bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling and measurement of sediment transport by waves in the vortex ripple regime
Authors: Davies A. G. , Thorne P. D.
Published: May 2005

Above steep, wave‐induced sand ripples, which occur extensively in shallow sea areas, the momentum transfer and suspended sediment dynamics are dominated by the formation and shedding at flow reversal of lee wake vortices. Since two‐dimensional models of this process are unduly complex for practical application, a simple, one‐dimensional vertical (1DV), two‐layer, model is presented here for the flow and transport above such ripples. In the lower layer of thickness equal to two ripple heights, vortex shedding is represented by a time‐varying eddy viscosity with peak values at flow reversal while, in the upper layer, a standard turbulence‐closure formulation is used. Suspended sediment is introduced at the ripple crest by a time‐varying pick‐up function. The ripple dimensions and suspended grain size are also predicted. The model results are compared with data obtained beneath weakly asymmetrical waves in a large‐scale flume. Intrawave measurements of suspended concentration were obtained using an acoustic backscatter system, and sediment profiles obtained above different locations on a moving rippled‐bed profile are used to provide intraripple and ripple‐averaged descriptions of the intrawave concentration field for comparison with the model. The results of a harmonic analysis suggest that the mean component and second harmonic (two‐peak symmetry term) of the concentration are well predicted, particularly near the bed. The modeled wave‐related component dominates the net sand transport rate; near‐bed transport is in the onshore direction, while transport in the outer boundary layer is offshore. The new 1DV formulation provides a simple, but realistic, modeling approach for the rippled regime.
Oxygenation changes in the deep western Arabian Sea during the last 190,000 years: Productivity versus deepwater circulation
Authors: Schmiedl Gerhard , Leuschner Dirk C.
Published: May 2005

Fluctuations in the abundance of selected foraminiferal indicator species and diversity allowed the reconstruction of changes in deepwater oxygenation and monsoon‐driven organic matter fluxes in the deep western Arabian Sea during the last 190 kyr. Times of maximum surface production coincide with periods of intensified SW monsoon as shown by the abundance of Globigerina bulloides and enhanced carbonate corrosion. Benthic ecosystem variability in the deep Arabian Sea is not exclusively driven by variations in monsoonal upwelling and related organic matter supply to the seafloor but also by changes in deepwater ventilation. Deepening of the base of the oxygen minimum zone (OMZ) below 1800 m water depth is strongly coherent on the precessional band but lags proxies of SW monsoon strength by 4 to 6 kyr. The “out‐of‐phase” relationship between OMZ deepening and maximum SW monsoon strength is explained by temporal changes in the advection of oxygen‐rich deepwater masses of North Atlantic and Antarctic origin. This process affected the remineralization and burial efficiency of organic matter in the deep Arabian Sea, resulting in the observed phase lag between maximum monsoon strength and organic carbon preservation.
Adaptive filters revisited: Radio frequency interference mitigation in pulsar observations
Authors: Kesteven M. , Hobbs G. , Clement R. , Dawson B. , Manchester R. , Uppal T.
Published: May 2005

Pulsar detection and timing experiments are applications where adaptive filters seem eminently suitable tools for radio frequency interference (RFI) mitigation. We describe a novel variant which works well in field trials of pulsar observations centered on an observing frequency of 675 MHz and a bandwidth of 64 MHz and with 2‐bit sampling. Adaptive filters have generally received bad press for RFI mitigation in radio astronomical observations with their most serious drawback being a spectral echo of the RFI embedded in the filtered signals. Pulsar observations are intrinsically less sensitive to this as they operate in the (pulsar period) time domain. The field trials have allowed us to identify those issues which limit the effectiveness of the adaptive filter. We conclude that adaptive filters can significantly improve pulsar observations in the presence of RFI.
Deep structure of the southern Apennines, Italy: Thin‐skinned or thick‐skinned?
Authors: Scrocca Davide , Carminati Eugenio , Doglioni Carlo
Published: May 2005

The deep structure of the southern Apennines (SA) accretionary wedge is still debated since industrial seismic reflection and well data provide reliable constraints only to a depth of about 10 km. As a consequence, two directly linked questions regard (1) the shortening in the accretionary prism (particularly within the buried Apulian thrust units) and (2) the degree of involvement of the lower plate basement (i.e., the Apulian crystalline basement). To address these issues, we have constructed a regional section along a recently released deep seismic reflection profile (CROP‐04) which intersects the entire SA. The resulting cross section, adequately constrained to a depth of about 15 km, has been framed in a geodynamic scenario characterized by the eastward roll‐back of the westward subducting Apulo‐Adriatic lithosphere. On the basis of this section we speculate on the deep structure, building both thin‐ and thick‐skinned thrust models. A cross‐check of these end‐members models against documented tectonic, geophysical, and geochemical features shows that the thin‐skinned model is generally more consistent with the available data. The development of basement slices with thicknesses of tens of kilometers is unlikely, while it remains possible that the Apulian basement could have been involved with its upper few kilometers. In the thin‐skinned model, the total shortening of the allochthonous units (i.e., Apennine and Apulian carbonate platforms and Lagonegro basin) is estimated to be greater than 280–300 km. Some 90 km of shortening can be attributed to the Apulian thrust units.
Saline tracer visualized with three‐dimensional electrical resistivity tomography: Field‐scale spatial moment analysis
Authors: Singha Kamini , Gorelick Steven M.
Published: May 2005

Cross‐well electrical resistivity tomography (ERT) was used to monitor the migration of a saline tracer in a two‐well pumping‐injection experiment conducted at the Massachusetts Military Reservation in Cape Cod, Massachusetts. After injecting 2200 mg/L of sodium chloride for 9 hours, ERT data sets were collected from four wells every 6 hours for 20 days. More than 180,000 resistance measurements were collected during the tracer test. Each ERT data set was inverted to produce a sequence of 3‐D snapshot maps that track the plume. In addition to the ERT experiment a pumping test and an infiltration test were conducted to estimate horizontal and vertical hydraulic conductivity values. Using modified moment analysis of the electrical conductivity tomograms, the mass, center of mass, and spatial variance of the imaged tracer plume were estimated. Although the tomograms provide valuable insights into field‐scale tracer migration behavior and aquifer heterogeneity, standard tomographic inversion and application of Archie's law to convert electrical conductivities to solute concentration results in underestimation of tracer mass. Such underestimation is attributed to (1) reduced measurement sensitivity to electrical conductivity values with distance from the electrodes and (2) spatial smoothing (regularization) from tomographic inversion. The center of mass estimated from the ERT inversions coincided with that given by migration of the tracer plume using 3‐D advective‐dispersion simulation. The 3‐D plumes seen using ERT exhibit greater apparent dispersion than the simulated plumes and greater temporal spreading than observed in field data of concentration breakthrough at the pumping well.
Role of the calibration process in reducing model predictive error
Authors: Moore Catherine , Doherty John
Published: May 2005

An equation is derived through which the variance of predictive error of a calibrated model can be calculated. This equation has two terms. The first term represents the contribution to predictive error variance that results from an inability of the calibration process to capture all of the parameterization detail necessary for the making of an accurate prediction. If a model is “uncalibrated,” with parameter values being supplied solely through “outside information,” this is the only term required. The second term represents the contribution to predictive error variance arising from measurement noise. In an overdetermined system, such as that which may be obtained through “parameter lumping” (e.g., through the introduction of a spatial zonation scheme), this is the only term required. It is shown, however, that parameter lumping is a form of “implicit regularization” and that ignoring the implied first term of the predictive error variance equation can potentially lead to underestimation of predictive error variance. A model's role as a predictor of environmental behavior can be enhanced if it is calibrated in such a way as to reduce the variance of those predictions which it is required to make. It is shown that in some circumstances this can be accomplished through “overfitting” against historical field data. It can also be accomplished by giving greater weight to those measurements which carry the greatest information content with respect to a required prediction. This suggests that a departure may be necessary from the custom of using a single “calibrated model” for the making of many different predictions. Instead, model calibration may need to be repeated many times so that in each case the calibration process is optimized for the making of a specific model prediction.
Seepage into drifts and tunnels in unsaturated fractured rock
Authors: Or Dani , Tuller Markus , Fedors Randall
Published: May 2005

Methods for obtaining estimates of seepage into drifts and tunnels excavated in unsaturated fractured rocks are of interest for engineering and environmental applications. For uniform porous media a tunnel surface may present a capillary barrier promoting water diversion around the opening through the porous matrix, hence reducing seepage into the opening. The presence of fractures intersecting the opening complicates flow behavior and presents a challenge to seepage prediction. We present a simple and physically based model for seepage estimation that preserves key physical processes associated with fracture flow, while avoiding complexity of detailed fracture network characterization. The processes of film and capillary‐driven flows are combined with a geometrically tractable representation of the dual‐continuum fractured rock with two disparate populations of matrix pores and fracture apertures. The large disparity in capillary forces between matrix and fractures rules out matrix seepage based on Philip's theory. We obtain estimates of seepage fraction for a given percolation flux from consideration of the hydraulic conductivity of the fracture domain only. Similar to previous studies, the new model shows existence of a percolation threshold for onset of seepage. The new model also exhibits a steep increase in seepage with increase in percolation flux that reflects the role of fracture film flow. In addition to consideration of physically based flow processes, computations for the proposed analytical model can be performed with common spreadsheet software, which is a distinct advantage over numerical equivalent porous media approaches that require a powerful computational environment, excessive computation time, and thorough characterization of the fracture domain.
Radionuclide and biomarker proxies of past ocean circulation and productivity in the Arabian Sea
Authors: Pourmand A. , Marcantonio F. , Bianchi T. S. , Canuel E. A. , Waterson E. J.
Published: May 2005

We present new excess 231Pa/230Th activity ratios and lipid biomarker results from northeastern Arabian Sea sediments (core 93KL) spanning the past 50 ka in an effort to constrain further the relationship between climate at low and high latitudes. 231Pa/230Th activity ratios are maintained at values significantly higher than the water‐column production ratio of 0.093. Average 231Pa/230Th activity ratios are lower during the last glacial period than during the Holocene. The lowest 231Pa/230Th activity ratios coincide with the timing of Heinrich Events 1–5. Profiles of lipid biomarker fluxes and 231Pa/230Th activity ratios from 32 to 12 ka show similar patterns, suggesting that 231Pa is more efficiently scavenged relative to 230Th at times when diatoms make up a proportionally larger part of the primary biomass signal. In the Holocene, high 231Pa/230Th activity ratios may indicate enhanced 231Pa export from the southern to the northern Indian Ocean via intensified thermohaline circulation.
Parameterization of drag and dissolution of rising CO2 drops in seawater
Authors: Gangstø Reidun , Haugan Peter M. , Alendal Guttorm
Published: May 2005

In this work the dynamics and dissolution of a hydrate‐covered CO2 drop were studied, using a numeric model and data from one of very few CO2 experiments performed in the real ocean. A theory including the standard drag curve of rigid spheres was shown not to fit the observed drop rise velocity. However, a drag parameterization supported by numerous laboratory experiments with gas bubbles provides a good match of the observed rise velocity of a liquid CO2 drop covered with hydrate. The results confirm laboratory results showing that shape is a key factor determining the CO2 drop dynamics. We also found that hydrate reduces the mass transfer of the observed drop by a factor of 2, which is compatible with laboratory experiments. Numerical experiments with different drop sizes showed that the choice of drag parameterization has a significant impact on the estimated vertical distribution of dissolved CO2.
Predicting lightning‐driven quasi‐electrostatic fields at sprite altitudes using in situ measurements and a numerical model
Authors: Thomas Jeremy N. , Holzworth Robert H. , McCarthy Michael P. , Pinto Osmar
Published: May 2005

Data from the largest electric field change (>140 V/m) above 30 km ever published, correlated with two positive cloud‐to‐ground (+CG) strokes, are compared with an axi‐symmetric quasi‐electrostatic field (QSF) model developed by the authors and based on the model of Pasko et al. (1997a). Using the best fit parameters of this comparison, the electric field change everywhere in the stratosphere and mesosphere is predicted and compared to various electrical breakdown thresholds needed for the initiation and/or growth of sprites.
Dissecting the anomaly: A closer look at the documented urban enhancement in summer season ground flash densities in and around the Houston area
Authors: Gauthier Michael L. , Petersen Walter A. , Carey Lawrence D. , Orville Richard E.
Published: May 2005

The Houston “lightning anomaly” was examined using nine years of cloud‐to‐ground (CG) lightning data (1995–2003). We find that the local Houston CG lightning anomaly, is a persistent feature, but statistically non‐unique along the Gulf Coast. The results also suggest that although the Houston area sees an increased frequency of lightning producing storms, storms occurring further inland appear to produce more lightning on an event basis. Although hypotheses invoking anthropogenic influences have been offered to explain the Houston flash density anomaly, it seems equally plausible that mesoscale influences along the coastline may also be important.
Small rampart craters in an equatorial region on Mars: Implications for near‐surface water or ice
Authors: Reiss D. , Hauber E. , Michael G. , Jaumann R. ,   G. Neukum and the HRSC Co‐Investigator Team
Published: May 2005

Small onset diameters (1 km) of rampart craters were identified in High Resolution Stereo Camera (HRSC) imagery in the equatorial region of the Valles Marineris plateaus. This is in contrast to previous global studies based on Viking imagery, which showed onset diameters in the range of 4 km to 7 km in equatorial regions. The observed small rampart craters show morphologically eroded ejecta blankets. This indicates a formation in the early Martian history, when erosion rates were higher. Volatile rich target material might have been available shortly after the formation of the Hesperian–aged plateaus surrounding Valles Marineris, and this is in agreement with the reported Hesperian fluvial activity in this region. The lack of fresh small rampart craters indicates a lowering of the ground ice table with time.
Near‐inertial oscillations interacting with mesoscale circulation in the southwestern Japan/East Sea
Authors: Park Jae‐Hun , Watts D. Randolph
Published: May 2005

The near‐inertial internal wave energy distribution is investigated in the southwestern Japan/East Sea using vertical round‐trip travel time of sound (τ) data from 23 pressure‐sensor‐equipped inverted echo sounders (PIESs) and data from Aanderaa recording current meters (CMs). Currents associated with low‐mode near‐inertial internal waves are slightly inclined and displace the thermocline vertically, which can be detected in τ. The band‐pass filtered τ records exhibit high near‐inertial energy distributions that vary interannually with changes observed in mesoscale circulation. An explanation for this is offered as trapping of near‐inertial energy in anticyclonic regions, which is supported by scatterplots of monthly‐rms band‐pass filtered τ at inertial frequency bands vs. monthly‐mean relative vorticity. The spectra from all but one deep CM exhibit a blue shift, consistent with the equatorward propagation of near‐inertial waves. The exception has the highest near‐inertial wave energy, and is located near the center of a warm anticyclonic eddy.
Compositional heterogeneity of the ancient Martian crust: Analysis of Ares Vallis bedrock with THEMIS and TES data
Authors: Rogers A. Deanne , Christensen Philip R. , Bandfield Joshua L.
Published: May 2005

THEMIS multispectral and thermophysical information combined with TES hyperspectral and albedo data is used as a powerful high spectral/spatial resolution tool to investigate the mineralogic heterogeneity of ancient Martian crust exposed in Ares Vallis bedrock. Three major spectral units are present in the upper Ares Vallis region: (1) a regional unit that is composed primarily of a high‐silica (Si/O > ∼0.35) component, with lesser amounts of plagioclase and pyroxene, and is associated with channel wall rock and surrounding plains; (2) a pyroxene‐ and olivine‐rich rock unit exposed as a ∼250 m thick contiguous layer in the wall rock of Ares Vallis, as well as in isolated exposures in the plains outside of the channel; and (3) a unit composed of plagioclase, pyroxene, and lesser high‐silica component(s) (Si/O > ∼0.35) that primarily occurs as low‐albedo sand. The spatial and stratigraphic distribution of these units suggests that the pyroxene‐ and olivine‐enriched unit may be extrusive and/or intrusive in origin, indicating that this region experienced either a single stage or repeated episodes of olivine‐enriched magmatism during the first 1.5 Gyr of crust formation. This olivine enrichment may have been caused by a larger degree of mantle partial melting, facilitated by higher mantle temperature, melting from a more depleted mantle source, and/or less olivine fractionation relative to regional rock parent magmas. The olivine‐rich unit is similar in thermophysical character to previously published olivine‐bearing terrains on Mars, but the derived modal mineralogy consists of >∼20% more pyroxene and less plagioclase than those terrains.
Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells
Authors: Kempuraj Duraisamy , Madhappan Bhuvaneshwari , Christodoulou Spyridon , Boucher William , Cao Jing , Papadopoulou Nikoletta , Cetrulo Curtis L , Theoharides Theoharis C
Published: May 2005

Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines.

Flavonoids are naturally occurring polyphenolic plant compounds, one group of which – the flavonols, inhibits histamine and some cytokine release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory mediator release and their possible mechanism of action in human mast cells is not well defined.

Human umbilical cord blood‐derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)‐6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 μM), followed by activation with anti‐IgE. Secretion was quantitated for IL‐6, IL‐8, tumor necrosis factor‐alpha (TNF‐α), histamine and tryptase levels.

Release of IL‐6, IL‐8 and TNF‐α was inhibited by 82–93% at 100 μM quercetin and kaempferol, and 31–70% by myricetin and morin. Tryptase release was inhibited by 79–96% at 100 μM quercetin, kampferol and myricetin, but only 39% by morin; histamine release was inhibited 52–77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose–response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium‐insensitive protein kinase C theta (PKC θ).

Flavonol inhibition of IgE‐mediated proinflammatory mediator release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC θ signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases.

British Journal of Pharmacology (2005) 145, 934–944. doi:10.1038/sj.bjp.0706246
Opioid antagonists differ according to negative intrinsic efficacy in a mouse model of acute dependence
Authors: Walker Ellen A , Sterious Steven N
Published: May 2005

The purpose of the present study is to compare the capacity of opioid antagonists to elicit withdrawal jumping in mice following two acute pretreatment doses of the opioid agonist morphine. Antagonists that precipitate vigorous withdrawal jumping across both morphine treatment doses are hypothesized to be strong inverse agonists at the μ‐opioid receptor, whereas antagonists that elicit withdrawal jumping in mice treated with the high but not the low dose of morphine are hypothesized to be weak inverse agonists.

Male, Swiss‐Webster mice (15–30 g) were acutely treated with 56 or 180 mg kg−1 morphine 4 h prior to injection with naloxone, naltrexone, diprenorphine, nalorphine, or naloxonazine. Vertical jumping, paw tremors, and weight loss were recorded. Naloxone, naltrexone, and diprenorphine produced withdrawal jumping after 56 and 180 mg kg−1morphine pretreatment. Nalorphine and naloxonazine produced moderate withdrawal jumping after 180 mg kg−1 morphine pretreatment, but failed to elicit significant withdrawal jumping after 56 mg kg−1 morphine pretreatment. Nalorphine and naloxonazine blocked the withdrawal jumping produced by naloxone. All antagonists produced paw tremors and weight loss although these effects were generally not dose‐dependent.

Taken together, these findings reveal a rank order of negative intrinsic efficacy for these opioid antagonists as follows: naloxone=naltrexonediprenorphine>nalorphine=naloxonazine. Furthermore, the observation that nalorphine and naloxonazine blocked the naloxone‐induced withdrawal jumping provides additional evidence that nalorphine and naloxonazine are weaker inverse agonists than naloxone.

British Journal of Pharmacology (2005) 145, 975–983. doi:10.1038/sj.bjp.0706247
Anticonvulsant enaminones depress excitatory synaptic transmission in the rat brain by enhancing extracellular GABA levels
Authors: Kombian Samuel B , Edafiogho Ivan O , Ananthalakshmi Kethireddy V V
Published: May 2005

Enaminones are a novel group of compounds that have been shown to possess anticonvulsant activity in in vivo animal models of seizures. The cellular mechanism by which these compounds produce their anticonvulsant effects is not yet known. This study examined the effects of enaminones on excitatory synaptic transmission.

We studied the effects of 3‐(4′‐chlorophenyl)aminocyclohex‐2‐enone (E118), methyl 4‐(4′‐bromophenyl)aminocyclohex‐3‐en‐6‐methyl‐2‐oxo‐1‐oate (E139) and ethyl 4‐(4′‐hydroxyphenyl)aminocyclohex‐3‐en‐6‐methyl‐2‐oxo‐1‐oate (E169) on isolated evoked, glutamate‐mediated excitatory synaptic responses by recording whole‐cell currents and potentials in cells of the nucleus accumbens (NAc) contained in forebrain slices.

The anticonvulsant enaminones (E118 and E139), but not E169, depressed NMDA and non‐NMDA receptor‐mediated synaptic responses. The inhibition of the non‐NMDA response was concentration‐dependent (1.0–100 μM) with a maximal depression of ∼−30%. E118 and E139 had similar potencies (EC50=3.0 and 3.5 μM, respectively) in depressing this response but E139 was more efficacious (Emax=−31.3±3.8%) than E118 (Emax=−22.6±1.6%).

The excitatory postsynaptic current (EPSC) depression caused by 10 μM E139 (−27.7±3.8%) was blocked by 1 μM CGP55845 (6.3±8.1%), a potent GABAB receptor antagonist.

Pretreatment of slices with γ‐vinylGABA and 1‐(2‐(((diphenylmethylene)imino)oxy)ethyl)‐1,2,5,6‐tetrahydro‐3‐pyridine‐carboxylic acid (NO‐711), an irreversible GABA transaminase (GABA‐T) inhibitor and a GABA reuptake blocker, respectively, like the anticonvulsant enaminones, also caused a depression of the evoked EPSC (−38.1±14.1 and −24.1±8.9%, respectively). In the presence of these compounds, E139 did not cause a further depression of the EPSC. Our data suggest that anticonvulsant enaminones cause EPSC depression by enhancing extracellular GABA levels possibly through the inhibition of either GABA reuptake or GABA‐T enzyme, or both.

British Journal of Pharmacology (2005) 145, 945–953. doi:10.1038/sj.bjp.0706250
Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABAA receptors supports an allosteric model of modulation
Authors: Downing Scott S , Lee Yan T , Farb David H , Gibbs Terrell T
Published: May 2005

Benzodiazepines (BZDs) have been used extensively for more than 40 years because of their high therapeutic index and low toxicity. Although BZDs are understood to act primarily as allosteric modulators of GABAA receptors, the mechanism of modulation is not well understood.

The applicability of an allosteric model with two binding sites for γ‐aminobutyric acid (GABA) and one for a BZD‐like modulator was investigated.

This model predicts that BZDs should enhance the efficacy of partial agonists.

Consistent with this prediction, diazepam increased the efficacy of the GABAA receptor partial agonist kojic amine in chick spinal cord neurons.

To further test the validity of the model, the effects of diazepam, flurazepam, and zolpidem were examined using wild‐type and spontaneously active mutant α1(L263S)β3γ2 GABAA receptors expressed in HEK‐293 cells.

In agreement with the predictions of the allosteric model, all three modulators acted as direct agonists for the spontaneously active receptors.

The results indicate that BZD‐like modulators enhance the amplitude of the GABA response by stabilizing the open channel active state relative to the inactive state by less than 1 kcal, which is similar to the energy of stabilization conferred by a single hydrogen bond.

British Journal of Pharmacology (2005) 145, 894–906. doi:10.1038/sj.bjp.0706251
Structural features of phenol derivatives determining potency for activation of chloride currents via α1 homomeric and α1β heteromeric glycine receptors
Authors: Haeseler Gertrud , Ahrens Jörg , Krampfl Klaus , Bufler Johannes , Dengler Reinhard , Hecker Hartmut , Aronson Jeffrey K , Leuwer Martin
Published: May 2005

Phenol derivatives constitute a family of neuroactive compounds. The aim of our study was to identify structural features that determine their modulatory effects at glycine receptors.

We investigated the effects of four methylated phenol derivatives and two halogenated analogues on chloride inward currents via rat α1 and α1β glycine receptors, heterologously expressed in HEK 293.

All compounds potentiated the effect of a submaximal glycine concentration in both α1 homomeric and α1β glycine receptors. While the degree of maximum potentiation of the glycine 10 μM effect in α1β receptors was not different between the compounds, the halogenated compounds achieved half‐maximum potentiating effects in the low μM range – at more than 20‐fold lower concentrations compared with their nonhalogenated analogues (P<0.0001). The coactivating effect was over‐ridden by inhibitory effects at concentrations >300 μM in the halogenated compounds. Neither the number nor the position of the methyl groups significantly affected the EC50 for coactivation.

Only the bimethylated compounds 2,6 and 3,5 dimethylphenol (at concentrations >1000 μM) directly activated both α1 and α1β receptors up to 30% of the maximum response evoked by 1000 μM glycine.

These results show that halogenation in the para position is a crucial structural feature for the potency of a phenolic compound to positively modulate glycine receptor function, while direct activation is only seen with high concentrations of compounds that carry at least two methyl groups. The presence of the β subunit is not required for both effects.

British Journal of Pharmacology (2005) 145, 916–925. doi:10.1038/sj.bjp.0706254
Sympathoadrenal‐dependent sexually dimorphic effect of nonhabituating stress on in vivo neutrophil recruitment in the rat
Authors: Barker Laura A , Dazin Paul F , Levine Jon D , Green Paul G
Published: May 2005

Since stress both activates the sympathoadrenal axis and profoundly affects inflammation and inflammatory diseases, many of which are sexually dimorphic, we tested whether the effect of stress on neutrophil recruitment, a primary component of the acute inflammatory response, is sexually dimorphic.

The effect of intermittent sound (over 4 days), a nonhabituating stress, on lipopolysaccharide (LPS)‐induced recruitment of neutrophils was evaluated in vivo in the rat air pouch model. At 24 h following the last stress exposure, LPS‐induced neutrophil recruitment was enhanced in male rats, but not in females.

When gonadectomized prepubertally and tested as adults, stress significantly inhibited the magnitude of LPS‐induced neutrophil recruitment in males, while it still had no effect in gonadectomized females. In males, following adrenal denervation, the increase in LPS‐induced neutrophil recruitment produced by stress was prevented. Since these data suggest that the effect of stress is dependent on the sympathoadrenal axis, we tested the hypothesis that catecholamines mediate the stress effects.

In male rats, the effect of stress on LPS‐induced neutrophil recruitment was significantly attenuated by continuous administration of the β‐adrenergic receptor antagonist, propranolol (4 mg kg−1 day−1), during sound stress exposure, and administration of isoproterenol (10 nmoles, i.v.) significantly increased neutrophil recruitment in males, an effect that was qualitatively and quantitatively similar to the effect of stress. Propranolol significantly increased neutrophil recruitment in nonstressed female rats, but did not significantly affect neutrophil recruitment in stressed females.

These findings indicate a marked male sex hormone‐dependent sexual dimorphism in the sympathoadrenal‐dependent effect of stress on neutrophil migration, a primary component of the inflammatory response, and suggest that the sympathoadrenal axis contributes to this effect via release of epinephrine.

British Journal of Pharmacology (2005) 145, 872–879. doi:10.1038/sj.bjp.0706257
Atorvastatin reverses age‐related reduction in rat hepatic PPARα and HNF‐4
Authors: Sanguino Elena , Roglans Nuria , Alegret Marta , Sánchez Rosa M , Vázquez‐Carrera Manuel , Laguna Juan C
Published: May 2005

Old rats are resistant to fibrate‐induced hypolipidemia owing to a reduction in hepatic peroxisome proliferator‐activated receptor α (PPARα). We tested whether the age‐related decrease in PPARα is prevented by atorvastatin (ATV), a hypolipidemic statin.

We determined the activity and expression of Liver X receptor α (LXRα) and PPARα in the liver of 18‐month‐old rats treated with 10 mg kg−1 of ATV for 21 days. We measured fatty acid oxidation (FAO), the expression of PPARα‐target genes, liver triglyceride (TG) and cholesteryl ester (CE) contents and plasma concentrations of TG, cholesterol, glucose, nonesterified fatty acids (NEFA), insulin and leptin. While old female rats were practically unresponsive, ATV‐treated old males showed lower liver TG (−41%) and CE (−48%), and plasma TG (−35%), glucose (−18%) and NEFA (−39%). Age‐related alterations in LXRα expression and binding activity were reverted in ATV‐treated old males. These changes were related to an increase in hepatic FAO (1.2‐fold), and PPARα mRNA (2.2‐fold), PPARα protein (1.6‐fold), and PPARα‐binding activity.

Hepatic nuclear factor‐4 (HNF‐4) and chicken ovalbumin upstream‐transcription factor‐II participate in the transcriptional regulation of the PPARα gene, while peroxisome proliferator‐activated receptor gamma coactivator 1 (PGC‐1) behaves as a PPAR coactivator. Ageing reduced the hepatic content of HNF‐4 (74%) and PGC‐1 (77%) exclusively in male rats. ATV administration to old males enhanced the hepatic expression and binding activity (two‐fold) of HNF‐4.

ATV‐induced changes in hepatic HNF‐4 and PPARα may be responsible for the improvement of the lipid metabolic phenotype produced by ATV administration to senescent male rats.

British Journal of Pharmacology (2005) 145, 853–861. doi:10.1038/sj.bjp.0706260
Modulation of mitochondrial Ca2+ uptake by estrogen receptor agonists and antagonists
Authors: Lobatón Carmen D , Vay Laura , Hernández‐SanMiguel Esther , SantoDomingo Jaime , Moreno Alfredo , Montero Mayte , Alvarez Javier
Published: May 2005

Ca2+ uptake by mitochondria is a key element in the control of cellular Ca2+ homeostasis and Ca2+‐dependent phenomena. It has been known for many years that this Ca2+ uptake is mediated by the mitochondrial Ca2+ uniporter, a specific Ca2+ channel of the inner mitochondrial membrane. We have shown previously that this channel is strongly activated by a series of natural phytoestrogenic flavonoids. We show here that several agonists and antagonists of estrogen receptors (ERs) also modulate the activity of the uniporter.

The specific α‐ER agonist 4,4′,4″‐(4‐propyl‐[1H]‐pyrazole‐1,3,5‐triyl)trisphenol (PPT) was the strongest activator, increasing the rate of mitochondrial Ca2+ uptake in permeabilized HeLa cells by 10‐fold at 2 μM. Consistently, PPT largely increased the histamine‐induced mitochondrial [Ca2+] peak and reduced the cytosolic one.

Diethylstilbestrol and 17‐β‐estradiol (but not 17‐α‐estradiol) were active at pharmacological concentrations while the β‐estrogen‐receptor agonist 2,3‐bis(4‐hydroxyphenyl)‐propionitrile (DPN) was little effective.

The ER modulators tamoxifen and 4‐hydroxy‐tamoxifen inhibited mitochondrial Ca2+ uptake (IC50 2.5±1.5 and 2.5±1.4 μM, mean±s.d., respectively) both in the presence and in the absence of PPT, but raloxifene and the pure estrogen antagonist ICI 182,780 produced no effect.

Activation by PPT was immediate and inhibition by tamoxifen or 4‐hydroxy‐tamoxifen required only 5 min to reach maximum.

Tamoxifen did not modify mitochondrial membrane potential and PPT induced a slow mitochondrial depolarization at higher concentrations than those required to activate mitochondrial Ca2+ uptake.

These results suggest that some kind of ER or related protein located in mitochondria controls the activity of the Ca2+ uniporter by a nongenomic mechanism. This novel mechanism of action of estrogen agonists and antagonists can provide a new interpretation for several previously reported effects of these compounds.

British Journal of Pharmacology (2005) 145, 862–871. doi:10.1038/sj.bjp.0706265
The KCa channel as a trigger for the cardioprotection induced by kappa‐opioid receptor stimulation – its relationship with protein kinase C
Authors: Cao Chun‐Mei , Chen Mai , Wong Tak‐Ming
Published: May 2005

We first determined whether the cardioprotection resulting from kappa opioid receptor (κ‐OR) stimulation was blocked by the KCa channel inhibitor, paxilline (Pax), administered before or during ischaemic insults in vitro.

In isolated rat hearts, 30 min of ischaemia and 120 min of reperfusion induced infarction and increased lactate dehydrogenase (LDH) release. In isolated ventricular myocytes subjected to 5 min of metabolic inhibition and anoxia followed by 10 min of reperfusion, the percentage of live cells and the amplitude of the electrically induced intracellular Ca2+ ([Ca2+]i) transient decreased, while diastolic [Ca2+]i increased. Pretreatment with 10 μM U50,488H, a κ‐OR agonist, attenuated the undesirable effects of ischaemic insults in both preparations. The beneficial effects of κ‐OR stimulation, that were abolished by 5 μM nor‐BNI, a κ‐OR antagonist, were also abolished by 1 μM Pax administered before ischaemic insults or 20 μM atractyloside, an opener of the mitochondrial permeability transition pore.

Activation of protein kinase C (PKC) with 0.1 μM phorbol 12‐myristate 13‐acetate decreased the infarct size and LDH release in isolated rat hearts subjected to ischaemia/reperfusion, and these effects were abolished by blockade of PKC with its inhibitors, 10 μM GF109203X or 5 μM chelerythrine, and more importantly by 1 μM Pax. On the other hand, the cardioprotective effects of opening the KCa channel with 10 μM NS1619 were not altered by either PKC inhibitor.

In conclusion, the high‐conductance KCa channel triggers cardioprotection induced by κ‐OR stimulation that involves inhibition of MPTP opening. The KCa channel is located downstream of PKC.

British Journal of Pharmacology (2005) 145, 984–991. doi:10.1038/sj.bjp.0706268
Glibenclamide depletes ATP in renal proximal tubular cells by interfering with mitochondrial metabolism
Authors: Engbersen Richard , Masereeuw Rosalinde , van Gestel Miriam A , van der Logt Elise M J , Smits Paul , Russel Frans G M
Published: May 2005

Sulfonylurea drugs, like glibenclamide, stimulate insulin secretion by blocking ATP‐sensitive potassium channels on pancreatic beta cells. Renal tubular epithelial cells possess a different class of KATP channels with much lower affinities for sulfonylurea drugs, necessitating the use of micromolar glibenclamide concentrations to study these channels.

Here, we describe the toxic effects of these concentrations on mitochondrial energy metabolism in freshly isolated renal proximal tubular cells. Glibenclamide, at concentrations of 50 and 100 μM, reduced intracellular ATP levels by 28±4 and 53±5%, respectively (P<0.01).

This decline in ATP could be attributed to a dose‐dependent inhibition of mitochondrial respiration. Glibenclamide (10–500 μM) inhibited ADP‐stimulated mitochondrial oxygen consumption.

In addition to this toxic effect, specific association of radiolabeled and fluorescent glibenclamide to renal mitochondria was found. Association of [3H]glibenclamide with renal mitochondria revealed a low‐affinity site with a KD of 16±6 μM and a Bmax of 167±29 pmol mg−1.

We conclude that micromolar concentrations of glibenclamide interfere with mitochondrial bioenergetics and, therefore, should be used with care for inhibition of epithelial KATP channels.

British Journal of Pharmacology (2005) 145, 1069–1075. doi:10.1038/sj.bjp.0706275
Inhibition of the cdk5/MEF2 pathway is involved in the antiapoptotic properties of calpain inhibitors in cerebellar neurons
Authors: Verdaguer Ester , Alvira Daniel , Jiménez Andrés , Rimbau Victor , Camins Antoni , Pallàs Mercè
Published: May 2005

Experimental data implicate calpain activation in the pathways involved in neuronal apoptosis. Indeed, calpain inhibitors confer neuroprotection in response to various neurotoxic stimuli. However, the pathways involved in calpain activation‐induced apoptosis are not well known.

We demonstrate that apoptosis (40%) induced by serum/potassium (S/K) withdrawal on cerebellar granule cells (CGNs) is inhibited by selective calpain inhibitors PD150606 (up to 15%) and PD151746 (up to 29%), but not PD145305 in CGNs. zVAD‐fmk, a broad spectrum inhibitor of caspases, attenuates apoptosis (up to 20%) mediated by S/K deprivation and protects against cell death, as measured by MTT ([3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium]) assay.

PD150606 and PD151746 prevented apoptosis mediated by S/K withdrawal through inhibition of calpain. Furthermore, PD151746 was able to inhibit caspase‐3 activity.

After S/K withdrawal, we observed an increase in cdk5/p25 formation and MEF2 phosphorylation that was prevented by 40 μM PD150606 and PD151746. This indicates that calpain inhibition may be an upstream molecular target that prevents neuronal apoptosis in vitro.

Taken together, these data suggest an apoptotic route in S/K withdrawal in CGNs mediated by calpain activation, cdk5/p25 formation and MEF2 inhibition. Calpain inhibitors may attenuate S/K withdrawal‐induced apoptosis and may provide a potential therapeutic target for drug treatment in a neurodegenerative process.

British Journal of Pharmacology (2005) 145, 1103–1111. doi:10.1038/sj.bjp.0706280
Differing mechanisms of leukocyte recruitment and sensitivity to conditioning by shear stress for endothelial cells treated with tumour necrosis factor‐α or interleukin‐1β
Authors: Sheikh Sajila , Rahman Mahbub , Gale Zoe , Luu N Thin , Stone Philip C W , Matharu Nick M , Rainger G Edward Luu , Nash Gerard B
Published: May 2005

The cytokines tumour necrosis factor‐α (TNFα) and interleukin‐1β (IL‐1B) induce endothelial cells to recruit leukocytes. However, the exact adhesion and activation mechanisms induced by each cytokine, and their relative sensitivities to modulation by endothelial exposure to shear stress remain unclear.

We cultured human umbilical vein endothelial cells (HUVEC) in glass capillaries at various shear stresses, with TNFα or IL‐1B added for the last 4 h. Subsequently, human neutrophils were perfused over the HUVEC, and adhesion and migration were recorded.

Both cytokines induced dose‐dependent capture of neutrophils. However, while conditioning of HUVEC by increasing shear stress for 24 h diminished their response to TNFα, the response of HUVEC to IL‐1B was similar at all shear stresses. The differing sensitivities were evident at levels of adhesive function and mRNA for adhesion molecules and chemokines.

Analysis of nuclear factor κB (NF‐κB)/Rel family of transcription factors showed that their expression and activation were modified by exposure to shear stress, but did not obviously explain differential responses to TNFα and IL‐1B.

Antibodies against selectins were effective against capture of neutrophils on TNFα‐treated but not IL‐1B‐treated HUVEC. Stable adhesion was supported by β2‐integrins in each case. Activation of neutrophils occurred dominantly through CXC‐chemokine receptor 2 (CXCR2) for TNFα‐treated HUVEC, while blockade of CXCR1, CXCR2 and of platelet‐activating factor receptors caused additive inhibition of migration on IL‐1B‐treated HUVEC.

The mechanisms which underlie neutrophil recruitment, and their modulation by the haemodynamic environment, differ between cytokines. Interventions aimed against leukocyte recruitment may not operate equally in different inflammatory milieu.

British Journal of Pharmacology (2005) 145, 1052–1061. doi:10.1038/sj.bjp.0706281
Representation and High‐Quality Annotation of the Physcomitrella patens Transcriptome Demonstrates a High Proportion of Proteins Involved in Metabolism in Mosses
Authors: Lang D. , Eisinger J. , Reski R. , Rensing S. A.
Published: May 2005

Abstract: To gain insight into the transcriptome of the well‐used plant model system Physcomitrella patens, several EST sequencing projects have been undertaken. We have clustered, assembled, and annotated all publicly available EST and CDS sequences in order to represent the transcriptome of this non‐seed plant. Here, we present our fully annotated knowledge resource for the Physcomitrella patens transcriptome, integrating annotation from the production process of the clustered sequences and from a high‐quality annotation pipeline developed during this study. Each transcript is represented as an entity containing full annotations and GO term associations. The whole production, filtering, clustering, and annotation process is being modelled and results in seven datasets, representing the annotated Physcomitrella transcriptome from different perspectives. We were able to annotate 63.4 % of the 26 123 virtual transcripts. The transcript archetype, as covered by our clustered data, is compared to a compilation based on all available Physcomitrella full length CDS. The distribution of the gene ontology annotations (GOA) for the virtual transcriptome of Physcomitrella patens demonstrates consistency in the ratios of the core molecular functions among the plant GOA. However, the metabolism subcategory is over‐represented in bryophytes as compared to seed plants. This observation can be taken as an indicator for the wealth of alternative metabolic pathways in moss in comparison to spermatophytes. All resources presented in this study have been made available to the scientific community through a suite of user‐friendly web interfaces via http:www.cosmoss.org and form the basis for assembly and annotation of the moss genome, which will be sequenced in 2005.
An RNAi System in Physcomitrella patens with an Internal Marker for Silencing Allows for Rapid Identification of Loss of Function Phenotypes
Authors: Bezanilla M. , Perroud P.‐F. , Pan A. , Klueh P. , Quatrano R. S.
Published: May 2005

Abstract: RNAi is a powerful method for generating loss of function mutants, especially for targeting genes belonging to large gene families. We have recently shown that RNAi functions in the moss Physcomitrella patens. We obtained stable lines that show constitutive silencing of a nuclearly localized GFP:GUS fusion protein (NLS:GFP:GUS). However, lines that display silencing of the protein do not necessarily have reduced transcript levels. Therefore, a system has been developed that silences the NLS:GFP:GUS reporter construct at the same time as it silences a gene of interest. Gateway™ (Invitrogen) recombination cassettes were incorporated into these vectors to facilitate cloning of many different cDNA sequences. In addition, vectors were generated that contain genomic moss DNA sequence information to increase the production of stable moss lines. Transformation with these constructs results in strong silencing within 24 h and is stable for at least a month after transformation. FtsZ2‐1, whose loss of function phenotype is known, was incorporated as a test case for analyzing phenotypes. One hundred per cent of regenerating colonies that have silenced GFP exhibit a loss of function FtsZ2‐1 phenotype, validating the use of this system to assay phenotypes for plant genes of unknown function.