Analysis of molecular determinants of affinity and relative efficacy of a series of R- and S-2-(dipropylamino)tetralins at the 5-HT1A serotonin receptor

1 Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT1A serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). 2 Ligand binding studies were used to determine dissociation constants for agonist binding to the 5HT(1A) receptor: (a) K-i values for agonists were determined in competition versus the binding of the agonist [H-3]-8-OH DPAT. Competition data were all fitted best by a one-binding site model. (b) K-i values for agonists were also determined in competition versus the binding of the antagonist [H-3]-NAD-199. Competition data were all fitted best by a two-binding site model, and agonist affinities for the higher (K-h) and lower affinity (K-1) sites were determined. 3 The ability of the agonists to activate the 5-HT1A receptor was determined using stimulation of [S-35]-GTPgammaS binding. Maximal effects of agonists (E-max) and their potencies (EC50) were determined from concentration/response curves for stimulation of [S-35]-GTPgammaS binding. 4 K-1/K-h determined from ligand binding assays correlated with the relative efficacy (relative Em) of agonists determined in [S-35]-GTPgammaS binding assays. There was also a correlation between K-1/K-h and K-1/EC50 for agonists determined from ligand binding and [S-35]-GTPgammaS binding assays. 5 Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of K-1/K-h for predicting the relative efficacy of agonists. British Journal of Pharmacology (2003) 138, 1129-1139. doi: 10. 1038/sj.bjp.705085.

Demographic models and the management of endangered species: a case study of the critically endangered Seychelles magpie robin

1. Demographic models are assuming an important role in management decisions for endangered species. Elasticity analysis and scope for management analysis are two such applications. Elasticity analysis determines the vital rates that have the greatest impact on population growth. Scope for management analysis examines the effects that feasible management might have on vital rates and population growth. Both methods target management in an attempt to maximize population growth. 2. The Seychelles magpie robin Copsychus sechellarum is a critically endangered island endemic, the population of which underwent significant growth in the early 1990s following the implementation of a recovery programme. We examined how the formal use of elasticity and scope for management analyses might have shaped management in the recovery programme, and assessed their effectiveness by comparison with the actual population growth achieved. 3. The magpie robin population doubled from about 25 birds in 1990 to more than 50 by 1995. A simple two-stage demographic model showed that this growth was driven primarily by a significant increase in the annual survival probability of first-year birds and an increase in the birth rate. Neither the annual survival probability of adults nor the probability of a female breeding at age 1 changed significantly over time. 4. Elasticity analysis showed that the annual survival probability of adults had the greatest impact on population growth. There was some scope to use management to increase survival, but because survival rates were already high (> 0.9) this had a negligible effect on population growth. Scope for management analysis showed that significant population growth could have been achieved by targeting management measures at the birth rate and survival probability of first-year birds, although predicted growth rates were lower than those achieved by the recovery programme when all management measures were in place (i.e. 1992-95). 5. Synthesis and applications. We argue that scope for management analysis can provide a useful basis for management but will inevitably be limited to some extent by a lack of data, as our study shows. This means that identifying perceived ecological problems and designing management to alleviate them must be an important component of endangered species management. The corollary of this is that it will not be possible or wise to consider only management options for which there is a demonstrable ecological benefit. Given these constraints, we see little role for elasticity analysis because, when data are available, a scope for management analysis will always be of greater practical value and, when data are lacking, precautionary management demands that as many perceived ecological problems as possible are tackled.

Mechanisms of inverse agonist action at D-2 dopamine receptors

1 Mechanisms of inverse agonist action at the D-2(short) dopamine receptor have been examined. 2 Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [H-3]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. 3 Competition of inverse agonists versus [H-3] NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. K-i values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. K-coupled and K-uncoupled were statistically different for the set of compounds tested ( ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. 4 These observations were supported by simulations of these competition experiments according to the extended ternary complex model. 5 Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [S-35]GTPγ S binding to varying degrees in concentration-response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (-)-sulpiride was unaffected. 6 These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism.

Fast northward energy transfer in the Atlantic due to Agulhas rings

The adiabatic transit time of wave energy radiated by an Agulhas ring released in the South Atlantic Ocean to the North Atlantic Ocean is investigated in a two-layer ocean model. Of particular interest is the arrival time of baroclinic energy in the northern part of the Atlantic, because it is related to variations in the meridional overturning circulation. The influence of the Mid-Atlantic Ridge is also studied, because it allows for the conversion from barotropic to baroclinic wave energy and the generation of topographic waves. Barotropic energy from the ring is present in the northern part of the model basin within 10 days. From that time, the barotropic energy keeps rising to attain a maximum 500 days after initiation. This is independent of the presence or absence of a ridge in the model basin. Without a ridge in the model, the travel time of the baroclinic signal is 1300 days. This time is similar to the transit time of the ring from the eastern to the western coast of the model basin. In the presence of the ridge, the baroclinic signal arrives in the northern part of the model basin after approximately 10 days, which is the same time scale as that of the barotropic signal. It is apparent that the ridge can facilitate the energy conversion from barotropic to baroclinic waves and the slow baroclinic adjustment can be bypassed. The meridional overturning circulation, parameterized in two ways as either a purely barotropic or a purely baroclinic phenomenon, also responds after 1300 days. The ring temporarily increases the overturning strength. Th presence of the ridge does not alter the time scales.

Assessing and understanding the impact of stratospheric dynamics and variability on the earth system

Advances in weather and climate research have demonstrated the role of the stratosphere in the Earth system across a wide range of temporal and spatial scales. Stratospheric ozone loss has been identified as a key driver of Southern Hemisphere tropospheric circulation trends, affecting ocean currents and carbon uptake, sea ice, and possibly even the Antarctic ice sheets. Stratospheric variability has also been shown to affect short term and seasonal forecasts, connecting the tropics and midlatitudes and guiding storm track dynamics. The two-way interactions between the stratosphere and the Earth system have motivated the World Climate Research Programme's (WCRP) Stratospheric Processes and Their Role in Climate (SPARC) DynVar activity to investigate the impact of stratospheric dynamics and variability on climate. This assessment will be made possible by two new multi-model datasets. First, roughly 10 models with a well resolved stratosphere are participating in the Coupled Model Intercomparison Project 5 (CMIP5), providing the first multi-model ensemble of climate simulations coupled from the stratopause to the sea floor. Second, the Stratosphere Historical Forecasting Project (SHFP) of WCRP's Climate Variability and predictability (CLIVAR) program is forming a multi-model set of seasonal hindcasts with stratosphere resolving models, revealing the impact of both stratospheric initial conditions and dynamics on intraseasonal prediction. The CMIP5 and SHFP model-data sets will offer an unprecedented opportunity to understand the role of the stratosphere in the natural and forced variability of the Earth system and to determine whether incorporating knowledge of the middle atmosphere improves seasonal forecasts and climate projections. Capsule New modeling efforts will provide unprecedented opportunities to harness our knowledge of the stratosphere to improve weather and climate prediction.

Estimation of the friction velocity in stably stratified boundary-layer flows over hills

A method is suggested for the calculation of the friction velocity for stable turbulent boundary-layer flow over hills. The method is tested using a continuous upstream mean velocity profile compatible with the propagation of gravity waves, and is incorporated into the linear model of Hunt, Leibovich and Richards with the modification proposed by Hunt, Richards and Brighton to include the effects of stability, and the reformulated solution of Weng for the near-surface region. Those theoretical results are compared with results from simulations using a non-hydrostatic microscale-mesoscale two-dimensional numerical model, and with field observations for different values of stability. These comparisons show a considerable improvement in the behaviour of the theoretical model when the friction velocity is calculated using the method proposed here, leading to a consistent variation of the boundary-layer structure with stability, and better agreement with observational and numerical data.

Sensitivity of simulated climate to conservation of momentum in gravity wave drag parameterization

The Canadian Middle Atmosphere Model is used to examine the sensitivity of simulated climate to conservation of momentum in gravity wave drag parameterization. Momentum conservation requires that the parameterized gravity wave momentum flux at the top of the model be zero and corresponds to the physical boundary condition of no momentum flux at the top of the atmosphere. Allowing momentum flux to escape the model domain violates momentum conservation. Here the impact of momentum conservation in two sets of model simulations is investigated. In the first set, the simulation of present-day climate for two model-lid height configurations, 0.001 and 10 hPa, which are identical below 10 hPa, is considered. The impact of momentum conservation on the climate with the model lid at 0.001 hPa is minimal, which is expected because of the small amount of gravity wave momentum flux reaching 0.001 hPa. When the lid is lowered to 10 hPa and momentum is conserved, there is only a modest impact on the climate in the Northern Hemisphere; however, the Southern Hemisphere climate is more adversely affected by the deflection of resolved waves near the model lid. When momentum is not conserved in the 10-hPa model the climate is further degraded in both hemispheres, particularly in winter at high latitudes, and the impact of momentum conservation extends all the way to the surface. In the second set of simulations, the impact of momentum conservation and model-lid height on the modeled response to ozone depletion in the Southern Hemisphere is considered, and it is found that the response can display significant sensitivity to both factors. In particular, both the lower-stratospheric polar temperature and surface responses are significantly altered when the lid is lowered, with the effect being most severe when momentum is not conserved. The implications with regard to the current round of Intergovernmental Panel on Climate Change model projections are discussed.

Ice Shelf Water plume flow beneath Filchner-Ronne Ice Shelf, Antarctica

[1] A two-dimensional plume model is used to study the interaction between Filchner-Ronne Ice Shelf, Antarctica and its underlying ocean cavity. Ice Shelf Water (ISW) plumes are initiated by the freshwater released from a melting ice shelf and, if they rise, may become supercooled and deposit marine ice due to the pressure increase in the in situ freezing temperature. The aim of this modeling study is to determine the origin of the thick accretions of marine ice at the base of Filchner-Ronne Ice Shelf and thus improve our understanding of ISW flow paths. The model domain is defined from measurements of ice shelf draft, and from this ISW the model is able to predict plumes that exit the cavity in the correct locations. The modeled plumes also produce basal freezing rates that account for measured marine ice thicknesses in the western part of Ronne Ice Shelf. We find that the freezing rate and plume properties are significantly influenced by the confluence of plumes from different meltwater sources. We are less successful in matching observations of marine ice under the rest of Filchner-Ronne Ice Shelf, which we attribute primarily to this model’s neglect of circulations in the ocean outside the plume.

Quantile forecasts of daily exchange rate returns from forecasts of realized volatility

Quantile forecasts are central to risk management decisions because of the widespread use of Value-at-Risk. A quantile forecast is the product of two factors: the model used to forecast volatility, and the method of computing quantiles from the volatility forecasts. In this paper we calculate and evaluate quantile forecasts of the daily exchange rate returns of five currencies. The forecasting models that have been used in recent analyses of the predictability of daily realized volatility permit a comparison of the predictive power of different measures of intraday variation and intraday returns in forecasting exchange rate variability. The methods of computing quantile forecasts include making distributional assumptions for future daily returns as well as using the empirical distribution of predicted standardized returns with both rolling and recursive samples. Our main findings are that the Heterogenous Autoregressive model provides more accurate volatility and quantile forecasts for currencies which experience shifts in volatility, such as the Canadian dollar, and that the use of the empirical distribution to calculate quantiles can improve forecasts when there are shifts

Multiple stationary solutions of an irradiated slab

A mathematical model describing the heat budget of an irradiated medium is introduced. The one-dimensional form of the equations and boundary conditions are presented and analysed. Heat transport at one face of the slab occurs by absorption (and reflection) of an incoming beam of short-wave radiation with a fraction of this radiation penetrating into the body of the slab, a diffusive heat flux in the slab and a prescribed incoming heat flux term. The other face of the slab is immersed in its own melt and is considered to be a free surface. Here, temperature continuity is prescribed and evolution of the surface is determined by a Stefan condition. These boundary conditions are flexible enough to describe a range of situations such as a laser shining on an opaque medium, or the natural environment of polar sea ice or lake ice. A two-stream radiation model is used which replaces the simple Beer’s law of radiation attenuation frequently used for semi-infinite domains. The stationary solutions of the governing equations are sought and it is found that there exists two possible stationary solutions for a given set of boundary conditions and a range of parameter choices. It is found that the existence of two stationary solutions is a direct result of the model of radiation absorption, due to its effect on the albedo of the medium. A linear stability analysis and numerical calculations indicate that where two stationary solutions exist, the solution corresponding to a larger thickness is always stable and the solution corresponding to a smaller thickness is unstable. Numerical simulations reveal that when there are two solutions, if the slab is thinner than the smaller stationary thickness it will melt completely, whereas if the slab is thicker than the smaller stationary thickness it will evolve toward the larger stationary thickness. These results indicate that other mechanisms (e.g. wave-induced agglomeration of crystals) are necessary to grow a slab from zero initial thickness in the parameter regime that yields two stationary solutions.

Tropical palaeoclimates at the Last Glacial Maximum: comparison of Palaeoclimate Modeling Intercomparison Project (PMIP)simulations and paleodata.

Seventeen simulations of the Last Glacial Maximum (LGM) climate have been performed using atmospheric general circulation models (AGCM) in the framework of the Paleoclimate Modeling Intercomparison Project (PMIP). These simulations use the boundary conditions for CO2, insolation and ice-sheets; surface temperatures (SSTs) are either (a) prescribed using CLIMAP data set (eight models) or (b) computed by coupling the AGCM with a slab ocean (nine models). The present-day (PD) tropical climate is correctly depicted by all the models, except the coarser resolution models, and the simulated geographical distribution of annual mean temperature is in good agreement with climatology. Tropical cooling at the LGM is less than at middle and high latitudes, but greatly exceeds the PD temperature variability. The LGM simulations with prescribed SSTs underestimate the observed temperature changes except over equatorial Africa where the models produce a temperature decrease consistent with the data. Our results confirm previous analyses showing that CLIMAP (1981) SSTs only produce a weak terrestrial cooling. When SSTs are computed, the models depict a cooling over the Pacific and Indian oceans in contrast with CLIMAP and most models produce cooler temperatures over land. Moreover four of the nine simulations, produce a cooling in good agreement with terrestrial data. Two of these model results over ocean are consistent with new SST reconstructions whereas two models simulate a homogeneous cooling. Finally, the LGM aridity inferred for most of the tropics from the data, is globally reproduced by the models with a strong underestimation for models using computed SSTs.

Impact of non-hydrostatic effects and trapped lee waves on mountain wave drag in directionally sheared flow

The orographic gravity wave drag produced in flow over an axisymmetric mountain when both vertical wind shear and non-hydrostatic effects are important was calculated using a semi-analytical two-layer linear model, including unidirectional or directional constant wind shear in a layer near the surface, above which the wind is constant. The drag behaviour is determined by partial wave reflection at the shear discontinuity, wave absorption at critical levels (both of which exist in hydrostatic flow), and total wave reflection at levels where the waves become evanescent (an intrinsically non-hydrostatic effect), which produces resonant trapped lee wave modes. As a result of constructive or destructive wave interference, the drag oscillates with the thickness of the constant-shear layer and the Richardson number within it (Ri), generally decreasing at low Ri and when the flow is strongly non-hydrostatic. Critical level absorption, which increases with the angle spanned by the wind velocity in the constant-shear layer, shields the surface from reflected waves, keeping the drag closer to its hydrostatic limit. While, for the parameter range considered here, the drag seldom exceeds this limit, a substantial drag fraction may be produced by trapped lee waves, particularly when the flow is strongly non-hydrostatic, the lower layer is thick and Ri is relatively high. In directionally sheared flows with Ri = O(1), the drag may be misaligned with the surface wind in a direction opposite to the shear, a behaviour which is totally due to non-trapped waves. The trapped lee wave drag, whose reaction force on the atmosphere is felt at low levels, may therefore have a distinctly different direction from the drag associated with vertically propagating waves, which acts on the atmosphere at higher levels.

Data Assimilation and Inverse Methods in Terms of a Probabilistic Formulation

The weak-constraint inverse for nonlinear dynamical models is discussed and derived in terms of a probabilistic formulation. The well-known result that for Gaussian error statistics the minimum of the weak-constraint inverse is equal to the maximum-likelihood estimate is rederived. Then several methods based on ensemble statistics that can be used to find the smoother (as opposed to the filter) solution are introduced and compared to traditional methods. A strong point of the new methods is that they avoid the integration of adjoint equations, which is a complex task for real oceanographic or atmospheric applications. they also avoid iterative searches in a Hilbert space, and error estimates can be obtained without much additional computational effort. the feasibility of the new methods is illustrated in a two-layer quasigeostrophic model.

The refreezing of melt ponds on Arctic sea ice

The presence of melt ponds on the surface of Arctic sea ice significantly reduces its albedo, inducing a positive feedback leading to sea ice thinning. While the role of melt ponds in enhancing the summer melt of sea ice is well known, their impact on suppressing winter freezing of sea ice has, hitherto, received less attention. Melt ponds freeze by forming an ice lid at the upper surface, which insulates them from the atmosphere and traps pond water between the underlying sea ice and the ice lid. The pond water is a store of latent heat, which is released during refreezing. Until a pond freezes completely, there can be minimal ice growth at the base of the underlying sea ice. In this work, we present a model of the refreezing of a melt pond that includes the heat and salt balances in the ice lid, trapped pond, and underlying sea ice. The model uses a two-stream radiation model to account for radiative scattering at phase boundaries. Simulations and related sensitivity studies suggest that trapped pond water may survive for over a month. We focus on the role that pond salinity has on delaying the refreezing process and retarding basal sea ice growth. We estimate that for a typical sea ice pond coverage in autumn, excluding the impact of trapped ponds in models overestimates ice growth by up to 265 million km3, an overestimate of 26%.

Electrochemical single-molecule transistors with optimized gate coupling

Electrochemical gating at the single molecule level of viologen molecular bridges in ionic liquids is examined. Contrary to previous data recorded in aqueous electrolytes, a clear and sharp peak in the single molecule conductance versus electrochemical potential data is obtained in ionic liquids. These data are rationalized in terms of a two-step electrochemical model for charge transport across the redox bridge. In this model the gate coupling in the ionic liquid is found to be fully effective with a modeled gate coupling parameter, ξ, of unity. This compares to a much lower gate coupling parameter of 0.2 for the equivalent aqueous gating system. This study shows that ionic liquids are far more effective media for gating the conductance of single molecules than either solid-state three-terminal platforms created using nanolithography, or aqueous media.