo; Zhou, Yuan-Guo

2018-06-27

Increasing evidence has suggested that bidirectional regulation of cell proliferation is one important effect of TGF-β1 in wound healing. Increased c-Ski expression plays a role in promoting fibroblast proliferation at low TGF-β1 concentrations, but the mechanism by which low TGF-β1 concentrations regulate c-Ski levels remains unclear. In this study, the proliferation of rat primary fibroblasts was assessed with an ELISA BrdU kit. The mRNA and protein expression and phosphorylation levels of corresponding factors were measured by RT-qPCR, immunohistochemistry or Western blotting. We first found that low TGF-β1 concentrations not only promoted c-Ski mRNA and protein expression in rat primary fibroblasts but also increased the phosphorylation levels of Extracellular Signal-Regulated Kinases (ERK) and cAMP response element binding (CREB) protein. An ERK kinase (mitogen-activated protein kinase kinase, MEK) inhibitor significantly inhibited ERK1/2 phosphorylation levels, markedly reducing c-Ski expression and CREB phosphorylation levels and abrogating the growth-promoting effect of low TGF-β1 concentrations. At the same time, Smad2/3 phosphorylation levels were not significantly changed. Taken together, these results suggest that the increased cell proliferation induced by low TGF-β1 concentrations mediates c-Ski expression potentially through the ERK/CREB pathway rather than through the classic TGF-β1/Smad pathway.

Adrenocortical Hormone Abnormalities in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome

PubMed Central

Dimitrakov, Jordan; Joffe, Hylton V.; Soldin, Steven J.; Bolus, Roger; Buffington, C.A. Tony; Nickel, J Curtis

2007-01-01

Objectives To identify adrenocortical hormone abnormalities as indicators of endocrine dysfunction in CP/CPPS. Methods We simultaneously measured the serum concentrations of 12 steroids in CP/CPPS and control patients, using isotope dilution liquid chromatography followed by atmospheric pressure photospray ionization and tandem mass spectrometry. Results Twenty-seven CP/CPPS patients and 29 age-matched asymptomatic healthy controls were evaluated. In the mineralocorticoid pathway, progesterone was significantly higher, whereas corticosterone and aldosterone concentrations were significantly lower, in CP/CPPS than in controls. In the glucocorticoid pathway, 11-deoxycortisol was significantly lower, and cortisol concentrations were not different between patients and controls. In the sex steroid pathway, androstenedione and testosterone concentrations were significantly higher in CP/CPPS than in controls. Estradiol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) concentrations were not different between patients and controls. NIH-CPSI total and pain domain scores correlated positively with 17-hydroxyprogesterone and aldosterone (P<0.001) and negatively with cortisol concentrations (P<0.001). Conclusions Results suggest reduced activity of CYP21A2 (P450c21), the enzyme that converts progesterone to corticosterone, and 17-hydroxyprogesterone to 11-deoxycortisol. Furthermore, these results provide insights into the biological basis of CP/CPPS. Follow-up studies should explore the possibility that CP/CPPS patients meet the diagnostic criteria for nonclassical CAH and if hormonal findings improve or worsen in parallel with symptom severity. PMID:18308097

Soil Nitrification and N2O Production: the connection with N concentration and Soil Water Content

NASA Astrophysics Data System (ADS)

Zhu-Barker, X.; Horwath, W. R.

2016-12-01

The development of mitigation strategies to reduce nitrous oxide (N2O) emission from soils is dependent on explicating the biophysical factors affecting different N2O production pathways. Ammonia oxidation and heterotrophic denitrification are the main pathways of N2O production, depending on soil conditions such as soil moisture content, oxygen (O2) content and N substrate. Many researchers have reported that N2O production increased as substrate concentration and soil moisture content increased. However, less understood is how N fertilizer concentration and moisture content interact to affect N2O production pathways. To investigate interaction and its effect on O2 consumption, we incubated three agricultural soils (clay, sandy loam, and peat) with different concentrations of (NH4)2SO4 (0-1000 µg N g-1) under 50 %, 75%, and 100% of water holding capacity. All treatments received 15N -KNO3 to bring the concentrations of NO3-_N in soils to 50 mg kg-1 soil and the NO3- pool to an enrichment of 10 atom% 15N. In all soils, the total amount of O2 consumption and N2O production increased as soil ammonical N concentration increased. The increased soil moisture significantly promoted N2O production in sandy loam and clay loam soils, compared to the peat soil. These results indicate that N2O production increased as substrate concentration increased likely due to the onset of O2 limitation caused by ammonia oxidation.

A mathematical model of the mevalonate cholesterol biosynthesis pathway.

PubMed

Pool, Frances; Currie, Richard; Sweby, Peter K; Salazar, José Domingo; Tindall, Marcus J

2018-04-14

We formulate, parameterise and analyse a mathematical model of the mevalonate pathway, a key pathway in the synthesis of cholesterol. Of high clinical importance, the pathway incorporates rate limiting enzymatic reactions with multiple negative feedbacks. In this work we investigate the pathway dynamics and demonstrate that rate limiting steps and negative feedbacks within it act in concert to tightly regulate intracellular cholesterol levels. Formulated using the theory of nonlinear ordinary differential equations and parameterised in the context of a hepatocyte, the governing equations are analysed numerically and analytically. Sensitivity and mathematical analysis demonstrate the importance of the two rate limiting enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and squalene synthase in controlling the concentration of substrates within the pathway as well as that of cholesterol. The role of individual feedbacks, both global (between that of cholesterol and sterol regulatory element-binding protein 2; SREBP-2) and local internal (between substrates in the pathway) are investigated. We find that whilst the cholesterol SREBP-2 feedback regulates the overall system dynamics, local feedbacks activate within the pathway to tightly regulate the overall cellular cholesterol concentration. The network stability is analysed by constructing a reduced model of the full pathway and is shown to exhibit one real, stable steady-state. We close by addressing the biological question as to how farnesyl-PP levels are affected by CYP51 inhibition, and demonstrate that the regulatory mechanisms within the network work in unison to ensure they remain bounded. Copyright © 2018 Elsevier Ltd. All rights reserved.

Issue Paper on Metal Exposure Assessment

EPA Pesticide Factsheets

This paper explores the best approaches for characterizing exposure pathways and routes, estimating the most relevant exposure concentrations, linking exposure to dose, and coping with natural or background concentrations.

Caveolins: targeting pro-survival signaling in the heart and brain

PubMed Central

Stary, Creed M.; Tsutsumi, Yasuo M.; Patel, Piyush M.; Head, Brian P.; Patel, Hemal H.; Roth, David M.

2012-01-01

The present review discusses intracellular signaling moieties specific to membrane lipid rafts (MLRs) and the scaffolding proteins caveolin and introduces current data promoting their potential role in the treatment of pathologies of the heart and brain. MLRs are discreet microdomains of the plasma membrane enriched in gylcosphingolipids and cholesterol that concentrate and localize signaling molecules. Caveolin proteins are necessary for the formation of MLRs, and are responsible for coordinating signaling events by scaffolding and enriching numerous signaling moieties in close proximity. Specifically in the heart and brain, caveolins are necessary for the cytoprotective phenomenon termed ischemic and anesthetic preconditioning. Targeted overexpression of caveolin in the heart and brain leads to induction of multiple pro-survival and pro-growth signaling pathways; thus, caveolins represent a potential novel therapeutic target for cardiac and neurological pathologies. PMID:23060817

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.

PubMed

Scott, Robert A; Lagou, Vasiliki; Welch, Ryan P; Wheeler, Eleanor; Montasser, May E; Luan, Jian'an; Mägi, Reedik; Strawbridge, Rona J; Rehnberg, Emil; Gustafsson, Stefan; Kanoni, Stavroula; Rasmussen-Torvik, Laura J; Yengo, Loïc; Lecoeur, Cecile; Shungin, Dmitry; Sanna, Serena; Sidore, Carlo; Johnson, Paul C D; Jukema, J Wouter; Johnson, Toby; Mahajan, Anubha; Verweij, Niek; Thorleifsson, Gudmar; Hottenga, Jouke-Jan; Shah, Sonia; Smith, Albert V; Sennblad, Bengt; Gieger, Christian; Salo, Perttu; Perola, Markus; Timpson, Nicholas J; Evans, David M; Pourcain, Beate St; Wu, Ying; Andrews, Jeanette S; Hui, Jennie; Bielak, Lawrence F; Zhao, Wei; Horikoshi, Momoko; Navarro, Pau; Isaacs, Aaron; O'Connell, Jeffrey R; Stirrups, Kathleen; Vitart, Veronique; Hayward, Caroline; Esko, Tõnu; Mihailov, Evelin; Fraser, Ross M; Fall, Tove; Voight, Benjamin F; Raychaudhuri, Soumya; Chen, Han; Lindgren, Cecilia M; Morris, Andrew P; Rayner, Nigel W; Robertson, Neil; Rybin, Denis; Liu, Ching-Ti; Beckmann, Jacques S; Willems, Sara M; Chines, Peter S; Jackson, Anne U; Kang, Hyun Min; Stringham, Heather M; Song, Kijoung; Tanaka, Toshiko; Peden, John F; Goel, Anuj; Hicks, Andrew A; An, Ping; Müller-Nurasyid, Martina; Franco-Cereceda, Anders; Folkersen, Lasse; Marullo, Letizia; Jansen, Hanneke; Oldehinkel, Albertine J; Bruinenberg, Marcel; Pankow, James S; North, Kari E; Forouhi, Nita G; Loos, Ruth J F; Edkins, Sarah; Varga, Tibor V; Hallmans, Göran; Oksa, Heikki; Antonella, Mulas; Nagaraja, Ramaiah; Trompet, Stella; Ford, Ian; Bakker, Stephan J L; Kong, Augustine; Kumari, Meena; Gigante, Bruna; Herder, Christian; Munroe, Patricia B; Caulfield, Mark; Antti, Jula; Mangino, Massimo; Small, Kerrin; Miljkovic, Iva; Liu, Yongmei; Atalay, Mustafa; Kiess, Wieland; James, Alan L; Rivadeneira, Fernando; Uitterlinden, Andre G; Palmer, Colin N A; Doney, Alex S F; Willemsen, Gonneke; Smit, Johannes H; Campbell, Susan; Polasek, Ozren; Bonnycastle, Lori L; Hercberg, Serge; Dimitriou, Maria; Bolton, Jennifer L; Fowkes, Gerard R; Kovacs, Peter; Lindström, Jaana; Zemunik, Tatijana; Bandinelli, Stefania; Wild, Sarah H; Basart, Hanneke V; Rathmann, Wolfgang; Grallert, Harald; Maerz, Winfried; Kleber, Marcus E; Boehm, Bernhard O; Peters, Annette; Pramstaller, Peter P; Province, Michael A; Borecki, Ingrid B; Hastie, Nicholas D; Rudan, Igor; Campbell, Harry; Watkins, Hugh; Farrall, Martin; Stumvoll, Michael; Ferrucci, Luigi; Waterworth, Dawn M; Bergman, Richard N; Collins, Francis S; Tuomilehto, Jaakko; Watanabe, Richard M; de Geus, Eco J C; Penninx, Brenda W; Hofman, Albert; Oostra, Ben A; Psaty, Bruce M; Vollenweider, Peter; Wilson, James F; Wright, Alan F; Hovingh, G Kees; Metspalu, Andres; Uusitupa, Matti; Magnusson, Patrik K E; Kyvik, Kirsten O; Kaprio, Jaakko; Price, Jackie F; Dedoussis, George V; Deloukas, Panos; Meneton, Pierre; Lind, Lars; Boehnke, Michael; Shuldiner, Alan R; van Duijn, Cornelia M; Morris, Andrew D; Toenjes, Anke; Peyser, Patricia A; Beilby, John P; Körner, Antje; Kuusisto, Johanna; Laakso, Markku; Bornstein, Stefan R; Schwarz, Peter E H; Lakka, Timo A; Rauramaa, Rainer; Adair, Linda S; Smith, George Davey; Spector, Tim D; Illig, Thomas; de Faire, Ulf; Hamsten, Anders; Gudnason, Vilmundur; Kivimaki, Mika; Hingorani, Aroon; Keinanen-Kiukaanniemi, Sirkka M; Saaristo, Timo E; Boomsma, Dorret I; Stefansson, Kari; van der Harst, Pim; Dupuis, Josée; Pedersen, Nancy L; Sattar, Naveed; Harris, Tamara B; Cucca, Francesco; Ripatti, Samuli; Salomaa, Veikko; Mohlke, Karen L; Balkau, Beverley; Froguel, Philippe; Pouta, Anneli; Jarvelin, Marjo-Riitta; Wareham, Nicholas J; Bouatia-Naji, Nabila; McCarthy, Mark I; Franks, Paul W; Meigs, James B; Teslovich, Tanya M; Florez, Jose C; Langenberg, Claudia; Ingelsson, Erik; Prokopenko, Inga; Barroso, Inês

2012-09-01

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Comparison of Direct and Indirect Photolysis in Imazosulfuron Photodegradation.

PubMed

Rering, Caitlin; Williams, Katryn; Hengel, Matt; Tjeerdema, Ronald

2017-04-19

Imazosulfuron, a sulfonylurea herbicide used in rice cultivation, has been shown to undergo photodegradation in water, but neither the photochemical mechanism nor the role of indirect photolysis is known. The purpose of this study was to investigate the underlying processes that operate on imazosulfuron during aqueous photodegradation. Our data indicate that in the presence of oxygen, most photochemical degradation proceeds through a direct singlet-excited state pathway, whereas triplet-excited state imazosulfuron enhanced decay rates under low dissolved oxygen conditions. Oxidation by hydroxyl radical and singlet oxygen were not significant. At dissolved organic matter (DOM) concentrations representative of rice field conditions, fulvic acid solutions exhibited faster degradation than rice field water containing both humic and fulvic acid fractions. Both enhancement, via reaction with triplet-state DOM, and inhibition, via competition for photons, of degradation was observed in DOM solutions.

Inhibition of the high affinity myo-inositol transport system: a common mechanism of action of antibipolar drugs?

PubMed

Lubrich, B; van Calker, D

1999-10-01

The mechanism of action of antibipolar drugs like lithium, carbamazepine, and valproate that are used in the treatment of manic-depressive illness, is unknown. Lithium is believed to act through uncompetitive inhibition of inositolmonophosphatase, which results in a depletion of neural cells of inositol and a concomitant modulation of phosphoinositol signaling. Here, we show that lithium ions, carbamazepine, and valproate, but not the tricyclic antidepressant amitriptyline, inhibit at therapeutically relevant concentrations and with a time course similar to their clinical actions the high affinity myo-inositol transport in astrocyte-like cells and downregulate the level of the respective mRNA. Inhibition of inositol uptake could thus represent an additional pathway for inositol depletion, which might be relevant in the mechanism of action of all three antibipolar drugs.

Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia.

PubMed Central

Lennard, L; Gibson, B E; Nicole, T; Lilleyman, J S

1993-01-01

Two children with acute lymphoblastic leukaemia (ALL) taking daily 6-mercaptopurine as part of a national UK therapeutic trial repeatedly developed profound myelosuppression on 25% of the standard protocol dose. Both were found to have undetectable intracellular activity of thiopurine methyltransferase (TPMT), an enzyme controlling one of the major alternative catabolic pathways of 6-mercaptopurine, and both produced higher concentrations of cytotoxic drug metabolites at 10-25% of the protocol dose than other patients taking 100%. It is supposed that these patients represent the 0.33% of the normal population constitutionally lacking TPMT. It is important to recognise such individuals both to avoid fatal bone marrow failure through inadvertent overdosage, and to be reassured that an adequate drug effect can be achieved at around 10% of the standard dose. PMID:8257179

Metabolic Changes Following Perinatal Asphyxia: Role of Astrocytes and Their Interaction with Neurons.

PubMed

Logica, Tamara; Riviere, Stephanie; Holubiec, Mariana I; Castilla, Rocío; Barreto, George E; Capani, Francisco

2016-01-01

Perinatal Asphyxia (PA) represents an important cause of severe neurological deficits including delayed mental and motor development, epilepsy, major cognitive deficits and blindness. The interaction between neurons, astrocytes and endothelial cells plays a central role coupling energy supply with changes in neuronal activity. Traditionally, experimental research focused on neurons, whereas astrocytes have been more related to the damage mechanisms of PA. Astrocytes carry out a number of functions that are critical to normal nervous system function, including uptake of neurotransmitters, regulation of pH and ion concentrations, and metabolic support for neurons. In this work, we aim to review metabolic neuron-astrocyte interactions with the purpose of encourage further research in this area in the context of PA, which is highly complex and its mechanisms and pathways have not been fully elucidated to this day.

The role stratification on Indian ocean mixing under global warming

NASA Astrophysics Data System (ADS)

Praveen, V.; Valsala, V.; Ravindran, A. M.

2017-12-01

The impact of changes in Indian ocean stratification on mixing under global warming is examined. Previous studies on global warming and associated weakening of winds reported to increase the stratification of the world ocean leading to a reduction in mixing, increased acidity, reduced oxygen and there by a reduction in productivity. However this processes is not uniform and are also modulated by changes in wind pattern of the future. Our study evaluate the role of stratification and surface fluxes on mixing focusing northern Indian ocean. A dynamical downscaling study using Regional ocean Modelling system (ROMS) forced with stratification and surface fluxes from selected CMIP5 models are presented. Results from an extensive set of historical and Representative Concentration Pathways 8.5 (rcp8.5) scenario simulations are used to quantify the distinctive role of stratification on mixing.

Northwestern Pacific typhoon intensity controlled by changes in ocean temperatures.

PubMed

Mei, Wei; Xie, Shang-Ping; Primeau, François; McWilliams, James C; Pasquero, Claudia

2015-05-01

Dominant climatic factors controlling the lifetime peak intensity of typhoons are determined from six decades of Pacific typhoon data. We find that upper ocean temperatures in the low-latitude northwestern Pacific (LLNWP) and sea surface temperatures in the central equatorial Pacific control the seasonal average lifetime peak intensity by setting the rate and duration of typhoon intensification, respectively. An anomalously strong LLNWP upper ocean warming has favored increased intensification rates and led to unprecedentedly high average typhoon intensity during the recent global warming hiatus period, despite a reduction in intensification duration tied to the central equatorial Pacific surface cooling. Continued LLNWP upper ocean warming as predicted under a moderate [that is, Representative Concentration Pathway (RCP) 4.5] climate change scenario is expected to further increase the average typhoon intensity by an additional 14% by 2100.

Metabolic Changes Following Perinatal Asphyxia: Role of Astrocytes and Their Interaction with Neurons

PubMed Central

Logica, Tamara; Riviere, Stephanie; Holubiec, Mariana I.; Castilla, Rocío; Barreto, George E.; Capani, Francisco

2016-01-01

Perinatal Asphyxia (PA) represents an important cause of severe neurological deficits including delayed mental and motor development, epilepsy, major cognitive deficits and blindness. The interaction between neurons, astrocytes and endothelial cells plays a central role coupling energy supply with changes in neuronal activity. Traditionally, experimental research focused on neurons, whereas astrocytes have been more related to the damage mechanisms of PA. Astrocytes carry out a number of functions that are critical to normal nervous system function, including uptake of neurotransmitters, regulation of pH and ion concentrations, and metabolic support for neurons. In this work, we aim to review metabolic neuron-astrocyte interactions with the purpose of encourage further research in this area in the context of PA, which is highly complex and its mechanisms and pathways have not been fully elucidated to this day. PMID:27445788

IL-1β-induced and p38MAPK-dependent activation of the mitogen-activated protein kinase-activated protein kinase 2 (MK2) in hepatocytes: Signal transduction with robust and concentration-independent signal amplification

PubMed Central

Kulawik, Andreas; Engesser, Raphael; Ehlting, Christian; Raue, Andreas; Albrecht, Ute; Hahn, Bettina; Lehmann, Wolf-Dieter; Gaestel, Matthias; Klingmüller, Ursula; Häussinger, Dieter; Timmer, Jens; Bode, Johannes G.

2017-01-01

The IL-1β induced activation of the p38MAPK/MAPK-activated protein kinase 2 (MK2) pathway in hepatocytes is important for control of the acute phase response and regulation of liver regeneration. Many aspects of the regulatory relevance of this pathway have been investigated in immune cells in the context of inflammation. However, very little is known about concentration-dependent activation kinetics and signal propagation in hepatocytes and the role of MK2. We established a mathematical model for IL-1β-induced activation of the p38MAPK/MK2 pathway in hepatocytes that was calibrated to quantitative data on time- and IL-1β concentration-dependent phosphorylation of p38MAPK and MK2 in primary mouse hepatocytes. This analysis showed that, in hepatocytes, signal transduction from IL-1β via p38MAPK to MK2 is characterized by strong signal amplification. Quantification of p38MAPK and MK2 revealed that, in hepatocytes, at maximum, 11.3% of p38MAPK molecules and 36.5% of MK2 molecules are activated in response to IL-1β. The mathematical model was experimentally validated by employing phosphatase inhibitors and the p38MAPK inhibitor SB203580. Model simulations predicted an IC50 of 1–1.2 μm for SB203580 in hepatocytes. In silico analyses and experimental validation demonstrated that the kinase activity of p38MAPK determines signal amplitude, whereas phosphatase activity affects both signal amplitude and duration. p38MAPK and MK2 concentrations and responsiveness toward IL-1β were quantitatively compared between hepatocytes and macrophages. In macrophages, the absolute p38MAPK and MK2 concentration was significantly higher. Finally, in line with experimental observations, the mathematical model predicted a significantly higher half-maximal effective concentration for IL-1β-induced pathway activation in macrophages compared with hepatocytes, underscoring the importance of cell type-specific differences in pathway regulation. PMID:28223354

A review of soil cadmium contamination in China including a health risk assessment.

PubMed

Wang, Lin; Cui, Xiangfen; Cheng, Hongguang; Chen, Fei; Wang, Jiantong; Zhao, Xinyi; Lin, Chunye; Pu, Xiao

2015-11-01

Cadmium (Cd) is one of the most serious soil contaminants in China, and it poses an increasing risk to human health as large amounts of Cd are emitted into the environment. However, knowledge about soil Cd concentrations and the human health risks of these concentrations at a national scale is limited. In this study, we conducted a review of 190 articles about soil Cd concentrations during 2001 to 2010. The study involved 146 cities in China, and we quantified the risks to human health according to different regions. The results showed that elevated Cd levels were present compared to the background value of soil in 1990, and the soil Cd concentrations in the Guangxi province exceeded even the class III Soil Environmental Quality standard, which is the limit for the normal growth of plants. The Chinese soil Cd concentrations ranged from 0.003 mg kg(-1) to 9.57 mg kg(-1). The soil Cd concentrations had the following trend: northwest > southwest > south central > east > northeast > north. The sources of soil Cd are mainly from smelting, mining, waste disposal, fertilizer and pesticide application, and vehicle exhaust, etc. but differentiated in various regions. The soil Cd contamination in urban areas was more serious than contamination in the agricultural areas. Currently, there is no significant non-carcinogenic risk in any of the provinces. Regarding the different exposure pathways, the dermal pathway is the primary source of soil Cd exposure, and the risk associated with this pathway is generally hundreds of times higher than the risk for an ingestion pathway. For most of the provinces, the health risk to the urban population was higher than the risk to the rural population. For each population, the carcinogenic risk was less than 10(-6) in most of the provinces, except for the urban population in the Hunan province. If the other exposure pathways are fully considered, then the people in these areas may have a higher carcinogenic risk. This review provides a comprehensive assessment of soil Cd pollution in China, and it identifies policy recommendations for pollution mitigation and environmental management in the relevant regions.

The combined effect of dissolved oxygen and nitrite on N2O production by ammonia oxidizing bacteria in an enriched nitrifying sludge.

PubMed

Peng, Lai; Ni, Bing-Jie; Ye, Liu; Yuan, Zhiguo

2015-04-15

Both nitrite [Formula: see text] and dissolved oxygen (DO) play important roles in nitrous oxide (N2O) production by ammonia oxidizing bacteria (AOB). However, few studies focused on the combined effect of them on N2O production by AOB as well as the corresponding mechanisms. In this study, N2O production by an enriched nitrifying sludge, consisting of both AOB and nitrite-oxidizing bacteria (NOB), was investigated under various [Formula: see text] and DO concentrations. At each investigated DO level, both the biomass specific N2O production rate and the N2O emission factor (the ratio between N2O nitrogen emitted and the ammonium nitrogen converted) increased as [Formula: see text] concentration increased from 3 mg N/L to 50 mg N/L. However, at each investigated [Formula: see text] level, the maximum biomass specific N2O production rate occurred at DO of 0.85 mg O2/L, while the N2O emission factor decreased as DO increased from 0.35 to 3.5 mg O2/L. The analysis of the process data using a mathematical N2O model incorporating both the AOB denitrification and hydroxylamine (NH2OH) oxidation pathways indicated that the contribution of AOB denitrification pathway increased as [Formula: see text] concentration increased, but decreased as DO concentration increased, accompanied by a corresponding change in the contribution of NH2OH oxidation pathway to N2O production. The AOB denitrification pathway was predominant in most cases, with the NH2OH oxidation pathway making a comparable contribution only at high DO level (e.g. 3.5 mg O2/L). Copyright © 2015 Elsevier Ltd. All rights reserved.

Modeling the flux of metabolites in the juvenile hormone biosynthesis pathway using generalized additive models and ordinary differential equations.

PubMed

Martínez-Rincón, Raúl O; Rivera-Pérez, Crisalejandra; Diambra, Luis; Noriega, Fernando G

2017-01-01

Juvenile hormone (JH) regulates development and reproductive maturation in insects. The corpora allata (CA) from female adult mosquitoes synthesize fluctuating levels of JH, which have been linked to the ovarian development and are influenced by nutritional signals. The rate of JH biosynthesis is controlled by the rate of flux of isoprenoids in the pathway, which is the outcome of a complex interplay of changes in precursor pools and enzyme levels. A comprehensive study of the changes in enzymatic activities and precursor pool sizes have been previously reported for the mosquito Aedes aegypti JH biosynthesis pathway. In the present studies, we used two different quantitative approaches to describe and predict how changes in the individual metabolic reactions in the pathway affect JH synthesis. First, we constructed generalized additive models (GAMs) that described the association between changes in specific metabolite concentrations with changes in enzymatic activities and substrate concentrations. Changes in substrate concentrations explained 50% or more of the model deviances in 7 of the 13 metabolic steps analyzed. Addition of information on enzymatic activities almost always improved the fitness of GAMs built solely based on substrate concentrations. GAMs were validated using experimental data that were not included when the model was built. In addition, a system of ordinary differential equations (ODE) was developed to describe the instantaneous changes in metabolites as a function of the levels of enzymatic catalytic activities. The results demonstrated the ability of the models to predict changes in the flux of metabolites in the JH pathway, and can be used in the future to design and validate experimental manipulations of JH synthesis.

Hanford Environmental Dose Reconstruction Project

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

McMakin, A.H.; Cannon, S.D.; Finch, S.M.

1992-07-01

The objective of the Hanford Environmental Dose Reconstruction (HEDR) Project is to estimate the radiation doses that individuals and populations could have received from nuclear operations at Hanford since 1944. The TSP consists of experts in environmental pathways, epidemiology, surface-water transport, ground-water transport, statistics, demography, agriculture, meteorology, nuclear engineering, radiation dosimetry, and cultural anthropology. Included are appointed technical members representing the states of Oregon, Washington, and Idaho, a representative of Native American tribes, and an individual representing the public. The project is divided into the following technical tasks. These tasks correspond to the path radionuclides followed from release to impactmore » on humans (dose estimates): Source terms, environmental transport, environmental monitoring data, demography, food consumption, and agriculture, and environmental pathways and dose estimates. Progress is discussed.« less

Hanford Environmental Dose Reconstruction Project. Monthly report

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

McMakin, A.H.; Cannon, S.D.; Finch, S.M.

1992-07-01

The objective of the Hanford Environmental Dose Reconstruction (HEDR) Project is to estimate the radiation doses that individuals and populations could have received from nuclear operations at Hanford since 1944. The TSP consists of experts in environmental pathways, epidemiology, surface-water transport, ground-water transport, statistics, demography, agriculture, meteorology, nuclear engineering, radiation dosimetry, and cultural anthropology. Included are appointed technical members representing the states of Oregon, Washington, and Idaho, a representative of Native American tribes, and an individual representing the public. The project is divided into the following technical tasks. These tasks correspond to the path radionuclides followed from release to impactmore » on humans (dose estimates): Source terms, environmental transport, environmental monitoring data, demography, food consumption, and agriculture, and environmental pathways and dose estimates. Progress is discussed.« less

New Targets and Inhibitors of Mycobacterial Sulfur Metabolism§

PubMed Central

Paritala, Hanumantharao; Carroll, Kate S.

2015-01-01

The identification of new antibacterial targets is urgently needed to address multidrug resistant and latent tuberculosis infection. Sulfur metabolic pathways are essential for survival and the expression of virulence in many pathogenic bacteria, including Mycobacterium tuberculosis. In addition, microbial sulfur metabolic pathways are largely absent in humans and therefore, represent unique targets for therapeutic intervention. In this review, we summarize our current understanding of the enzymes associated with the production of sulfated and reduced sulfur-containing metabolites in Mycobacteria. Small molecule inhibitors of these catalysts represent valuable chemical tools that can be used to investigate the role of sulfur metabolism throughout the Mycobacterial lifecycle and may also represent new leads for drug development. In this light, we also summarize recent progress made in the development of inhibitors of sulfur metabolism enzymes. PMID:23808874

Spontaneous and evolutionary changes in the antibiotic resistance of Burkholderia cenocepacia observed by global gene expression analysis.

PubMed

Sass, Andrea; Marchbank, Angela; Tullis, Elizabeth; Lipuma, John J; Mahenthiralingam, Eshwar

2011-07-22

Burkholderia cenocepacia is a member of the Burkholderia cepacia complex group of bacteria that cause infections in individuals with cystic fibrosis. B. cenocepacia isolate J2315 has been genome sequenced and is representative of a virulent, epidemic CF strain (ET12). Its genome encodes multiple antimicrobial resistance pathways and it is not known which of these is important for intrinsic or spontaneous resistance. To map these pathways, transcriptomic analysis was performed on: (i) strain J2315 exposed to sub-inhibitory concentrations of antibiotics and the antibiotic potentiator chlorpromazine, and (ii) on spontaneous mutants derived from J2315 and with increased resistance to the antibiotics amikacin, meropenem and trimethoprim-sulfamethoxazole. Two pan-resistant ET12 outbreak isolates recovered two decades after J2315 were also compared to identify naturally evolved gene expression changes. Spontaneous resistance in B. cenocepacia involved more gene expression changes and different subsets of genes than those provoked by exposure to sub inhibitory concentrations of each antibiotic. The phenotype and altered gene expression in the resistant mutants was also stable irrespective of the presence of the priming antibiotic. Both known and novel genes involved in efflux, antibiotic degradation/modification, membrane function, regulation and unknown functions were mapped. A novel role for the phenylacetic acid (PA) degradation pathway genes was identified in relation to spontaneous resistance to meropenem and glucose was found to repress their expression. Subsequently, 20 mM glucose was found to produce greater that 2-fold reductions in the MIC of multiple antibiotics against B. cenocepacia J2315. Mutation of an RND multidrug efflux pump locus (BCAM0925-27) and squalene-hopene cyclase gene (BCAS0167), both upregulated after chlorpromazine exposure, confirmed their role in resistance. The recently isolated outbreak isolates had altered the expression of multiple genes which mirrored changes seen in the antibiotic resistant mutants, corroborating the strategy used to model resistance. Mutation of an ABC transporter gene (BCAS0081) upregulated in both outbreak strains, confirmed its role in B. cenocepacia resistance. Global mapping of the genetic pathways which mediate antibiotic resistance in B. cenocepacia has revealed that they are multifactorial, identified potential therapeutic targets and also demonstrated that putative catabolite repression of genes by glucose can improve antibiotic efficacy.

Selection for rapid embryo development correlates with embryo exposure to maternal androgens among passerine birds

USGS Publications Warehouse

Schwabl, H.; Palacios, M.G.; Martin, T.E.

2007-01-01

Greater offspring predation favors evolution of faster development among species. We hypothesized that greater offspring predation exerts selection on mothers to increase levels of anabolic androgens in egg yolks to achieve faster development. Here, we tested whether (1) concentrations of yolk androgens in passerine species were associated with offspring predation and (2) embryo and nestling development rates were associated with yolk androgen concentrations. We examined three androgens that increase in potency along the synthesis pathway: androstenedione (A4) to testosterone (T) to 5??- dihydrotestosterone (5??-DHT). Concentrations of none of these steroids were related to clutch size; only A4 was allometrically related to egg volume. Species that experience greater predation showed higher yolk concentrations of T and 5??-DHT. Higher concentrations of T and particularly 5??-DHT were strongly correlated with faster development during the embryo period and less so during the nestling period. Development rates were most strongly correlated with 5??-DHT, suggesting that potency increases along the androgen synthesis pathway and that effects are mediated by the androgen receptor pathway. These results are consistent with the hypothesis that selection for faster development by time-dependent offspring mortality may be achieved epigenetically by varying embryo exposure to maternal anabolic steroids. ?? 2007 by The University of Chicago. All rights reserved.

Decomposition of complex microbial behaviors into resource-based stress responses

PubMed Central

Carlson, Ross P.

2009-01-01

Motivation: Highly redundant metabolic networks and experimental data from cultures likely adapting simultaneously to multiple stresses can complicate the analysis of cellular behaviors. It is proposed that the explicit consideration of these factors is critical to understanding the competitive basis of microbial strategies. Results: Wide ranging, seemingly unrelated Escherichia coli physiological fluxes can be simply and accurately described as linear combinations of a few ecologically relevant stress adaptations. These strategies were identified by decomposing the central metabolism of E.coli into elementary modes (mathematically defined biochemical pathways) and assessing the resource investment cost–benefit properties for each pathway. The approach capitalizes on the inherent tradeoffs related to investing finite resources like nitrogen into different pathway enzymes when the pathways have varying metabolic efficiencies. The subset of ecologically competitive pathways represented 0.02% of the total permissible pathways. The biological relevance of the assembled strategies was tested against 10 000 randomly constructed pathway subsets. None of the randomly assembled collections were able to describe all of the considered experimental data as accurately as the cost-based subset. The results suggest these metabolic strategies are biologically significant. The current descriptions were compared with linear programming (LP)-based flux descriptions using the Euclidean distance metric. The current study's pathway subset described the experimental fluxes with better accuracy than the LP results without having to test multiple objective functions or constraints and while providing additional ecological insight into microbial behavior. The assembled pathways seem to represent a generalized set of strategies that can describe a wide range of microbial responses and hint at evolutionary processes where a handful of successful metabolic strategies are utilized simultaneously in different combinations to adapt to diverse conditions. Contact: rossc@biofilms.montana.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:19008248

Benzo[a]pyrene affects Jurkat T cells in the activated state via the antioxidant response element dependent Nrf2 pathway leading to decreased IL-2 secretion and redirecting glutamine metabolism

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

Murugaiyan, Jayaseelan; Rockstroh, Maxie; Wagner, Juliane

2013-06-15

There is a clear evidence that environmental pollutants, such as benzo[a]pyrene (B[a]P), can have detrimental effects on the immune system, whereas the underlying mechanisms still remain elusive. Jurkat T cells share many properties with native T lymphocytes and therefore are an appropriate model to analyze the effects of environmental pollutants on T cells and their activation. Since environmental compounds frequently occur at low, not acute toxic concentrations, we analyzed the effects of two subtoxic concentrations, 50 nM and 5 μM, on non- and activated cells. B[a]P interferes directly with the stimulation process as proven by an altered IL-2 secretion. Furthermore,more » B[a]P exposure results in significant proteomic changes as shown by DIGE analysis. Pathway analysis revealed an involvement of the AhR independent Nrf2 pathway in the altered processes observed in unstimulated and stimulated cells. A participation of the Nrf2 pathway in the change of IL-2 secretion was confirmed by exposing cells to the Nrf2 activator tBHQ. tBHQ and 5 μM B[a]P caused similar alterations of IL-2 secretion and glutamine/glutamate metabolism. Moreover, the proteome changes in unstimulated cells point towards a modified regulation of the cytoskeleton and cellular stress response, which was proven by western blotting. Additionally, there is a strong evidence for alterations in metabolic pathways caused by B[a]P exposure in stimulated cells. Especially the glutamine/glutamate metabolism was indicated by proteome pathway analysis and validated by metabolite measurements. The detrimental effects were slightly enhanced in stimulated cells, suggesting that stimulated cells are more vulnerable to the environmental pollutant model compound B[a]P. - Highlights: • B[a]P affects the proteome of Jurkat T cells also at low concentrations. • Exposure to B[a]P (50 nM, 5 μM) did not change Jurkat T cell viability. • Both B[a]P concentrations altered the IL-2 secretion of stimulated cells. • 608 different protein spots of Jurkat T cells were quantified using 2-DE-DIGE. • Pathway analysis identified Nrf2 and AhR pathway as regulated.« less

Adaptive Landscapes of Resistance Genes Change as Antibiotic Concentrations Change.

PubMed

Mira, Portia M; Meza, Juan C; Nandipati, Anna; Barlow, Miriam

2015-10-01

Most studies on the evolution of antibiotic resistance are focused on selection for resistance at lethal antibiotic concentrations, which has allowed the detection of mutant strains that show strong phenotypic traits. However, solely focusing on lethal concentrations of antibiotics narrowly limits our perspective of antibiotic resistance evolution. New high-resolution competition assays have shown that resistant bacteria are selected at relatively low concentrations of antibiotics. This finding is important because sublethal concentrations of antibiotics are found widely in patients undergoing antibiotic therapies, and in nonmedical conditions such as wastewater treatment plants, and food and water used in agriculture and farming. To understand the impacts of sublethal concentrations on selection, we measured 30 adaptive landscapes for a set of TEM β-lactamases containing all combinations of the four amino acid substitutions that exist in TEM-50 for 15 β-lactam antibiotics at multiple concentrations. We found that there are many evolutionary pathways within this collection of landscapes that lead to nearly every TEM-genotype that we studied. While it is known that the pathways change depending on the type of β-lactam, this study demonstrates that the landscapes including fitness optima also change dramatically as the concentrations of antibiotics change. Based on these results we conclude that the presence of multiple concentrations of β-lactams in an environment result in many different adaptive landscapes through which pathways to nearly every genotype are available. Ultimately this may increase the diversity of genotypes in microbial populations. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Disease-specific clinical pathways - are they feasible in primary care? A mixed-methods study.

PubMed

Grimsmo, Anders; Løhre, Audhild; Røsstad, Tove; Gjerde, Ingunn; Heiberg, Ina; Steinsbekk, Aslak

2018-06-01

To explore the feasibility of disease-specific clinical pathways when used in primary care. A mixed-method sequential exploratory design was used. First, merging and exploring quality interview data across two cases of collaboration between the specialist care and primary care on the introduction of clinical pathways for four selected chronic diseases. Secondly, using quantitative data covering a population of 214,700 to validate and test hypothesis derived from the qualitative findings. Primary care and specialist care collaborating to manage care coordination. Primary-care representatives expressed that their patients often have complex health and social needs that clinical pathways guidelines seldom consider. The representatives experienced that COPD, heart failure, stroke and hip fracture, frequently seen in hospitals, appear in low numbers in primary care. The quantitative study confirmed the extensive complexity among home healthcare nursing patients and demonstrated that, for each of the four selected diagnoses, a homecare nurse on average is responsible for preparing reception of the patient at home after discharge from hospital, less often than every other year. The feasibility of disease-specific pathways in primary care is limited, both from a clinical and organisational perspective, for patients with complex needs. The low prevalence in primary care of patients with important chronic conditions, needing coordinated care after hospital discharge, constricts transferring tasks from specialist care. Generic clinical pathways are likely to be more feasible and efficient for patients in this setting. Key points Clinical pathways in hospitals apply to single-disease guidelines, while more than 90% of the patients discharged to community health care for follow-up have multimorbidity. Primary care has to manage the health care of the patient holistically, with all his or her complex needs. Patients most frequently admitted to hospitals, i.e. patients with COPD, heart failure, stroke and hip fracture are infrequent in primary care and represent a minority among patients in need of coordinated community health care. In primary care, the low rate of receiving patients discharged from hospitals of major chronic diseases hampers maintenance of required specific skills, thus constricting the transfer of tasks to primary care. Generic clinical pathways are suggested to be more feasible than disease-specific pathways for most patients with complex needs.

Salt stress signals shape the plant root.

PubMed

Galvan-Ampudia, Carlos S; Testerink, Christa

2011-06-01

Plants use different strategies to deal with high soil salinity. One strategy is activation of pathways that allow the plant to export or compartmentalise salt. Relying on their phenotypic plasticity, plants can also adjust their root system architecture (RSA) and the direction of root growth to avoid locally high salt concentrations. Here, we highlight RSA responses to salt and osmotic stress and the underlying mechanisms. A model is presented that describes how salinity affects auxin distribution in the root. Possible intracellular signalling pathways linking salinity to root development and direction of root growth are discussed. These involve perception of high cytosolic Na+ concentrations in the root, activation of lipid signalling and protein kinase activity and modulation of endocytic pathways. Copyright © 2011 Elsevier Ltd. All rights reserved.

Updated aerosol module and its application to simulate secondary organic aerosols during IMPACT campaign May 2008

NASA Astrophysics Data System (ADS)

Li, Y. P.; Elbern, H.; Lu, K. D.; Friese, E.; Kiendler-Scharr, A.; Mentel, Th. F.; Wang, X. S.; Wahner, A.; Zhang, Y. H.

2013-03-01

The formation of Secondary organic aerosol (SOA) was simulated with the Secondary ORGanic Aerosol Model (SORGAM) by a classical gas-particle partitioning concept, using the two-product model approach, which is widely used in chemical transport models. In this study, we extensively updated SORGAM including three major modifications: firstly, we derived temperature dependence functions of the SOA yields for aromatics and biogenic VOCs, based on recent chamber studies within a sophisticated mathematic optimization framework; secondly, we implemented the SOA formation pathways from photo oxidation (OH initiated) of isoprene; thirdly, we implemented the SOA formation channel from NO3-initiated oxidation of reactive biogenic hydrocarbons (isoprene and monoterpenes). The temperature dependence functions of the SOA yields were validated against available chamber experiments. Moreover, the whole updated SORGAM module was validated against ambient SOA observations represented by the summed oxygenated organic aerosol (OOA) concentrations abstracted from Aerosol Mass Spectrometer (AMS) measurements at a rural site near Rotterdam, the Netherlands, performed during the IMPACT campaign in May 2008. In this case, we embedded both the original and the updated SORGAM module into the EURopean Air pollution and Dispersion-Inverse Model (EURAD-IM), which showed general good agreements with the observed meteorological parameters and several secondary products such as O3, sulfate and nitrate. With the updated SORGAM module, the EURAD-IM model also captured the observed SOA concentrations reasonably well especially those during nighttime. In contrast, the EURAD-IM model before update underestimated the observations by a factor of up to 5. The large improvements of the modeled SOA concentrations by updated SORGAM were attributed to the mentioned three modifications. Embedding the temperature dependence functions of the SOA yields, including the new pathways from isoprene photo oxidations, and switching on the SOA formation from NO3 initiated biogenic VOCs oxidations contributed to this enhancement by 10%, 22% and 47%, respectively. However, the EURAD-IM model with updated SORGAM still clearly underestimated the afternoon SOA observations up to a factor of two. More work such as to improve the simulated OH concentrations under high VOCs and low NOx concentrations, further including the SOA formation from semi-volatile organic compounds, the correct aging process of aerosols, oligomerization process and the influence on the biogenic SOA by the anthropogenic SOA, are still required to fill the gap.

Clostridium perfringens Phospholipase C Induced ROS Production and Cytotoxicity Require PKC, MEK1 and NFκB Activation

PubMed Central

Monturiol-Gross, Laura; Flores-Díaz, Marietta; Pineda-Padilla, Maria Jose; Castro-Castro, Ana Cristina; Alape-Giron, Alberto

2014-01-01

Clostridium perfringens phospholipase C (CpPLC), also called α-toxin, is the most toxic extracellular enzyme produced by this bacteria and is essential for virulence in gas gangrene. At lytic concentrations, CpPLC causes membrane disruption, whereas at sublytic concentrations this toxin causes oxidative stress and activates the MEK/ERK pathway, which contributes to its cytotoxic and myotoxic effects. In the present work, the role of PKC, ERK 1/2 and NFκB signalling pathways in ROS generation induced by CpPLC and their contribution to CpPLC-induced cytotoxicity was evaluated. The results demonstrate that CpPLC induces ROS production through PKC, MEK/ERK and NFκB pathways, the latter being activated by the MEK/ERK signalling cascade. Inhibition of either of these signalling pathways prevents CpPLC's cytotoxic effect. In addition, it was demonstrated that NFκB inhibition leads to a significant reduction in the myotoxicity induced by intramuscular injection of CpPLC in mice. Understanding the role of these signalling pathways could lead towards developing rational therapeutic strategies aimed to reduce cell death during a clostridialmyonecrosis. PMID:24466113

Noise characteristics of the Escherichia coli rotary motor

PubMed Central

2011-01-01

Background The chemotaxis pathway in the bacterium Escherichia coli allows cells to detect changes in external ligand concentration (e.g. nutrients). The pathway regulates the flagellated rotary motors and hence the cells' swimming behaviour, steering them towards more favourable environments. While the molecular components are well characterised, the motor behaviour measured by tethered cell experiments has been difficult to interpret. Results We study the effects of sensing and signalling noise on the motor behaviour. Specifically, we consider fluctuations stemming from ligand concentration, receptor switching between their signalling states, adaptation, modification of proteins by phosphorylation, and motor switching between its two rotational states. We develop a model which includes all signalling steps in the pathway, and discuss a simplified version, which captures the essential features of the full model. We find that the noise characteristics of the motor contain signatures from all these processes, albeit with varying magnitudes. Conclusions Our analysis allows us to address how cell-to-cell variation affects motor behaviour and the question of optimal pathway design. A similar comprehensive analysis can be applied to other two-component signalling pathways. PMID:21951560

A non-capacitative pathway activated by arachidonic acid is the major Ca2+ entry mechanism in rat A7r5 smooth muscle cells stimulated with low concentrations of vasopressin

PubMed Central

Broad, Lisa M; Cannon, Toby R; Taylor, Colin W

1999-01-01

Depletion of the Ca2+ stores of A7r5 cells stimulated Ca2+, though not Sr2+, entry. Vasopressin (AVP) or platelet-derived growth factor (PDGF) stimulated Sr2+ entry. The cells therefore express a capacitative pathway activated by empty stores and a non-capacitative pathway stimulated by receptors; only the former is permeable to Mn2+ and only the latter to Sr2+. Neither empty stores nor inositol 1,4,5-trisphosphate (InsP3) binding to its receptors are required for activation of the non-capacitative pathway, because microinjection of cells with heparin prevented PDGF-evoked Ca2+ mobilization but not Sr2+ entry. Low concentrations of Gd3+ irreversibly blocked capacitative Ca2+ entry without affecting AVP-evoked Sr2+ entry. After inhibition of the capacitative pathway with Gd3+, AVP evoked a substantial increase in cytosolic [Ca2+], confirming that the non-capacitative pathway can evoke a significant increase in cytosolic [Ca2+]. Arachidonic acid mimicked the effect of AVP on Sr2+ entry without stimulating Mn2+ entry; the Sr2+ entry was inhibited by 100 μM Gd3+, but not by 1 μM Gd3+ which completely inhibited capacitative Ca2+ entry. The effects of arachidonic acid did not require its metabolism. AVP-evoked Sr2+ entry was unaffected by isotetrandrine, an inhibitor of G protein-coupled phospholipase A2. U73122, an inhibitor of phosphoinositidase C, inhibited AVP-evoked formation of inositol phosphates and Sr2+ entry. The effects of phorbol esters and Ro31-8220 (a protein kinase C inhibitor) established that protein kinase C did not mediate the effects of AVP on the non-capacitative pathway. An inhibitor of diacylglycerol lipase, RHC-80267, inhibited AVP-evoked Sr2+ entry without affecting capacitative Ca2+ entry or release of Ca2+ stores. Selective inhibition of capacitative Ca2+ entry with Gd3+ revealed that the non-capacitative pathway is the major route for the Ca2+ entry evoked by low AVP concentrations. We conclude that in A7r5 cells, the Ca2+ entry evoked by low concentrations of AVP is mediated largely by a non-capacitative pathway directly regulated by arachidonic acid produced by the sequential activities of phosphoinositidase C and diacylglycerol lipase. PMID:10226154

Using Community-Based Participatory Research to Explore Backyard Gardening Practices and Soil Lead Concentrations in Urban Neighborhoods.

PubMed

Johnson, Sheri; Cardona, Dalila; Davis, Jeremy; Gramling, Benjamin; Hamilton, Chelsea; Hoffmann, Ray; Ruis, Sabrina; Soldat, Doug; Ventura, Steve; Yan, Ke

2016-01-01

Lead exposure is a serious health threat for children. Soil is an important exposure pathway, primarily through ingestion and inhalation. Urban agriculture is increasing. Potential environmental health risks associated with residential gardening may not be well known to community residents. A community-based participatory research (CBPR) approach was implemented to explore the relationship between urban residential vegetable gardening and lead exposure in children. The primary objectives were to characterize local backyard vegetable gardening practices, measure residential and commercial soil lead concentrations and spatial distributions, and identify priorities for individual and collective action. Participants were recruited in two stages. In phase 1, adult gardeners participated in structured interviews. In phase 2, a multistage representative sampling approach was implemented to recruit adult gardeners for interviews and soil testing. Twenty adults participated in gardening practice interviews. Adults perceive many benefits from backyard gardening and initially expressed few concerns about lead exposure risk. Results indicate that children are actively involved in backyard gardening. Total soil lead concentrations from 17 residential properties ranged from 7 to 3,234 mg kg-1(median, 187; mean, 432). Commercial soils had lead concentrations that ranged from 6 to 13 mg kg(-1) (median, 6.5; mean, 7.6). Nonparametric Mann-Whitney comparisons indicated a significant difference in lead concentration between commercial soil and residential soil (p<0.0001). Advocacy for resources needed to eliminate dangerous levels of lead from the environment, especially in communities where divestment has occurred, is enhanced through CBPR. Increasing access to soil testing is an important action step.

Disruptions in AUX1-dependent auxin influx alter hypocotyl phototropism in Arabidopsis.

PubMed

Stone, Bethany B; Stowe-Evans, Emily L; Harper, Reneé M; Celaya, R Brandon; Ljung, Karin; Sandberg, Göran; Liscum, Emmanuel

2008-01-01

Phototropism represents a differential growth response by which plant organs can respond adaptively to changes in the direction of incident light to optimize leaf/stem positioning for photosynthetic light capture and root growth orientation for water/nutrient acquisition. Studies over the past few years have identified a number of components in the signaling pathway(s) leading to development of phototropic curvatures in hypocotyls. These include the phototropin photoreceptors (phot1 and phot2) that perceive directional blue-light (BL) cues and then stimulate signaling, leading to relocalization of the plant hormone auxin, as well as the auxin response factor NPH4/ARF7 that responds to changes in local auxin concentrations to directly mediate expression of genes likely encoding proteins necessary for development of phototropic curvatures. While null mutations in NPH4/ARF7 condition an aphototropic response to unidirectional BL, seedlings carrying the same mutations recover BL-dependent phototropic responsiveness if co-irradiated with red light (RL) or pre-treated with either ethylene. In the present study, we identify second-site enhancer mutations in the nph4 background that abrogate these recovery responses. One of these mutations--map1 (modifier of arf7 phenotypes 1)--was found to represent a missense allele of AUX1--a gene encoding a high-affinity auxin influx carrier previously associated with a number of root responses. Pharmacological studies and analyses of additional aux1 mutants confirmed that AUX1 functions as a modulator of hypocotyl phototropism. Moreover, we have found that the strength of dependence of hypocotyl phototropism on AUX1-mediated auxin influx is directly related to the auxin responsiveness of the seedling in question.

Metabolomic and high-throughput sequencing analysis-modern approach for the assessment of biodeterioration of materials from historic buildings.

PubMed

Gutarowska, Beata; Celikkol-Aydin, Sukriye; Bonifay, Vincent; Otlewska, Anna; Aydin, Egemen; Oldham, Athenia L; Brauer, Jonathan I; Duncan, Kathleen E; Adamiak, Justyna; Sunner, Jan A; Beech, Iwona B

2015-01-01

Preservation of cultural heritage is of paramount importance worldwide. Microbial colonization of construction materials, such as wood, brick, mortar, and stone in historic buildings can lead to severe deterioration. The aim of the present study was to give modern insight into the phylogenetic diversity and activated metabolic pathways of microbial communities colonized historic objects located in the former Auschwitz II-Birkenau concentration and extermination camp in Oświecim, Poland. For this purpose we combined molecular, microscopic and chemical methods. Selected specimens were examined using Field Emission Scanning Electron Microscopy (FESEM), metabolomic analysis and high-throughput Illumina sequencing. FESEM imaging revealed the presence of complex microbial communities comprising diatoms, fungi and bacteria, mainly cyanobacteria and actinobacteria, on sample surfaces. Microbial diversity of brick specimens appeared higher than that of the wood and was dominated by algae and cyanobacteria, while wood was mainly colonized by fungi. DNA sequences documented the presence of 15 bacterial phyla representing 99 genera including Halomonas, Halorhodospira, Salinisphaera, Salinibacterium, Rubrobacter, Streptomyces, Arthrobacter and nine fungal classes represented by 113 genera including Cladosporium, Acremonium, Alternaria, Engyodontium, Penicillium, Rhizopus, and Aureobasidium. Most of the identified sequences were characteristic of organisms implicated in deterioration of wood and brick. Metabolomic data indicated the activation of numerous metabolic pathways, including those regulating the production of primary and secondary metabolites, for example, metabolites associated with the production of antibiotics, organic acids and deterioration of organic compounds. The study demonstrated that a combination of electron microscopy imaging with metabolomic and genomic techniques allows to link the phylogenetic information and metabolic profiles of microbial communities and to shed new light on biodeterioration processes.

Metabolomic and high-throughput sequencing analysis—modern approach for the assessment of biodeterioration of materials from historic buildings

PubMed Central

Gutarowska, Beata; Celikkol-Aydin, Sukriye; Bonifay, Vincent; Otlewska, Anna; Aydin, Egemen; Oldham, Athenia L.; Brauer, Jonathan I.; Duncan, Kathleen E.; Adamiak, Justyna; Sunner, Jan A.; Beech, Iwona B.

2015-01-01

Preservation of cultural heritage is of paramount importance worldwide. Microbial colonization of construction materials, such as wood, brick, mortar, and stone in historic buildings can lead to severe deterioration. The aim of the present study was to give modern insight into the phylogenetic diversity and activated metabolic pathways of microbial communities colonized historic objects located in the former Auschwitz II–Birkenau concentration and extermination camp in Oświecim, Poland. For this purpose we combined molecular, microscopic and chemical methods. Selected specimens were examined using Field Emission Scanning Electron Microscopy (FESEM), metabolomic analysis and high-throughput Illumina sequencing. FESEM imaging revealed the presence of complex microbial communities comprising diatoms, fungi and bacteria, mainly cyanobacteria and actinobacteria, on sample surfaces. Microbial diversity of brick specimens appeared higher than that of the wood and was dominated by algae and cyanobacteria, while wood was mainly colonized by fungi. DNA sequences documented the presence of 15 bacterial phyla representing 99 genera including Halomonas, Halorhodospira, Salinisphaera, Salinibacterium, Rubrobacter, Streptomyces, Arthrobacter and nine fungal classes represented by 113 genera including Cladosporium, Acremonium, Alternaria, Engyodontium, Penicillium, Rhizopus, and Aureobasidium. Most of the identified sequences were characteristic of organisms implicated in deterioration of wood and brick. Metabolomic data indicated the activation of numerous metabolic pathways, including those regulating the production of primary and secondary metabolites, for example, metabolites associated with the production of antibiotics, organic acids and deterioration of organic compounds. The study demonstrated that a combination of electron microscopy imaging with metabolomic and genomic techniques allows to link the phylogenetic information and metabolic profiles of microbial communities and to shed new light on biodeterioration processes. PMID:26483760

CellNetVis: a web tool for visualization of biological networks using force-directed layout constrained by cellular components.

PubMed

Heberle, Henry; Carazzolle, Marcelo Falsarella; Telles, Guilherme P; Meirelles, Gabriela Vaz; Minghim, Rosane

2017-09-13

The advent of "omics" science has brought new perspectives in contemporary biology through the high-throughput analyses of molecular interactions, providing new clues in protein/gene function and in the organization of biological pathways. Biomolecular interaction networks, or graphs, are simple abstract representations where the components of a cell (e.g. proteins, metabolites etc.) are represented by nodes and their interactions are represented by edges. An appropriate visualization of data is crucial for understanding such networks, since pathways are related to functions that occur in specific regions of the cell. The force-directed layout is an important and widely used technique to draw networks according to their topologies. Placing the networks into cellular compartments helps to quickly identify where network elements are located and, more specifically, concentrated. Currently, only a few tools provide the capability of visually organizing networks by cellular compartments. Most of them cannot handle large and dense networks. Even for small networks with hundreds of nodes the available tools are not able to reposition the network while the user is interacting, limiting the visual exploration capability. Here we propose CellNetVis, a web tool to easily display biological networks in a cell diagram employing a constrained force-directed layout algorithm. The tool is freely available and open-source. It was originally designed for networks generated by the Integrated Interactome System and can be used with networks from others databases, like InnateDB. CellNetVis has demonstrated to be applicable for dynamic investigation of complex networks over a consistent representation of a cell on the Web, with capabilities not matched elsewhere.

PathFinder: reconstruction and dynamic visualization of metabolic pathways.

PubMed

Goesmann, Alexander; Haubrock, Martin; Meyer, Folker; Kalinowski, Jörn; Giegerich, Robert

2002-01-01

Beyond methods for a gene-wise annotation and analysis of sequenced genomes new automated methods for functional analysis on a higher level are needed. The identification of realized metabolic pathways provides valuable information on gene expression and regulation. Detection of incomplete pathways helps to improve a constantly evolving genome annotation or discover alternative biochemical pathways. To utilize automated genome analysis on the level of metabolic pathways new methods for the dynamic representation and visualization of pathways are needed. PathFinder is a tool for the dynamic visualization of metabolic pathways based on annotation data. Pathways are represented as directed acyclic graphs, graph layout algorithms accomplish the dynamic drawing and visualization of the metabolic maps. A more detailed analysis of the input data on the level of biochemical pathways helps to identify genes and detect improper parts of annotations. As an Relational Database Management System (RDBMS) based internet application PathFinder reads a list of EC-numbers or a given annotation in EMBL- or Genbank-format and dynamically generates pathway graphs.

Food chain transfer of selenium in lentic and lotic habitats of a western Canadian watershed

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

Orr, P.L.; Guiguer, K.R.; Russel, C.K.

2006-02-15

Selenium (Se) is an essential micronutrient, exhibiting a narrow margin between nutritionally optimal and potentially toxic concentrations. Egg-laying vertebrates at the top of aquatic food chains are most at risk in environments with elevated aqueous Se concentrations. The Elk River watershed in British Columbia, Canada receives effluents containing Se from five coal mine operations. This study tested three hypotheses that might account for higher Se concentrations in fish from lentic compared to lotic habitats in the watershed: (1) enhanced uptake by aquatic primary producers, (2) longer food chain length, or (3) greater food web accumulation through sediment-detrital pathways. Stable isotopemore » and Se concentration data demonstrated that Se concentrations in aquatic primary producers and food chain lengths were comparable in lentic and lotic habitats. Enhanced formation of organoselenium and subsequent uptake and cycling via sediment detrital pathways likely account for higher fish tissue Se concentrations in lentic than in lotic areas.« less

Conceptual Model Scenarios for the Vapor Intrusion Pathway

EPA Pesticide Factsheets

This report provides simplified simulation examples to illustrate graphically how subsurface conditions and building-specific characteristics determine the distribution chemical distribution and indoor air concentration relative to a source concentration.

Isolation and purification of C3 from human plasma.

PubMed

O'Rear, L D; Ross, G D

2001-05-01

The alternative pathway of complement shares its terminal components (C3 and C5 through 9) with the classical pathway, but has several unique components, including factors D, B, and P (properdin). This unit presents methods for assaying total alternative pathway activity and the activity of factors B and D. Radial immunodiffusion (RID) can also be used to measure factor D, B, and P concentrations.

Transcriptome and key genes expression related to carbon fixation pathways in Chlorella PY-ZU1 cells and their growth under high concentrations of CO2.

PubMed

Huang, Yun; Cheng, Jun; Lu, Hongxiang; He, Yong; Zhou, Junhu; Cen, Kefa

2017-01-01

The biomass yield of Chlorella PY-ZU1 drastically increased when cultivated under high CO 2 condition compared with that cultivated under air condition. However, less attention has been given to the microalgae photosynthetic mechanisms response to different CO 2 concentrations. The genetic reasons for the higher growth rate, CO 2 fixation rate, and photosynthetic efficiency of microalgal cells under higher CO 2 concentration have not been clearly defined yet. In this study, the Illumina sequencing and de novo transcriptome assembly of Chlorella PY-ZU1 cells cultivated under 15% CO 2 were performed and compared with those of cells grown under air. It was found that carbonic anhydrase (CAs, enzyme for interconversion of bicarbonate to CO 2 ) dramatically decreased to near 0 in 15% CO 2 -grown cells, which indicated that CO 2 molecules directly permeated into cells under high CO 2 stress without CO 2 -concentrating mechanism. Extrapolating from the growth conditions and quantitative Real-Time PCR of CCM-related genes, the K m (CO 2 ) (the minimum intracellular CO 2 concentration that rubisco required) of Chlorella PY-ZU1 might be in the range of 80-192 μM. More adenosine triphosphates was saved for carbon fixation-related pathways. The transcript abundance of rubisco (the most important enzyme of CO 2 fixation reaction) was 16.3 times higher in 15% CO 2 -grown cells than that under air. Besides, the transcript abundances of most key genes involved in carbon fixation pathways were also enhanced in 15% CO 2 -grown cells. Carbon fixation and nitrogen metabolism are the two most important metabolisms in the photosynthetic cells. These genes related to the two most metabolisms with significantly differential expressions were beneficial for microalgal growth (2.85 g L -1 ) under 15% CO 2 concentration. Considering the micro and macro growth phenomena of Chlorella PY-ZU1 under different concentrations of CO 2 (0.04-60%), CO 2 transport pathways responses to different CO 2 (0.04-60%) concentrations was reconstructed.

Decadal application of WRF/chem for regional air quality and climate modeling over the U.S. under the representative concentration pathways scenarios. Part 2: Current vs. future simulations

NASA Astrophysics Data System (ADS)

Yahya, Khairunnisa; Campbell, Patrick; Zhang, Yang

2017-03-01

Following a comprehensive model evaluation, this Part II paper presents projected changes in future (2046-2055) climate, air quality, and their interactions under the RCP4.5 and RCP8.5 scenarios using the Weather, Research and Forecasting model with Chemistry (WRF/Chem). In general, both WRF/Chem RCP4.5 and RCP8.5 simulations predict similar increases on average (∼2 °C) for 2-m temperature (T2) but different spatial distributions of the projected changes in T2, 2-m relative humidity, 10-m wind speed, precipitation, and planetary boundary layer height, due to differences in the spatial distributions of projected emissions, and their feedbacks into climate. Future O3 mixing ratios will decrease for most parts of the U.S. under the RCP4.5 scenario but increase for all areas under the RCP8.5 scenario due to higher projected temperature, greenhouse gas concentrations and biogenic volatile organic compounds (VOC) emissions, higher O3 values for boundary conditions, and disbenefit of NOx reduction and decreased NO titration over VOC-limited O3 chemistry regions. Future PM2.5 concentrations will decrease for both RCP4.5 and RCP8.5 scenarios with different trends in projected concentrations of individual PM species. Total cloud amounts decrease under both scenarios in the future due to decreases in PM and cloud droplet number concentration thus increased radiation. Those results illustrate the impacts of carbon policies with different degrees of emission reductions on future climate and air quality. The WRF/Chem and WRF simulations show different spatial patterns for projected changes in T2 for future decade, indicating different impacts of prognostic and prescribed gas/aerosol concentrations, respectively, on climate change.

Evolved aniline catabolism in Acinetobacter calcoaceticus during continuous culture of river water.

PubMed Central

Wyndham, R C

1986-01-01

Adaptation of Acinetobacter calcoaceticus from river water to aniline depends on the dynamics of parent and mutant populations. The parent, Acinetobacter strain DON26 phenotype Ani0, was common in river water and assimilated aniline effectively at micromolar concentrations, but was inhibited at higher concentrations of aniline. The Ani0 phenotype was also characterized by a broad specificity for oxidation of chloroanilines by aniline-induced cells. The mutant Ani+ phenotype was represented by DON2, isolated from a population of less than 100 cells ml-1 in a mixed river water culture, and by DON261, isolated during continuous culture of DON26. Ani+ strains assimilated aniline at a greater maximum specific rate than the parent and were able to grow at concentrations of aniline greater than 16 mM. These strains cooxidized phenol after growth at high aniline concentrations, but showed reduced activity toward chloroanilines. These changes plus kinetic data, oxygen uptake data, and the results of auxanography indicate that the mutant has an increased activity and altered specificity of the initial enzyme in the aniline catabolic pathway. The parent strain, DON26, was at a selective advantage relative to the mutant at low concentrations of aniline, but was replaced by the mutant when aniline concentrations increased. Adaptation of the mixed river water community to aniline involved selection of both phenotypes. Reversion of the Ani+ to Ani0 phenotype occurred at a frequency of 10(-2) in the absence of aniline selection. Plasmid content was not altered during either acquisition or loss of the Ani+ phenotype. Adaptive changes in Acinetobacter spp. populations illustrate important differences in the catabolic activities of natural and pollutant selected strains.(ABSTRACT TRUNCATED AT 250 WORDS) Images PMID:3707123

Water diffusion in silicate glasses: the effect of glass structure

NASA Astrophysics Data System (ADS)

Kuroda, M.; Tachibana, S.

2016-12-01

Water diffusion in silicate melts (glasses) is one of the main controlling factors of magmatism in a volcanic system. Water diffusivity in silicate glasses depends on its own concentration. However, the mechanism causing those dependences has not been fully understood yet. In order to construct a general model for water diffusion in various silicate glasses, we performed water diffusion experiments in silica glass and proposed a new water diffusion model [Kuroda et al., 2015]. In the model, water diffusivity is controlled by the concentration of both main diffusion species (i.e. molecular water) and diffusion pathways, which are determined by the concentrations of hydroxyl groups and network modifier cations. The model well explains the water diffusivity in various silicate glasses from silica glass to basalt glass. However, pre-exponential factors of water diffusivity in various glasses show five orders of magnitude variations although the pre-exponential factor should ideally represent the jump frequency and the jump distance of molecular water and show a much smaller variation. Here, we attribute the large variation of pre-exponential factors to a glass structure dependence of activation energy for molecular water diffusion. It has been known that the activation energy depends on the water concentration [Nowak and Behrens, 1997]. The concentration of hydroxyls, which cut Si-O-Si network in the glass structure, increases with water concentration, resulting in lowering the activation energy for water diffusion probably due to more fragmented structure. Network modifier cations are likely to play the same role as water. With taking the effect of glass structure into account, we found that the variation of pre-exponential factors of water diffusivity in silicate glasses can be much smaller than the five orders of magnitude, implying that the diffusion of molecular water in silicate glasses is controlled by the same atomic process.

Future heat waves and surface ozone

NASA Astrophysics Data System (ADS)

Meehl, Gerald A.; Tebaldi, Claudia; Tilmes, Simone; Lamarque, Jean-Francois; Bates, Susan; Pendergrass, Angeline; Lombardozzi, Danica

2018-06-01

A global Earth system model is used to study the relationship between heat waves and surface ozone levels over land areas around the world that could experience either large decreases or little change in future ozone precursor emissions. The model is driven by emissions of greenhouse gases and ozone precursors from a medium-high emission scenario (Representative Concentration Pathway 6.0–RCP6.0) and is compared to an experiment with anthropogenic ozone precursor emissions fixed at 2005 levels. With ongoing increases in greenhouse gases and corresponding increases in average temperature in both experiments, heat waves are projected to become more intense over most global land areas (greater maximum temperatures during heat waves). However, surface ozone concentrations on future heat wave days decrease proportionately more than on non-heat wave days in areas where ozone precursors are prescribed to decrease in RCP6.0 (e.g. most of North America and Europe), while surface ozone concentrations in heat waves increase in areas where ozone precursors either increase or have little change (e.g. central Asia, the Mideast, northern Africa). In the stabilized ozone precursor experiment, surface ozone concentrations increase on future heat wave days compared to non-heat wave days in most regions except in areas where there is ozone suppression that contributes to decreases in ozone in future heat waves. This is likely associated with effects of changes in isoprene emissions at high temperatures (e.g. west coast and southeastern North America, eastern Europe).

Rhizosphere C flux from tree roots to soil: spatial and temporal differences between sugar maple and yellow birch saplings

NASA Astrophysics Data System (ADS)

Phillips, R. P.; Fahey, T. J.

2003-12-01

Rhizosphere carbon flux (RCF) has rarely been measured for intact root-soil systems. We measured RCF for eight year-old saplings of sugar maple (Acer saccharum) and yellow birch (Betula allegheniensis) collected from Hubbard Brook Experimental Forest and transplanted into 35 cm diameter pots with native soil horizons intact. We hypothesized birch roots which support ectomycorrhizal fungi would release more C to the rhizosphere than sugar maple roots which support vesicular-arbuscular mycorrhizal fungi. Saplings (n=5) were pulse-labeled with 13CO2 at ambient CO2 concentrations for 4-6 hours, and the label was chased through rhizosphere and bulk soil pools in organic and mineral horizons for 7 days. We observed immediate appearance of the label in rhizosphere soil, and there was a striking difference in the temporal pattern of 13C concentration between species. In maple, peak concentration of the label appeared at day 1 and declined over time whereas in birch the label increased in concentration over the 7 day chase period. As a result, total RCF was 2-3 times greater from birch roots. We estimate at least 5% and 10% of NPP may be released from this flux pathway in sugar maple and yellow birch saplings respectively. These results suggest that rhizosphere C flux likely represents a substantial proportion of NPP in northern hardwood forests, and may be influenced by trees species and mycorrhizal association.

Concentration and retention of Toxoplasma gondii oocysts by marine snails demonstrate a novel mechanism for transmission of terrestrial zoonotic pathogens in coastal ecosystems

USGS Publications Warehouse

Krusor, Colin; Smith, Woutrina A.; Tinker, M. Tim; Silver, Mary; Conrad, Patricia A.; Shapiro, Karen

2015-01-01

The parasite Toxoplasma gondii is an environmentally persistent pathogen that can cause fatal disease in humans, terrestrial warm-blooded animals and aquatic mammals. Although an association between T. gondii exposure and prey specialization on marine snails was identified in threatened California sea otters, the ability of kelp-dwelling snails to transmit terrestrially derived pathogens has not been previously investigated. The objective of this study was to measure concentration and retention of T. gondii by marine snails in laboratory aquaria, and to test for natural T. gondii contamination in field-collected snails. Following exposure to T. gondii-containing seawater, oocysts were detected by microscopy in snail faeces and tissues for 10 and 3 days respectively. Nested polymerase chain reaction was also applied as a method for confirming putative T. gondii oocysts detected in snail faeces and tissues by microscopy. Toxoplasma gondiiwas not detected in field-collected snails. Results suggest that turban snails are competent transport hosts for T. gondii. By concentrating oocysts in faecal pellets, snails may facilitate entry of T. gondii into the nearshore marine food web. This novel mechanism also represents a general pathway by which marine transmission of terrestrially derived microorganisms can be mediated via pathogen concentration and retention by benthic invertebrates.

Mercury and Dissolved Organic Matter Dynamics During Snowmelt in the Upper Provo River, Utah, USA

NASA Astrophysics Data System (ADS)

Packer, B. N.; Carling, G. T.; Nelson, S.; Aanderud, Z.; Shepherd Barkdull, N.; Gabor, R. S.

2017-12-01

Mercury (Hg) is deposited to mountains by atmospheric deposition and mobilized during snowmelt runoff, leading to Hg contamination in otherwise pristine watersheds. Mercury is typically transported with dissolved organic matter (DOM) from soils to streams and lakes. This study focused on Hg and DOM dynamics in the snowmelt-dominated upper Provo River watershed, northern Utah, USA. We sampled Hg, dissolved organic carbon (DOC) concentrations, and DOM fluorescence in river water, snowpack, and ephemeral streams over four years from 2014-2017 to investigate Hg transport mechanisms. During the snowmelt season (April through June), Hg concentrations typically increased from 1 to 8 ng/L showing a strong positive correlation with DOC. The dissolved Hg fraction was dominant in the river, averaging 75% of total Hg concentrations, suggesting that DOC is more important for transport than suspended particulate matter. Ephemeral channels, which represent shallow flow paths with strong interactions with soils, had the highest Hg (>10 ng/L) and DOC (>10 mg/L) concentrations, suggesting a soil water source of Hg and organic matter. Fluorescence spectroscopy results showed important changes in DOM type and quality during the snowmelt season and the soil water flow paths are activated. Changes in DOM characteristics during snowmelt improve the understanding of Hg dynamics with organic matter and elucidate transport pathways from the soil surface, ephemeral channels and groundwater to the Provo River. This study has implications for understanding Hg sources and transport mechanisms in mountain watersheds.

Concentration and Risk Evaluation of Polycyclic Aromatic Hydrocarbons in Urban Soil in the Typical Semi-Arid City of Xi'an in Northwest China.

PubMed

Wang, Lijun; Zhang, Shengwei; Wang, Li; Zhang, Wenjuan; Shi, Xingmin; Lu, Xinwei; Li, Xiaoping; Li, Xiaoyun

2018-03-27

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants, presenting potential threats to the ecological environment and human health. Sixty-two urban soil samples were collected in the typical semi-arid city of Xi'an in Northwest China. They were analyzed for concentration, pollution, and ecological and health risk of sixteen U.S. Environmental Protection Agency priority PAHs. The total concentrations of the sixteen PAHs (Σ16PAHs) in the urban soil ranged from 390.6 to 10,652.8 µg/kg with an average of 2052.6 µg/kg. The concentrations of some individual PAHs in the urban soil exceeded Dutch Target Values of Soil Quality and the Σ16PAHs represented heavy pollution. Pyrene and dibenz[a,h]anthracene had high ecological risk to aquatic/soil organisms, while other individual PAHs showed low ecological risk. The total ecological risk of PAHs to aquatic/soil organisms is classified as moderate. Toxic equivalency quantities (TEQs) of the sixteen PAHs varied between 21.16 and 1625.78 µg/kg, with an average of 423.86 µg/kg, indicating a relatively high toxicity potential. Ingestion and dermal adsorption of soil dust were major pathways of human exposure to PAHs from urban soil. Incremental lifetime cancer risks (ILCRs) of human exposure to PAHs were 2.86 × 10 -5 for children and 2.53 × 10 -5 for adults, suggesting that the cancer risk of human exposure to PAHs from urban soil is acceptable.

Distinct Signaling Pathways Mediate Stimulation of Cell Cycle Progression and Prevention of Apoptotic Cell Death by Estrogen in Rat Pituitary Tumor PR1 Cells

PubMed Central

Caporali, Simona; Imai, Manami; Altucci, Lucia; Cancemi, Massimo; Caristi, Silvana; Cicatiello, Luigi; Matarese, Filomena; Penta, Roberta; Sarkar, Dipak K.; Bresciani, Francesco; Weisz, Alessandro

2003-01-01

Estrogens control cell growth and viability in target cells via an interplay of genomic and extragenomic pathways not yet elucidated. Here, we show evidence that cell proliferation and survival are differentially regulated by estrogen in rat pituitary tumor PR1 cells. Pico- to femtomolar concentrations of 17β-estradiol (E2) are sufficient to foster PR1 cell proliferation, whereas nanomolar concentrations of the same are needed to prevent cell death that occurs at a high rate in these cells in the absence of hormone. Activation of endogenous (PRL) or transfected estrogen-responsive genes occurs at the same, higher concentrations of E2 required to promote cell survival, whereas stimulation of cyclin D3 expression and DNA synthesis occur at lower E2 concentrations. Similarly, the pure antiestrogen ICI 182,780 inhibits estrogen response element-dependent trans-activation and cell death more effectively than cyclin-cdk activity, G1-S transition, or DNA synthesis rate. In antiestrogen-treated and/or estrogen-deprived cells, death is due predominantly to apoptosis. Estrogen-induced cell survival, but not E2-dependent cell cycle progression, can be prevented by an inhibitor of c-Src kinase or by blockade of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathway. These data indicate the coexistence of two distinguishable estrogen signaling pathways in PR1 cells, characterized by different functions and sensitivity to hormones and antihormones. PMID:12960425

Quadrupolar transfer pathways

NASA Astrophysics Data System (ADS)

Antonijevic, Sasa; Bodenhausen, Geoffrey

2006-06-01

A set of graphical conventions called quadrupolar transfer pathways is proposed to describe a wide range of experiments designed for the study of quadrupolar nuclei with spin quantum numbers I = 1, 3/2, 2, 5/2, etc. These pathways, which inter alea allow one to appreciate the distinction between quadrupolar and Zeeman echoes, represent a generalization of the well-known coherence transfer pathways. Quadrupolar transfer pathways not merely distinguish coherences with different orders -2 I ⩽ p ⩽ +2 I, but allow one to follow the fate of coherences associated with single transitions that have the same coherence orderp=mIr-mIs but can be distinguished by a satellite orderq=(mIr)2-(mIs)2.

Quadrupolar transfer pathways.

PubMed

Antonijevic, Sasa; Bodenhausen, Geoffrey

2006-06-01

A set of graphical conventions called quadrupolar transfer pathways is proposed to describe a wide range of experiments designed for the study of quadrupolar nuclei with spin quantum numbers I=1, 3/2, 2, 5/2, etc. These pathways, which inter alea allow one to appreciate the distinction between quadrupolar and Zeeman echoes, represent a generalization of the well-known coherence transfer pathways. Quadrupolar transfer pathways not merely distinguish coherences with different orders -2I < or = p< or = +2I, but allow one to follow the fate of coherences associated with single transitions that have the same coherence order p=m(I)(r)-m(I)(s) but can be distinguished by a satellite order q=(m(I)(r))(2)-(m(I)(s))(2).

Vasopressin activates Akt/mTOR pathway in smooth muscle cells cultured in high glucose concentration

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

Montes, Daniela K.; Brenet, Marianne; Muñoz, Vanessa C.

Highlights: •AVP induces mTOR phosphorylation in A-10 cells cultured in high glucose concentration. •The mTOR phosphorylation is mediated by the PI3K/Akt pathway activation. •The AVP-induced mTOR phosphorylation inhibited autophagy and stimulated cell proliferation. -- Abstract: Mammalian target of rapamycin (mTOR) complex is a key regulator of autophagy, cell growth and proliferation. Here, we studied the effects of arginine vasopressin (AVP) on mTOR activation in vascular smooth muscle cells cultured in high glucose concentration. AVP induced the mTOR phosphorylation in A-10 cells grown in high glucose, in contrast to cells cultured in normal glucose; wherein, only basal phosphorylation was observed. Themore » AVP-induced mTOR phosphorylation was inhibited by a PI3K inhibitor. Moreover, the AVP-induced mTOR activation inhibited autophagy and increased thymidine incorporation in cells grown in high glucose. This increase was abolished by rapamycin which inhibits the mTORC1 complex formation. Our results suggest that AVP stimulates mTOR phosphorylation by activating the PI3K/Akt signaling pathway and, subsequently, inhibits autophagy and raises cell proliferation in A-10 cells maintained in high glucose concentration.« less

Concentrations and annual fluxes of sediment-associated chemical constituents from conterminous US coastal rivers using bed sediment data

USGS Publications Warehouse

Horowitz, Arthur J.; Stephens, Verlin C.; Elrick, Kent A.; Smith, James J.

2012-01-01

Coastal rivers represent a significant pathway for the delivery of natural and anthropogenic sediment-associated chemical constituents to the Atlantic, Pacific and Gulf of Mexico coasts of the conterminous USA. This study entails an accounting segment using published average annual suspended sediment fluxes with published sediment-associated chemical constituent concentrations for (1) baseline, (2) land-use distributions, (3) population density, and (4) worldwide means to estimate concentrations/annual fluxes for trace/major elements and total phosphorus, total organic and inorganic carbon, total nitrogen, and sulphur, for 131 coastal river basins. In addition, it entails a sampling and subsequent chemical analysis segment that provides a level of ‘ground truth’ for the calculated values, as well as generating baselines for sediment-associated concentrations/fluxes against which future changes can be evaluated. Currently, between 260 and 270 Mt of suspended sediment are discharged annually from the conterminous USA; about 69% is discharged from Gulf rivers (n = 36), about 24% from Pacific rivers (n = 42), and about 7% from Atlantic rivers (n = 54). Elevated sediment-associated chemical concentrations relative to baseline levels occur in the reverse order of sediment discharges:Atlantic rivers (49%)>Pacific rivers (40%)>Gulf rivers (23%). Elevated trace element concentrations (e.g. Cu, Hg, Pb, Zn) frequently occur in association with present/former industrial areas and/or urban centres, particularly along the northeast Atlantic coast. Elevated carbon and nutrient concentrations occur along both the Atlantic and Gulf coasts but are dominated by rivers in the urban northeast and by southeastern and Gulf coast (Florida) ‘blackwater’ streams. Elevated Ca, Mg, K, and Na distributions tend to reflect local petrology, whereas elevated Ti, S, Fe, and Al concentrations are ubiquitous, possibly because they have substantial natural as well as anthropogenic sources. Almost all the elevated sediment-associated chemical concentrations found in conterminous US coastal rivers are lower than worldwide averages.

Cognitive Pathways: Analysis of Students' Written Texts for Science Understanding

ERIC Educational Resources Information Center

Grimberg, Bruna Irene; Hand, Brian

2009-01-01

The purpose of this study was to reconstruct writers' reasoning process as reflected in their written texts. The codes resulting from the text analysis were related to cognitive operations, ranging from simple to more sophisticated ones. The sequence of the cognitive operations as the text unfolded represents the writer's cognitive pathway at the…

A Missing Link for California's Pathways Movement: CTE Instructional Staff

ERIC Educational Resources Information Center

Lundy-Wagner, Valerie

2016-01-01

Recently, the State of California committed nearly one billion dollars to the development of career and technical education (CTE) pathways that lead to locally relevant, high-growth, high-demand careers. This investment represents a pivot from relatively disjointed approaches to CTE in high schools and community colleges, and reflects an…

Building Blocks: Laying the Groundwork for Guided Pathways Reform in Ohio

ERIC Educational Resources Information Center

Jenkins, Davis; Lahr, Hana; Fink, John

2017-01-01

This report describes how Ohio's two-year colleges are approaching guided pathways reforms, based on on-site interviews with faculty, administrators, staff, and students at six selected community colleges and telephone interviews with representatives from all 23 Ohio community colleges. In these interviews participants were asked to describe their…

PKG-Mediated MAPK Signaling Is Necessary for Long-Term Operant Memory in "Aplysia"

ERIC Educational Resources Information Center

Michel, Maximilian; Green, Charity L.; Eskin, Arnold; Lyons, Lisa C.

2011-01-01

Signaling pathways necessary for memory formation, such as the mitogen-activated protein kinase (MAPK) pathway, appear highly conserved across species and paradigms. Learning that food is inedible (LFI) represents a robust form of associative, operant learning that induces short- (STM) and long-term memory (LTM) in "Aplysia." We investigated the…

An overview of bioinformatics methods for modeling biological pathways in yeast

PubMed Central

Hou, Jie; Acharya, Lipi; Zhu, Dongxiao

2016-01-01

The advent of high-throughput genomics techniques, along with the completion of genome sequencing projects, identification of protein–protein interactions and reconstruction of genome-scale pathways, has accelerated the development of systems biology research in the yeast organism Saccharomyces cerevisiae. In particular, discovery of biological pathways in yeast has become an important forefront in systems biology, which aims to understand the interactions among molecules within a cell leading to certain cellular processes in response to a specific environment. While the existing theoretical and experimental approaches enable the investigation of well-known pathways involved in metabolism, gene regulation and signal transduction, bioinformatics methods offer new insights into computational modeling of biological pathways. A wide range of computational approaches has been proposed in the past for reconstructing biological pathways from high-throughput datasets. Here we review selected bioinformatics approaches for modeling biological pathways in S. cerevisiae, including metabolic pathways, gene-regulatory pathways and signaling pathways. We start with reviewing the research on biological pathways followed by discussing key biological databases. In addition, several representative computational approaches for modeling biological pathways in yeast are discussed. PMID:26476430

Treatment of Aqueous Film-Forming Foam by Heat-Activated Persulfate Under Conditions Representative of In Situ Chemical Oxidation

PubMed Central

2017-01-01

Poly- and perfluoroalkyl substances (PFASs) have been detected in an increasing number of water supplies. In many instances, the contamination is associated with the use of PFAS-containing aqueous film-forming foams (AFFF) in firefighting activities. To investigate the potential for remediating AFFF contamination in groundwater with heat-activated persulfate, PFAS oxidation and the generation of transformation products was evaluated under well-controlled conditions. Fluorotelomer- and perfluoroalkyl sulfonamide-based polyfluorinated compounds were transformed to perfluorinated carboxylic acids, which underwent further degradation under acidic conditions produced after persulfate decomposed. The presence of aquifer sediments decreased the efficiency of the remedial process but did not alter the transformation pathways. At high concentrations, the presence of organic solvents, such as those present in AFFF formulations, inhibited transformation of a representative perfluorinated compound, perfluorooctanoic acid. Heat-activated persulfate did not transform perfluorooctanesulfonic acid or perfluorohexanesulfonic acid under any conditions. Despite challenges associated with the creation of acidic conditions in the subsurface, the potential for generation of undesirable transformation products, and the release of toxic metals, heat-activated persulfate may be a useful in situ treatment for sites contaminated with polyfluoroalkyl substances and perfluorocarboxylic acids. PMID:29164864

Respiromics - An integrative analysis linking mitochondrial bioenergetics to molecular signatures.

PubMed

Walheim, Ellen; Wiśniewski, Jacek R; Jastroch, Martin

2018-03-01

Energy metabolism is challenged upon nutrient stress, eventually leading to a variety of metabolic diseases that represent a major global health burden. Here, we combine quantitative mitochondrial respirometry (Seahorse technology) and proteomics (LC-MS/MS-based total protein approach) to understand how molecular changes translate to changes in mitochondrial energy transduction during diet-induced obesity (DIO) in the liver. The integrative analysis reveals that significantly increased palmitoyl-carnitine respiration is supported by an array of proteins enriching lipid metabolism pathways. Upstream of the respiratory chain, the increased capacity for ATP synthesis during DIO associates strongest to mitochondrial uptake of pyruvate, which is routed towards carboxylation. At the respiratory chain, robust increases of complex I are uncovered by cumulative analysis of single subunit concentrations. Specifically, nuclear-encoded accessory subunits, but not mitochondrial-encoded or core units, appear to be permissive for enhanced lipid oxidation. Our integrative analysis, that we dubbed "respiromics", represents an effective tool to link molecular changes to functional mechanisms in liver energy metabolism, and, more generally, can be applied for mitochondrial analysis in a variety of metabolic and mitochondrial disease models. Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Contribution of the Hair Follicular Pathway to Total Skin Permeation of Topically Applied and Exposed Chemicals

PubMed Central

Mohd, Fadli; Todo, Hiroaki; Yoshimoto, Masato; Yusuf, Eddy; Sugibayashi, Kenji

2016-01-01

Generally, the blood and skin concentration profiles and steady-state skin concentration of topically applied or exposed chemicals can be calculated from the in vitro skin permeation profile. However, these calculation methods are particularly applicable to chemicals for which the main pathway is via the stratum corneum. If the contribution of hair follicles to the total skin permeation of chemicals can be obtained in detail, their blood and skin concentrations can be more precisely predicted. In the present study, the contribution of the hair follicle pathway to the skin permeation of topically applied or exposed chemicals was calculated from the difference between their permeability coefficients through skin with and without hair follicle plugging, using an in vitro skin permeation experiment. The obtained results reveal that the contribution of the hair follicle pathway can be predicted by using the chemicals’ lipophilicity. For hydrophilic chemicals (logarithm of n-octanol/water partition coefficient (log Ko/w) < 0), a greater reduction of permeation due to hair follicle plugging was observed than for lipophilic chemicals (log Ko/w ≥ 0). In addition, the ratio of this reduction was decreased with an increase in log Ko/w. This consideration of the hair follicle pathway would be helpful to investigate the efficacy and safety of chemicals after topical application or exposure to them because skin permeation and disposition should vary among skins in different body sites due to differences in the density of hair follicles. PMID:27854289

Contribution of the Hair Follicular Pathway to Total Skin Permeation of Topically Applied and Exposed Chemicals.

PubMed

Mohd, Fadli; Todo, Hiroaki; Yoshimoto, Masato; Yusuf, Eddy; Sugibayashi, Kenji

2016-11-15

Generally, the blood and skin concentration profiles and steady-state skin concentration of topically applied or exposed chemicals can be calculated from the in vitro skin permeation profile. However, these calculation methods are particularly applicable to chemicals for which the main pathway is via the stratum corneum. If the contribution of hair follicles to the total skin permeation of chemicals can be obtained in detail, their blood and skin concentrations can be more precisely predicted. In the present study, the contribution of the hair follicle pathway to the skin permeation of topically applied or exposed chemicals was calculated from the difference between their permeability coefficients through skin with and without hair follicle plugging, using an in vitro skin permeation experiment. The obtained results reveal that the contribution of the hair follicle pathway can be predicted by using the chemicals' lipophilicity. For hydrophilic chemicals (logarithm of n -octanol/water partition coefficient (log K o/w ) < 0), a greater reduction of permeation due to hair follicle plugging was observed than for lipophilic chemicals (log K o/w ≥ 0). In addition, the ratio of this reduction was decreased with an increase in log K o/w . This consideration of the hair follicle pathway would be helpful to investigate the efficacy and safety of chemicals after topical application or exposure to them because skin permeation and disposition should vary among skins in different body sites due to differences in the density of hair follicles.

Elementary Mode Analysis: A Useful Metabolic Pathway Analysis Tool for Characterizing Cellular Metabolism

PubMed Central

Trinh, Cong T.; Wlaschin, Aaron; Srienc, Friedrich

2010-01-01

Elementary Mode Analysis is a useful Metabolic Pathway Analysis tool to identify the structure of a metabolic network that links the cellular phenotype to the corresponding genotype. The analysis can decompose the intricate metabolic network comprised of highly interconnected reactions into uniquely organized pathways. These pathways consisting of a minimal set of enzymes that can support steady state operation of cellular metabolism represent independent cellular physiological states. Such pathway definition provides a rigorous basis to systematically characterize cellular phenotypes, metabolic network regulation, robustness, and fragility that facilitate understanding of cell physiology and implementation of metabolic engineering strategies. This mini-review aims to overview the development and application of elementary mode analysis as a metabolic pathway analysis tool in studying cell physiology and as a basis of metabolic engineering. PMID:19015845

Selection of a Representative Subset of Global Climate Models that Captures the Profile of Regional Changes for Integrated Climate Impacts Assessment

NASA Technical Reports Server (NTRS)

Ruane, Alex C.; Mcdermid, Sonali P.

2017-01-01

We present the Representative Temperature and Precipitation (T&P) GCM Subsetting Approach developed within the Agricultural Model Intercomparison and Improvement Project (AgMIP) to select a practical subset of global climate models (GCMs) for regional integrated assessment of climate impacts when resource limitations do not permit the full ensemble of GCMs to be evaluated given the need to also focus on impacts sector and economics models. Subsetting inherently leads to a loss of information but can free up resources to explore important uncertainties in the integrated assessment that would otherwise be prohibitive. The Representative T&P GCM Subsetting Approach identifies five individual GCMs that capture a profile of the full ensemble of temperature and precipitation change within the growing season while maintaining information about the probability that basic classes of climate changes (relatively cool/wet, cool/dry, middle, hot/wet, and hot/dry) are projected in the full GCM ensemble. We demonstrate the selection methodology for maize impacts in Ames, Iowa, and discuss limitations and situations when additional information may be required to select representative GCMs. We then classify 29 GCMs over all land areas to identify regions and seasons with characteristic diagonal skewness related to surface moisture as well as extreme skewness connected to snow-albedo feedbacks and GCM uncertainty. Finally, we employ this basic approach to recognize that GCM projections demonstrate coherence across space, time, and greenhouse gas concentration pathway. The Representative T&P GCM Subsetting Approach provides a quantitative basis for the determination of useful GCM subsets, provides a practical and coherent approach where previous assessments selected solely on availability of scenarios, and may be extended for application to a range of scales and sectoral impacts.

Interleukins and their signaling pathways in the Reactome biological pathway database.

PubMed

Jupe, Steve; Ray, Keith; Roca, Corina Duenas; Varusai, Thawfeek; Shamovsky, Veronica; Stein, Lincoln; D'Eustachio, Peter; Hermjakob, Henning

2018-04-01

There is a wealth of biological pathway information available in the scientific literature, but it is spread across many thousands of publications. Alongside publications that contain definitive experimental discoveries are many others that have been dismissed as spurious, found to be irreproducible, or are contradicted by later results and consequently now considered controversial. Many descriptions and images of pathways are incomplete stylized representations that assume the reader is an expert and familiar with the established details of the process, which are consequently not fully explained. Pathway representations in publications frequently do not represent a complete, detailed, and unambiguous description of the molecules involved; their precise posttranslational state; or a full account of the molecular events they undergo while participating in a process. Although this might be sufficient to be interpreted by an expert reader, the lack of detail makes such pathways less useful and difficult to understand for anyone unfamiliar with the area and of limited use as the basis for computational models. Reactome was established as a freely accessible knowledge base of human biological pathways. It is manually populated with interconnected molecular events that fully detail the molecular participants linked to published experimental data and background material by using a formal and open data structure that facilitates computational reuse. These data are accessible on a Web site in the form of pathway diagrams that have descriptive summaries and annotations and as downloadable data sets in several formats that can be reused with other computational tools. The entire database and all supporting software can be downloaded and reused under a Creative Commons license. Pathways are authored by expert biologists who work with Reactome curators and editorial staff to represent the consensus in the field. Pathways are represented as interactive diagrams that include as much molecular detail as possible and are linked to literature citations that contain supporting experimental details. All newly created events undergo a peer-review process before they are added to the database and made available on the associated Web site. New content is added quarterly. The 63rd release of Reactome in December 2017 contains 10,996 human proteins participating in 11,426 events in 2,179 pathways. In addition, analytic tools allow data set submission for the identification and visualization of pathway enrichment and representation of expression profiles as an overlay on Reactome pathways. Protein-protein and compound-protein interactions from several sources, including custom user data sets, can be added to extend pathways. Pathway diagrams and analytic result displays can be downloaded as editable images, human-readable reports, and files in several standard formats that are suitable for computational reuse. Reactome content is available programmatically through a REpresentational State Transfer (REST)-based content service and as a Neo4J graph database. Signaling pathways for IL-1 to IL-38 are hierarchically classified within the pathway "signaling by interleukins." The classification used is largely derived from Akdis et al. The addition to Reactome of a complete set of the known human interleukins, their receptors, and established signaling pathways linked to annotations of relevant aspects of immune function provides a significant computationally accessible resource of information about this important family. This information can be extended easily as new discoveries become accepted as the consensus in the field. A key aim for the future is to increase coverage of gene expression changes induced by interleukin signaling. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Orexin: a Missing Link Between Sleep Disorders and Heart Failure?

PubMed

Pan, Stephen; Cabral, Carolina S; Ashley, Euan A; Perez, Marco V

2017-04-01

Sleep disorders represent a significant comorbidity in the heart failure population, and there is mounting evidence that treatment of sleep disorders such as obstructive sleep apnea can significantly improve cardiac function. However, the link between these two disorders is still not entirely clear. Recently, a novel neurohormonal pathway has been elucidated involving signaling molecules now collectively known as the orexins, which have been implicated in regulating autonomic function during sleep/wake cycles. Further evidence has mounted that orexin signaling is deeply perturbed in the setting of sleep disorders, and furthermore that abnormal orexin signaling may be implicated in the pathology of heart failure. The orexin signaling pathway represents an enticing novel target for both the treatment of sleep disorders as well as heart failure, and may represent one facet of the "missing link" between these two prevalent and often comorbid diseases.

Physically driven Patchy O2 Changes in the North Atlantic Ocean simulated by the CMIP5 Earth System Models

NASA Astrophysics Data System (ADS)

Tagklis, Filippos; Bracco, Annalisa; Ito, Takamitsu

2017-04-01

Centennial trends of oxygen in the upper 700 m of the North Atlantic Ocean are investigated in Earth System Models (ESMs) included in the Coupled Model Intercomparison Project Phase 5. The focus is on the subpolar region, which is key for the oceanic uptake of oxygen and carbon dioxide. Historical simulations covering the twentieth century and projections for the twenty-first century under the Representative Concentration Pathway 8.5 scenario are investigated. Although the representation of convective activity differs among the models in space and strength, and most models have a cold bias south of Greenland resulting from a poor representation of the pathway of the North Atlantic Current, the observed climatological distribution of dissolved O2 averaged for the recent past period (1975-2005) is generally well captured. By the end of the 21st century, all models predict an increase in depth-integrated temperature of 2-3oC, a consequent solubility decrease, a weakening of the vertical mass transport, a decrease in nutrient supply into the euphotic layer, and a spatially variable change in apparent oxygen utilization (AOU). Despite an overall tendency of the North Atlantic to lose oxygen by the end of twenty-first century, patchy regions of O2 increase are observed in a subset of models. This regional resistance to deoxygenation is explained by the weakening of the North Atlantic Current that causes a regional solubility increase exceeding the effect of increasing stratification. Our results imply that potential shifts in the North Atlantic Current play a crucial role in the future projection of the regional oxygen concentration in the warming climate.

A gene-environment interaction analysis of plasma selenium with prevalent and incident diabetes: The Hortega study.

PubMed

Galan-Chilet, Inmaculada; Grau-Perez, Maria; De Marco, Griselda; Guallar, Eliseo; Martin-Escudero, Juan Carlos; Dominguez-Lucas, Alejandro; Gonzalez-Manzano, Isabel; Lopez-Izquierdo, Raul; Briongos-Figuero, Laisa Socorro; Redon, Josep; Chaves, Felipe Javier; Tellez-Plaza, Maria

2017-08-01

Selenium and single-nucleotide-polymorphisms in selenoprotein genes have been associated to diabetes. However, the interaction of selenium with genetic variation in diabetes and oxidative stress-related genes has not been evaluated as a potential determinant of diabetes risk. We evaluated the cross-sectional and prospective associations of plasma selenium concentrations with type 2 diabetes, and the interaction of selenium concentrations with genetic variation in candidate polymorphisms, in a representative sample of 1452 men and women aged 18-85 years from Spain. The geometric mean of plasma selenium levels in the study sample was 84.2µg/L. 120 participants had diabetes at baseline. Among diabetes-free participants who were not lost during the follow-up (N=1234), 75 developed diabetes over time. The multivariable adjusted odds ratios (95% confidence interval) for diabetes prevalence comparing the second and third to the first tertiles of plasma selenium levels were 1.80 (1.03, 3.14) and 1.97 (1.14, 3.41), respectively. The corresponding hazard ratios (95% CI) for diabetes incidence were 1.76 (0.96, 3.22) and 1.80 (0.98, 3.31), respectively. In addition, we observed significant interactions between selenium and polymorphisms in PPARGC1A, and in genes encoding mitochondrial proteins, such as BCS1L and SDHA, and suggestive interactions of selenium with other genes related to selenoproteins and redox metabolism. Plasma selenium was positively associated with prevalent and incident diabetes. While the statistical interactions of selenium with polymorphisms involved in regulation of redox and insulin signaling pathways provide biological plausibility to the positive associations of selenium with diabetes, further research is needed to elucidate the causal pathways underlying these associations. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Children's Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making.

PubMed

Zartarian, Valerie; Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

2017-09-12

Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)'s National Drinking Water Advisory Council (NDWAC) recommended establishment of a "health-based, household action level" for lead in drinking water based on children's exposure. The primary objective was to develop a coupled exposure-dose modeling approach that can be used to determine what drinking water lead concentrations keep children's blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. A modeling approach using the EPA's Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Modeled BLLs compared well with nationally representative BLLs (0-23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605.

Children’s Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making

PubMed Central

Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

2017-01-01

Background: Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)’s National Drinking Water Advisory Council (NDWAC) recommended establishment of a “health-based, household action level” for lead in drinking water based on children’s exposure. Objectives: The primary objective was to develop a coupled exposure–dose modeling approach that can be used to determine what drinking water lead concentrations keep children’s blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. Methods: A modeling approach using the EPA’s Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Results: Modeled BLLs compared well with nationally representative BLLs (0–23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. Conclusions: This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605 PMID:28934096

Involvement of β3-adrenoceptors in the inhibitory control of cholinergic activity in human bladder: Direct evidence by [(3)H]-acetylcholine release experiments in the isolated detrusor.

PubMed

D' Agostino, Gianluigi; Maria Condino, Anna; Calvi, Paolo

2015-07-05

Bladder overactivity (OAB) is a multifactorial bladder disorder that requires therapeutics superior to the current pharmacological treatment with muscarinic antagonists. β3-adrenoceptor (β3-ADR) agonists represent a novel promising approach that differently addresses the parasympathetic pathway, but the clinical efficacy of these drugs has not been fully elucidated to date. Therefore, we aimed to study the pharmacological mechanisms activated by β3-ADR agonists at muscular and neural sites in the isolated human bladder. Detrusor smooth muscle strips obtained from male patients undergoing total cystectomy were labelled with tritiated choline and stimulated with electrical field stimulation (EFS). EFS produced smooth muscle contraction and simultaneous acetylcholine ([(3)H]-ACh) release, which mostly reflects the neural origin of acetylcholine. Isoprenaline (INA), BRL37344 and mirabegron inhibited the EFS-evoked contraction and [(3)H]-ACh release in a concentration-dependent manner, yielding concentration-response curves (CRCs) that were shifted to the right by the selective β3-ADR antagonists L-748,337 and SR59230A. Based on the agonist potency estimates (pEC50) and apparent affinities (pKb) of antagonists evaluated from the CRCs of agonists, our data confirm the occurrence of β3-ADRs at muscle sites. Moreover, our data are consistent with the presence of inhibitory β3-ADRs that are functionally expressed at the neural site. Taken together, these findings elucidate the mechanisms activated by β3-ADR agonists because neural β3-ADRs participate in the inhibition of detrusor motor drive by reducing the amount of acetylcholine involved in the cholinergic pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Correlation between citric acid and nitrate metabolisms during CAM cycle in the atmospheric bromeliad Tillandsia pohliana.

PubMed

Freschi, Luciano; Rodrigues, Maria Aurineide; Tiné, Marco Aurélio Silva; Mercier, Helenice

2010-12-15

Crassulacean acid metabolism (CAM) confers crucial adaptations for plants living under frequent environmental stresses. A wide metabolic plasticity can be found among CAM species regarding the type of storage carbohydrate, organic acid accumulated at night and decarboxylating system. Consequently, many aspects of the CAM pathway control are still elusive while the impact of this photosynthetic adaptation on nitrogen metabolism has remained largely unexplored. In this study, we investigated a possible link between the CAM cycle and the nitrogen assimilation in the atmospheric bromeliad Tillandsia pohliana by simultaneously characterizing the diel changes in key enzyme activities and metabolite levels of both organic acid and nitrate metabolisms. The results revealed that T. pohliana performed a typical CAM cycle in which phosphoenolpyruvate carboxylase and phosphoenolpyruvate carboxykinase phosphorylation seemed to play a crucial role to avoid futile cycles of carboxylation and decarboxylation. Unlike all other bromeliads previously investigated, almost equimolar concentrations of malate and citrate were accumulated at night. Moreover, a marked nocturnal depletion in the starch reservoirs and an atypical pattern of nitrate reduction restricted to the nighttime were also observed. Since reduction and assimilation of nitrate requires a massive supply of reducing power and energy and considering that T. pohliana lives overexposed to the sunlight, we hypothesize that citrate decarboxylation might be an accessory mechanism to increase internal CO₂ concentration during the day while its biosynthesis could provide NADH and ATP for nocturnal assimilation of nitrate. Therefore, besides delivering photoprotection during the day, citrate might represent a key component connecting both CAM pathway and nitrogen metabolism in T. pohliana; a scenario that certainly deserves further study not only in this species but also in other CAM plants that nocturnally accumulate citrate. Copyright © 2010 Elsevier GmbH. All rights reserved.

Olive phenolic compounds: metabolic and transcriptional profiling during fruit development

PubMed Central

2012-01-01

Background Olive (Olea europaea L.) fruits contain numerous secondary metabolites, primarily phenolics, terpenes and sterols, some of which are particularly interesting for their nutraceutical properties. This study will attempt to provide further insight into the profile of olive phenolic compounds during fruit development and to identify the major genetic determinants of phenolic metabolism. Results The concentration of the major phenolic compounds, such as oleuropein, demethyloleuropein, 3–4 DHPEA-EDA, ligstroside, tyrosol, hydroxytyrosol, verbascoside and lignans, were measured in the developing fruits of 12 olive cultivars. The content of these compounds varied significantly among the cultivars and decreased during fruit development and maturation, with some compounds showing specificity for certain cultivars. Thirty-five olive transcripts homologous to genes involved in the pathways of the main secondary metabolites were identified from the massive sequencing data of the olive fruit transcriptome or from cDNA-AFLP analysis. Their mRNA levels were determined using RT-qPCR analysis on fruits of high- and low-phenolic varieties (Coratina and Dolce d’Andria, respectively) during three different fruit developmental stages. A strong correlation was observed between phenolic compound concentrations and transcripts putatively involved in their biosynthesis, suggesting a transcriptional regulation of the corresponding pathways. OeDXS, OeGES, OeGE10H and OeADH, encoding putative 1-deoxy-D-xylulose-5-P synthase, geraniol synthase, geraniol 10-hydroxylase and arogenate dehydrogenase, respectively, were almost exclusively present at 45 days after flowering (DAF), suggesting that these compounds might play a key role in regulating secoiridoid accumulation during fruit development. Conclusions Metabolic and transcriptional profiling led to the identification of some major players putatively involved in biosynthesis of secondary compounds in the olive tree. Our data represent the first step towards the functional characterisation of important genes for the determination of olive fruit quality. PMID:22963618

Differentiating transpiration from evaporation in seasonal agricultural wetlands and the link to advective fluxes in the root zone

USGS Publications Warehouse

Bachand, P.A.M.; S. Bachand,; Fleck, Jacob A.; Anderson, Frank E.; Windham-Myers, Lisamarie

2014-01-01

The current state of science and engineering related to analyzing wetlands overlooks the importance of transpiration and risks data misinterpretation. In response, we developed hydrologic and mass budgets for agricultural wetlands using electrical conductivity (EC) as a natural conservative tracer. We developed simple differential equations that quantify evaporation and transpiration rates using flowrates and tracer concentrations atwetland inflows and outflows. We used two ideal reactormodel solutions, a continuous flowstirred tank reactor (CFSTR) and a plug flow reactor (PFR), to bracket real non-ideal systems. From those models, estimated transpiration ranged from 55% (CFSTR) to 74% (PFR) of total evapotranspiration (ET) rates, consistent with published values using standard methods and direct measurements. The PFR model more appropriately represents these nonideal agricultural wetlands in which check ponds are in series. Using a fluxmodel, we also developed an equation delineating the root zone depth at which diffusive dominated fluxes transition to advective dominated fluxes. This relationship is similar to the Peclet number that identifies the dominance of advective or diffusive fluxes in surface and groundwater transport. Using diffusion coefficients for inorganic mercury (Hg) and methylmercury (MeHg) we calculated that during high ET periods typical of summer, advective fluxes dominate root zone transport except in the top millimeters below the sediment–water interface. The transition depth has diel and seasonal trends, tracking those of ET. Neglecting this pathway has profound implications: misallocating loads along different hydrologic pathways; misinterpreting seasonal and diel water quality trends; confounding Fick's First Law calculations when determining diffusion fluxes using pore water concentration data; and misinterpreting biogeochemicalmechanisms affecting dissolved constituent cycling in the root zone. In addition,our understanding of internal root zone cycling of Hg and other dissolved constituents, benthic fluxes, and biological irrigation may be greatly affected.

Organic Acids: The Pools of Fixed Carbon Involved in Redox Regulation and Energy Balance in Higher Plants

PubMed Central

Igamberdiev, Abir U.; Eprintsev, Alexander T.

2016-01-01

Organic acids are synthesized in plants as a result of the incomplete oxidation of photosynthetic products and represent the stored pools of fixed carbon accumulated due to different transient times of conversion of carbon compounds in metabolic pathways. When redox level in the cell increases, e.g., in conditions of active photosynthesis, the tricarboxylic acid (TCA) cycle in mitochondria is transformed to a partial cycle supplying citrate for the synthesis of 2-oxoglutarate and glutamate (citrate valve), while malate is accumulated and participates in the redox balance in different cell compartments (via malate valve). This results in malate and citrate frequently being the most accumulated acids in plants. However, the intensity of reactions linked to the conversion of these compounds can cause preferential accumulation of other organic acids, e.g., fumarate or isocitrate, in higher concentrations than malate and citrate. The secondary reactions, associated with the central metabolic pathways, in particularly with the TCA cycle, result in accumulation of other organic acids that are derived from the intermediates of the cycle. They form the additional pools of fixed carbon and stabilize the TCA cycle. Trans-aconitate is formed from citrate or cis-aconitate, accumulation of hydroxycitrate can be linked to metabolism of 2-oxoglutarate, while 4-hydroxy-2-oxoglutarate can be formed from pyruvate and glyoxylate. Glyoxylate, a product of either glycolate oxidase or isocitrate lyase, can be converted to oxalate. Malonate is accumulated at high concentrations in legume plants. Organic acids play a role in plants in providing redox equilibrium, supporting ionic gradients on membranes, and acidification of the extracellular medium. PMID:27471516

The effect of the indoor environment on the fate of organic chemicals in the urban landscape.

PubMed

Cousins, Anna Palm

2012-11-01

To assess the effect of the indoor environment on the urban fate of organic chemicals, an 8-compartment indoor-inclusive steady state multimedia chemical fate model was developed. The model includes typical urban compartments (air, soil, water, sediment, and urban film) and a novel module representing a generic indoor environment. The model was parameterized to the municipality of Stockholm, Sweden and applied to four organic chemicals with different physical-chemical characteristics and use patterns: formaldehyde, 2,4,6-tribromophenol, di-ethylhexylphthalate and decabromodiphenyl ether. The results show that emissions to indoor air may increase the steady state mass and residence time in the urban environment by a factor of 1.1 to 22 for the four chemicals, compared to if emissions are assigned to outdoor air. This is due to the nested nature of the indoor environment, which creates a physical barrier that prevents chemicals from leaving the urban system with outflowing air. For DEHP and BDE 209, the additional partitioning to indoor surfaces results in a greater importance of the indoor removal pathways from surfaces. The outdoor environmental concentrations of these chemicals are predicted to be lower if emitted to indoor air than if emitted to outdoor air because of the additional indoor removal pathways of dust and indoor film, leading to loss of chemical from the system. For formaldehyde and 2,4,6-TBP outdoor environmental concentrations are not affected by whether the release occurs indoors or outdoors because of the limited partitioning to indoor surfaces. A sensitivity analysis revealed that there appears to be a relationship between logK(OA) and the impact of the ventilation rate on the urban fate of organic chemicals. Copyright © 2012 Elsevier B.V. All rights reserved.

A link between central kynurenine metabolism and bone strength in rats with chronic kidney disease

PubMed Central

Pawlak, Krystyna; Oksztulska-Kolanek, Ewa; Domaniewski, Tomasz; Znorko, Beata; Karbowska, Malgorzata; Citkowska, Aleksandra; Rogalska, Joanna; Roszczenko, Alicja; Brzoska, Malgorzata M.; Pawlak, Dariusz

2017-01-01

Background Disturbances in mineral and bone metabolism represent one of the most complex complications of chronic kidney disease (CKD). Serotonin, a monoamine synthesized from tryptophan, may play a potential role in bone metabolism. Brain-derived serotonin exerts a positive effect on the bone structure by limiting bone resorption and enhancing bone formation. Tryptophan is the precursor not only to the serotonin but also and primarily to kynurenine metabolites. The ultimate aim of the present study was to determine the association between central kynurenine metabolism and biomechanical as well as geometrical properties of bone in the experimental model of the early stage of CKD. Methods Thirty-three Wistar rats were randomly divided into two groups (sham-operated and subtotal nephrectomized animals). Three months after surgery, serum samples were obtained for the determination of biochemical parameters, bone turnover biomarkers, and kynurenine pathway metabolites; tibias were collected for bone biomechanical, bone geometrical, and bone mass density analysis; brains were removed and divided into five regions for the determination of kynurenine pathway metabolites. Results Subtotal nephrectomized rats presented higher serum concentrations of creatinine, urea nitrogen, and parathyroid hormone, and developed hypocalcemia. Several biomechanical and geometrical parameters were significantly elevated in rats with experimentally induced CKD. Subtotal nephrectomized rats presented significantly higher kynurenine concentrations and kynurenine/tryptophan ratio and significantly lower tryptophan levels in all studied parts of the brain. Kynurenine in the frontal cortex and tryptophan in the hypothalamus and striatum correlated positively with the main parameters of bone biomechanics and bone geometry. Discussion In addition to the complex mineral, hormone, and metabolite changes, intensified central kynurenine turnover may play an important role in the development of bone changes in the course of CKD. PMID:28439468

Functional and molecular characterization of kinin B1 and B 2 receptors in human bladder cancer: implication of the PI3Kγ pathway.

PubMed

Sgnaolin, V; Pereira, T C B; Bogo, M R; Zanin, R; Battastini, A M O; Morrone, F B; Campos, M M

2013-08-01

Kinins and their receptors have been recently implicated in cancer. Using functional and molecular approaches, we investigated the relevance of kinin B1 and B2 receptors in bladder cancer. Functional studies were conducted using bladder cancer cell lines, and human biopsies were employed for molecular studies. Both B1 des-Arg(9)-BK and B2 BK receptor agonists stimulated the proliferation of grade 3-derived T24 bladder cancer cells. Furthermore, treatment with B1 and B2 receptor antagonists (SSR240612 and HOE140) markedly inhibited the proliferation of T24 cells. Only higher concentrations of BK increased the proliferation of the grade 1 bladder cancer cell line RT4, while des-Arg(9)-BK completely failed to induce its proliferation. Real-time PCR revealed that the mRNA expression of kinin receptors, particularly B1 receptors, was increased in T24 cells relative to RT4 cells. Data from bladder cancer human biopsies revealed that B1 receptor expression was increased in all tumor samples and under conditions of chronic inflammation. We also show novel evidence demonstrating that the pharmacological inhibition of PI3Kγ (phosphatidylinositol 3-kinase) with AS252424, concentration-dependently reduced T24 cell proliferation induced by BK or des-Arg(9)-BK. Finally, the incubation of T24 cells with kinin agonists led to a marked activation of the PI3K/AKT and ERK 1/2 signaling pathways, whereas p38 MAP kinase remained unaffected. Kinin receptors, especially B1 receptors, appear to be implicated in bladder cancer progression. It is tempting to suggest that selective kinin antagonists might represent potential alternative therapies for bladder cancer.

Apical electrolyte concentration modulates barrier function and tight junction protein localization in bovine mammary epithelium.

PubMed

Quesnell, Rebecca R; Erickson, Jamie; Schultz, Bruce D

2007-01-01

In vitro mammary epithelial cell models typically fail to form a consistently tight barrier that can effectively separate blood from milk. Our hypothesis was that mammary epithelial barrier function would be affected by changes in luminal ion concentration and inflammatory cytokines. Bovine mammary epithelial (BME-UV cell line) cells were grown to confluence on permeable supports with a standard basolateral medium and either high-electrolyte (H-elec) or low-electrolyte (L-elec) apical medium for 14 days. Apical media were changed to/from H-elec medium at predetermined times prior to assay. Transepithelial electrical resistance (R(te)) was highest in monolayers continuously exposed to apical L-elec. A time-dependent decline in R(te) began within 24 h of H-elec medium exposure. Change from H-elec medium to L-elec medium time-dependently increased R(te). Permeation by FITC-conjugated dextran was elevated across monolayers exposed to H-elec, suggesting compromise of a paracellular pathway. Significant alteration in occludin distribution was evident, concomitant with the changes in R(te), although total occludin was unchanged. Neither substitution of Na(+) with N-methyl-d-glucosamine (NMDG(+)) nor pharmacological inhibition of transcellular Na(+) transport pathways abrogated the effects of apical H-elec medium on R(te). Tumor necrosis factor alpha, but not interleukin-1beta nor interleukin-6, in the apical compartment caused a significant decrease in R(te) within 8 h. These results indicate that mammary epithelium is a dynamic barrier whose cell-cell contacts are acutely modulated by cytokines and luminal electrolyte environment. Results not only demonstrate that BME-UV cells are a model system representative of mammary epithelium but also provide critical information that can be applied to other mammary model systems to improve their physiological relevance.

Modelling the impact of future socio-economic and climate change scenarios on river microbial water quality.

PubMed

Islam, M M Majedul; Iqbal, Muhammad Shahid; Leemans, Rik; Hofstra, Nynke

2018-03-01

Microbial surface water quality is important, as it is related to health risk when the population is exposed through drinking, recreation or consumption of irrigated vegetables. The microbial surface water quality is expected to change with socio-economic development and climate change. This study explores the combined impacts of future socio-economic and climate change scenarios on microbial water quality using a coupled hydrodynamic and water quality model (MIKE21FM-ECOLab). The model was applied to simulate the baseline (2014-2015) and future (2040s and 2090s) faecal indicator bacteria (FIB: E. coli and enterococci) concentrations in the Betna river in Bangladesh. The scenarios comprise changes in socio-economic variables (e.g. population, urbanization, land use, sanitation and sewage treatment) and climate variables (temperature, precipitation and sea-level rise). Scenarios have been developed building on the most recent Shared Socio-economic Pathways: SSP1 and SSP3 and Representative Concentration Pathways: RCP4.5 and RCP8.5 in a matrix. An uncontrolled future results in a deterioration of the microbial water quality (+75% by the 2090s) due to socio-economic changes, such as higher population growth, and changes in rainfall patterns. However, microbial water quality improves under a sustainable scenario with improved sewage treatment (-98% by the 2090s). Contaminant loads were more influenced by changes in socio-economic factors than by climatic change. To our knowledge, this is the first study that combines climate change and socio-economic development scenarios to simulate the future microbial water quality of a river. This approach can also be used to assess future consequences for health risks. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

Wnt signalling pathway parameters for mammalian cells.

PubMed

Tan, Chin Wee; Gardiner, Bruce S; Hirokawa, Yumiko; Layton, Meredith J; Smith, David W; Burgess, Antony W

2012-01-01

Wnt/β-catenin signalling regulates cell fate, survival, proliferation and differentiation at many stages of mammalian development and pathology. Mutations of two key proteins in the pathway, APC and β-catenin, have been implicated in a range of cancers, including colorectal cancer. Activation of Wnt signalling has been associated with the stabilization and nuclear accumulation of β-catenin and consequential up-regulation of β-catenin/TCF gene transcription. In 2003, Lee et al. constructed a computational model of Wnt signalling supported by experimental data from analysis of time-dependent concentration of Wnt signalling proteins in Xenopus egg extracts. Subsequent studies have used the Xenopus quantitative data to infer Wnt pathway dynamics in other systems. As a basis for understanding Wnt signalling in mammalian cells, a confocal live cell imaging measurement technique is developed to measure the cell and nuclear volumes of MDCK, HEK293T cells and 3 human colorectal cancer cell lines and the concentrations of Wnt signalling proteins β-catenin, Axin, APC, GSK3β and E-cadherin. These parameters provide the basis for formulating Wnt signalling models for kidney/intestinal epithelial mammalian cells. There are significant differences in concentrations of key proteins between Xenopus extracts and mammalian whole cell lysates. Higher concentrations of Axin and lower concentrations of APC are present in mammalian cells. Axin concentrations are greater than APC in kidney epithelial cells, whereas in intestinal epithelial cells the APC concentration is higher than Axin. Computational simulations based on Lee's model, with this new data, suggest a need for a recalibration of the model.A quantitative understanding of Wnt signalling in mammalian cells, in particular human colorectal cancers requires a detailed understanding of the concentrations of key protein complexes over time. Simulations of Wnt signalling in mammalian cells can be initiated with the parameters measured in this report.

Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways

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

Vickers, Alison E.M., E-mail: vickers_alison@allergan.com; Heale, Jason; Sinclair, John R.

Drug induced thyroid effects were evaluated in organotypic models utilizing either a rat thyroid lobe or human thyroid slices to compare rodent and human response. An inhibition of thyroid peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and release pathways. The clinically used thiourea drugs, methimazole (MMI) and 6-n-propyl-2-thioruacil (PTU), were used to evaluate thyroid drug response in these models. Inhibition of TPO occurred early as shown in rat thyroid lobes (2 h) and was sustained in both rat (24–48 h) and human (24 h) with ≥ 10 μM MMI. Thyroidmore » from rats treated with single doses of MMI (30–1000 mg/kg) exhibited sustained TPO inhibition at 48 h. The MMI in vivo thyroid concentrations were comparable to the culture concentrations (∼ 15–84 μM), thus demonstrating a close correlation between in vivo and ex vivo thyroid effects. A compensatory response to TPO inhibition was demonstrated in the rat thyroid lobe with significant up-regulation of genes involved in the pathway of thyroid hormone synthesis (Tpo, Dio1, Slc5a5, Tg, Tshr) and the megalin release pathway (Lrp2) by 24 h with MMI (≥ 10 μM) and PTU (100 μM). Similarly, thyroid from the rat in vivo study exhibited an up-regulation of Dio1, Slc5a5, Lrp2, and Tshr. In human thyroid slices, there were few gene expression changes (Slc5a5, ∼ 2-fold) and only at higher MMI concentrations (≥ 1500 μM, 24 h). Extended exposure (48 h) resulted in up-regulation of Tpo, Dio1 and Lrp2, along with Slc5a5 and Tshr. In summary, TPO was inhibited by similar MMI concentrations in rat and human tissue, however an increased sensitivity to drug treatment in rat is indicated by the up-regulation of thyroid hormone synthesis and release gene pathways at concentrations found not to affect human tissue. -- Highlights: ► Novel model of rat thyroid or human thyroid slices to evaluate pathways of injury. ► TPO inhibition by MMI or PTU altered hormone synthesis and release genes. ► Rat thyroid was more sensitive to the drug effects than human tissue.« less

Functional toxicogenomic assessment of triclosan in human ...

EPA Pesticide Factsheets

Thousands of chemicals for which limited toxicological data are available are used and then detected in humans and the environment. Rapid and cost-effective approaches for assessing the toxicological properties of chemicals are needed. We used CRISPR-Cas9 functional genomic screening to identify potential molecular mechanism of a widely used antimicrobial triclosan (TCS) in HepG2 cells. Resistant genes (whose knockout gives potential resistance) at IC50 (50% Inhibition concentration of cell viability) were significantly enriched in adherens junction pathway, MAPK signaling pathway and PPAR signaling pathway, suggesting a potential molecular mechanism in TCS induced cytotoxicity. Evaluation of top-ranked resistant genes, FTO (encoding an mRNA demethylase) and MAP2K3 (a MAP kinase kinase family gene), revealed that their loss conferred resistance to TCS. In contrast, sensitive genes (whose knockout enhances potential sensitivity) at IC10 and IC20 were specifically enriched in pathways involved with immune responses, which was concordant with the transcriptomic profiling of TCS at concentrations

Boron Tolerance in Aspergillus nidulans Is Sustained by the SltA Pathway Through the SLC-Family Transporters SbtA and SbtB

PubMed Central

Villarino, María; Mendizabal, Gorka; Garzia, Aitor; Ugalde, Unai

2017-01-01

Microbial cells interact with the environment by adapting to external changes. Signal transduction pathways participate in both sensing and responding in the form of modification of gene expression patterns, enabling cell survival. The filamentous fungal-specific SltA pathway regulates tolerance to alkalinity, elevated cation concentrations and, as shown in this work, also stress conditions induced by borates. Growth of sltA− mutants is inhibited by increasing millimolar concentrations of boric acid or borax (sodium tetraborate). In an attempt to identify genes required for boron-stress response, we determined the boric acid or borax-dependent expression of sbtA and sbtB, orthologs of Saccharomyces cerevisiae bor1, and a reduction in their transcript levels in a ΔsltA mutant. Deletion of sbtA, but mainly that of sbtB, decreased the tolerance to boric acid or borax. In contrast, null mutants of genes coding for additional transporters of the Solute Carrier (SLC) family, sB, sbtD or sbtE, showed an unaltered growth pattern under the same stress conditions. Taken together, our results suggest that the SltA pathway induces, through SbtA and SbtB, the export of toxic concentrations of borates, which have largely recognized antimicrobial properties. PMID:28753996

Experimental Evaluation of Seaweeds as a Vector for Microplastics into Marine Food Webs.

PubMed

Gutow, Lars; Eckerlebe, Antonia; Giménez, Luis; Saborowski, Reinhard

2016-01-19

The ingestion of microplastics has been shown for a great variety of marine organisms. However, benthic marine mesoherbivores such as the common periwinkle Littorina littorea have been largely disregarded in studies about the effects of microplastics on the marine biota, probably because the pathway for microplastics to this functional group of organisms was not obvious. In laboratory experiments we showed that the seaweed Fucus vesiculosus retains suspended microplastics on its surface. The numbers of microplastics that adhered to the algae correlated with the concentrations of suspended particles in the water. In choice feeding assays L. littorea did not distinguish between algae with adherent microplastics and clean algae without microplastics, indicating that the snails do not recognize solid nonfood particles in the submillimeter size range as deleterious. In periwinkles that were feeding on contaminated algae, microplastics were found in the stomach and in the gut. However, no microplastics were found in the midgut gland, which is the principle digestive organ of gastropods. Microplastics in the fecal pellets of the periwinkles indicate that the particles do not accumulate rapidly inside the animals but are mostly released with the feces. Our results provide the first evidence that seaweeds may represent an efficient pathway for microplastics from the water to marine benthic herbivores.

Leveraging existing data for prioritization of the ecological risks of human and veterinary pharmaceuticals to aquatic organisms

PubMed Central

LaLone, Carlie A.; Berninger, Jason P.; Villeneuve, Daniel L.; Ankley, Gerald T.

2014-01-01

Medicinal innovation has led to the discovery and use of thousands of human and veterinary drugs. With this comes the potential for unintended effects on non-target organisms exposed to pharmaceuticals inevitably entering the environment. The impracticality of generating whole-organism chronic toxicity data representative of all species in the environment has necessitated prioritization of drugs for focused empirical testing as well as field monitoring. Current prioritization strategies typically emphasize likelihood for exposure (i.e. predicted/measured environmental concentrations), while incorporating only rather limited consideration of potential effects of the drug to non-target organisms. However, substantial mammalian pharmacokinetic and mechanism/mode of action (MOA) data are produced during drug development to understand drug target specificity and efficacy for intended consumers. An integrated prioritization strategy for assessing risks of human and veterinary drugs would leverage available pharmacokinetic and toxicokinetic data for evaluation of the potential for adverse effects to non-target organisms. In this reiview, we demonstrate the utility of read-across approaches to leverage mammalian absorption, distribution, metabolism and elimination data; analyse cross-species molecular target conservation and translate therapeutic MOA to an adverse outcome pathway(s) relevant to aquatic organisms as a means to inform prioritization of drugs for focused toxicity testing and environmental monitoring. PMID:25405975

Prelysosomal Compartments in the Unconventional Secretion of Amyloidogenic Seeds

PubMed Central

Borland, Helena; Vilhardt, Frederik

2017-01-01

A mechanistic link between neuron-to-neuron transmission of secreted amyloid and propagation of protein malconformation cytopathology and disease has recently been uncovered in animal models. An enormous interest in the unconventional secretion of amyloids from neurons has followed. Amphisomes and late endosomes are the penultimate maturation products of the autophagosomal and endosomal pathways, respectively, and normally fuse with lysosomes for degradation. However, under conditions of perturbed membrane trafficking and/or lysosomal deficiency, prelysosomal compartments may instead fuse with the plasma membrane to release any contained amyloid. After a brief introduction to the endosomal and autophagosomal pathways, we discuss the evidence for autophagosomal secretion (exophagy) of amyloids, with a comparative emphasis on Aβ1–42 and α-synuclein, as luminal and cytosolic amyloids, respectively. The ESCRT-mediated import of cytosolic amyloid into late endosomal exosomes, a known vehicle of transmission of macromolecules between cells, is also reviewed. Finally, mechanisms of lysosomal dysfunction, deficiency, and exocytosis are exemplified in the context of genetically identified risk factors, mainly for Parkinson’s disease. Exocytosis of prelysosomal or lysosomal organelles is a last resort for clearance of cytotoxic material and alleviates cytopathy. However, they also represent a vehicle for the concentration, posttranslational modification, and secretion of amyloid seeds. PMID:28124989

Aerobic Mercury-resistant bacteria alter Mercury speciation and retention in the Tagus Estuary (Portugal).

PubMed

Figueiredo, Neusa L; Canário, João; O'Driscoll, Nelson J; Duarte, Aida; Carvalho, Cristina

2016-02-01

Aerobic mercury-resistant bacteria were isolated from the sediments of two highly mercury-polluted areas of the Tagus Estuary (Barreiro and Cala do Norte) and one natural reserve area (Alcochete) in order to test their capacity to transform mercury. Bacterial species were identified using 16S rRNA amplification and sequencing techniques and the results indicate the prevalence of Bacillus sp. Resistance patterns to mercurial compounds were established by the determination of minimal inhibitory concentrations. Representative Hg-resistant bacteria were further tested for transformation pathways (reduction, volatilization and methylation) in cultures containing mercury chloride. Bacterial Hg-methylation was carried out by Vibrio fluvialis, Bacillus megaterium and Serratia marcescens that transformed 2-8% of total mercury into methylmercury in 48h. In addition, most of the HgR bacterial isolates showed Hg(2+)-reduction andHg(0)-volatilization resulting 6-50% mercury loss from the culture media. In summary, the results obtained under controlled laboratory conditions indicate that aerobic Hg-resistant bacteria from the Tagus Estuary significantly affect both the methylation and reduction of mercury and may have a dual face by providing a pathway for pollution dispersion while forming methylmercury, which is highly toxic for living organisms. Copyright © 2015 Elsevier Inc. All rights reserved.

Assessing cost-effectiveness of bioretention on stormwater in response to climate change and urbanization for future scenarios

NASA Astrophysics Data System (ADS)

Wang, Mo; Zhang, Dongqing; Adhityan, Appan; Ng, Wun Jern; Dong, Jianwen; Tan, Soon Keat

2016-12-01

Bioretention, as a popular low impact development practice, has become more important to mitigate adverse impacts on urban stormwater. However, there is very limited information regarding ensuring the effectiveness of bioretention response to uncertain future challenges, especially when taking into consideration climate change and urbanization. The main objective of this paper is to identify the cost-effectiveness of bioretention by assessing the hydrology performance under future scenarios modeling. First, the hydrology model was used to obtain peak runoff and TSS loads of bioretention with variable scales under different scenarios, i.e., different Representative Concentration Pathways (RCPs) and Shared Socio-economic reference Pathways (SSPs) for 2-year and 10-year design storms in Singapore. Then, life cycle costing (LCC) and life cycle assessment (LCA) were estimated for bioretention, and the cost-effectiveness was identified under different scenarios. Our finding showed that there were different degree of responses to 2-year and 10-year design storms but the general patterns and insights deduced were similar. The performance of bioretenion was more sensitive to urbanization than that for climate change in the urban catchment. In addition, it was noted that the methodology used in this study was generic and the findings could be useful as reference for other LID practices in response to climate change and urbanization.

Enhanced marine sulphur emissions offset global warming and impact rainfall.

PubMed

Grandey, B S; Wang, C

2015-08-21

Artificial fertilisation of the ocean has been proposed as a possible geoengineering method for removing carbon dioxide from the atmosphere. The associated increase in marine primary productivity may lead to an increase in emissions of dimethyl sulphide (DMS), the primary source of sulphate aerosol over remote ocean regions, potentially causing direct and cloud-related indirect aerosol effects on climate. This pathway from ocean fertilisation to aerosol induced cooling of the climate may provide a basis for solar radiation management (SRM) geoengineering. In this study, we investigate the transient climate impacts of two emissions scenarios: an RCP4.5 (Representative Concentration Pathway 4.5) control; and an idealised scenario, based on RCP4.5, in which DMS emissions are substantially enhanced over ocean areas. We use mini-ensembles of a coupled atmosphere-ocean configuration of CESM1(CAM5) (Community Earth System Model version 1, with the Community Atmosphere Model version 5). We find that the cooling effect associated with enhanced DMS emissions beneficially offsets greenhouse gas induced warming across most of the world. However, the rainfall response may adversely affect water resources, potentially impacting human livelihoods. These results demonstrate that changes in marine phytoplankton activity may lead to a mixture of positive and negative impacts on the climate.

Arabidopsis AIP1-2 restricted by WER-mediated patterning modulates planar polarity

PubMed Central

Kiefer, Christian S.; Claes, Andrea R.; Nzayisenga, Jean-Claude; Pietra, Stefano; Stanislas, Thomas; Hüser, Anke; Ikeda, Yoshihisa; Grebe, Markus

2015-01-01

The coordination of cell polarity within the plane of the tissue layer (planar polarity) is crucial for the development of diverse multicellular organisms. Small Rac/Rho-family GTPases and the actin cytoskeleton contribute to planar polarity formation at sites of polarity establishment in animals and plants. Yet, upstream pathways coordinating planar polarity differ strikingly between kingdoms. In the root of Arabidopsis thaliana, a concentration gradient of the phytohormone auxin coordinates polar recruitment of Rho-of-plant (ROP) to sites of polar epidermal hair initiation. However, little is known about cytoskeletal components and interactions that contribute to this planar polarity or about their relation to the patterning machinery. Here, we show that ACTIN7 (ACT7) represents a main actin isoform required for planar polarity of root hair positioning, interacting with the negative modulator ACTIN-INTERACTING PROTEIN1-2 (AIP1-2). ACT7, AIP1-2 and their genetic interaction are required for coordinated planar polarity of ROP downstream of ethylene signalling. Strikingly, AIP1-2 displays hair cell file-enriched expression, restricted by WEREWOLF (WER)-dependent patterning and modified by ethylene and auxin action. Hence, our findings reveal AIP1-2, expressed under control of the WER-dependent patterning machinery and the ethylene signalling pathway, as a modulator of actin-mediated planar polarity. PMID:25428588

Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay

PubMed Central

He, Miao; Kratz, Lisa E.; Michel, Joshua J.; Vallejo, Abbe N.; Ferris, Laura; Kelley, Richard I.; Hoover, Jacqueline J.; Jukic, Drazen; Gibson, K. Michael; Wolfe, Lynne A.; Ramachandran, Dhanya; Zwick, Michael E.; Vockley, Jerry

2011-01-01

Defects in cholesterol synthesis result in a wide variety of symptoms, from neonatal lethality to the relatively mild dysmorphic features and developmental delay found in individuals with Smith-Lemli-Opitz syndrome. We report here the identification of mutations in sterol-C4-methyl oxidase–like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay. This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4-methylsterols in the cholesterol synthesis pathway. C4-Methylsterols are meiosis-activating sterols (MASs). They exist at high concentrations in the testis and ovary and play roles in meiosis activation. In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood. SMO deficiency also substantially altered immunocyte phenotype and in vitro function. MASs serve as ligands for liver X receptors α and β (LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity. Deficiency of SMO represents a biochemical defect in the cholesterol synthesis pathway, the clinical spectrum of which remains to be defined. PMID:21285510

Assessing the potential impact and uncertainty of climate, land use change and demographic trends on malaria transmission in Africa by 2050.

NASA Astrophysics Data System (ADS)

Tompkins, Adrian; Caporaso, Luca; Colon-Gonzalez, Felipe

2014-05-01

Previous analyses of data has shown that in addition to variability and longer term trends in climate variables, both land use change (LUC) and population mobility and urbanisation trends can impact malaria transmission intensities and socio-economic burden. With the new regional VECTRI dynamical malaria model it is now possible to examine these in an integrated modelling framework. Using 5 global climate models which were bias corrected using the WATCH data for the recent ISIMIP project, the four Representative Concentration Pathways (RCP), population projections disaggregated from the Shared Socioeconomic Pathways (SSP) and Land use change from the HYDE model output used in the CMIP5 process, we construct a multi-member ensemble of malaria transmission intensity projections for 2050. The ensemble integrations indicate that climate has the leading impact on malaria changes, but that population growth and urbanisation can offset the effect of climate locally. LUC impacts can also be significant on the local scale but their assessment is highly uncertain and only indicative in this study. It is argued that the study should be repeated with a range of malaria models or VECTRI configurations in order to assess the additional uncertainty due to the malaria model assumptions.

Enhanced marine sulphur emissions offset global warming and impact rainfall

PubMed Central

Grandey, B. S.; Wang, C.

2015-01-01

Artificial fertilisation of the ocean has been proposed as a possible geoengineering method for removing carbon dioxide from the atmosphere. The associated increase in marine primary productivity may lead to an increase in emissions of dimethyl sulphide (DMS), the primary source of sulphate aerosol over remote ocean regions, potentially causing direct and cloud-related indirect aerosol effects on climate. This pathway from ocean fertilisation to aerosol induced cooling of the climate may provide a basis for solar radiation management (SRM) geoengineering. In this study, we investigate the transient climate impacts of two emissions scenarios: an RCP4.5 (Representative Concentration Pathway 4.5) control; and an idealised scenario, based on RCP4.5, in which DMS emissions are substantially enhanced over ocean areas. We use mini-ensembles of a coupled atmosphere-ocean configuration of CESM1(CAM5) (Community Earth System Model version 1, with the Community Atmosphere Model version 5). We find that the cooling effect associated with enhanced DMS emissions beneficially offsets greenhouse gas induced warming across most of the world. However, the rainfall response may adversely affect water resources, potentially impacting human livelihoods. These results demonstrate that changes in marine phytoplankton activity may lead to a mixture of positive and negative impacts on the climate. PMID:26293204

Enhanced marine sulphur emissions offset global warming and impact rainfall

NASA Astrophysics Data System (ADS)

Grandey, B. S.; Wang, C.

2015-08-01

Artificial fertilisation of the ocean has been proposed as a possible geoengineering method for removing carbon dioxide from the atmosphere. The associated increase in marine primary productivity may lead to an increase in emissions of dimethyl sulphide (DMS), the primary source of sulphate aerosol over remote ocean regions, potentially causing direct and cloud-related indirect aerosol effects on climate. This pathway from ocean fertilisation to aerosol induced cooling of the climate may provide a basis for solar radiation management (SRM) geoengineering. In this study, we investigate the transient climate impacts of two emissions scenarios: an RCP4.5 (Representative Concentration Pathway 4.5) control; and an idealised scenario, based on RCP4.5, in which DMS emissions are substantially enhanced over ocean areas. We use mini-ensembles of a coupled atmosphere-ocean configuration of CESM1(CAM5) (Community Earth System Model version 1, with the Community Atmosphere Model version 5). We find that the cooling effect associated with enhanced DMS emissions beneficially offsets greenhouse gas induced warming across most of the world. However, the rainfall response may adversely affect water resources, potentially impacting human livelihoods. These results demonstrate that changes in marine phytoplankton activity may lead to a mixture of positive and negative impacts on the climate.

Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

NASA Astrophysics Data System (ADS)

Margiotta-Casaluci, Luigi; Owen, Stewart F.; Huerta, Belinda; Rodríguez-Mozaz, Sara; Kugathas, Subramanian; Barceló, Damià; Rand-Weaver, Mariann; Sumpter, John P.

2016-02-01

The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-species uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

Assessing uncertainties in global cropland futures using a conditional probabilistic modelling framework

NASA Astrophysics Data System (ADS)

Engström, Kerstin; Olin, Stefan; Rounsevell, Mark D. A.; Brogaard, Sara; van Vuuren, Detlef P.; Alexander, Peter; Murray-Rust, Dave; Arneth, Almut

2016-11-01

We present a modelling framework to simulate probabilistic futures of global cropland areas that are conditional on the SSP (shared socio-economic pathway) scenarios. Simulations are based on the Parsimonious Land Use Model (PLUM) linked with the global dynamic vegetation model LPJ-GUESS (Lund-Potsdam-Jena General Ecosystem Simulator) using socio-economic data from the SSPs and climate data from the RCPs (representative concentration pathways). The simulated range of global cropland is 893-2380 Mha in 2100 (± 1 standard deviation), with the main uncertainties arising from differences in the socio-economic conditions prescribed by the SSP scenarios and the assumptions that underpin the translation of qualitative SSP storylines into quantitative model input parameters. Uncertainties in the assumptions for population growth, technological change and cropland degradation were found to be the most important for global cropland, while uncertainty in food consumption had less influence on the results. The uncertainties arising from climate variability and the differences between climate change scenarios do not strongly affect the range of global cropland futures. Some overlap occurred across all of the conditional probabilistic futures, except for those based on SSP3. We conclude that completely different socio-economic and climate change futures, although sharing low to medium population development, can result in very similar cropland areas on the aggregated global scale.

Systems Genetics Analysis of GWAS reveals Novel Associations between Key Biological Processes and Coronary Artery Disease

PubMed Central

Ghosh, Sujoy; Vivar, Juan; Nelson, Christopher P; Willenborg, Christina; Segrè, Ayellet V; Mäkinen, Ville-Petteri; Nikpay, Majid; Erdmann, Jeannette; Blankenberg, Stefan; O'Donnell, Christopher; März, Winfried; Laaksonen, Reijo; Stewart, Alexandre FR; Epstein, Stephen E; Shah, Svati H; Granger, Christopher B; Hazen, Stanley L; Kathiresan, Sekar; Reilly, Muredach P; Yang, Xia; Quertermous, Thomas; Samani, Nilesh J; Schunkert, Heribert; Assimes, Themistocles L; McPherson, Ruth

2016-01-01

Objective Genome-wide association (GWA) studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Approaches and Results Employing pathways (gene sets) from Reactome, we carried out a two-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CADGWAS data sets (9,889 cases/11,089 controls), nominally significant gene-sets were tested for replication in a meta-analysis of 9 additional studies (15,502 cases/55,730 controls) from the CARDIoGRAM Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication p<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix integrity, innate immunity, axon guidance, and signaling by PDRF, NOTCH, and the TGF-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (e.g. semaphorin regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared to random networks (p<0.001). Network centrality analysis (‘degree’ and ‘betweenness’) further identified genes (e.g. NCAM1, FYN, FURIN etc.) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. Conclusions These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD. PMID:25977570