bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of emission factors for indirect N2O emission due to nitrogen leaching in agro‐ecosystems
Authors: Sawamoto Takuji , Nakajima Yasuhiro , Kasuya Masahiro , Tsuruta Haruo , Yagi Kazuyuki
Published: February 2005

We reviewed the available data of NO3− and dissolved N2O concentration in leached water in agro‐ecosystems from 11 published papers and four unpublished studies, to reevaluate the IPCC default emission factor (N2O‐N/NO3−‐N) for indirect N2O emission in agro‐ecosystems. The emission factor was estimated to be 0.0024, indicating that the IPCC's present emission factor (0.015) and estimate of indirect N2O emission are too high. Using the estimated value of 0.0024 as the emission factor revises the global indirect N2O emission from N leaching and runoff in agro‐ecosystems downward from 1.6 to 0.80 Tg N y−1 and the sum of direct and indirect global N2O emission due to agriculture from 6.3 to 5.5 Tg N y−1.
Extracting time‐domain Green's function estimates from ambient seismic noise
Authors: Sabra Karim G. , Gerstoft Peter , Roux Philippe , Kuperman W. A. , Fehler Michael C.
Published: February 2005

It has been demonstrated experimentally and theoretically that an estimate of the Green's function between two seismic stations can be obtained from the time‐derivative of the long‐time average cross correlation of ambient noise between these two stations. This TDGF estimate from just the noise field includes all tensor components of the Green's function and these Green's function estimates can be used to infer Earth structure. We have computed cross correlations using 1 to 30 continuous days of ambient noise recorded by over 150 broadband seismic stations located in Southern California. The data processing yielded thousands of cross‐correlation pairs, for receiver separations from 4–500 km, which clearly exhibit coherent broadband propagating dispersive wavetrains across frequency band 0.1–2 Hz.
An emissions‐based view of climate forcing by methane and tropospheric ozone
Authors: Shindell Drew T. , Faluvegi Greg , Bell Nadine , Schmidt Gavin A.
Published: February 2005

We simulate atmospheric composition changes in response to increased methane and tropospheric ozone precursor emissions from the preindustrial to present‐day in a coupled chemistry‐aerosol‐climate model. The global annual average composition response to all emission changes is within 10% of the sum of the responses to individual emissions types, a more policy‐relevant quantity. This small non‐linearity between emission types permits attribution of past global mean methane and ozone radiative forcings to specific emissions despite the well‐known non‐linear response to emissions of a single type. The emissions‐based view indicates that methane emissions have contributed a forcing of ∼0.8–0.9 W m−2, nearly double the abundance‐based value, while the forcing from other ozone precursors has been quite small (∼−0.1 for NOx, ∼0.2 for CO + VOCs).
On the variability of ENSO over the past six centuries
Authors: D'Arrigo Rosanne , Cook Edward R. , Wilson Rob J. , Allan Rob , Mann Michael E.
Published: February 2005

The instrumental record is too brief for evaluation of the El Niño‐Southern Oscillation (ENSO) system and its long‐term response to climate forcing. To supplement these data, we use a new reconstruction of December–February Niño‐3 sea surface temperatures based on subtropical North American tree‐ring records to investigate aspects of ENSO variability over the past six centuries (AD 1408–1978). Spectral analyses reveal that the reconstruction best resolves variability within the “classical” ENSO band of 2–8 years. A low amplitude ENSO epoch in the 17th to 18th centuries broadly coincides with “Little Ice Age” conditions over much of the globe. The detailed behavior shows good agreement with shorter tree‐ring reconstructions of ENSO over the past few centuries, but differs at times from other longer coral ENSO records and recent model simulations of past ENSO behavior. We discuss possible reasons for these discrepancies.
High‐altitude cusp flow dependence on IMF orientation: A 3‐year Cluster statistical study
Authors: Lavraud B. , Fedorov A. , Budnik E. , Thomsen M. F. , Grigoriev A. , Cargill P. J. , Dunlop M. W. , Rème H. , Dandouras I. , Balogh A.
Published: February 2005

We report on the statistical properties of the plasma flows measured by the Cluster spacecraft in the high‐altitude cusp region of the Northern Hemisphere as a function of the interplanetary magnetic field (IMF) orientation, with selected clock angle intervals. The technique uses a magnetic field model, taking into account the actual solar wind conditions and level of geomagnetic activity, in order to model the magnetopause and cusp displacements as a function of these conditions. The distributions of the magnetic field vector show a clear consistency with the IMF clock angle intervals chosen and demonstrate that the technique used here fixes the positions of the cusp boundaries adequately. The antisunward convection observed in the exterior cusp suggests that this region is statistically quite convective under southward IMF, while for northward IMF the region appears more stagnant. The presence of large parallel (downward) flows at the equatorward edge of the cusp shows that plasma penetration occurs preferentially at the dayside low‐latitude magnetopause for southward IMF conditions; in contrast, under northward IMF the results are suggestive of plasma penetration from the poleward edge of the cusp, combined with a substantial sunward convection, but no flows are observed at all at the dayside boundary with the plasma sheet. The comparison of the measured flow speed with the Alfvén speed suggests that the magnetosheath adjacent to the external boundary is more sub‐Alfvénic, even for high magnetic latitudes, under northward IMF than under southward IMF. This result is consistent with the preference for the plasma depletion layer to develop under such conditions. The transverse plasma convection in the exterior cusp appears to be controlled by the IMF BY component as well; for dawnward (duskward) IMF orientations the convection is preferentially directed toward dusk (dawn). These results are interpreted as strong arguments in favor of the cusp being structured, at large scales, by the occurrence of magnetic reconnection at the high‐latitude magnetopause for northward IMF and at the low‐latitude magnetopause for southward IMF.
In situ X‐ray observations of phase assemblages in peridotite and basalt compositions at lower mantle conditions: Implications for density of subducted oceanic plate
Authors: Ono Shigeaki , Ohishi Yasuo , Isshiki Maiko , Watanuki Tetsu
Published: February 2005

Phase relationships in KLB‐1 peridotite, normal‐type mid‐oceanic ridge basalt (NMORB) and K‐rich basalt compositions were investigated experimentally from 28 to 143 GPa and 2050 to 3000 K. A laser‐heated diamond anvil cell with the synchrotron X‐ray diffraction was developed to perform in situ observations of samples at simultaneous high pressures and temperatures. We confirmed that the peridotite composition crystallized into an assemblage of Mg perovskite + Ca perovskite + magnesiowüstite at pressures below 97 GPa and that NMORB and K‐rich basalt compositions both crystallized as Mg perovskite + Ca perovskite + stishovite + an aluminous phase with a CaFe2O4‐type structure at pressures below 68 GPa. The orthorhombic Mg perovskite is stable in natural rock compositions at pressures less than 97 GPa, corresponding to about 2200 km depth. Phase transition of silica phase from stishovite to CaCl2‐type phase was observed at 78 GPa in NMORB composition. Moreover, we observed that NMORB crystallized in to an assemblage of CaIrO3‐type (Mg,Fe)SiO3 + Ca perovskite + α‐PbO2‐type silica + an aluminous phase with a calcium CaTi2O4‐type structure at 143 GPa, corresponding to the core‐mantle boundary depth. We measured the unit cell volumes of minerals in the NMORB composition at high P‐T and thereby estimated the density of subducted MORB to a depth of 1800 km in the lower mantle. In this depth regime, MORB is denser than model mantle densities, e.g., PREM and AK135. The estimated density of MORB may contribute to an understanding of dynamics of the subducted slab in the deep lower mantle.
Reflectivity of the 410‐km discontinuity from PP and SS precursors
Authors: Chambers K. , Deuss A. , Woodhouse J. H.
Published: February 2005

A number of studies have confirmed the global existence of a transition zone discontinuity at 410 km depth by aligning large numbers of long‐period seismograms on a surface reflection phase before stacking. In particular, SS and PP precursors from the 410‐km discontinuity (termed P410P and S410S) have revealed long‐wavelength topography of this discontinuity. Here we extend these techniques to examine the reflection coefficient of the 410‐km discontinuity. Using our measurements of P410P and S410S amplitudes, we constrain the impedance contrasts across the 410‐km discontinuity. We also show lateral variations in the P wave impedance contrast at 410 km, which is typically low under North America and China and higher beneath the North Pacific. The S wave impedance contrast shows less variability on the regional scale. However, analysis of P410P and S410S amplitudes over smaller areas (by binning traces into spherical caps) shows that the S wave reflection coefficient varies over much shorter scale lengths than that for P waves. The different patterns of variation for P410P and S410S reflection amplitudes could be due to the presence of melt, water, or other chemical heterogeneities in the transition zone. Other factors such as temperature or mantle olivine content variations could also influence precursor amplitudes, but they would be expected to lead to correlated variations, and so they cannot explain all the variation that we observe.
Formation of a tropopause cirrus layer observed over Florida during CRYSTAL‐FACE
Authors: Jensen Eric , Pfister Leonhard , Bui Thaopaul , Weinheimer Andrew , Weinstock Elliot , Smith Jessica , Pittman Jasna , Baumgardner Darrel , Lawson Paul , McGill Mathew J.
Published: February 2005

On 13 July 2002 a widespread, subvisible tropopause cirrus layer occurred over the Florida region. This cloud was observed in great detail with the NASA Cirrus Regional Study of Tropical Anvils and Cirrus Layers–Florida Area Cirrus Experiment (CRYSTAL‐FACE) instrumentation, including in situ measurements with the WB‐57 aircraft. In this paper, we use the 13 July cloud as a case study to evaluate the physical processes controlling the formation and evolution of tropopause cirrus layers. Microphysics measurements indicate that ice crystal diameters in the cloud layer ranged from about 7 to 50 μm, and the peak number mode was about 10–25 μm. In situ water vapor and temperature measurements in the cloud indicated supersaturation with respect to ice throughout, with ice saturation ratios as large as 1.8. Even when the ice surface area density was as high as about 500 μm2 cm−3, ice supersaturations of 20–30% were observed. Trajectory analysis shows that the air sampled near the tropopause on this day generally came from the north and cooled considerably during the previous few days. Examination of infrared satellite imagery along air parcel back trajectories from the WB‐57 flight track indicates that the tropopause cloud layer formation was, in general, not simply left over ice from recently generated anvil cirrus. Simulations of cloud formation using time‐height curtains of temperature along the trajectory paths show that the cloud could have formed in situ near the tropopause as the air was advected into the south Florida region and cooled to unusually low temperatures. If we assume a high threshold for ice nucleation via homogeneous freezing of aqueous sulfate aerosols, the model reproduces the observed cloud structure, ice crystal size distributions, and ice supersaturation statistics. Inclusion of observed gravity wave temperature perturbations in the simulations is essential to reproduce the observed cloud properties. Without waves, crystal number densities are too low, crystal sizes are too large, and the crystals fall out too fast, leaving very little cloud persisting at the end of the simulations. In the cloud simulations, coincidence of high supersaturations and high surface areas can be produced by either recent nucleation or sedimentation of crystals into supersaturated layers. The agreement between model results and observed supersaturations is improved somewhat if we assume that the steady state relative humidity within cirrus at T < 200 K is enhanced by about 30%. The WB‐57 measurements and the model results suggest that the cloud layer irreversibly dehydrated air near the tropopause.
Water vapor heterogeneity related to tropopause folds over the North Atlantic revealed by airborne water vapor differential absorption lidar
Authors: Flentje H. , Dörnbrack A. , Ehret G. , Fix A. , Kiemle C. , Poberaj G. , Wirth M.
Published: February 2005

Airborne differential absorption lidar (DIAL) measurements of tropospheric water vapor and aerosol/clouds are presented from transfers across the North Atlantic on 13–15 May and 16–18 June 2002. The intense dynamical activity over the Atlantic is reflected in complex structures like deep tropopause folds, extended dry layers, and tilted aerosol filaments. Intrusions with H2O mixing ratios below 0.03 g kg−1 regularly develop along the storm track over intense cyclones and correspond to analyzed (European Centre for Medium‐Range Weather Forecasts (ECMWF)) or simulated (MM5) potential vorticity anomalies. Sloping folds are typically 1 km thick in vertical profiles but on horizontal sections resemble long filaments with widths of a few hundred kilometers. Filaments of solid, roughly micron‐sized particles occur inside and along the axes of the tropopause folds. The particles most likely originate in forest fires, from where they are injected to the lower stratosphere by deep convection and later on reenter the troposphere in developing baroclinic disturbances. Their laminar appearance indicates that these intrusions have not yet been mixed but are eroded on timescales significantly larger than a few days by stretching‐thinning, stirring, and only finally, turbulent diffusion. MM5 mesoscale model simulations and, with less accuracy, also ECMWF analyses are capable of reproducing the dynamical structures associated with the observed dry intrusions. However, deep inside the intrusions where scales are small, even the MM5‐simulated water vapor mixing ratios are more than twice those observed. The large dynamical range of water vapor mixing ratios (3 orders of magnitude) and large gradients (>2 g kg−1 km−1 at the intrusions' boundaries) constitute a challenge for future space‐borne water vapor DIAL systems.
Intercomparison of general purpose clear sky atmospheric radiative transfer models for the millimeter/submillimeter spectral range
Authors: Melsheimer C. , Verdes C. , Buehler S. A. , Emde C. , Eriksson P. , Feist D. G. , Ichizawa S. , John V. O. , Kasai Y. , Kopp G. , Koulev N. , Kuhn T. , Lemke O. , Ochiai S. , Schreier F. , Sreerekha T. R. , Suzuki M. , Takahashi C. , Tsujimaru S. , Urban J.
Published: February 2005

We compare a number of radiative transfer models for atmospheric sounding in the millimeter and submillimeter wavelength range, check their consistency, and investigate their deviations from each other. This intercomparison deals with three different aspects of radiative transfer models: (1) the inherent physics of gaseous absorption lines and how they are modeled, (2) the calculation of absorption coefficients, and (3) the full calculation of radiative transfer for different geometries, i.e., up‐looking, down‐looking, and limb‐looking. The correctness and consistency of the implementations are tested by comparing calculations with predefined input such as spectroscopic data, line shape, continuum absorption model, and frequency grid. The absorption coefficients and brightness temperatures calculated by the different models are generally within about 1% of each other. Furthermore, the variability or uncertainty of the model results is estimated if (except for the atmospheric scenario) the input such as spectroscopic data, line shape, and continuum absorption model could be chosen freely. Here the models deviate from each other by about 10% around the center of major absorption lines. The main cause of such discrepancies is the variability of reported spectroscopic data for line absorption and of the continuum absorption model. Further possible causes of discrepancies are different frequency and pressure grids and differences in the corresponding interpolation routines, as well as differences in the line shape functions used, namely a prefactor of (ν/ν0) or (ν/ν0)2 of the Van‐Vleck‐Weisskopf line shape function. Whether or not the discrepancies affect retrieval results remains to be investigated for each application individually.
Assessing water company customer preferences and willingness to pay for service improvements: A stated choice analysis
Authors: Willis Kenneth G. , Scarpa Riccardo , Acutt Melinda
Published: February 2005

Water and sewerage companies are regional monopolies in the UK. A government agency regulates these companies, setting standards on quality of service to customers, and every 5 years sets prices that companies can charge customers over the ensuing quinquennium. We use a stated choice experiment model to estimate benefits to water company customers of changes across 14 water service factors. The estimated values were quite similar for each service factor across models (conditional logit (CL), CL quadratic, nested logit (NL), or NL quadratic). Estimates of the cost of infrastructure maintenance and improvement with risk of asset failure, along with CL benefit estimates, permit economic optimization across the water company's whole investment program.
GABAB receptor modulators potentiate baclofen‐induced depression of dopamine neuron activity in the rat ventral tegmental area
Authors: Chen Ying , Phillips Keith , Minton Gareth , Sher Emanuele
Published: February 2005

2,6‐Di‐tert‐butyl‐4‐(3‐hydroxy‐2,2‐dimethyl‐propyl)‐phenol (CGP7930) is a recently reported positive allosteric modulator of γ‐aminobutyric acid (GABA)B receptors. In this study, we assessed the ability of CGP7930 to modulate the baclofen‐induced depression of dopamine (DA) neuron activity via the activation of GABAB receptors in the ventral tegmental area in rat midbrain slices.

The selective GABAB receptor agonist, baclofen, depressed the spontaneous firing rate of DA neurons in a concentration‐dependent manner (EC50=0.27 μM, n=11). CGP7930 (30 μM) significantly (P<0.05) shifted the baclofen concentration–response curve to the left (EC50=0.15 μM, n=5). The effects of baclofen alone or baclofen coapplied with CGP7930 were fully blocked by 1 μM (2S)‐3‐[[(1S)‐1‐(3,4‐dichloropheny)ethyl]amino‐2‐hydroxypropyl] (phenylmethyl) phosphinic acid (CGP55845), a potent and selective GABAB receptor antagonist.

In similar experiments, N‐[3,3‐diphenylpropyl]‐α‐methylbenzylamine (fendiline) (30 or 50 μM), a compound shown to potentiate GABAB receptor‐mediated cortical hyperpolarisation, also significantly enhanced the inhibitory effect of baclofen.

It is therefore concluded that the recently reported GABAB receptor modulators, CGP7930 and fendiline, can enhance GABAB receptor‐mediated depression of DA neuronal activity. This finding suggests a therapeutic potential for GABAB potentiators for the treatment of diseases associated with a hyperfunctional mesocorticolimbic system.

British Journal of Pharmacology (2005) 144, 926–932. doi:10.1038/sj.bjp.0706100
High doses of simvastatin upregulate dopamine D1 and D2 receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase
Authors: Wang Qing , Ting Wee Lee , Yang Hongyuan , Wong Peter T‐H
Published: February 2005

This study aims to investigate whether or not long‐term statin treatment causes upregulation of D1 and D2 receptor gene expression with concomitant increase in endothelial nitric oxide synthase (eNOS) expression in Sprague–Dawley rats.

Serum triglyceride levels were dose dependently reduced in the simvastatin‐treated rats reaching statistical significance at the highest dose (49% reduction), while pravastatin caused similar effects (52%) at the same dose. Cholesterol levels remained unchanged in both groups at all doses.

Simvastatin, 10 or 30 mg kg−1 day−1, increased D1 and D2 receptor expressions in the prefrontal cortex. Similar upregulation was observed neither with simvastatin in the striatum nor with pravastatin in both brain regions.

Simvastatin (10 mg kg−1 day−1) also increased eNOS expression in the prefrontal cortex but not neuronal NOS or inducible NOS.

D1 receptor activation by chloro‐APB (5 μM) increased cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin‐treated rats by 88 and 285%, respectively. This effect was markedly attenuated by the selective D1 antagonist SCH‐23390 (25 μM).

D2 receptor activation by quinpirole (5 μM) had no effect on the basal cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin‐treated rats, while the same concentration of quinpirole completely abolished the D1 receptor‐mediated increase.

These results suggest that lipophilic statins can alter dopaminergic functions in the prefrontal cortex possibly via a central mechanism. The possibility of a nitric oxide mechanism involving eNOS requires further investigation.

British Journal of Pharmacology (2005) 144, 933–939. doi:10.1038/sj.bjp.0706106
Neuritic regeneration and synaptic reconstruction induced by withanolide A
Authors: Kuboyama Tomoharu , Tohda Chihiro , Komatsu Katsuko
Published: February 2005

We investigated whether withanolide A (WL‐A), isolated from the Indian herbal drug Ashwagandha (root of Withania somnifera), could regenerate neurites and reconstruct synapses in severely damaged neurons. We also investigated the effect of WL‐A on memory‐deficient mice showing neuronal atrophy and synaptic loss in the brain. Axons, dendrites, presynapses, and postsynapses were visualized by immunostaining for phosphorylated neurofilament‐H (NF‐H), microtubule‐associated protein 2 (MAP2), synaptophysin, and postsynaptic density‐95 (PSD‐95), respectively.

Treatment with Aβ(25–35) (10 μM) induced axonal and dendritic atrophy, and pre‐ and postsynaptic loss in cultured rat cortical neurons. Subsequent treatment with WL‐A (1 μM) induced significant regeneration of both axons and dendrites, in addition to the reconstruction of pre‐ and postsynapses in the neurons.

WL‐A (10 μmol kg−1 day−1, for 13 days, p.o.) recovered Aβ(25–35)‐induced memory deficit in mice. At that time, the decline of axons, dendrites, and synapses in the cerebral cortex and hippocampus was almost recovered.

WL‐A is therefore an important candidate for the therapeutic treatment of neurodegenerative diseases, as it is able to reconstruct neuronal networks.

British Journal of Pharmacology (2005) 144, 961–971. doi:10.1038/sj.bjp.0706122
The immunosuppressive drugs cyclosporin A and tacrolimus inhibit membrane depolarization‐induced CREB transcriptional activity at the coactivator level
Authors: Oetjen Elke , Thoms Kai‐Martin , Laufer Yvonne , Pape Daniela , Blume Roland , Li Pingfeng , Knepel Willhart
Published: February 2005

Cyclosporin A and tacrolimus are clinically important immunosuppressive drugs directly targeting the transcription factor nuclear factor of activated T cells (NFAT). Through inhibition of calcineurin phosphatase activity they block the dephosphorylation and thus activation of NFAT. Cyclosporin A and tacrolimus also inhibit other calcineurin‐dependent transcription factors including the ubiquitously expressed cAMP response element‐binding protein (CREB). Membrane depolarization by phosphorylating CREB on Ser119 leads to the recruitment of its coactivator CREB‐binding protein (CBP) that stimulates initiation of transcription.

It was unknown at what step in CREB‐mediated transcription cyclosporin A and tacrolimus interfere.

In transient transfection experiments, using GAL4‐CREB fusion proteins and a pancreatic islet β‐cell line, cyclosporin A inhibited depolarization‐induced activation of CREB proteins which carried various deletions or mutations throughout their sequence providing no evidence for the existence of a distinct CREB domain conferring cyclosporin A sensitivity. In a mammalian two‐hybrid assay, cyclosporin A did not inhibit Ser119‐dependent interaction of CREB with its coactivator CBP.

Using GAL4‐CBP fusion proteins, cyclosporin A inhibited depolarization‐induced CBP activity, with cyclosporin A‐sensitive domains mapped to both the N‐ (aa 1–451) and C‐terminal (aa 2040–2305) ends of CBP. The depolarization‐induced transcriptional activity of the CBP C‐terminus was enhanced by overexpression of calcineurin and was inhibited by cyclosporin A and tacrolimus in a concentration‐dependent manner with IC50 values (10 and 1 nM, respectively) consistent with their known IC50 values for inhibition of calcineurin.

These data suggest that, in contrast to NFAT, cyclosporin A and tacrolimus inhibit CREB transcriptional activity at the coactivator level.

British Journal of Pharmacology (2005) 144, 982–993. doi:10.1038/sj.bjp.0706127
Antisecretory actions of a novel vasoactive intestinal polypeptide (VIP) antagonist in human and rat small intestine
Authors: Banks Matthew R , Farthing Michael J G , Robberecht Patrick , Burleigh David E
Published: February 2005

Vasoactive intestinal peptide (VIP) has been demonstrated in intestinal mucosal neurones and elicits chloride secretion from enterocytes. These findings have led to the proposal that VIP is a secretomotor neurotransmitter. Confirmation of such a role may now be possible with the development of PG 97–269, a high‐affinity, selective antagonist of VIP type 1 (VPAC1) receptor, which is expressed by gut epithelial cells. We have evaluated the VIP antagonism and antisecretory potential of this novel compound using in vitro and in vivo models of intestinal secretion.

Monolayers of the human colonic cell line (T84) and muscle‐stripped preparations of rat jejunum and human ileum were set up in Ussing chambers for recording of transepithelial resistance and short‐circuit current. Ussing chambers were modified to allow electrical stimulation of mucosal neurones. Effects of PG 97–269 on enterotoxin‐induced secretion were investigated in perfused rat jejunum in vivo.

PG 97–269 competitively antagonised VIP in T84 monolayers. In rat jejunum and human ileum, responses to VIP were inhibited as were responses of rat jejunum to electrical stimulation of mucosal neurons.

In perfused rat jejunum, PG 97–269 abolished the effects of VIP on fluid and electrolyte transport and attenuated cholera toxin and Escherichia coli heat labile toxin‐induced net fluid and electrolyte secretion.

PG 97–269 is a competitive antagonist of enterocyte VIP receptors and effectively inhibits responses of rat and human intestinal mucosa to VIP. Antagonism of secretory responses to electrical stimulation of mucosal neurons and lumenal application of enterotoxins imply a secretory role for VIP in these processes.

British Journal of Pharmacology (2005) 144, 994–1001. doi:10.1038/sj.bjp.0706128
Pentamidine reduces hERG expression to prolong the QT interval
Authors: Cordes Jason S , Sun Zhuoqian , Lloyd David B , Bradley Jenifer A , Opsahl Alan C , Tengowski Mark W , Chen Xian , Zhou Jun
Published: February 2005

Pentamidine, an antiprotozoal agent, has been traditionally known to cause QT prolongation and arrhythmias; however, its ionic mechanism has not been illustrated.

In a stable HEK‐293 cell line, we observed a concentration‐dependent inhibition of the hERG current with an IC50 of 252 μM.

In freshly isolated guinea‐pig ventricular myocytes, pentamidine showed no effect on the L‐type calcium current at concentrations up to 300 μM, with a slight prolongation of the action potential duration at this concentration.

Since the effective concentrations of pentamidine on the hERG channel and APD were much higher than clinically relevant exposures (∼1 μM free or lower), we speculated that this drug might not prolong the QT interval through direct inhibition of IKr channel. We therefore incubated hERG‐HEK cells in 1 and 10 μM pentamidine‐containing media (supplemented with 10% serum) for 48 h, and examined the hERG current densities in the vehicle control and pentamidine‐treated cells.

In all, 36 and 85% reductions of the current densities were caused by 1‐ and 10‐μM pentamidine treatment (P<0.001 vs control), respectively. A similar level of reduction of the hERG polypeptides and a reduced intensity of the hERG protein on the surface membrane in treated cells were observed by Western blot analysis and laser‐scanning confocal microscopy, respectively.

Taken together, our data imply that chronic administration of pentamidine at clinically relevant exposure reduces the membrane expression of the hERG channel, which may most likely be the major mechanism of QT prolongation and torsade de pointes reported in man.

British Journal of Pharmacology (2005) 145, 15–23. doi:10.1038/sj.bjp.0706140
The mutation Y1206S increases the affinity of the sulphonylurea receptor SUR2A for glibenclamide and enhances the effects of coexpression with Kir6.2
Authors: Stephan Damian , Stauß Eva , Lange Ulf , Felsch Holger , Löffler‐Walz Cornelia , Hambrock Annette , Russ Ulrich , Quast Ulrich
Published: February 2005

ATP‐sensitive K+ channels (KATP channels) are tetradimeric complexes of inwardly rectifying K+ channels (Kir6.x) and sulphonylurea receptors (SURs). The SURs SUR2A (cardiac) and SUR2B (smooth muscle) differ only in the last 42 amino acids. In SUR2B, the mutation Y1206S, located at intracellular loop 8, increases the affinity for glibenclamide (GBC) about 10‐fold. Here, we examined whether the mutation Y1206S in SUR2A had effects similar to those in SUR2B.

GBC bound to SUR2A with KD=20 nM; the mutation increased affinity ∼5 ×.

In cells, coexpression of SUR2A with Kir6.2 increased the affinity for GBC∼3 ×; with the mutant, the increase was 9 ×.

The mutation did not affect the affinity of SUR2A for openers; coexpression with Kir6.2 reduced opener affinity of wild‐type and mutant SUR2A by about 2 ×.

The negative allosteric interaction between the opener, P1075, and GBC at wild‐type and mutant SUR2A was markedly affected by the presence of MgATP and by coexpression with Kir6.2.

In inside‐out patches, GBC inhibited the wild‐type Kir6.2/SUR2A and 2B channels with IC50 values of 27 nM; the mutation shifted the IC50 values to ∼1 nM.

The data show that the mutation Y1206S increased the affinity of SUR2A for GBC and modulated the effects of coexpression. Overall, the changes were similar to those observed with SUR2B(Y1206S), suggesting that the differences in the last 42 carboxy‐terminal amino acids of SUR2A and 2B are of limited influence on the binding of GBC and P1075 to the SUR2 isoforms.

British Journal of Pharmacology (2005) 144, 1078–1088. doi:10.1038/sj.bjp.0706142
Protein trafficking abnormalities: a new mechanism in drug‐induced long QT syndrome
Authors: Eckhardt Lee L , Rajamani Sridharan , January Craig T
Published: February 2005

Drug induced long QT syndrome (LQTS) can lead to cardiac arrhythmias and sudden death, and has emerged as a worldwide problem. Most drugs that cause this are thought to directly block a specific cardiac ion channel (KCNH2 or hERG) that carries the rapidly activating delayed rectifier potassium current, IKr. In this issue of the British Journal of Pharmacology, evidence is presented to support a new mechanism for causing drug induced LQTS. The drug pentamidine, at near therapeutic concentrations that do not cause direct KCNH2 channel block, disrupts normal KCNH2 channel protein processing and maturation to reduce its surface membrane expression. This indirect mechanism for reducing IKr is novel, and whether other drugs may cause similar protein trafficking abnormalities is largely unknown.

British Journal of Pharmacology (2005) 145, 3–4. doi:10.1038/sj.bjp.0706143
Hepatic pharmacokinetics of taurocholate in the normal and cholestatic rat liver
Authors: Hung Daniel Y , Siebert Gerhard A , Chang Ping , Roberts Michael S
Published: February 2005

The disposition kinetics of [3H]taurocholate ([3H]TC) in perfused normal and cholestatic rat livers were studied using the multiple indicator dilution technique and several physiologically based pharmacokinetic models.

The serum biochemistry levels, the outflow profiles and biliary recovery of [3H]TC were measured in three experimental groups: (i) control; (ii) 17α‐ethynylestradiol (EE)‐treated (low dose); and (iii) EE‐treated (high dose) rats. EE treatment caused cholestasis in a dose‐dependent manner.

A hepatobiliary TC transport model, which recognizes capillary mixing, active cellular uptake, and active efflux into bile and plasma described the disposition of [3H]TC in the normal and cholestatic livers better than the other pharmacokinetic models.

An estimated five‐ and 18‐fold decrease in biliary elimination rate constant, 1.7‐ and 2.7‐fold increase in hepatocyte to plasma efflux rate constant, and 1.8‐ and 2.8‐fold decrease in [3H]TC biliary recovery ratio was found in moderate and severe cholestasis, respectively, relative to normal.

There were good correlations between the predicted and observed pharmacokinetic parameters of [3H]TC based on liver pathophysiology (e.g. serum bilirubin level and biliary excretion of [3H]TC). In conclusion, these results show that altered hepatic TC pharmacokinetics in cholestatic rat livers can be correlated with the relevant changes in liver pathophysiology in cholestasis.

British Journal of Pharmacology (2005) 145, 57–65. doi:10.1038/sj.bjp.0706148
Noradrenaline and extracellular nucleotide cotransmission involves activation of vasoconstrictive P2X1,3‐ and P2Y6‐like receptors in mouse perfused kidney
Authors: Vonend Oliver , Stegbauer Johannes , Sojka Johann , Habbel Sina , Quack Ivo , Robaye Bernard , Boeynaems Jean‐Marie , Rump Lars Christian
Published: February 2005

Nucleotides like ATP and UTP act as potent extracellular signalling molecules. Released from sympathetic nerve endings as cotransmitters of noradrenaline or paracrine from nonexcitatory cells, they activate specific receptors (ion‐gated P2X1–7 and G‐protein‐coupled P2Y1,2,4,6,11–15). Which of these subtypes, however, are able to modulate vasoconstriction in the kidney is unclear.

Wild‐type‐ and P2Y4‐receptor‐deficient mice kidneys were isolated and perfused with Krebs–Henseleit solution. Pressor responses to renal nerve stimulations (RNS) and added drugs were recorded. Release of endogenous noradrenaline was measured by HPLC.

RNS (1–15 Hz) induced a frequency‐dependent increase in the perfusion pressor (14.2±5.1–67.3±6.9 mmHg) and noradrenaline release (1.4±0.3–24.2±3.4 ng g−1 kidney).

Pressor responses to RNS were not (1–2 Hz) or only partially (5–15 Hz) blocked by the α‐adrenoceptor antagonist phentolamine (1 μM). Combination of phentolamine and the P2‐receptor blocker PPADS (5 μM) prevented RNS‐induced pressor responses. The P2X1,3‐receptor selective antagonist NF279 (10 μM) reduced RNS‐induced pressor responses in a frequency‐dependent manner.

Perfusion of ATP, ADP, UTP, UDP and α,β‐meATP concentration dependently increased perfusion pressor with the following rank order of potency α,β‐meATP>ADP≈ATP≈UDPUTP. NF279 (10 μM) reduced α,β‐meATP‐ (0.1 μM) (21.7±3.9% of control) but not UTP‐ (0.3 μM) (102.6±15.3% of control) induced pressor responses. No differences in nucleotide‐induced effects were detected among wild‐type and P2Y4‐receptor knockout mice.

Continuous perfusion of α,β‐meATP (0.01 μM) potentiated UTP‐, UDP‐ and ATP‐γS‐induced pressor responses.

Neuronally and paracrine‐released nucleotides evoked renal vasoconstriction by activation of P2X1,3‐ and P2Y6‐like receptors in mice. Pretreatment with the P2X1,3‐receptor agonist α,β‐meATP potentiated P2Y6‐like receptor‐mediated vasoconstrictions.

British Journal of Pharmacology (2005) 145, 66–74. doi:10.1038/sj.bjp.0706151
New anticoagulants: beyond heparin, low‐molecular‐weight heparin and warfarin
Authors: Bates Shannon M , Weitz Jeffrey I
Published: February 2005

The limitations of traditional anticoagulants, heparin and warfarin, have prompted the development of new anticoagulant drugs for prevention and treatment of both venous and arterial thromboembolism. After a brief review of thrombogenesis and its regulation, this paper focuses on new anticoagulant agents in more advanced stages of clinical testing.

British Journal of Pharmacology (2005) 144, 1017–1028. doi:10.1038/sj.bjp.0706153
Cyclic GMP, sodium nitroprusside and sodium azide reduce aqueous humour formation in the isolated arterially perfused pig eye
Authors: Shahidullah Mohammad , Yap Maurice , To Chi‐ho
Published: February 2005

The effect of nitric oxide (NO) on aqueous humour formation (AHF) and intraocular pressure (IOP) was studied using NO donors, sodium azide (AZ) and sodium nitroprusside (SNP).

Using the porcine arterially perfused eye preparation, drug effects on AHF and IOP were measured by fluorescein dilution and manometry, respectively. Perfusion pressure of the ocular vasculature was also monitored using digital pressure transducer and pen recorder.

L‐Arginine (1.0 mM), a precursor of NO, but not D‐arginine (1.0 mM), the inactive analogue, produced a significant reduction in AHF (28.5%) and IOP (21.1%). L‐NAME (L‐nitro‐L‐arginine) (10–100 μM), an NO synthase inhibitor, had no effect on AHF and IOP. However, L‐NAME (100 μM) completely reversed L‐arginine's effect.

AZ and SNP reduced the AHF and IOP dose‐dependently. AZ at 100 nM, 1 and 10 μM reduced AHF by 26.0, 39.7 and 51.7% and IOP by 10.8, 17.3 and 24.0%, respectively. SNP at 1, 10 and 100 μM reduced the AHF by 6.0, 24.2 and 35.4% and IOP by 3.5, 9.5 and 15.5%, respectively. 8‐pCPT‐cGMP (8‐para‐chlorophenyl‐thioguanosine‐3′,5′‐cyclic guanosine monophosphate, 10 μM), a cGMP analogue, also reduced the AHF (34.9%) and IOP (15.9%).

The effects of AZ and SNP on the AHF and IOP were blocked by a soluble guanylate cyclase inhibitor ODQ (10 μM), whereas ODQ alone or combined with 8‐pCPT‐cGMP had no effect on the AHF and IOP.

None of the drugs had any significant effect on ocular vasculature.

The reduction of the AHF and IOP in the arterially perfused pig eye by nitrovasodilators is likely to involve the NO‐cGMP pathway.

British Journal of Pharmacology (2005) 145, 84–92. doi:10.1038/sj.bjp.0706156
The Brownian Motion of the Resonance Radiometer
Authors: Van Lear G. A.
Published: February 2005

A completely analytical treatment is given of the effect of Brownian motion on the useful sensitivity of the resonance radiometer; the assumption of particular values for the constants is not necessary, as heretofore. Care is taken that the assumption regarding what is to be considered a detectable e.m.f. shall be equivalent to the corresponding assumption for the critically-damped galvanometer. On this basis it is found that a resonance radiometer with the same resistance and time of observation as a given critically-damped galvanometer would be limited by its Brownian motion to the measurement of e.m.f.'s approximately three times as large as for the latter, but attention is called to the much greater suitability of the resonance radiometer for operation with a long time of observation and correspondingly greater sensitivity. The treatment is further generalized to include the case of differently-damped galvanometers, and it is found that no advantage is to be gained (from the Brownian-motion standpoint) by departing from the original conditions of equal damping. The same analysis permits of the calculation of the Brownian-motion limitation for the usual arrangement of two critically-damped galvanometers coupled by a Moll thermorelay; the result is the same as that already given by Ising for one galvanometer alone. A proof of the fact that the magnetic coupling does not affect the mean-square Brownian-motion deflection of a galvanometer coil is also indicated; this proof is independent of the damping conditions.
A Direct-Current Amplifier with Good Operating Characteristics
Authors: Taylor A. H. , Kerr George P.
Published: February 2005

Characteristic curves for various types of radiotrons are presented, together with a discussion of some of the characteristics desired. A portable amplifier is described, and it shows that proper utilization of these characteristics has resulted in an amplifier practically free from the effects of A and B-battery drifts. It was found that when it was used to amplify the current from a cadmium photocell, to measure ultraviolet radiation, its calibration was reproducible from day to day with an average deviation of less than 0.8 percent.
A New Wave-Length Comparator
Authors: Glockler George , Fullerton F. W.
Published: February 2005

A wave-length comparator has been constructed, in which the microscope moves along the direction of the measuring screw and the platform carrying the photographic plate has an independent motion at right angles to the direction of the screw. A split nut which is part of the microscope carriage permits release from the screw and a quick motion of the microscope from one end of the photographic plate to the other.
An Improved d.c. Amplifying Circuit
Authors: DuBridge Lee A. , Brown Hart
Published: February 2005

The sensitivity of d.c. amplifying circuits with FP-54 tubes is limited by the stability which can be obtained. In single-tube circuits it is necessary to balance out fluctuations caused by changes in battery e.m.f. and in filament emission. Soller's circuit for balancing out e.m.f. changes has been studied in detail and a modified circuit has been developed in which the adjustments are less critical and which allows balancing out of changes in filament emission also. The latter is accomplished by balancing the plate current against the current to the space-charge grid. Details of construction and manipulation of the new circuit are given, as well as data on its stability.
A New Radiofrequency Phase Meter
Authors: Law R. R.
Published: February 2005

A new type radiofrequency phase meter, wherein the original voltages to be studied are heterodyned to convenient audiofrequencies for phase measurement, is described. By heterodyning both above and below the frequencies of the voltages being tested, the effects of undesired phase shifts within the apparatus are eliminated. Circuit constants which have given satisfactory results in practice are included. Accuracies of one-tenth degree on angles up to ten degrees are readily attained at frequencies of 106 cycles per second.
An Electrostatic Generating Voltmeter
Authors: Harnwell G. P. , Van Voorhis S. N.
Published: February 2005

An electrostatic generating voltmeter is described which has a strictly linear scale, which has no commutators, and whose calibration is substantially independent of the speed of the driving motor and of the characteristics of the associated vacuum tube amplifier. A means of calibration by use of a wire grid in front of the voltmeter is also described.
A New Form of a Dew-Point Hygrometer
Authors: Williams S. R.
Published: February 2005

Because of difficulties in securing consistent results with the Alluard form of dew-point hygrometer, a new form has been suggested. The important features of the new form are the small heat capacity of the dew forming surface, a polished concave surface in which the spot of dew forms and the application of a thermocouple to the measurement of the temperature at which the dew forms.
A Wide Angle Magnetic Spectrometer
Authors: Bock Charles D.
Published: February 2005

It is pointed out that in certain problems advantages in current intensity would be gained by having a magnetic spectrometer which would focus widely divergent ions. The usual semicircular type of spectrometer brings divergent rays to a first order focus. By making the proper variation in the intensity of the deflecting magnetic field one can obtain a second order focus. An integral equation is developed to determine the required variation of the magnetic field and a simple method of obtaining the field is given. An instrument now in use for the study of aged ions in gases is briefly described.
An Inherent Limitation of Soller (Multiple) Slits
Authors: White T. N.
Published: February 2005

The characteristic x-radiation reflected from a crystal may at certain deviations from the Bragg angle be partly obstructed by the separating strips of the multiple slits, resulting in minima which give a single spectral line the appearance of a multiplet. Geometrical analysis and experimental proof are given.
A Light Beam of Uniform Intensity of Cross Section
Authors: Lay J. Tracy , Cornog I. Clyde
Published: February 2005

The article deals with a photoelectric method of measuring the intensity of a beam of light at any point of its cross-sectional area. The application of this method led to the production of a light beam the intensity of which over an area 30 cm×30 cm varied by less than one-third percent.
A Supersonic Interferometer for the Study of the Pressure Coefficient of Velocity
Authors: Swanson J. Chester
Published: February 2005

The fundamental principles of the interferometer, particularly the liquid supersonic interferometer of Hubbard and Loomis, are incorporated in an instrument in which the liquid under examination may be put under pressures up to about 10,000 lb./sq. in. The instrument and the pressure device are built into a block of special cast steel 8×5×4½ inches. The results given are preliminary and merely show the performance and precision of the instrument. A curve is given showing the change of velocity of a high frequency acoustic wave of 195 kc from 1143 meters per second at atmospheric pressure to 1233 meters per second at a pressure of 3105 lb./sq. in. in carbon disulphide at room temperature. (The room temperature varied at different readings from 22.25°C to 25.41°C.)
The ``Spread'' as a Measure of Deviation in Physical Measurements
Authors: Adams Elliot Q.
Published: February 2005

To compare results of incandescent lamp tests expressed in terms of the spread (maximum difference) observed in sets of various numbers of lamps, factors were required to convert these results to a comparable basis. The average deviation of a single observation was chosen as the basis of comparison. To avoid the necessity of computing the probable error, a table of the probability integral for the argument τ = π½t is given. Assuming a Gaussian distribution of errors, the factors have been tabulated for numbers of observations up to 100,000. They are given approximately by the semi-empirical formulas: spread/ave. deviation=f(n)=2π12ta≐(50296−20086/(0045+lg n))(lg n)12≐507 (lg n)12−1075. While the average deviation so computed is less precise than that computed from the sum of the residuals, or a fortiori of their squares, the difference seldom exceeds the uncertainty of the more refined measures. Conventions are suggested for the retention of figures and for the statement of measures of deviation. The labor of computing the average deviation from the spread is so slight that an expression of the internal consistency of all results of physical measurements may reasonably be required.
A Ring-Target X-Ray Generator Adapted to Scattering, Fluorescence and Irradiation Experiments
Authors: Kirkpatrick Paul , Ross P. A.
Published: February 2005

An x-ray generator is described which is especially adapted to the production of strong scattered and fluorescent x-rays. Geometrical conditions are well suited to the study of spectra of scattered radiation. The essential novelty of the apparatus is a ring-shaped target 3 inches in diameter. Sample spectra are presented.
Air Ionization Chamber for Measuring Low Voltage X-Ray Intensities in Roentgens
Authors: Uber Fred M.
Published: February 2005

A detailed structural design of a parallel plate ionization chamber for measuring low voltage x-ray intensities in roentgens is described. Intended for use in dosage-meters where stability and simplicity are important factors, it permits the entire apparatus to be housed in a single cabinet without external accessories. Air absorption corrections are made directly and conveniently.