The brain signature of paracetamol in healthy volunteers: a double-blind randomized trial

International audienceBackground: Paracetamol’s (APAP) mechanism of action suggests the implication of supraspinal structures but no neuroimaging study has been performed in humans.Methods and results: This randomized, double-blind, crossover, placebo-controlled trial in 17 healthy volunteers (NCT01562704) aimed to evaluate how APAP modulates pain-evoked functional magnetic resonance imaging signals. We used behavioral measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli with APAP or placebo administration. Region-of-interest analysis revealed that activity in response to noxious stimulation diminished with APAP compared to placebo in prefrontal cortices, insula, thalami, anterior cingulate cortex, and periaqueductal gray matter.Conclusion: These findings suggest an inhibitory effect of APAP on spinothalamic tracts leading to a decreased activation of higher structures, and a top-down influence on descending inhibition. Further binding and connectivity studies are needed to evaluate how APAP modulates pain, especially in the context of repeated administration to patients with pain

Economic risk assessment of drought impacts on irrigated agriculture

[EN] In this paper, we present an innovative framework for an economic risk analysis of drought impacts on irrigated agriculture. It consists on the integration of three components: stochastic time series modelling for prediction of inflows and future reservoir storages at the beginning of the irrigation season; statistical regression for the evaluation of water deliveries based on projected inflows and storages; and econometric modelling for economic assessment of the production value of agriculture based on irrigation water deliveries and crop prices. Therefore, the effect of the price volatility can be isolated from the losses due to water scarcity in the assessment of the drought impacts. Monte Carlo simulations are applied to generate probability functions of inflows, which are translated into probabilities of storages, deliveries, and finally, production value of agriculture. The framework also allows the assessment of the value of mitigation measures as reduction of economic losses during droughts. The approach was applied to the Jucar river basin, a complex system affected by multiannual severe droughts, with irrigated agriculture as the main consumptive demand. Probability distributions of deliveries and production value were obtained for each irrigation season. In the majority of the irrigation districts, drought causes a significant economic impact. The increase of crop prices can partially offset the losses from the reduction of production due to water scarcity in some districts. Emergency wells contribute to mitigating the droughts' impacts on the Jucar river system. (C) 2017 Elsevier B.V. All rights reserved.This study has been supported by the IMPADAPT project (CGL2013-48424-C2-1-R) with Spanish MINECO (Ministerio de Economia y Competitividad) and European FEDER funds; the European Union's Horizon 2020 research and innovation programme under the IMPREX project (GA 641.811) and the FP7 project ENHANCE (FP7, 308438).Lopez-Nicolas, A.; Pulido-Velazquez, M.; Macian-Sorribes, H. (2017). Economic risk assessment of drought impacts on irrigated agriculture. Journal of Hydrology. 550:580-589. https://doi.org/10.1016/j.jhydrol.2017.05.004S58058955

Integrated assessment of the impact of climate and land use changes on groundwater quantity and quality in the Mancha Oriental system (Spain)

[EN] Climate and land use change (global change) impacts on groundwater systems cannot be studied in isolation. Land use and land cover (LULC) changes have a great impact on the water cycle and contaminant production and transport. Groundwater flow and storage are changing in response not only to climatic changes but also to human impacts on land uses and demands, which will alter the hydrologic cycle and subsequently impact the quantity and quality of regional water systems. Predicting groundwater recharge and discharge conditions under future climate and land use changes is essential for integrated water management and adaptation. In the Mancha Oriental system (MOS), one of the largest groundwater bodies in Spain, the transformation from dry to irrigated lands during the last decades has led to a significant drop of the groundwater table, with the consequent effect on stream-aquifer interaction in the connected Jucar River. Understanding the spatial and temporal distribution of water quantity and water quality is essential for a proper management of the system. On the one hand, streamflow depletion is compromising the dependent ecosystems and the supply to the downstream demands, provoking a complex management issue. On the other hand, the intense use of fertilizer in agriculture is leading to locally high groundwater nitrate concentrations. In this paper we analyze the potential impacts of climate and land use change in the system by using an integrated modeling framework that consists in sequentially coupling a watershed agriculturally based hydrological model (Soil and Water Assessment Tool, SWAT) with a groundwater flow model developed in MODFLOW, and with a nitrate mass-transport model in MT3DMS. SWAT model outputs (mainly groundwater recharge and pumping, considering new irrigation needs under changing evapotranspiration (ET) and precipitation) are used as MODFLOW inputs to simulate changes in groundwater flow and storage and impacts on stream-aquifer interaction. SWAT and MODFLOW outputs (nitrate loads from SWAT, groundwater velocity field from MODFLOW) are used as MT3DMS inputs for assessing the fate and transport of nitrate leached from the topsoil. Three climate change scenarios have been considered, corresponding to three different general circulation models (GCMs) for emission scenario A1B that covers the control period, and short-, medium-and long-term future periods. A multi-temporal analysis of LULC change was carried out, helped by the study of historical trends (from remote-sensing images) and key driving forces to explain LULC transitions. Markov chains and European scenarios and projections were used to quantify trends in the future. The cellular automata technique was applied for stochastic modeling future LULC maps. Simulated values of river discharge, crop yields, groundwater levels and nitrate concentrations fit well to the observed ones. The results show the response of groundwater quantity and quality (nitrate pollution) to climate and land use changes, with decreasing groundwater recharge and an increase in nitrate concentrations. The sequential modeling chain has been proven to be a valuable assessment tool for supporting the development of sustainable management strategies.This study was partially funded by the EU FP7 GENESIS project (no. 226.536) on groundwater systems, the Plan Nacional de I+D+I 2008-2011 of the Ministry of Science and Innovation of Spain (projects CGL2009-13238-C02-01/02 on climate change impacts and adaptation), and the IMPADAPT project (CGL2013-48424-C2-1-R) with Spanish MINECO (Ministerio de Economia y Competitividad) and Feder funds. We also want to thank SMHI for the climate scenarios provided in the context of the GENESIS project, as well as the anonymous reviewer and the handling editor, for the constructive and helpful review of the paper.Pulido-Velazquez, M.; Peña Haro, S.; García Prats, A.; Mocholí Almudéver, AF.; Henriquez-Dole, L.; Macian-Sorribes, H.; Lopez-Nicolas, A. (2015). Integrated assessment of the impact of climate and land use changes on groundwater quantity and quality in the Mancha Oriental system (Spain). Hydrology and Earth System Sciences. 19(4):1677-1693. https://doi.org/10.5194/hess-19-1677-2015S16771693194Abbaspour, K.: SWAT-CUP 2012: SWAT Calibration and Uncertainty Programs – A User Manual, available at: http://www.neprashtechnology.ca/Downloads/SwatCup/Manual/Usermanual_Swat_Cup.pdf, 2012.Apperl, B., Pulido-Velazquez, M., Andreu, J., and Karjalainen, T. P.: Contribution of the multi-attribute value theory to conflict resolution in groundwater management – application to the Mancha Oriental groundwater system, Spain, Hydrol. Earth Syst. Sci., 19, 1325–1337, https://doi.org/10.5194/hess-19-1325-2015, 2015.Arnold, J. G. and Williams, J. R.: SWRRB – A watershed scale model for soil and water resources management, in: Computer models of watershed hydrology, edited by: Singh, V. P., Water Resources Publications, 847–908, 1995.Arnold, J. G., Srinivasan, R., Muttiah, R. S., and Williams, J. R.: Large area hydrologic modeling and assessment part I: model development, J. Am. Water Resour. As., 34, 73–89, 1998.Arnold, J. G., Moriasi, D. N., Gassman, P. W., Abbaspour, K. C., White, M. J., Srinivasan, R., Santhi, C., Harmel, R. D., van Griensven, A., Van Liew, M. W., Kannan, N., and Jha, M. K.: SWAT: Model Use, Calibration, and Validation, T. ASABE, 55, 1491–1508, 2012.Calera, A., Medrano, J., Vela, A., and Castaño, S.: GIS tools applied to the sustainable management of hydric resources: application to the aquifer system 08-29, Agr. Water Manage., 40, 207–220, 1999.Calera, A., Jochum, A. M., Cuesta, A., Montoro, A., and Lopez, P.: Irrigation management from space: Towards user-friendly products, Irrig. Drain., 19, 337–353, 2005.Calera, A., Osann, A., D'Urso, G., Neale, C., and Moreno, J. M.: Earth Observation for irrigation and river basin management in an operational way: The SPIDER system, IAHS-AISH P., 352, 423–426, 2012.Caballero, S., Voirin-Morel, F., Habets, J., Noilhan, P., LeMoigne, A., and Lehenaff, A. B.: Hydrological sensitivity of the Adour-Garonne river basin to climate change, Water Resour. Res., 43, WO7448, https://doi.org/10.1029/2005WR004192, 2007.Candela, L., von Igel, W., Elorza, F. J., and Aronica, G.: Impact assessment of combined climate and management scenarios on groundwater resources and associated wetland (Majorca, Spain), J. Hydrol., 376, 510–527, 2009.Candela, L., Elorza, F. J., Jiménez-Martínez, J., and von Igel, W.: Global change and agricultural management options for groundwater sustainability, Comput. Electron. Agr., 86, 120–130, 2012.Castaño, S., Sanz, D., and Gómez-Alday, J. J.: Methodology for quantifying 13 groundwater abstractions for agricultura via remote sensing and GIS, Water Resour. Manage., 24, 795–814, 2010.Chaouche, K., Neppel, L., Dieulin, C., Pujol, N., Ladouche, B., Martin, E., Salas, D., and Caballero, Y.: Analyses of precipitation, temperatura and evapotranspiration in a French Mediterranean región in the context of climate change, C.R. Geosci., 342, 234–243, 2010.CHJ: Documento Técnico de Referencia: Evaluación del Estado de las Masas de Agua Superficial y Subterránea, Ámbito territorial de la Confederación Hidrográfica del Júcar, Ministerio de Medio Ambiente y Medio Rural y Marino. Confederación Hidrográfica del Júcar, Spain, 2009a (in Spanish).CHJ: Esquema provisional de Temas Importantes, Ministerio de Medio Ambiente y Medio Rural y Marino. Confederación Hidrográfica del Júcar, Spain, 2009b (in Spanish).CHJ: Memoria del Proyecto del Plan Hidrológico, Ministerio de Medio Ambiente y Medio Rural y Marino, Confederación Hidrográfica del Júcar, Spain, 2013 (in Spanish).Eastman, J. R.: IDRISI Andes, Guide to GIS and image processing Clark University, Worcester, MA, 2006.Ertürk, A., Ekdal, A., Gürel, M., Karakaya, N., Guzel, C., and Gönenç, E.: Evaluating the impact of climate change on groundwater resources in a small Mediterranean watershed, Sci. Total Environ., 499, 437–447, 2014.Feranec, J., Hazeu, G., Soukup, T., and Jaffrain, G.: Determining changes and flows in European landscapes 1990–2000 using CORINE land cover data, Appl. Geogr., 30, 19–35, ISSN 0143-6228, 2010.Gassman, P. W., Reyes, M. R., Green, C. H., and Arnold, J. G.: The Soil and Water Assessment Tool: Historical Development, Applications, and Future Research Directions, T. ASABE, 50, 1211–1250, 2007.Gassman, P. W., Sadeghi, A. M., and Srinivasan, R.: Applications of the SWAT model special section: overview and insights, J. Environ. Qual., 43, 1–8, https://doi.org/10.2134/jeq2013.11.0466, 2014.Henriquez-Dole, L. E.: Escenarios futuros de uso del suelo para el análisis del efecto del cambio global en los recursos hídricos aplicado al acuífero de la Mancha Oriental. Master Thesis dissertation. Universitat Politècnica de València, Spain, 2012 (in Spanish).Holman, I. P., Allen, D. M., Cuthbert, M. O., and Goderniaux, P.: Towards best practice for assessing the impacts of climate change on groundwater, Hydrogeol. J., 20, 1–4, 2012.IGME-DGA: Trabajos de la Actividad 4 "Identificación y caracterización de la interrelación entre aguas subterráneas, cursos fluviales, descargas por manantiales, zonas húmedas y otros ecosistemas naturales de especial interés hídrico", Encomienda de gestión para la realización de trabajos científico-técnicos de apoyo a la sostenibilidad y protección de las aguas subterráneas, Demarcación Hidrográfica del Júcar, Instituto Geológico y Minero de España (Ministerio de Ciencia e Innovación) y Dirección General del Agua (Ministerio de Medio y Medio Rural y Marino), 2010.INE (Instituto Nacional de Estadística): available at: http://www.ine.es, last access: December 2011.Jyrkama, I. M. and Sykes, J. F.: The impact of climate change on spatially varying groundwater recharge in the grand river watershed, J. Hydrol., 338, 237–250, 2007.Kim, N. W., Chung, I. M, Won, Y. S., and Arnold, J. G.: Development and application of the integrated SWAT-MODFLOW model, J. Hydrology, 356, 1–16, 2008.Kingston, D. G. and Taylor, R. G.: Sources of uncertainty in climate change impacts on river discharge and groundwater in a headwater catchment of the Upper Nile Basin, Uganda, Hydrol. Earth Syst. Sci., 14, 1297–1308, https://doi.org/10.5194/hess-14-1297-2010, 2010.Kjellstrom, E., Nikulin, G., Hasson, U., Strandberg, G., and Ullerstig, A.: 21st century changes in the European climate: uncertainties derived from an ensemble of regional climate model simulations, Tellus A, 63, 24–40, 2011.Klijn, J. A., Vullings, L. A. E., van den Berg, M., van Meijl, H., van Lammeren, R., van Rheenen, T., Veldkamp, A., Verburg, P. H., Westhoek, H., and Eickhout, B.: The EURURALIS study: Technical document, Alterra, Wageningen, available at: http://www.eururalis.nl/background.htm (last access: 29 March 2014), 2005.Kløve, B., Ala-Aho, P., Bertrand, G., Gurdak, J. J., Kupfersberger, H., Kvœrner, J., Muotka, T., Mykrä, H., Preda, E., Rossi, P., Uvo, C. B., Velasco, E., and Pulido-Velázquez, M.: Climate Change Impacts on Groundwater and Dependent Ecosystems, J. Hydrol., 518, 250–266, 2014.Lopez-Gunn, E.: The Role of Collective Action in Water Governance: A Comparative 15 Study of Groundwater User Associations in La Mancha Aquifers in Spain, Water 16 International, 28, 367–378, 2003.López Urrea, R., López Córcoles, H., López Fuster, P., Montoro Rodríguez, A., Martín de Santa Olalla Mañas, F., and Calero Martínez, J. A.: Ensayos de programación de riegos en kenaf, trigo blando y bróculi, available at: http://www.itap.es/media/3279/4.programación riegos 2003.pdf (last access: February 2015), 2003.Ma, X., Lu, X. X., van Noordwijk, M., Li, J. T., and Xu, J. C.: Attribution of climate change, vegetation restoration, and engineering measures to the reduction of suspended sediment in the Kejie catchment, southwest China, Hydrol. Earth Syst. Sci., 18, 1979–1994, https://doi.org/10.5194/hess-18-1979-2014, 2014.Mango, L. M., Melesse, A. M., McClain, M. E., Gann, D., and Setegn, S. G.: Land use and climate change impacts on the hydrology of the upper Mara River Basin, Kenya: results of a modeling study to support better resource management, Hydrol. Earth Syst. Sci., 15, 2245–2258, https://doi.org/10.5194/hess-15-2245-2011, 2011.Martin-Benlloch, A.: Obtención de Curvas de Producción y Lixiviado Mediante el Modelo Distribuído GEPIC en Escenarios de Cambio Climático, Degree Dissertation, Universitat Politècnica de València, 2012 (in Spanish).McDonald, M. G. and Harbaugh, A. W.: A modular three-dimensional finite difference groundwater flow model, US Geological Survey Techniques of Water-Resources Investigation Book 6, Chapter A1, 586 pp., 1988.Molina-Navarro, E., Trolle, D., Martínez-Pérez, S., Sastre-Merlín, A., and Jepsen, E.: Hydrological and water quality impact assessment of a Mediterranean limno-reservoir under climate change and land use change scenarios, J. Hydrol., 509, 354–366, 2014.Moratalla, A., Gómez-Alday, J. J., De las Heras, J., Sanz, D., and Castaño, S.: Nitrate in the Water-Supply Wells in the Mancha Oriental Hydrogeological System (SE Spain), Water Resour. Manage., 23, 1621–1640, https://doi.org/10.1007/s11269-008-9344-7, 2009.Nakicenovic, N. and Swart, R. (Eds.): Special Report on Emissions Scenarios, IPCC, Cambridge University Press, Cambridge, UK, 570 pp., 2000.Narula, K. K. and Gosain, A. K.: Modeling hydrology, groundwater recharge and non-point nitrate loadings in the Himalayan Upper Yamuna basin, Sci. Total Environ., 468–469, S102–S116, https://doi.org/10.1016/j.scitotenv.2013.01.022, 2013.Neitsch, S. L., Arnold, J. G., Kiniry, J. R., Srinivasan, R., and Williams, J. R.: Soil and water assessment tool input/output file documentation (version 2005), Temple, Texas: Grassland, Soil and Water Research Laboratory, Agriculture Research Service, Blackland Research Center, Texas Agricultural Experiment Station, 2005.Nikulin, G., Kjellstrom, E., Hasson, U., Strandberg, G., and Ullerstig, A.: Evaluation and future projections of temperature, precipitation and wind extremes over Europe in an ensemble of regional climate simulations, Tellus, 63A, 41–55, 2011.Oñate-Valdivieso, F. and Bosque Sendra, J.: Application of GIS and remote sensing techniques in generation of land use scenarios for hydrological modeling, J. Hydrol., 395, 256–263, 2010.Peña-Haro, S., Llopis-Albert, C., Pulido-Velazquez, M., and Pulido-Velazquez, D.: Fertilizer standards for controlling groundwater nitrate pollution from agriculture: El Salobral-Los Llanos case study, Spain, J. Hydrol., 392, 174–187, 2010.Peña-Haro, S., García-Prats, A., and Pulido-Velazquez, M.: Influence of soil and climate heterogeneity on the performance of economic instruments for reducing nitrate leaching from agriculture, Sci. Total Environ., 499, 510–519, https://doi.org/10.1016/j.scitotenv.2014.07.029, 2014.Pulido-Velazquez, D., García-Aróstegui, J. L., Molina, J. L., and Pulido-Velazquez, M.: Assessment of future groundwater recharge in semi-arid regions under climate change scenarios (Serral-Salinas aquifer, SE Spain). Could increased rainfall variability increase the recharge rate?, Hydrol. Process., 29, 828–844, https://doi.org/10.1002/hyp.10191, 2015.Reifen, C. and Toumi, R.: Climate projections: Past performance no guarantee of future skill?, Geophys. Res. Lett., 36, L13704, https://doi.org/10.1029/2009GL038082, 2009.Rienks, W. A. (Ed.): The future of rural Europe, An anthology based on the results of the Eururalis 2.0 scenario study. Wageningen UR and Netherlands Environmental Assesment Agency (MNP), Wageningen and Vilthoben, the Netherlands, 2007.Sanz, D.: Contribución a la caracterización geométrica de las unidades hidrogeológicas que integran el sistema de acuíferos de la Mancha oriental [Contribution to the geometrical characterization of the hydrogeological unit which forms the Mancha Oriental aquifers system], PhD Thesis, Univ. Complutense de Madrid, Spain, 2005 (in Spanish).Sanz, D., Gómez-Alday, J. J., Castaño, S., Moratalla, A., De las Heras, L., and Martínez Alfaro, P. P.: Hydrostratigraphic framework and hydrogeological behaviour of the Mancha Oriental System (SE Spain), Hydrogeol. J., 17, 1375–1391, 2009.Sanz, D., Castaño, S., Cassiraga, E., Sahuquillo, A., Gómez-Alday, J. J., Peña, S., and Calera, A.: Modeling aquifer-river interactions under the influence of groundwater abstraction in the Mancha Oriental System (SE Spain), Hydrogeol. J., 19, 475–487, 2011.Seiller, K. P. and Gat, J. R.: Groundwater Recharge from Run-off, Infiltration and Percolation. Series: Water Science and Technology Library, Vol. 55, 2007.Shrestha, B., Babel, M. S., Maskey, S., van Griensven, A., Uhlenbrook, S., Green, A., and Akkharath, I.: Impact of climate change on sediment yield in the Mekong River basin: a case study of the Nam Ou basin, Lao PDR, Hydrol. Earth Syst. Sci., 17, 1–20, https://doi.org/10.5194/hess-17-1-2013, 2013.Sophocleous, M. and Perkins, S. P.: Methodology and application of combined watershed and ground-water models in Kansas, J. Hydrol., 236, 185–201, 2000.Stuart, M. E., Goody, D. C., Bllomfield, J. P., and Williams, A. T.: A review of the impact of climate change on future nitrate concentrations in groundwater of the UK, Sci. Total Environ., 409, 2859–2873, 2011.Teutschbein, C. and Seibert, J.: Bias correction of regional climate model simulations for hydrological climate-change impact studies: Review and evaluation of different methods, J. Hydrol., 456–457, 12–29, 2012.Westhoek, H. J., van den Berg, M., and Bakkes, J. A.: Scenario development to explore the future of Europe's rural areas, Agr. Ecosyst. Environ., 114, 7–20, 2006.Williams, J. R.: Flood routing with variable travel time or variable storage coefficients, T. ASAE, 12, 100–103, 1969.Xu, H., Taylor, R. G., and Xu, Y.: Quantifying uncertainty in the impacts of climate change on river discharge in sub-catchments of the Yangtze and Yellow River Basins, China, Hydrol. Earth Syst. Sci., 15, 333–344, https://doi.org/10.5194/hess-15-333-2011, 2011.Zheng, C. and Wang, P. P.: MT3DMS: a modular three-dimensional multispecies transport model for simulation of advection, dispersion, and chemical reactions of contaminants in groundwater systems; documentation and user's guide SERDP-99-1, Washington, DC, US Army Corps of Engineers, 1999

Assessing brain function in stressed healthy individuals following the use of a combination of green tea, Rhodiola, magnesium, and B vitamins: an fMRI study

IntroductionThis randomized, controlled, single-blinded trial assessed the effect of magnesium (Mg)-Teadiola (Mg, vitamins B6, B9, B12, Rhodiola, and green tea/L-theanine) versus placebo on the brain response to stressful thermal stimulus in chronically stressed, but otherwise healthy subjects. Impacts on stress-related quality-of-life parameters (depression, anxiety, sleep, and perception of pain) were also explored.MethodsThe study recruited a total of 40 adults (20 per group), suffering from stress for more than 1 month and scaling ≥14 points on the Depression Anxiety Stress Scale (DASS)-42 questionnaire at the time of inclusion. Individuals received oral Mg-Teadiola or placebo for 28 days (D). fMRI analysis was used to visualize the interplay between stress and pain cerebral matrices, using thermal stress model, at baseline (D0) and after D28.ResultsBased on blood-oxygen-level-dependent (BOLD) signal variations during the stress stimulation (before pain perception), a significantly increased activation between D0 and D28 was observed for left and right frontal area (p = 0.001 and p = 0.002, respectively), left and right anterior cingulate cortex (ACC) (p = 0.035 and p = 0.04, respectively), and left and right insula (p = 0.034 and p = 0.0402, respectively) in Mg-Teadiola versus placebo group. During thermal pain stimulation, a significantly diminished activation of the pain matrix was observed between D0 and D28, for left and right prefrontal area (both p = 0.001), left and right insula (p = 0.008 and p = 0.019, respectively), and left and right ventral striatum (both p = 0.001) was observed in Mg-Teadiola versus placebo group. These results reinforce the clinical observations, showing a perceived benefit of Mg-Teadiola on several parameters. After 1 month of treatment, DASS-42 stress score significantly decreased in Mg-Teadiola group [effect size (ES) −0.46 (−0.91; −0.01), p = 0.048]. Similar reductions were observed on D14 (p = 0.011) and D56 (p = 0.008). Sensitivity to cold also improved from D0 to D28 for Mg-Teadiola versus placebo [ES 0.47 (0.02; 0.92) p = 0.042].ConclusionSupplementation with Mg-Teadiola reduced stress on D28 in chronically stressed but otherwise healthy individuals and modulated the stress and pain cerebral matrices during stressful thermal stimulus

Circulating human serum metabolites derived from the intake of a saffron extract (Safr’Inside™) protect neurons from oxidative stress: Consideration for depressive disorders

Increases in oxidative stress have been reported to play a central role in the vulnerability to depression, and antidepressant drugs may reduce increased oxidative stress in patients. Among the plants exerting anti-inflammatory and anti-oxidant properties, saffron, a spice derived from the flower of Crocus sativus, is also known for its positive effects on depression, potentially through its SSRI-like properties. However, the molecular mechanisms underlying these effects and their health benefits for humans are currently unclear. Using an original ex vivo clinical approach, we demonstrated for the first time that the circulating human metabolites produced following saffron intake (Safr’Inside™ ) protect human neurons from oxidative-stress-induced neurotoxicity by preserving cell viability and increasing BNDF production. In particular, the metabolites significantly stimulated both dopamine and serotonin release. In addition, the saffron’s metabolites were also able to protect serotonergic tone by inhibiting the expression of the serotonin transporter SERT and down-regulating serotonin metabolism. Altogether, these data provide new biochemical insights into the mechanisms underlying the beneficial impact of saffron on neuronal viability and activity in humans, in the context of oxidative stress related to depression

Physical and functional characterization of the genetic locus of IBtk, an inhibitor of Bruton's tyrosine kinase: evidence for three protein isoforms of IBtk

Bruton's tyrosine kinase (Btk) is required for B-cell development. Btk deficiency causes X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Btk lacks a negative regulatory domain and may rely on cytoplasmic proteins to regulate its activity. Consistently, we identified an inhibitor of Btk, IBtk, which binds to the PH domain of Btk and down-regulates the Btk kinase activity. IBtk is an evolutionary conserved protein encoded by a single genomic sequence at 6q14.1 cytogenetic location, a region of recurrent chromosomal aberrations in lymphoproliferative disorders; however, the physical and functional organization of IBTK is unknown. Here, we report that the human IBTK locus includes three distinct mRNAs arising from complete intron splicing, an additional polyadenylation signal and a second transcription start site that utilizes a specific ATG for protein translation. By northern blot, 5′RACE and 3′RACE we identified three IBTKα, IBTKβ and IBTKγ mRNAs, whose transcription is driven by two distinct promoter regions; the corresponding IBtk proteins were detected in human cells and mouse tissues by specific antibodies. These results provide the first characterization of the human IBTK locus and may assist in understanding the in vivo function of IBtk

In vitro nuclear interactome of the HIV-1 Tat protein

<p>Abstract</p> <p>Background</p> <p>One facet of the complexity underlying the biology of HIV-1 resides not only in its limited number of viral proteins, but in the extensive repertoire of cellular proteins they interact with and their higher-order assembly. HIV-1 encodes the regulatory protein Tat (86–101aa), which is essential for HIV-1 replication and primarily orchestrates HIV-1 provirus transcriptional regulation. Previous studies have demonstrated that Tat function is highly dependent on specific interactions with a range of cellular proteins. However they can only partially account for the intricate molecular mechanisms underlying the dynamics of proviral gene expression. To obtain a comprehensive nuclear interaction map of Tat in T-cells, we have designed a proteomic strategy based on affinity chromatography coupled with mass spectrometry.</p> <p>Results</p> <p>Our approach resulted in the identification of a total of 183 candidates as Tat nuclear partners, 90% of which have not been previously characterised. Subsequently we applied <it>in silico </it>analysis, to validate and characterise our dataset which revealed that the Tat nuclear interactome exhibits unique signature(s). First, motif composition analysis highlighted that our dataset is enriched for domains mediating protein, RNA and DNA interactions, and helicase and ATPase activities. Secondly, functional classification and network reconstruction clearly depicted Tat as a polyvalent protein adaptor and positioned Tat at the nexus of a densely interconnected interaction network involved in a range of biological processes which included gene expression regulation, RNA biogenesis, chromatin structure, chromosome organisation, DNA replication and nuclear architecture.</p> <p>Conclusion</p> <p>We have completed the <it>in vitro </it>Tat nuclear interactome and have highlighted its modular network properties and particularly those involved in the coordination of gene expression by Tat. Ultimately, the highly specialised set of molecular interactions identified will provide a framework to further advance our understanding of the mechanisms of HIV-1 proviral gene silencing and activation.</p

Syndrome fibromyalgique : vers la catégorisation de sous-groupes

Fibromyalgia syndrome (FMS), a public health problem, affects 2% of people in France, with a higher female prevalence. This syndrome is characterized by increased sensitivity to nociceptive stimuli, joint and muscle pain, also associated with fatigue, sleep and cognitive disorders, as well as numerous comorbidities such as migraine or intestinal disorders. The presentation of these various symptoms is very variable according to the patients, with a great heterogeneity of clinical, physical, social, psychological characteristics, as well as therapeutic responses. The etiology of FMS remains poorly understood and many studies exploring pathophysiological hypotheses ranging from central sensitization and pain modulation systems to genes involved in pain hypersensitivity, including small fiber neuropathy and biological alterations have been explored over the years. Rather than a single entity, FMS consist in several subtypes or clusters, which could require individualized treatments.This work focuses on the categorization of patient subgroups. Through four clinical studies conducted within the Clinical Investigation Platform / CIC Inserm 1405, we pursued the objective of categorizing patients suffering from FMS by exploring the major known pathophysiological hypotheses and by focusing on clinical and biological data, psychophysical tests, pharmacological and non-pharmacological interventions.Our results show that the severity and impact of FMS are weakly related to psychophysical tests or therapeutic interventions, but mainly to clinical features. These results highlight the complexity of FMS and the difficulty in its characterization.These subgroups of patients provide template for studying the temporal evolution of FMS and will allow to identify predictive factors, in order to set up actions in 4P medicine (Predictive, Personalized, Preventive, Participatory) and improve the care of patients suffering from FMS.Le syndrome fibromyalgique, problème de santé publique, touche 2% des personnes en France, avec une prévalence féminine. Ce syndrome se caractérise par une sensibilité augmentée aux stimuli nociceptifs, des douleurs articulaires et musculaires, également associées à de la fatigue, des troubles du sommeil et cognitifs, ainsi que de nombreuses comorbidités incluant migraines ou troubles intestinaux. La présentation de ces divers symptômes est très variable selon les patients, avec une grande hétérogénéité des atteintes cliniques, physiques, sociales, psychologiques, ainsi que des réponses thérapeutiques. L'étiologie du SFM reste encore mal connue et de nombreux travaux explorant des hypothèses physiopathologiques allant de la sensibilisation centrale et des systèmes de modulation de la douleur jusqu'aux gènes impliqués dans l'hypersensibilité à la douleur en passant par les neuropathies à petites fibres et les altérations biologiques ont été étudiés au fil des années. Le SFM apparait donc aujourd'hui comme pouvant consister en plusieurs sous-types ou clusters, qui pourraient bénéficier de traitements individualisés.Ce travail s'est intéressé à la catégorisation de sous-groupes de patients. À travers quatre études cliniques menées au sein de la Plateforme d'Investigation Clinique (PIC) / CIC Inserm 1405, nous avons poursuivi l'objectif de catégoriser des patients souffrant de SFM en explorant les grandes hypothèses physiopathologiques connues et en s'intéressant à des données cliniques, biologiques, des tests psychophysiques, des interventions pharmacologiques et non pharmacologiques.Nos résultats montrent que la sévérité et l'impact du SFM sont peu liés aux tests psychophysiques ou interventions thérapeutiques, mais sont surtout liés aux données cliniques. Ces résultats soulignent la complexité du SFM et la difficulté à le caractériser.Ces sous-groupes de patients offrent une base sur laquelle l'évolution temporelle des caractéristiques du SFM permettra d'identifier des facteurs prédictifs, de mettre en place des actions dans l'axe de la médecine 4P (Prédictive, Personnalisée, Préventive, Participative) et d'améliorer la prise en charge des patients souffrant de SFM

Paracetamol and Pain Modulation by TRPV1, UGT2B15, SULT1A1 Genotypes: A Randomized Clinical Trial in Healthy Volunteers

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