Highlights • CRFs are mediators of gut, heart, skin, immune system and CNS homeostasis. • First antagonist α-helical CRF(9–41) is potent in the brain, less though in the periphery. • CRF antagonists ...will likely play a major role in stress-related diseases. • Astressin2 -B was designed to be a CRFR2 selective long acting antagonist. • Stressin1 was designed to be a CRFR1 selective agonist.
This paper documents a global Bayesian variational inversion of CO2 surface fluxes during the period 1988–2008. Weekly fluxes are estimated on a 3.75° × 2.5° (longitude‐latitude) grid throughout the ...21 years. The assimilated observations include 128 station records from three large data sets of surface CO2 mixing ratio measurements. A Monte Carlo approach rigorously quantifies the theoretical uncertainty of the inverted fluxes at various space and time scales, which is particularly important for proper interpretation of the inverted fluxes. Fluxes are evaluated indirectly against two independent CO2 vertical profile data sets constructed from aircraft measurements in the boundary layer and in the free troposphere. The skill of the inversion is evaluated by the improvement brought over a simple benchmark flux estimation based on the observed atmospheric growth rate. Our error analysis indicates that the carbon budget from the inversion should be more accurate than the a priori carbon budget by 20% to 60% for terrestrial fluxes aggregated at the scale of subcontinental regions in the Northern Hemisphere and over a year, but the inversion cannot clearly distinguish between the regional carbon budgets within a continent. On the basis of the independent observations, the inversion is seen to improve the fluxes compared to the benchmark: the atmospheric simulation of CO2 with the Bayesian inversion method is better by about 1 ppm than the benchmark in the free troposphere, despite possible systematic transport errors. The inversion achieves this improvement by changing the regional fluxes over land at the seasonal and at the interannual time scales.
ANDREW V. TURNBULL AND
CATHERINE L. RIVIER
The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California; and North Western Injury Research Centre, University of ...Manchester, Manchester, United Kingdom
Turnbull, Andrew V., and Catherine L. Rivier. Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action. Physiol. Rev. 79: 1-71, 1999. Glucocorticoids are hormone products of the adrenal gland, which have long been recognized to have a profound impact on immunologic processes. The communication between immune and neuroendocrine systems is, however, bidirectional. The endocrine and immune systems share a common "chemical language," with both systems possessing ligands and receptors of "classical" hormones and immunoregulatory mediators. Studies in the early to mid 1980s demonstrated that monocyte-derived or recombinant interleukin-1 (IL-1) causes secretion of hormones of the hypothalamic-pituitary-adrenal (HPA) axis, establishing that immunoregulators, known as cytokines, play a pivotal role in this bidirectional communication between the immune and neuroendocrine systems. The subsequent 10-15 years have witnessed demonstrations that numerous members of several cytokine families increase the secretory activity of the HPA axis. Because this neuroendocrine action of cytokines is mediated primarily at the level of the central nervous system, studies investigating the mechanisms of HPA activation produced by cytokines take on a more broad significance, with findings relevant to the more fundamental question of how cytokines signal the brain. This article reviews published findings that have documented which cytokines have been shown to influence hormone secretion from the HPA axis, determined under what physiological/pathophysiological circumstances endogenous cytokines regulate HPA axis activity, established the possible sites of cytokine action on HPA axis hormone secretion, and identified the potential neuroanatomic and pharmacological mechanisms by which cytokines signal the neuroendocrine hypothalamus.
Clinical studies link disruption of the neuroendocrine stress system with alcoholism, but remaining unknown is whether functional differences in the hypothalamic‐pituitary‐adrenal (HPA) axis precede ...alcohol abuse and dependence or result from chronic exposure to this drug. Using an operant self‐administration animal model of alcohol dependence and serial blood sampling, we show that long‐term exposure to alcohol causes significant impairment of HPA function in adult male Wistar rats. Acute alcohol (voluntary self‐administration or experimenter‐administered) stimulated the release of corticosterone and its upstream regulator, adrenocorticotropic hormone, but chronic exposure sufficient to produce dependence led to a dampened neuroendocrine state. HPA responses to alcohol were most robust in ‘low‐responding’ non‐dependent animals (averaging < 0.2 mg/kg/session), intermediate in non‐dependent animals (averaging ∼0.4 mg/kg/session), and most blunted in dependent animals (averaging ∼1.0 mg/kg/session) following several weeks of daily 30‐min self‐administration sessions, suggesting that neuroendocrine tolerance can be initiated prior to dependence and relates to the amount of alcohol consumed. Decreased expression of corticotropin‐releasing factor (CRF) mRNA expression in the paraventricular nucleus of the hypothalamus and reduced sensitivity of the pituitary to CRF may contribute to, but do not completely explain, neuroendocrine tolerance. The present results, combined with previous studies, suggest that multiple adaptations to stress regulatory systems may be brought about by excessive drinking, including a compromised hormonal response and a sensitized brain stress response that together contribute to dependence.
We present a performance assessment of the European Integrated Carbon Observing System (ICOS) atmospheric network for constraining European biogenic CO2 fluxes (hereafter net ecosystem exchange, ...NEE). The performance of the network is assessed in terms of uncertainty in the fluxes, using a state-of-the-art mesoscale variational atmospheric inversion system assimilating hourly averages of atmospheric data to solve for NEE at 6 h and 0.5∘ resolution. The performance of the ICOS atmospheric network is also assessed in terms of uncertainty reduction compared to typical uncertainties in the flux estimates from ecosystem models, which are used as prior information by the inversion. The uncertainty in inverted fluxes is computed for two typical periods representative of northern summer and winter conditions in July and in December 2007, respectively. These computations are based on a observing system simulation experiment (OSSE) framework. We analyzed the uncertainty in a 2-week-mean NEE as a function of the spatial scale with a focus on the model native grid scale (0.5∘), the country scale and the European scale (including western Russia and Turkey). Several network configurations, going from 23 to 66 sites, and different configurations of the prior uncertainties and atmospheric model transport errors are tested in order to assess and compare the improvements that can be expected in the future from the extension of the network, from improved prior information or transport models. Assimilating data from 23 sites (a network comparable to present-day capability) with errors estimated from the present prior information and transport models, the uncertainty reduction on a 2-week-mean NEE should range between 20 and 50 % for 0.5∘ resolution grid cells in the best sampled area encompassing eastern France and western Germany. At the European scale, the prior uncertainty in a 2-week-mean NEE is reduced by 50 % (66 %), down to ∼ 43 Tg C month-1 (26 Tg C month-1) in July (December). Using a larger network of 66 stations, the prior uncertainty of NEE is reduced by the inversion by 64 % (down to∼ 33 Tg C month-1) in July and by 79 % (down to∼ 15 Tg C month-1) in December. When the results are integrated over the well-observed western European domain, the uncertainty reduction shows no seasonal variability. The effect of decreasing the correlation length of the prior uncertainty, or of reducing the transport model errors compared to their present configuration (when conducting real-data inversion cases) can be larger than that of the extension of the measurement network in areas where the 23 station observation network is the densest. We show that with a configuration of the ICOS atmospheric network containing 66 sites that can be expected on the long-term, the uncertainties in a 2-week-mean NEE will be reduced by up to 50–80 % for countries like Finland, Germany, France and Spain, which could significantly improvement (and at least a high complementarity to) our knowledge of NEE derived from biomass and soil carbon inventories at multi-annual scales.
A forward atmospheric transport modeling experiment has been coordinated by the TransCom group to investigate synoptic and diurnal variations in CO2. Model simulations were run for biospheric, ...fossil, and air‐sea exchange of CO2 and for SF6 and radon for 2000–2003. Twenty‐five models or model variants participated in the comparison. Hourly concentration time series were submitted for 280 sites along with vertical profiles, fluxes, and meteorological variables at 100 sites. The submitted results have been analyzed for diurnal variations and are compared with observed CO2 in 2002. Mean summer diurnal cycles vary widely in amplitude across models. The choice of sampling location and model level account for part of the spread suggesting that representation errors in these types of models are potentially large. Despite the model spread, most models simulate the relative variation in diurnal amplitude between sites reasonably well. The modeled diurnal amplitude only shows a weak relationship with vertical resolution across models; differences in near‐surface transport simulation appear to play a major role. Examples are also presented where there is evidence that the models show useful skill in simulating seasonal and synoptic changes in diurnal amplitude.
Early life experiences can shape brain function and behavior in adulthood. The present study sought to elucidate the effects of repetitive, predictable vs. varied, unpredictable prenatal stress on ...sexually dichotomous neuroendocrine and anxiety-related behavioral responses in adult offspring. Rat dams were exposed repeatedly during the last week of pregnancy to no stress, only restraint stress prenatal stress (PS)-restraint, or a randomized sequence of varied stressors (PS-random), and several behavioral and endocrine measures were assessed in adult male and female offspring. Repeated exposure to the same stressor (restraint) generated the most robust changes, including increased anxiety-related behaviors (both passive, measured on the elevated plus maze, and active, measured using defensive burying tests), a delayed and prolonged hypothalamic-pituitary-adrenal (HPA) axis response to stress in female offspring. Conversely, PS-restraint males showed no changes in anxiety-like behavior and had elevated basal ACTH and a blunted HPA response to stress; consistent with attenuated HPA responsivity was an increase in glucocorticoid receptor immunoreactivity in the hippocampus, suggesting increased negative feedback on the HPA axis in these animals. Prenatal exposure to a varied, unpredictable pattern of stressors did not have as much effect on HPA function, with most neuroendocrine measures residing intermediate to PS-restraint and control animals within each sex. Gonadal steroids were altered independent of the type of prenatal stress, but changes were measurable only in males (lower testosterone). The present data exemplify the differential sensitivity of the developing nervous and endocrine systems to stress, depending on not only gender but also the nature of the stressful experience endured by the mother during pregnancy.
We present a performance assessment of the European Integrated Carbon Observing System (ICOS) atmospheric network for constraining European biogenic CO2 fluxes (hereafter net ecosystem exchange, ...NEE). The performance of the network is assessed in terms of uncertainty in the fluxes, using a state-of-the-art mesoscale variational atmospheric inversion system assimilating hourly averages of atmospheric data to solve for NEE at 6 h and 0.5° resolution. The performance of the ICOS atmospheric network is also assessed in terms of uncertainty reduction compared to typical uncertainties in the flux estimates from ecosystem models, which are used as prior information by the inversion. The uncertainty in inverted fluxes is computed for two typical periods representative of northern summer and winter conditions in July and in December 2007, respectively. These computations are based on a observing system simulation experiment (OSSE) framework. We analyzed the uncertainty in a 2-week-mean NEE as a function of the spatial scale with a focus on the model native grid scale (0.5°), the country scale and the European scale (including western Russia and Turkey). Several network configurations, going from 23 to 66 sites, and different configurations of the prior uncertainties and atmospheric model transport errors are tested in order to assess and compare the improvements that can be expected in the future from the extension of the network, from improved prior information or transport models. Assimilating data from 23 sites (a network comparable to present-day capability) with errors estimated from the present prior information and transport models, the uncertainty reduction on a 2-week-mean NEE should range between 20 and 50 % for 0.5° resolution grid cells in the best sampled area encompassing eastern France and western Germany. At the European scale, the prior uncertainty in a 2-week-mean NEE is reduced by 50 % (66 %), down to ~ 43 Tg C month−1 (26 Tg C month−1) in July (December). Using a larger network of 66 stations, the prior uncertainty of NEE is reduced by the inversion by 64 % (down to ~ 33 Tg C month−1) in July and by 79 % (down to ~ 15 Tg C month−1) in December. When the results are integrated over the well-observed western European domain, the uncertainty reduction shows no seasonal variability. The effect of decreasing the correlation length of the prior uncertainty, or of reducing the transport model errors compared to their present configuration (when conducting real-data inversion cases) can be larger than that of the extension of the measurement network in areas where the 23 station observation network is the densest. We show that with a configuration of the ICOS atmospheric network containing 66 sites that can be expected on the long-term, the uncertainties in a 2-week-mean NEE will be reduced by up to 50–80 % for countries like Finland, Germany, France and Spain, which could significantly improvement (and at least a high complementarity to) our knowledge of NEE derived from biomass and soil carbon inventories at multi-annual scales.
We analyzed the magnitude, the trends and the uncertainties of fossil-fuel CO₂ emissions in the European Union 25 member states (hereafter EU-25), based on emission inventories from energy-use ...statistics. The stability of emissions during the past decade at EU-25 scale masks decreasing trends in some regions, offset by increasing trends elsewhere. In the recent 4 years, the new Eastern EU-25 member states have experienced an increase in emissions, reversing after a decade-long decreasing trend. Mediterranean and Nordic countries have also experienced a strong acceleration in emissions. In Germany, France and United Kingdom, the stability of emissions is due to the decrease in the industry sector, offset by an increase in the transportation sector. When four different inventories models are compared, we show that the between-models uncertainty is as large as 19% of the mean for EU-25, and even bigger for individual countries. Accurate accounting for fossil CO₂ emissions depends on a clear understanding of system boundaries, i.e. emitting activities included in the accounting. We found that the largest source of errors between inventories is the use of distinct systems boundaries (e.g. counting or not bunker fuels, cement manufacturing, nonenergy products). Once these inconsistencies are corrected, the between-models uncertainty can be reduced down to 7% at EU-25 scale. The uncertainty of emissions at smaller spatial scales than the country scale was analyzed by comparing two emission maps based upon distinct economic and demographic activities. A number of spatial and temporal biases have been found among the two maps, indicating a significant increase in uncertainties when increasing the resolution at scales finer than almost equal to200 km. At 100 km resolution, for example, the uncertainty of regional emissions is estimated to be 60 g C m⁻² yr⁻¹, up to 50% of the mean. The uncertainty on regional fossil-fuel CO₂ fluxes to the atmosphere could be reduced by making accurate ¹⁴C measurements in atmospheric CO₂, and by combining them with transport models.
We investigated the contribution of corticotropin-releasing factor (CRF) receptors types 1 and 2 (CRF1 and CRF2) in mediating the ACTH response to shock, alcohol injection, or endotoxemia in the rat. ...Peptidic (Astressin B and Astressin2-B) and nonpeptidic (NBI 30775) CRF antagonists were injected iv before the stressors at doses previously shown to be effective in blocking the corresponding receptors. Because NBI 30775, which specifically blocks CRF1, penetrates the brain following systemic injection, we also compared its effect with that of Astressin B, which primarily, though not exclusively, targets CRF1 but does not cross the blood-brain barrier. Shocks, alcohol (4.5 g/kg, intragastrically) or lipopolysaccharide (LPS, 1 μg/kg, iv) all significantly released ACTH. Astressin B or NBI 30775 markedly decreased the effect of shocks or alcohol and also interfered, though less significantly so, with the influence of LPS. In contrast, specific blockade of CRF2 with Astressin2-B, although not significantly altering the overall ACTH response to shocks, alcohol, or LPS, slightly enhanced ACTH levels during the early phase of some of these responses. Interestingly, combined administration of NBI 30775 and Astressin2-B decreased ACTH levels more than NBI 30775 alone, although this difference did not reach statistical significance. Finally, blockade of CRF1 and/or CRF2 augmented LPS- induced TNF-α and IL-6 release. Collectively, there results confirm the critical role played by CRF1 in mediating the ACTH response to shocks, alcohol and LPS, whereas the influence of CRF2 remains subtle. Finally, we showed that peripheral endogenous CRF restrains the ability of LPS to release cytokines.
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