bluuebunny/crossref_metadata_2025 huggingface dataset:
Onset of convection in the icy Galilean satellites: Influence of rheology
Authors: Barr Amy C. , Pappalardo Robert T.
Published: December 2005

Ice I exhibits a complex rheology at temperature and pressure conditions appropriate for the interiors of the ice I shells of Europa, Ganymede, and Callisto. We use numerical methods and existing parameterizations of the critical Rayleigh number to determine the conditions required to trigger convection in an ice I shell with each of the stress‐, temperature‐ and grain size–dependent rheologies measured in laboratory experiments by Goldsby and Kohlstedt (2001). The critical Rayleigh number depends on the ice grain size and the amplitude and wavelength of temperature perturbation issued to an initially conductive ice I shell. If the shells have an assumed uniform grain size <0.4 mm, deformation during initial plume growth is accommodated by Newtonian volume diffusion. If the ice grain size is between 0.4 mm and 3 cm, deformation during plume growth is accommodated by weakly non‐Newtonian grain boundary sliding, where the critical ice shell thickness for convection depends on the amplitude of temperature perturbation to the −0.5 power. If the ice grain size exceeds 2 cm, convection can not occur in the ice I shells of the Galilean satellites regardless of the amplitude or wavelength of temperature perturbation. If the grain size in a convecting ice I shell evolves to effective values greater than 2 cm, convection will cease. If the ice shell has a grain size large enough to permit flow by dislocation creep, the ice is too stiff to permit convection, even in the thickest possible ice I shell. Consideration of the complex ice rheology implies that estimates of the grain size in the satellites and knowledge of their initial thermal states are required when judging the convective instability of their ice I shells.
Health and climate policy impacts on sulfur emission control
Authors: Ming Yi , Russell Lynn M. , Bradford David F.
Published: December 2005

Sulfate aerosol from burning fossil fuels not only has strong cooling effects on the Earth's climate but also imposes substantial costs on human health. To assess the impact of addressing air pollution on climate policy, we incorporate both the climate and health effects of sulfate aerosol into an integrated‐assessment model of fossil fuel emission control. Our simulations show that a policy that adjusts fossil fuel and sulfur emissions to address both warming and health simultaneously will support more stringent fossil fuel and sulfur controls. The combination of both climate and health objectives leads to an acceleration of global warming in the 21st century as a result of the short‐term climate response to the decreased cooling from the immediate removal of short‐lived sulfate aerosol. In the long term (more than 100 years), reducing sulfate aerosol emissions requires that we decrease fossil fuel combustion in general, thereby removing some of the coemitted carbon emissions and leading to a reduction in global warming.
Thermohaline circulation hysteresis: A model intercomparison
Authors: Rahmstorf Stefan , Crucifix Michel , Ganopolski Andrey , Goosse Hugues , Kamenkovich Igor , Knutti Reto , Lohmann Gerrit , Marsh Robert , Mysak Lawrence A. , Wang Zhaomin , Weaver Andrew J.
Published: December 2005

We present results from an intercomparison of 11 different climate models of intermediate complexity, in which the North Atlantic Ocean was subjected to slowly varying changes in freshwater input. All models show a characteristic hysteresis response of the thermohaline circulation to the freshwater forcing; which can be explained by Stommel's salt advection feedback. The width of the hysteresis curves varies between 0.2 and 0.5 Sv in the models. Major differences are found in the location of present‐day climate on the hysteresis diagram. In seven of the models, present‐day climate for standard parameter choices is found in the bi‐stable regime, in four models this climate is in the mono‐stable regime. The proximity of the present‐day climate to the Stommel bifurcation point, beyond which North Atlantic Deep Water formation cannot be sustained, varies from less than 0.1 Sv to over 0.5 Sv.
On fine structure emission associated with plasmaspheric density irregularities
Authors: Yoon P. H. , Menietti J. D.
Published: December 2005

The eigenvalue analysis for the upper‐hybrid/Langmuir waves trapped in cylindrical density structures is carried out. Under physical parameters typical for kilometric continuum (KC) source region, it is found that the frequency spacing between individual fine structure spectrum is within a reasonable observed range of 0.1∼1 kHz. It is also found that the quasi field‐aligned modes are associated with density cavities, while the radial modes are excited within enhanced density column, thus showing that density irregularities of various types can support discrete wave spectrum featuring wide‐ranging frequency gaps.
Impact of improved air quality on the future evolution of climate
Authors: Brasseur G. P. , Roeckner E.
Published: December 2005

Calculations performed with the Hamburg Climate Model suggest that climate change resulting from increasing greenhouse gas emissions would become considerably more pronounced if air quality were dramatically improved in the future. Specifically, the globally averaged surface air temperature and amount of precipitation could increase in less than a decade by 0.8 K and 3%, respectively, if the entire amount of anthropogenic sulfate aerosols were removed from the atmosphere. The geographic patterns of the calculated changes bear resemblance with those found in greenhouse gas and aerosol scenario experiments (annual mean temperature increase of approximately 1 K on most continents, 4 K in the Arctic). This study suggests that possible future changes as well as the general issue of the stability of atmospheric aerosol loads should be considered in strategies aiming to maintain global warming below a prescribed threshold. It also underscores the need to account for associated possible changes in precipitation in such strategies.
The third Arctic climate pattern: 1930s and early 2000s
Authors: Overland James E. , Wang Muyin
Published: December 2005

Persistent near‐surface warm temperature anomalies have occurred in two localized areas, eastern Siberia/East Siberian Sea and northeastern Canada/Baffin Bay, during winter and spring in recent years (2000–2005) in contrast to previous decades. The proximate cause in winter was a northward displacement and strengthening of the Aleutian Low and a weakening of the Icelandic Low. Spring showed a dipole pattern with higher sea‐level pressure (SLP) on the North American side of the Arctic and lower pressures over Eurasia. Phase space trajectories of arctic climate for 1951–2005 based on the first two EOFs of SLP, the Arctic Oscillation and a Pacific North American‐like (PNA*) pattern, show multi‐annual variability leading to lower SLP and warmer temperatures in the last decades of the 20th century. Recent winters have some projection onto PNA*, but the SLP dipole in recent springs does not strongly project onto either of the two basic climate patterns. The period from 1928–1935 also had a dipole structure in SLP, which contributed to the interdecadal arctic‐wide warm temperature anomalies in the first half of the 20th century. Recognition of the recent persistent and somewhat unique Arctic climate pattern is important as it contributes to the ongoing reorganization of arctic ecosystems.
A distributed‐circuit return‐stroke model allowing time and height parameter variation to match lightning electromagnetic field waveform signatures
Authors: Visacro S. , De Conti A.
Published: December 2005

A new lightning return‐stroke model based on a distributed circuit approach is formulated. The DNUTL (Dynamic Non‐Uniform Transmission Line) model allows the computation of the time and height dependence of the channel parameters and contemplates the corona sheath and core losses representation. The capacitance and inductance of the channel are calculated by applying an original approach based on simple recursive equations. Electromagnetic fields generated by the DNUTL model at several distances from the channel base are presented for a given set of parameters. The obtained results indicate that the proposed model is able to successfully reproduce the main features of electromagnetic field waveshapes associated to natural and triggered lightning.
A variable resolution surface wave dispersion study of Eurasia, North Africa, and surrounding regions
Authors: Pasyanos Michael E.
Published: December 2005

This paper presents the results of a large‐scale study of surface wave dispersion performed across Eurasia and North Africa. Improvements were made to previous surface wave work by enlarging the study region, increasing path density, improving spatial resolution, and expanding the period range. This study expands the coverage area northward and eastward relative to a previous dispersion analysis, which covered only North Africa and the Middle East. We have significantly increased the number of seismograms examined and group velocity measurements made. We have now made good quality dispersion measurements for about 30,000 Rayleigh wave and 20,000 Love wave paths and have incorporated measurements from several other researchers into the study. We have improved the inversion from the previous study by adopting a variable smoothness with the conjugate gradient method for the group velocity tomography. This technique produces higher‐resolution models where the concentration of data allows it without producing artifacts. The current results include both Love and Rayleigh wave inversions across the region for periods from 7 to 100 s on a 1° × 1° grid and at resolutions approaching 1° under some conditions. Short‐period group velocities are sensitive to slow velocities associated with large sedimentary features such as the Caspian Sea, West Siberian Platform, Mediterranean Sea, Bay of Bengal, Tarim Basin, and Persian Gulf. Intermediate periods are sensitive to differences in crustal thickness, such as those between oceanic and continental crust or along orogenic zones and continental plateaus. At longer periods, fast velocities are consistently found beneath cratons, while slow upper mantle velocities occur along rift systems, subduction zones, and collision zones such as the Tethys Belt. We have compared the group velocities at various periods with features such as sediment thickness, topographic height, crustal thickness, proximity to plate boundaries, lithospheric age, and lithospheric thickness, and we find significant correlations. We have developed an empirical relationship between long‐period group velocity and lithospheric thickness that works well for both oceanic and continental lithosphere. We do not find any similar correlation between the longest‐period surface waves and hot spots.
Chamber studies of secondary organic aerosol growth by reactive uptake of simple carbonyl compounds
Authors: Kroll Jesse H. , Ng Nga L. , Murphy Shane M. , Varutbangkul Varuntida , Flagan Richard C. , Seinfeld John H.
Published: December 2005

Recent experimental evidence indicates that heterogeneous chemical reactions play an important role in the gas‐particle partitioning of organic compounds, contributing to the formation and growth of secondary organic aerosol in the atmosphere. Here we present laboratory chamber studies of the reactive uptake of simple carbonyl species (formaldehyde, octanal, trans,trans‐2,4‐hexadienal, glyoxal, methylglyoxal, 2,3‐butanedione, 2,4‐pentanedione, glutaraldehyde, and hydroxyacetone) onto inorganic aerosol. Gas‐phase organic compounds and aqueous seed particles (ammonium sulfate or mixed ammonium sulfate/sulfuric acid) are introduced into the chamber, and particle growth and composition are monitored using a differential mobility analyzer and an Aerodyne Aerosol Mass Spectrometer. No growth is observed for most carbonyls studied, even at high concentrations (500 ppb to 5 ppm), in contrast with the results from previous studies. The single exception is glyoxal (CHOCHO), which partitions into the aqueous aerosol much more efficiently than its Henry's law constant would predict. No major enhancement in particle growth is observed for the acidic seed, suggesting that the large glyoxal uptake is not a result of particle acidity but rather of ionic strength of the seed. This increased partitioning into the particle phase still cannot explain the high levels of glyoxal measured in ambient aerosol, indicating that additional (possibly irreversible) pathways of glyoxal uptake may be important in the atmosphere.
Changes in precipitation and temperature extremes in Central America and northern South America, 1961–2003
Authors: Aguilar E. , Peterson T. C. , Obando P. Ramírez , Frutos R. , Retana J. A. , Solera M. , Soley J. , García I. González , Araujo R. M. , Santos A. Rosa , Valle V. E. , Brunet M. , Aguilar L. , Álvarez L. , Bautista M. , Castañón C. , Herrera L. , Ruano E. , Sinay J. J. , Sánchez E. , Oviedo G. I. Hernández , Obed F. , Salgado J. E. , Vázquez J. L. , Baca M. , Gutiérrez M. , Centella C. , Espinosa J. , Martínez D. , Olmedo B. , Espinoza C. E. Ojeda , Núñez R. , Haylock M. , Benavides H. , Mayorga R.
Published: December 2005

In November 2004, a regional climate change workshop was held in Guatemala with the goal of analyzing how climate extremes had changed in the region. Scientists from Central America and northern South America brought long‐term daily temperature and precipitation time series from meteorological stations in their countries to the workshop. After undergoing careful quality control procedures and a homogeneity assessment, the data were used to calculate a suite of climate change indices over the 1961–2003 period. Analysis of these indices reveals a general warming trend in the region. The occurrence of extreme warm maximum and minimum temperatures has increased while extremely cold temperature events have decreased. Precipitation indices, despite the large and expected spatial variability, indicate that although no significant increases in the total amount are found, rainfall events are intensifying and the contribution of wet and very wet days are enlarging. Temperature and precipitation indices were correlated with northern and equatorial Atlantic and Pacific Ocean sea surface temperatures. However, those indices having the largest significant trends (percentage of warm days, precipitation intensity, and contribution from very wet days) have low correlations to El Niño–Southern Oscillation. Additionally, precipitation indices show a higher correlation with tropical Atlantic sea surface temperatures.
Connectivity between Eurasian snow cover extent and Canadian snow water equivalent and river discharge
Authors: Déry Stephen J. , Sheffield Justin , Wood Eric F.
Published: December 2005

We explore pan‐Arctic climate connectivity by examining historical time series of satellite‐based measurements of Eurasian snow cover extent and of observed Canadian snow water equivalent (SWE) and freshwater discharge, with a focus on the Churchill River Basin of Labrador and the Chesterfield Inlet Basin of Nunavut. Analysis of the data reveals statistically significant positive (negative) correlations between spring and summer Eurasian standardized snow cover extent anomalies and annual maximum monthly SWE as well as freshwater discharge in the Churchill River (Chesterfield Inlet) Basin the following year. A spatially coherent response to the forcing is observed since 19 rivers draining more than 0.6 × 106 km2 of northern Quebec and Labrador and with a mean annual total discharge of 320 km3 yr−1 show statistically significant positive correlations to the annual Eurasian standardized snow cover extent anomalies. The origin of this pan‐Arctic climate connectivity is related to the persistent nature of the Eurasian snow cover extent anomalies and the associated accumulated gains or deficits in the surface radiation and water budgets that impose a memory in the climate system. The Eurasian snow cover extent anomalies provide some degree of predictability (up to 1 year in advance) of the surface water budget in the Churchill River and Chesterfield Inlet Basins. They further suggest that a declining trend in Eurasian snow cover extent will yield decreasing (increasing) SWE and river discharge in the Churchill River (Chesterfield Inlet) Basin in the 21st century.
Processes that account for the ozone maximum at the mesopause
Authors: Smith Anne K. , Marsh Daniel R.
Published: December 2005

The presence of a maximum in ozone density and mixing ratio in the mesopause region has been known for several decades although the measurement database is still quite limited. This ozone layer is formed in the vicinity of the maximum in atomic oxygen number density. In this paper, we present simulations of the ozone maximum from a three‐dimensional dynamical chemical model. Ozone variability is dominated by the diurnal cycle in ozone, which fluctuates between low concentrations in sunlight and high concentrations in darkness. However, the diurnal variability also has strong contributions from atmospheric tides and from slow changes in chemical concentrations following sunrise and sunset. In this study, we find that the magnitude of the ozone secondary maximum is closely tied to the temperature. The very low temperatures at the mesopause accelerate the formation of ozone and inhibit the loss. This factor and the location of the atomic oxygen density maximum both contribute in approximately equal measure to determining the altitude of the ozone layer. The magnitude of the nighttime ozone maximum is sensitive to the eddy and molecular diffusion rates primarily through the influence of these processes on the concentration of hydrogen.
Use of modern tree‐fall patterns as a guideline for interpreting prostrate trees at a pre–Last Glacial Maximum paleoforest site, upper North Island, New Zealand
Authors: Lorrey Andrew , Martin Timothy
Published: December 2005

Wind throw, as evidenced by a tree bole with an attached root plate, is an indicator of forest disturbance, and can often be used as direct evidence of surface winds during a single storm event. We assess tree‐fall patterns resulting from the 1982 Cyclone Bernie event in the North Island, New Zealand, and apply these findings to interpretation of a pre–Last Glacial Maximum (LGM) tree‐fall site to determine if the subfossil tree‐fall pattern could have been caused by a single extropical cyclone. There is insufficient evidence to recommend that a single extropical storm event could have caused the forest destruction observed at our pre‐LGM tree‐fall site, and therefore multiple possibilities for enhanced wind flow that could have caused tree throw are possible.
Angle of arrival estimation for all‐sky interferometric meteor radar systems
Authors: Holdsworth David A.
Published: December 2005

Simulations have been used to investigate angle of arrival (AOA) estimation for all‐sky interferometric meteor radars using the Jones et al. (1998) antenna configuration. The results suggest that the use of 2λ spacing phase differences significantly improves AOA accuracy, while use of wraparound and differencing the sines of the zenith angles lead to small improvements in AOA accuracy. The combined use of 2λ spacing, wraparound, and differencing the sines of the zenith angles reduces the percentage of estimates outside ±1° of the actual AOA by a factor of 2.5. The results suggest that the use of 2.5, 3, and 5.5λ spacing produces more accurate AOA estimates than the standard 2, 2.5, and 4.5λ spacing and that the optimal spacing for the addition of a fourth antenna to each antenna arm is around 20λ.
Bayesian training of artificial neural networks used for water resources modeling
Authors: Kingston Greer B. , Lambert Martin F. , Maier Holger R.
Published: December 2005

Artificial neural networks have proven to be superior prediction models in many hydrology‐related areas; however, failure of ANN practitioners to account for uncertainty in the predictions has limited the wider use of ANNs as forecasting models. Conventional methods for quantifying parameter uncertainty are difficult to apply to ANN weights because of the complexity of these models, and complicated methods developed for this purpose have been not been adopted by water resources practitioners because of the difficulty in implementing them. This paper presents a relatively straightforward Bayesian training method that enables weight uncertainty to be accounted for in ANN predictions. The method is applied to a salinity forecasting case study, and the resulting ANN is shown to significantly outperform an ANN developed using standard approaches in a real‐time forecasting scenario. Moreover, the Bayesian approach produces prediction limits that indicate the level of uncertainty in the predictions, which is extremely important if forecasts are to be used with confidence in water resources applications.
An integrated environmental tracer approach to characterizing groundwater circulation in a mountain block
Authors: Manning Andrew H. , Solomon D. Kip
Published: December 2005

The subsurface transfer of water from a mountain block to an adjacent basin (mountain block recharge (MBR)) is a commonly invoked mechanism of recharge to intermountain basins. However, MBR estimates are highly uncertain. We present an approach to characterize bulk fluid circulation in a mountain block and thus MBR that utilizes environmental tracers from the basin aquifer. Noble gas recharge temperatures, groundwater ages, and temperature data combined with heat and fluid flow modeling are used to identify clearly improbable flow regimes in the southeastern Salt Lake Valley, Utah, and adjacent Wasatch Mountains. The range of possible MBR rates is reduced by 70%. Derived MBR rates (5.5–12.6 × 104 m3 d−1) are on the same order of magnitude as previous large estimates, indicating that significant MBR to intermountain basins is plausible. However, derived rates are 50–100% of the lowest previous estimate, meaning total recharge is probably less than previously thought.
Flow paths, rainfall properties, and antecedent soil moisture controlling lags to peak discharge in a granitic unchanneled catchment
Authors: Haga Hirokazu , Matsumoto Yoshitaka , Matsutani Jun , Fujita Masafumi , Nishida Kei , Sakamoto Yasushi
Published: December 2005

The lag time between peak rainfall and peak discharge is an important index reflecting hydrological properties in a catchment. To characterize lag times, we studied the effects of rainfall properties, antecedent moisture conditions, and flow paths on runoff response in a forested unchanneled catchment, using a hydrometric and hydrochemical approach. Soil moisture, soil pore water pressure, and piezometric surface were monitored. Also, dissolved silica and organic carbon concentrations of spring water and subsurface water were observed. Runoff response was characterized by two types of lag times: a short lag time (<2 hours) or a long lag time (>24 hours). During events with short lag times, saturation excess overland flow was dominant, and the source area was limited to the near‐spring area. During events with long lag times, saturated subsurface flow above the soil‐bedrock interface was dominant, and the source area near the spring was connected to the upslope area via saturated zone above soil‐bedrock interface. The spring‐hillslope hydrological connection to generate peak discharges with long lag times occurred when the sum of cumulative rainfall and an antecedent soil moisture index, which was derived from initial storage of surface soil layer, was greater than 135 mm. Moreover, the time between the upslope connection of source area and subsequent peak discharge decreased with the average rainfall intensity in the time. We conclude that consideration of antecedent soil moisture conditions as well as rainfall amount and intensity is essential for understanding the regional characteristics of lag times and subsurface water movement.
Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle
Authors: Vargas Maria Luisa , Hernandez Jesus , Kaumann Alberto J
Published: December 2005

The cardiostimulant effects of CGP12177, mediated through aβ1‐adrenoceptor site with low affinity for (−)‐propranolol, are potentiated by the nonselective PDE inhibitor IBMX but the role of PDE isoenzymes is unknown. We studied the effects of the PDE3‐selective inhibitor cilostamide (300 nM) and PDE4‐selective inhibitor rolipram (1 μM) on the positive inotropic and cyclic AMP‐enhancing effects of CGP12177 and noradrenaline in right ventricular strips of rat.

CGP12177 (under (−)‐propranolol 200 nM) only increased contractile force in the presence of either cilostamide or rolipram with −logEC50M 6.7 (Emax=23% over basal) and 7.1 (Emax=50%) respectively. The combination of cilostamide and rolipram caused CGP12177 to enhance contractile force with −logEC50M=7.7 andEmax=178%.

The positive inotropic effects of noradrenaline (−logEC50M=6.9) were potentiated by rolipram (−logEC50M=7.4) but not by cilostamide (−logEC50M=7.0).

In the presence of rolipram and (−)‐propranolol, noradrenaline (2 μM) and CGP12177 (10 μM) produced matching inotropic effects but failed to increase cyclic AMP levels. 20 μM(−)‐noradrenaline increased cyclic AMP levels, a response further enhanced by rolipram.

Both PDE3 and PDE4 of rat ventricle appear to hydrolyse cyclic AMP generated through the low‐affinityβ1‐adrenoceptor site, thereby preventing inotropic responses of CGP12177. When (−)‐noradrenaline interacts with theβ1‐adrenoceptor, the generated cyclic AMP is hydrolysed only by PDE4, thereby reducing cardiostimulation.

British Journal of Pharmacology(2006)147, 158–163. doi:10.1038/sj.bjp.0706498
Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models
Authors: Jayamanne Angelo , Greenwood Ruth , Mitchell Vanessa A , Aslan Sevda , Piomelli Daniele , Vaughan Christopher W
Published: December 2005

While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB1receptor‐mediated motor and psychotropic side effects. The actions of endocannabinoids, such as anandamide are terminated by removal from the extracellular space, then subsequent enzymatic degradation by fatty‐acid amide hydrolase (FAAH). In the present study, we compared the effect of a selective FAAH inhibitor, URB597, to that of a pan‐cannabinoid receptor agonist HU210 in rat models of chronic inflammatory and neuropathic pain.

Systemic administration of URB597 (0.3 mg kg−1) and HU210 (0.03 mg kg−1) both reduced the mechanical allodynia and thermal hyperalgesia in the CFA model of inflammatory pain. In contrast, HU210, but not URB597, reduced mechanical allodynia in the partial sciatic nerve‐ligation model of neuropathic pain. HU210, but not URB597, produced a reduction in motor performance in unoperated rats.

The effects of URB597 in the CFA model were dose dependent and were reduced by coadministration with the cannabinoid CB1antagonist AM251 (1 mg kg−1), or the CB2and SR144528 (1 mg kg−1). Coadministration with AM251 plus SR144528 completely reversed the effects of URB597.

These findings suggest that the FAAH inhibitor URB597 produces cannabinoid CB1and CB2receptor‐mediated analgesia in inflammatory pain states, without causing the undesirable side effects associated with cannabinoid receptor activation.

British Journal of Pharmacology(2006)147, 281–288. doi:10.1038/sj.bjp.0706510
Differential behavioral effects of low efficacy positive GABAAmodulators in combination with benzodiazepines and a neuroactive steroid in rhesus monkeys
Authors: McMahon Lance R , France Charles P
Published: December 2005

In the clinic, low efficacy positive GABAAmodulators might be preferred to high efficacy positive modulators insofar as low efficacy modulators might have comparatively less abuse and dependence liability.

Drug discrimination was used to examine the behavioral effects of L‐838,417 and bretazenil, two low efficacy positive GABAAmodulators that act at benzodiazepine sites, alone and in combination with benzodiazepines and a neuroactive steroid (alfaxolone). In rhesus monkeys (n=5) discriminating midazolam, alfaxolone substituted for midazolam. In four monkeys, L‐838,417 and bretazenil did not substitute for, but rather dose‐dependently antagonized, midazolam; L‐838‐417 and bretazenil, as well as flumazenil, enhanced the midazolam‐like effects of alfaxolone. L‐838,417 and bretazenil substituted for midazolam in a fifth monkey. In a separate group of rhesus monkeys (n=3) that received 5.6 mg kg−1per day of diazepam and that discriminated flumazenil, L‐838,417 and bretazenil substituted for flumazenil.

These results demonstrate that L‐838,417, bretazenil, and flumazenil can have agonist or antagonist actions in the same animal depending upon whether they are studied in combination with a higher efficacy positive GABAAmodulator acting at the same (benzodiazepine) or a different (neuroactive steroid) site. Thus, combinations of low efficacy positive modulators acting at different sites on the GABAAreceptor complex could yield drug mixtures with significant therapeutic effects and with reduced abuse and dependence liability, as compared to higher efficacy positive modulators such as currently available benzodiazepines.

British Journal of Pharmacology(2006)147, 260–268. doi:10.1038/sj.bjp.0706550
Differential phosphorylation and dephosphorylation of β2‐adrenoceptor sites Ser262 and Ser355,356
Authors: Iyer Varsha , Tran Tuan M , Foster Estrella , Dai Wenping , Clark Richard B , Knoll Brian J
Published: December 2005

Activated β2‐adrenoceptors are rapidly desensitized by phosphorylation of Ser262 by protein kinase A (PKA) and of Ser355,356 by G‐protein‐coupled receptor kinase (GRK). We sought to determine whether the phosphorylation and subsequent dephosphorylation of these sites had similar kinetics and requirements for receptor endocytosis.

The phosphorylation of the PKA and GRK sites were measured using antibodies that recognize phosphoserine 262 and phosphoserine 355,356. Endocytosis in stably transfected HEK293 cells was blocked by inducible expression of dominant‐negative dynamin‐1 K44A or by treatment with hypertonic sucrose.

The phosphorylation of the GRK site Ser355,356 during a 10 μM isoprenaline treatment rapidly reached a steady state, and the extent of kinetics of phosphorylation were unaffected by dynamin‐1 K44A expression, and minimally by hypertonic sucrose.

In contrast, phosphorylation of the PKA site Ser262 during a 10 μM isoprenaline treatment peaked after 2 min and then rapidly declined, while inhibition of endocytosis enhanced and prolonged phosphorylation. Treatment with 300 pM isoprenaline, a concentration too low to provoke endocytosis, also resulted in prolonged PKA site phosphorylation.

The dephosphorylation of these sites was measured after removal of agonist. Significant dephosphorylation of phosphoserines 262 and 355,356 was observed under conditions of very low endocytosis, however dephosphorylation of the GRK site was greater if antagonist was present after removal of agonist.

The results indicate that the kinetics of β2‐adrenoceptor GRK and PKA site phosphorylation are distinct and differently affected by endocytosis, and that receptor dephosphorylation can occur either at the plasma membrane or in internal compartments.

British Journal of Pharmacology (2006) 147, 249–259. doi:10.1038/sj.bjp.0706551
Modulating GABA modulators
Authors: Paronis Carol A
Published: December 2005

Benzodiazepines produce a broad spectrum of behavioral effects, which may be clinically desirable or undesirable, by positively or negatively modulating the effects of GABA at GABAA receptors. Over the past 20 years, much effort has been devoted towards identifying new compounds with limited undesirable effects. Most of this work has focused on developing drugs either with lower intrinsic activity than drugs such as diazepam, or with different binding profiles at subtypes of GABAA receptors. However, the benzodiazepine binding site is only one of multiple binding sites contained within the GABAA receptor complex, and other endogenous or exogenous compounds also may positively or negatively modulate the effects of GABA. Despite the availability of ligands for each of these distinct binding sites, very little research has examined the effects of GABA modulators given in combination. This may be due, in part, to the noncompelling results of those few studies which, depending on the particular drugs, have demonstrated site‐selective antagonism or only additive effects, suggesting that each site modulates the effects of GABA independently. In this issue, McMahon and France challenge this view by showing that low‐efficacy benzodiazepine ligands will effectively antagonize midazolam and, at the same doses, will enhance the effects of a neuroactive steroid. These studies raise interesting questions regarding the nature of the interaction between the benzodiazepine and neurosteroid binding sites on GABAA receptors.

British Journal of Pharmacology (2006) 147, 237–238. doi:10.1038/sj.bjp.0706552
RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists
Authors: Bley Keith R , Bhattacharya Anindya , Daniels Don V , Gever Joel , Jahangir Alam , O'Yang Counde , Smith Steven , Srinivasan Dinesh , Ford Anthony P D W , Jett Mary‐Frances
Published: December 2005

Prostacyclin (PGI2) possesses various physiological functions, including modulation of nociception, inflammation and cardiovascular activity. Elucidation of these functions has been hampered by the absence of selective IP receptor antagonists.

Two structurally distinct series of IP receptor antagonists have been developed: 4,5‐dihydro‐1H‐imidazol‐2‐yl)‐[4‐(4‐isopropoxy‐benzyl)‐phenyl]‐amine (RO1138452) andR‐3‐(4‐fluoro‐phenyl)‐2‐[5‐(4‐fluoro‐phenyl) ‐benzofuran‐2‐ylmethoxycarbonylamino]‐propionic acid (RO3244794).

RO1138452 and RO3244794 display high affinity for IP receptors. In human platelets, the receptor affinities (pKi) were 9.3±0.1 and 7.7±0.03, respectively; in a recombinant IP receptor system, pKivalues were 8.7±0.06 and 6.9±0.1, respectively.

Functional antagonism of RO1138452 and RO3244794 was studied by measuring inhibition of carbaprostacyclin‐induced cAMP accumulation in CHO‐K1 cells stably expressing the human IP receptor. The antagonist affinities (pKi) of RO1138452 and RO3244794 were 9.0±0.06 and 8.5±0.11, respectively.

Selectivity profiles for RO1138452 and RO3244794 were determinedviaa panel of receptor binding and enzyme assays. RO1138452 displayed affinity at I2(8.3) and PAF (7.9) receptors, while RO3244794 was highly selective for the IP receptor: pKivalues for EP1(<5), EP3(5.38), EP4(5.74) and TP (5.09).

RO1138452 (1–10 mg kg−1, i.v.) and RO3244794 (1–30 mg kg−1, i.v.) significantly reduced acetic acid‐induced abdominal constrictions. RO1138452 (3–100 mg kg−1, p.o.) and RO3244794 (0.3–30 mg kg−1, p.o.) significantly reduced carrageenan‐induced mechanical hyperalgesia and edema formation. RO3244794 (1 and 10 mg kg−1, p.o.) also significantly reduced chronic joint discomfort induced by monoiodoacetate.

These data suggest that RO1138452 and RO3244794 are potent and selective antagonists for both human and rat IP receptors and that they possess analgesic and anti‐inflammatory potential.

British Journal of Pharmacology(2006)147, 335–345. doi:10.1038/sj.bjp.0706554
Selectivity of imidazole–dioxolane compounds forin vitroinhibition of microsomal haem oxygenase isoforms
Authors: Kinobe Robert T , Vlahakis Jason Z , Vreman Hendrik J , Stevenson David K , Brien James F , Szarek Walter A , Nakatsu Kanji
Published: December 2005

Haem oxygenases (HO) are involved in the catalytic breakdown of haem to generate carbon monoxide (CO), iron and biliverdin. It is widely accepted that products of haem catabolism are involved in biological signaling in many physiological processes. Conclusions to most studies in this field have gained support from the judicious use of synthetic metalloporphyrins such as chromium mesoporphyrin (CrMP) to selectively inhibit HO. However, metalloporphyrins have also been found to inhibit other haem‐dependent enzymes, such as nitric oxide synthase (NOS), cytochromes P‐450 (CYPs) and soluble guanylyl cyclase (sGC), induce the expression of HO‐1 or exhibit varied toxic effects.

To obviate some of these problems, we have been examining non‐porphyrin HO inhibitors and the present study describes imidazole–dioxolane compounds with high selectivity for inhibition of HO‐1 (rat spleen microsomes) compared to HO‐2 (rat brain microsomes)in vitro. (2R,4R)‐2‐[2‐(4‐chlorophenyl)ethyl]‐2‐[(1H‐imidazol‐1‐yl)methyl]‐4‐methyl‐1,3‐dioxolane hydrochloride) was identified as the most selective inhibitor with a concentration of 0.6 μMinhibiting HO‐1(inducible) by 50% compared with 394 μMfor HO‐2 (constitutive).

These compounds were found to have no effects on the catalytic activities of rat brain NOS and lung sGC, but were potent inhibitors of microsomalCYP2E1 andCYP3A1/3A2 activities.

In conclusion, we have identified imidazole–dioxolanes that are able to inhibit microsomal HOin vitrowith high selectivity for HO‐1 compared to HO‐2, and little or no effect on the activities of neuronal NOS and sGC. These molecules could be used to facilitate studies on the elucidation of physiological roles of HO/CO in biological systems.

British Journal of Pharmacology(2006)147, 307–315. doi:10.1038/sj.bjp.0706555
Vigabatrin transport across the human intestinal epithelial (Caco‐2) brush‐border membrane isviathe H+‐coupled amino‐acid transporter hPAT1
Authors: Abbot Emily L , Grenade Danielle S , Kennedy David J , Gatfield Kelly M , Thwaites David T
Published: December 2005

The aim of this investigation was to determine if the human proton‐coupled amino‐acid transporter 1 (hPAT1 or SLC36A1) is responsible for the intestinal uptake of the orally‐administered antiepileptic agent 4‐amino‐5‐hexanoic acid (vigabatrin).

The Caco‐2 cell line was used as a model of the human small intestinal epithelium. Competition experiments demonstrate that [3H]GABA uptake across the apical membrane was inhibited by vigabatrin and the GABA analoguestrans‐4‐aminocrotonic acid (TACA) and guvacine, whereas 1‐(aminomethyl)cyclohexaneacetic acid (gabapentin) had no affect.

Experiments with 2′,7′‐bis(2‐carboxyethyl)‐5(6)‐carboxyfluorescein (BCECF)‐loaded Caco‐2 cells demonstrate that apical exposure to vigabatrin and TACA induce comparable levels of intracellular acidification (due to H+/amino‐acid symport) to that generated by GABA, suggesting that they are substrates for a H+‐coupled absorptive transporter such as hPAT1.

In hPAT1 and mPAT1‐expressingXenopus laevisoocytes [3H]GABA uptake was inhibited by vigabatrin, TACA and guvacine, whereas gabapentin failed to inhibit [3H]GABA uptake.

In Na+‐free conditions, vigabatrin and TACA evoked similar current responses (due to H+/amino‐acid symport) in hPAT1‐expressing oocytes under voltage‐clamp conditions to that induced by GABA (whereas no current was observed in water‐injected oocytes) consistent with the ability of these GABA analogues to inhibit [3H]GABA uptake.

This study demonstrates that hPAT1 is the carrier responsible for the uptake of vigabatrin across the brush‐border membrane of the small intestine and emphasises the therapeutic potential of hPAT1 as a delivery route for orally administered, clinically significant GABA‐related compounds.

British Journal of Pharmacology(2006)147, 298–306. doi:10.1038/sj.bjp.0706557
The kinetics of oxidation of GSH by protein radicals
Authors: Nauser Thomas , Koppenol Willem H. , Gebicki Janusz M.
Published: December 2005

Current studies provide evidence that proteins are initial targets of ROS (reactive oxygen species) in biological systems and that the damaged proteins can in turn damage other cell constituents. This study was designed to test the possibility that protein radicals generated by ROS can oxidize GSH and assess the probability of this reaction in vivo by measurement of the rate constant of this reaction. Lysozyme radicals were generated by hydroxyl and azide radicals in steady-state gamma ray radiolysis. In the absence of dioxygen, a range of protein carbon-centred amino acid radicals were produced by the hydroxyl radicals, and defined tryptophan radicals by the azide radicals. In the presence of dioxygen, each carbon-centred radical was converted to a protein peroxyl radical. Each of the peroxyl radicals was able to oxidize a molecule of GSH, regardless of its location in the protein. The peroxyl radicals were 10 and 20 times more effective GSH oxidants than the carbon-centred radicals produced randomly in the lysozyme, or the defined tryptophan lysozyme radicals respectively. We obtained for the first time the rate constant of reaction between a protein free-radical and GSH. Lysozyme tryptophan carbon radicals generated by nanosecond pulse radiolysis and flash photolysis oxidized GSH with a rate constant of (1.05±0.05)×105 M−1·s−1. Overall, the results are consistent with the hypothesis that protein radicals may be important intermediates in the pathway linking oxidative stress and damage in living organisms and emphasize the strongly enhancing role of dioxygen in this process.
Cloning and functional identification of slc5a12 as a sodium-coupled low-affinity transporter for monocarboxylates (SMCT2)
Authors: Srinivas Sonne R. , Gopal Elangovan , Zhuang Lina , Itagaki Shirou , Martin Pamela M. , Fei You-Jun , Ganapathy Vadivel , Prasad Puttur D.
Published: December 2005

We report in the present paper, on the isolation and functional characterization of slc5a12, the twelfth member of the SLC5 gene family, from mouse kidney. The slc5a12 cDNA codes for a protein of 619 amino acids. Heterologous expression of slc5a12 cDNA in mammalian cells induces Na+-dependent transport of lactate and nicotinate. Several other short-chain monocarboxylates compete with nicotinate for the cDNA-induced transport process. Expression of slc5a12 in Xenopus oocytes induces electrogenic and Na+-dependent transport of lactate, nicotinate, propionate and butyrate. The substrate specificity of slc5a12 is similar to that of slc5a8, an Na+-coupled transporter for monocarboxylates. However, the substrate affinities of slc5a12 were much lower than those of slc5a8. slc5a12 mRNA is expressed in kidney, small intestine and skeletal muscle. In situ hybridization with sagittal sections of mouse kidney showed predominant expression of slc5a12 in the outer cortex. This is in contrast with slc5a8, which is expressed in the cortex as well as in the medulla. The physiological function of slc5a12 in the kidney is likely to mediate the reabsorption of lactate. In the intestinal tract, slc5a12 is expressed in the proximal parts, whereas slc5a8 is expressed in the distal parts. The expression of slc5a12 in the proximal parts of the intestinal tract, where there is minimal bacterial colonization, suggests that the physiological function of slc5a12 is not to mediate the absorption of short-chain monocarboxylates derived from bacterial fermentation but rather to mediate the absorption of diet-derived short-chain monocarboxylates. Based on the functional and structural similarities between slc5a8 and slc5a12, we suggest that the two transporters be designated as SMCT1 (sodium-coupled monocarboxylate transporter 1) and SMCT2 respectively.
The role of Ca2+ in triggering inositol 1,4,5-trisphosphate receptor ubiquitination
Authors: Alzayady Kamil J. , Wojcikiewicz Richard J. H.
Published: December 2005

The IP3R (inositol 1,4,5-trisphosphate receptor) forms tetrameric Ca2+ channels in ER (endoplasmic reticulum) membranes, where channel activity is largely under the control of the co-agonists IP3 and Ca2+. In cells stimulated using extracellular ligands that persistently elevate phosphoinositidase C activity, IP3Rs are rapidly ubiquitinated and then degraded by the proteasome through as yet undefined mechanisms. Whereas binding of IP3 has been suggested to be a key event in the triggering of IP3R ubiquitination the role of Ca2+ in this process remains unknown. In the present study we use αT3-1 mouse pituitary cells expressing exogenous wild-type or mutant-type-I IP3Rs (IP3R1) to provide several lines of evidence that Ca2+ is also a trigger. Firstly, depletion of ER Ca2+ stores with thapsigargin blocked wild-type IP3R1 ubiquitination. Secondly, ubiquitination was blocked by mutating Glu2100 to Asp, which is known to markedly suppress Ca2+-binding to IP3R1 and the potency of Ca2+ as a stimulus for channel opening. Thirdly, mutating Asp2550 to Ala, which inhibits Ca2+ flux through the channel pore, partially inhibited ubiquitination indicating that Ca2+ released via wild-type IP3R1 contributes to triggering ubiquitination. Fourthly, and consistent with this conclusion, although suppression of increases in cytoplasmic Ca2+ concentration did not inhibit the ubiquitination of wild-type IP3R1, it strongly inhibited the ubiquitination of the Asp2550 to Ala mutant. Overall, these results show that Ca2+ plays an important role in triggering IP3R ubiquitination. Additional experiments with IP3R1 containing an Arg265 to Gln mutation, which decreases IP3-binding affinity, confirmed that IP3-binding also plays a role. Finally, the mutations at Glu2100, Asp2550 and Arg265 inhibited IP3R1 degradation to an extent that paralleled their inhibitory effects on ubiquitination. We conclude that IP3R ubiquitination and degradation are triggered by the concerted action of IP3- and Ca2+-binding.
Physical and biochemical properties of mammalian DNase X proteins: non-AUG translation initiation of porcine and bovine mRNAs for DNase X
Authors: Shiokawa Daisuke , Shika Yukari , Saito Kazuki , Yamazaki Kosuke , Tanuma Sei-ichi
Published: December 2005

DNase X is the first human DNase protein identified as being homologous with DNase I. In the present study we describe the isolation of several mammalian DNase X cDNAs and the molecular characterization of their coding proteins. A sequence comparison reveals some conserved characteristics: all the mammalian DNase X proteins have an N-terminal signal peptide, a potential N-linked glycosylation site and a C-terminal hydrophobic domain. Human DNase X, ectopically expressed in HeLa S3 cells, is located in the ER (endoplasmic reticulum) and is modified by an N-linked glycosylation at Asn-243. Gene expression analyses show that the high expression level in muscular tissues, a known feature of human DNASE X, is also observed in mouse DNase X. Interestingly, the translation of porcine and bovine DNase X proteins occurs in the absence of an in-frame AUG initiation codon. We show that their mRNAs utilize a conserved CUG triplet for translation initiation.
Ab initio configuration-interaction investigation of optical transitions in K+He and K+H2
Authors: Santra Robin , Kirby Kate
Published: December 2005

The potassium resonance line (4s→4p) centered around 770 nm is a major contributor to the optical extinction in the atmospheres of certain classes of brown dwarfs and extrasolar giant planets. The resonance line is significantly broadened by collisions with He and H2, and an accurate calculation of the line profile is needed for astrophysical models of these objects. As a first step, we report an accurate ab initio study of the K+He and K+H2 potential-energy curves correlating to the K 4s and 4p atomic energy levels, together with the dipole moments governing the transitions between these potential-energy curves. The molecular calculations have been carried out using a multireference configuration-interaction method, with the molecular orbitals expanded in a large Gaussian basis set. The transition dipole moments show significant variation with the molecular geometry. Calculations for the K+H2 system have been carried out for a range of H2 orientations and internuclear separations, so that the effect of H2 rotation and vibration may be explicitly included in future calculations of the pressure-broadened line profiles.