bluuebunny/crossref_metadata_2025 huggingface dataset:
A simplified physical model for assessing solar radiation over Brazil using GOES 8 visible imagery
Authors: Ceballos Juan Carlos , Bottino Marcus Jorge , de Souza Jaidete Monteiro
Published: January 2004

Solar radiation assessment by satellite is constrained by physical limitations of imagery and by the accuracy of instantaneous local atmospheric parameters, suggesting that one should use simplified but physically consistent models for operational work. Such a model is presented for use with GOES 8 imagery applied to atmospheres with low aerosol optical depth. Fundamental satellite‐derived parameters are reflectance and cloud cover. A classification method applied to a set of images shows that reflectance, usually defined as upper‐threshold Rmax in algorithms assessing cloud cover, would amount ∼0.465, corresponding to the transition between a cumuliform and a stratiform cloud field. Ozone absorption is limited to the stratosphere. The model considers two spectral broadband intervals for tropospheric radiative transfer: ultraviolet and visible intervals are essentially nonabsorbing and can be processed as a single interval, while near‐infrared intervals have negligible atmospheric scattering and very low cloud transmittance. Typical values of CO2 and O3 content and of precipitable water are considered. A comparison of daily values of modeled mean irradiance with data of three sites (in rural, urban industrial, and urban coastal environments), September–October 2002, exhibits a bias of +5 W m−2 and a standard deviation of ∼15 W m−2 (0.4 and 1.3 MJ m−2 for daily irradiation). A comparison with monthly means from about 80 automatic weather stations (covering a large area throughout the Brazilian territory) still shows a bias generally within ±10 W m−2 and a low standard deviation (<20 W m−2), but the bias has a trend in September–December 2002, suggesting an annual cycle of local Rmax values. Systematic (mean) errors in partial cloud cover and in nearly clear‐sky situations may be enhanced using regional values for atmospheric and surface parameters, such as precipitable water, Rmax, and ground reflectance. The larger errors are observed in situations of high aerosol load (especially in regions with industrial activity or forest or agricultural fires). The last case is evident when sites in the Amazonian region or São Paulo city are selected. When considering daily values averaged within 2.5° × 2.5° cells, the standard error is lower than 20 W m−2; present results suggest an annual cycle of mean bias ranging from +10 to −10 W m−2, with an amplitude of ∼10 W m−2. These values are close to the proposed requirements of 10 W m−2 for the mean deviation and 25 W m−2 for the standard deviation. It is expected that the introduction of a reference grid containing mean values of parameters within a cell could induce a decrease in the standard deviation of mean errors and the correction of their annual cycle. A model adaptation for assessing the effect of high aerosol loads is needed in order to extend improvements to the whole Brazilian area.
Equatorial aerosol‐ozone structure and variations as observed by balloon‐borne backscattersondes since 1995 at Natal, Brazil (6°S)
Authors: Rosen James M. , Morales Raymond M. , Kjome Norman T. , Kirchhoff Volker W. J. H. , da Silva Francisco R.
Published: February 2004

Simultaneous aerosol and ozone profiles have been measured near Natal, Brazil (6.07°S, 35.34°W) in an irregular but continuing effort since 1995 using balloon‐borne backscattersondes. This study introduces the primary features of the data set and our preliminary interpretation. Although measurements from ground level to ∼32 km are made, the results reported here focus on the free troposphere (FT). An apparent clear annual cycle in the occurrence of FT aerosol layers is observed, which peaks during the biomass burning season, similar to the previously reported annual cycle in tropical ozone layers. A majority of the layers occurring during the burning season contain enhancements of both aerosol and ozone. The comparatively low amounts of aerosol backscatter enhancements found in the FT layers indicate that any aerosols originating in the much higher concentrations of the planetary boundary layer (PBL) must have been greatly reduced in backscatter before they were observed in the soundings. In general, the FT backscatter profile over Natal can be described as displaying a background or baseline character that is frequently perturbed by layers of various concentrations and thicknesses. Although only the last stages of the Pinatubo volcanic aerosol decay were observed, a curious multiple‐step reduction in the aerosol was seen in the profiles near 20 km. Because the soundings were conducted with varying regularity in a limited time period, current interpretation of results can only be considered tentative.
Mixing and ozone loss in the 1999–2000 Arctic vortex: Simulations with the three‐dimensional Chemical Lagrangian Model of the Stratosphere (CLaMS)
Authors: Konopka Paul , Steinhorst Hildegard‐Maria , Grooß Jens‐Uwe , Günther Gebhard , Müller Rolf , Elkins James W. , Jost Hans‐Jürg , Richard Erik , Schmidt Ulrich , Toon Geoffrey , McKenna Daniel S.
Published: February 2004

The three‐dimensional (3‐D) formulation of the Chemical Lagrangian Model of the Stratosphere (CLaMS‐3d) is presented that extends the isentropic version of CLaMS to cross‐isentropic transport. The cross‐isentropic velocities of the Lagrangian air parcels are calculated with a radiation module and by taking into account profiles of ozone and water vapor derived from a HALOE climatology. The 3‐D extension of mixing maintains the most important feature of the 2‐D version as mixing is mainly controlled by the horizontal deformations of the wind fields. In the 3‐D version, mixing is additionally driven by the vertical shear in the flow. The impact of the intensity of mixing in the 3‐D model formulation on simulated tracer distributions is elucidated by comparing observations of CH4, Halon‐1211, and ozone from satellite, balloon, and ER‐2 aircraft during the SOLVE/THESEO‐2000 campaign. CLaMS‐3d simulations span the time period from early December 1999 to the middle of March 2000, with air parcels extending over the Northern Hemisphere in the vertical range between 350 and 1400 K. The adjustment of the CLaMS‐3d mixing parameters to optimize agreement with observations was obtained for strongly inhomogeneous, deformation‐induced mixing that affects only about 10% of the air parcels per day. The optimal choice of the aspect ratio α defining the ratio of the mean horizontal and vertical separation between the air parcels was determined to be 250 for model configuration with a horizontal resolution r0 = 100 km. By transporting ozone in CLaMS‐3d as a passive tracer, the chemical ozone loss was inferred as the difference between the observed and simulated ozone profiles. The results show, in agreement with previous studies, a substantial ozone loss between 380 and 520 K with a maximum loss at 460 K of about 1.9 ppmv, i.e., of over 60% locally, from December to the middle of March 2000. During this period, the impact of isentropic mixing across the vortex edge outweighs the effect of the spatially inhomogeneous (differential) descent on the tracer/ozone correlations in the vortex. Mixing into the vortex shifts the early winter reference tracer/ozone correlation to higher values, which may lead to an underestimate of chemical ozone loss, on average by 0.4 and 0.1 ppmv in the entire vortex and the vortex core, respectively.
Are the TRACE‐P measurements representative of the western Pacific during March 2001?
Authors: Hsu Juno , Prather Michael J. , Wild Oliver , Sundet Jostein K. , Isaksen Ivar S. A. , Browell Edward V. , Avery Melody A. , Sachse Glen W.
Published: February 2004

Observations of CO and O3 from the Transport and Chemical Evolution over the Pacific (TRACE‐P) campaign are compared with modeled distributions from the FRSGC/UCI CTM driven by the Oslo T63L40 ECMWF forecast meteorology. The model‐measurement comparison is made within the context of how well the TRACE‐P observations represent the springtime chemistry and ozone distributions over eastern Asia and the western Pacific in March 2001 and uses the four‐dimensional (4‐D) extended domain from the model to provide unbiased statistics. A key question is whether the limited sampling density or mission strategy led to a statistically biased sample. To address this question, we examine a diverse range of statistical analyses of the observations of CO and O3. The middle percentiles of the cumulative probability functions for CO in the free troposphere are representative (and reproduced by the CTM), but those in the boundary layer are not. The frequency of low‐CO, stratospheric influence is well matched along flight tracks but is atypical of the extended domain. The percentiles of the latitude‐by‐height distribution of lidar O3 show how the CTM reproduces the nonrepresentative clumpy nature of the observations but has too low a tropopause about the jet region (30–35N). Adaptive kernel estimation of the 2‐D probability density of O3‐CO correlations shows a very good simulation of two different chemical regimes (stratospheric and polluted) that is quite different from the extended domain but also highlights the failure to predict CO > 400 ppb. Empirical orthogonal function analysis of the O3 vertical profiles shows how six EOFs can effectively describe the 4‐D structures of O3 over this entire domain. The latitude‐by‐longitude maps of the principal components provide an excellent test of the CTM simulation along flight tracks and clearly show the unique sampling of O3 events by the TRACE‐P flights. In many cases the ability of the model to simulate the nonrepresentative observations implies a clear skill in matching the unique meteorological and chemical features of the region.
Minimized standing waves in microwave radiometer balancing calibration
Authors: Deuber Beat , Kämpfer Niklaus
Published: February 2004

We report on investigations of the reflective properties of reference loads used for the balancing calibration of a water vapor radiometer at 22 GHz. Besides the commonly used egg‐shaped ECCOSORB® CV3, a set of different absorbers in different orientations with respect to the reference beam was investigated. Our measurements show that the commonly used material and the common orientation of the reference load are not optimal, and we present a better solution that minimizes baseline artifacts.
Active shortening of the Cascadia forearc and implications for seismic hazards of the Puget Lowland
Authors: Johnson Samuel Y. , Blakely Richard J. , Stephenson William J. , Dadisman Shawn V. , Fisher Michael A.
Published: February 2004

Margin‐parallel shortening of the Cascadia forearc is a consequence of oblique subduction of the Juan de Fuca plate beneath North America. Strike‐slip, thrust, and oblique crustal faults beneath the densely populated Puget Lowland accommodate much of this north‐south compression, resulting in large crustal earthquakes. To better understand this forearc deformation and improve earthquake hazard assessment, we here use seismic reflection surveys, coastal exposures of Pleistocene strata, potential‐field data, and airborne laser swath mapping to document and interpret a significant structural boundary near the City of Tacoma. This boundary is a complex structural zone characterized by two distinct segments. The northwest trending, eastern segment, extending from Tacoma to Carr Inlet, is formed by the broad (∼11.5 km), southwest dipping (∼11°–20°) Rosedale monocline. This monocline raises Crescent Formation basement about 2.5 km, resulting in a moderate gravity gradient. We interpret the Rosedale monocline as a fault‐bend fold, forming above a deep thrust fault. Within the Rosedale monocline, inferred Quaternary strata thin northward and form a growth triangle that is 4.1 to 6.6 km wide at its base, suggesting ∼2–3 mm/yr of slip on the underlying thrust. The western section of the >40‐km‐long, north dipping Tacoma fault, extending from Hood Canal to Carr Inlet, forms the western segment of the Tacoma basin margin. Structural relief on this portion of the basin margin may be several kilometers, resulting in steep gravity and aeromagnetic anomalies. Quaternary structural relief along the Tacoma fault is as much as 350–400 m, indicating a minimum slip rate of about 0.2 mm/yr. The inferred eastern section of the Tacoma fault (east of Carr Inlet) crosses the southern part of the Seattle uplift, has variable geometry along strike, and diminished structural relief. The Tacoma fault is regarded as a north dipping backthrust to the Seattle fault, so that slip on a master thrust fault at depth could result in movement on the Seattle fault, the Tacoma fault, or both.
Multivariate analysis of cross‐hole georadar velocity and attenuation tomograms for aquifer zonation
Authors: Tronicke Jens , Holliger Klaus , Barrash Warren , Knoll Michael D.
Published: February 2004

We have investigated the potential of combining cross‐hole georadar velocity and attenuation tomography as a method for characterizing heterogeneous alluvial aquifers. A multivariate statistical technique, known as k‐means cluster analysis, is used to correlate and integrate information contained in velocity and attenuation tomograms. Cluster analysis allows us to identify objectively the major common trends in the tomographic data and thus to “reduce” the information to a limited number of characteristic parameter combinations. The application of this procedure to two synthetic data sets indicates that it is a powerful tool for converting the complex relationships between the tomographically derived velocity and attenuation structures into a lithologically and hydrologically meaningful zonation of the probed region. In addition, these synthetic examples allow us to evaluate the reliability of further petrophysical parameter estimates. We find that although absolute values of the tomographically inferred petrophysical parameters often differ significantly from the actual parameters, the clustering approach enables us to reliably identify the major trends in the petrophysical properties. Finally, we have applied the approach to a cross‐hole georadar data set collected in a well‐studied alluvial aquifer. A comparison of the clustered tomographic section with well‐log data demonstrates that our approach delineates the hydrostratigraphic zonation.
On the objective identification of flood seasons
Authors: Cunderlik Juraj M. , Ouarda Taha B. M. J. , Bobée Bernard
Published: February 2004

The determination of seasons of high and low probability of flood occurrence is a task with many practical applications in contemporary hydrology and water resources management. Flood seasons are generally identified subjectively by visually assessing the temporal distribution of flood occurrences and, then at a regional scale, verified by comparing the temporal distribution with distributions obtained at hydrologically similar neighboring sites. This approach is subjective, time consuming, and potentially unreliable. The main objective of this study is therefore to introduce a new, objective, and systematic method for the identification of flood seasons. The proposed method tests the significance of flood seasons by comparing the observed variability of flood occurrences with the theoretical flood variability in a nonseasonal model. The method also addresses the uncertainty resulting from sampling variability by quantifying the probability associated with the identified flood seasons. The performance of the method was tested on an extensive number of samples with different record lengths generated from several theoretical models of flood seasonality. The proposed approach was then applied on real data from a large set of sites with different flood regimes across Great Britain. The results show that the method can efficiently identify flood seasons from both theoretical and observed distributions of flood occurrence. The results were used for the determination of the main flood seasonality types in Great Britain.
Patterns of changes in temperament and character inventory scales in subjects with obsessive–compulsive disorder following a 4‐month treatment
Authors: Lyoo I. K. , Yoon T. , Kang D. H. , Kwon J. S.
Published: January 2004

Objective:  The purpose of this study was to assess changes in the temperament and character patterns in subjects with obsessive–compulsive disorder (OCD) following the treatment for obsessive/compulsive and accompanying depressive symptoms.

Method:  Study subjects were 35 patients who met the DSM‐IV criteria for OCD. All subjects were assessed with the Temperament and Character Inventory (TCI), the Yale‐Brown Obsessive–Compulsive Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory before and after a 4‐month treatment.

Results:  Harm Avoidance (HA) scores in OCD subjects before treatment significantly decreased after treatment. However, the Self‐Directedness scores, which were significantly lower than healthy comparison subjects before treatment, did not change. In addition, Reward Dependence scores in OCD subjects, which were not significantly different from healthy comparison subjects before treatment, significantly increased after treatment.

Conclusion:  The TCI pattern of untreated OCD subjects (high HA and low Self‐Directedness, relative to healthy comparison subjects) and the decrease of HA scores and no change in Self‐Directedness scores following a successful treatment suggest that temperaments are more amenable to treatment than characters.
Anterior cingulotomy for refractory obsessive–compulsive disorder
Authors: Kim C.‐H. , Chang J. W. , Koo M.‐S. , Kim J. W. , Suh H. S. , Park I. H. , Lee H. S.
Published: January 2004

Objective: This study was designed to prospectively investigate the efficacy and cognitive adverse effects of stereotactic bilateral anterior cingulotomy as a treatment for refractory obsessive–compulsive (OCD) patients for 12 months.

Method: Patients were eligible if they had severe OCD and rigorous treatments had been unsuccessful. Yale‐Brown Obsessive–Compulsive Scale (Y‐BOCS), Clinical Global Impression (CGI) and neuropsychological tests were used to assess the efficacy and cognitive changes of cingulotomy before and 12 months after operation.

Results: The mean improvement rate of the Y‐BOCS scores achieved from baseline was 36.0%. Out of 14 patients six met responder criteria; 35% or higher improvement rate on Y‐BOCS and CGI improvement of very much or much better at 12‐month follow‐up. There was no significant cognitive dysfunction after cingulotomy.

Conclusion: Anterior cingulotomy shows few cognitive adverse effects, with about half of the OCD patients demonstrating significant symptomatic improvement.
Does prophylaxis‐delay in bipolar disorder influence outcome? Results from a long‐term study of 147 patients
Authors: Baethge C. , Smolka M. N. , Gruschka P. , Berghöfer A. , Schlattmann P. , Bauer M. , Altshuler L. , Grof P. , Müller‐Oerlinghausen B.
Published: January 2004

Objective: This study investigated the impact of latency (the time between illness onset and initiation of prophylactic treatment) on the outcome of prophylaxis in bipolar disorders.

Method: The effect of prophylaxis delay (latency) on the course of illness was assessed in 147 patients. Dependent variables were: reduction of days spent in the hospital (prior to vs. during prophylaxis), time to first recurrence, and Morbidity‐Index during prophylaxis (lithium or carbamazepine). Latency and other independent variables were tested using a multivariate approach.

Results: Latency (9.3 years on average) had no significant effect on the subsequent response. Illness severity prior to prophylaxis, however, did predict the relative response. The course of illnessduringtreatment could not be predicted by any one factor.

Conclusion: The delay in initiating prophylaxis appears to have no influence on prophylaxis outcome. Instead, those whose illness was more severe were treated earlier and these patients subsequently showed a relatively greater response. If severity is not controlled for as part of the analysis, latency may be mistaken as an important predictor for response.
Children of parents with obsessive‐compulsive disorder – a 2‐year follow‐up study
Authors: Black D. W. , Gaffney G. R. , Schlosser S. , Gabel J.
Published: January 2004

Objective:  To examine the association between parental obsessive‐compulsive disorder (OCD) and emotional and behavioural disorders in offspring.

Method:  Demographic, clinical, and diagnostic data were collected from parents with OCD, control subjects, and their respective offspring. Offspring were reassessed at a 2‐year follow‐up.

Results:  Probands with OCD and controls were relatively well matched for age, gender, race, educational rating, and marital status. Offspring of OCD probands were at greater risk than offspring of controls for dimensionally measured anxiety, depression, somatization, and social problems. OCD offspring were significantly more likely than control offspring to have lifetime overanxious disorder, separation anxiety disorder, OCD, or ‘any anxiety disorder’. Female gender in the parent with OCD, evidence of family dysfunction, and high symptom levels in offspring were predictive of broadly defined OCD at follow‐up.

Conclusion:  Children having a parent with OCD are more likely than control offspring to have social, emotional, and behavioural disorders.
Affective (depressive) morbidity in puerperal Nigerian women: validation of the Edinburgh postnatal depression scale
Authors: Uwakwe Richard
Published: January 2004

Objective:  To determine the rate of depression in a group of postpartum Nigerian women and to validate the Edinburgh Postnatal Depression Scale (EPDS) in this group.

Method:  Between April and August 2000, all postpartum women who remained in the maternity ward for up to 7 days, and those who attended the postnatal clinics of Nnamdi Azikiwe University Teaching Hospital were recruited. Translated local language versions of the EPDS and the Zung Self‐Rating Depression Scale were used to screen the subjects. A structured interview schedule was adapted from the depression section of the Composite International Diagnostic Interview and affective module of the ICD‐10 Symptom Check List to assess screened subjects.

Results:  The total rejection rate was 23%, with 225 women participating in the study. Twenty‐four subjects (10.7%) had depression. At the optimal cut‐off score of 9, the EPDS had a sensitivity of 0.75, and specificity of 0.97.

Conclusion:  The EPDS clearly distinguished between depressed and non‐depressed postpartum mothers (t = 7.63, P < 0.001, df = 222). Because of its brevity and acceptability, it is recommended that the EPDS be used in routine postnatal screening.
Protein kinase C modulation of the regulation of sarcoplasmic reticular function by protein kinase A‐mediated phospholamban phosphorylation in diabetic rats
Authors: Watanuki Satoko , Matsuda Naoyuki , Sakuraya Fumika , Jesmin Subrina , Hattori Yuichi
Published: January 2004

The goal of this study was to elucidate the possible mechanisms by which protein kinase A (PKA)‐mediated regulation of the sarcoplasmic reticulum (SR) via phospholambin protein phosphorylation is functionally impaired in streptozotocin‐induced diabetic rats.

Phospholamban (PLB) protein and mRNA levels were 1.3‐fold higher in diabetic than in control hearts, while protein expression of cardiac SR Ca2+‐ATPase (SERCA2a) was unchanged.

Basal and isoprenaline‐stimulated phosphorylation of PLB at Ser16 or Thr17 was unchanged in diabetic hearts. However, stronger immunoreactivity was observed at the basal level in diabetic hearts when antiphosphoserine antibody was used.

Basal 32P incorporation into PLB was significantly higher in diabetic than in control SR vesicles, but the extent of the PKA‐mediated increase in PLB phosphorylation was the same in the two groups of vesicles.

Stimulation of Ca2+ uptake by PKA‐catalyzed PLB phosphorylation was weaker in diabetic than in control SR vesicles. The PKA‐induced increase in Ca2+ uptake was attenuated when control SR vesicles were preincubated with protein kinase C (PKC).

PKC activities were increased by more than two‐fold in the membranous fractions from diabetic hearts in comparison with control values, regardless of whether Ca2+ was present. This was associated with increases in the protein content of PKCδ, PKCη, PKCι, and PKCλ in diabetic membranous fractions.

The changes observed in diabetic rats were reversed by insulin therapy.

These results suggest that PKA‐dependent phosphorylation may incompletely counteract the function of PLB as an inhibitor of SERCA2a activity in diabetes in which PKC expression and activity are enhanced.

British Journal of Pharmacology (2004) 141, 347–359. doi:10.1038/sj.bjp.0705455
Endosome sorting of β2‐adrenoceptors is GRK5 independent
Authors: Millman Ellen E , Rosenfeld Jennifer L , Vaughan David J , Nguyen Jacqueline , Dai WenPing , Alpizar‐Foster Estrella , Clark Richard B , Knoll Brian J , Moore Robert H
Published: January 2004

We have investigated the role of G protein‐coupled receptor kinase 5 (GRK5) in the regulation of endosome sorting of human β2‐adrenoceptors.

Expressing GRK5 at a high level significantly increased the extent of internalization of wild‐type β2‐adrenoceptors and of an internalization‐defective mutant receptor, and increased receptor phosphorylation at serines 355 and 356 in the cytoplasmic tail.

Overexpressing GRK5 did not alter β2‐adrenoceptor recycling as assessed by immunofluorescence microscopy and radioligand binding assays nor was there any change in receptor downregulation.

These data indicate that GRK5 does not regulate the sorting of β2‐adrenoceptors in the endocytic pathway.

British Journal of Pharmacology (2004) 141, 277–284. doi:10.1038/sj.bjp.0705504
A1 and A2A adenosine receptor modulation of α1‐adrenoceptor‐mediated contractility in human cultured prostatic stromal cells
Authors: Preston A , Frydenberg M , Haynes J M
Published: January 2004

This study investigated the possibility that adenosine receptors modulate the α1‐adrenoceptor‐mediated contractility of human cultured prostatic stromal cells (HCPSC).

The nonselective adenosine receptor agonist, 5′‐N‐ethylcarboxamido‐adenosine (NECA; 10 nM–10 μM), and the A1 adenosine receptor selective agonist, cyclopentyladenosine (CPA; 10 nM–10 μM), elicited significant contractions in HCPSC, with maximum contractile responses of 18±3% and 17±2% reduction in initial cell length, respectively.

In the presence of a threshold concentration of phenylephrine (PE) (100 nM), CPA (1 nM–10 μM) caused contractions, with an EC50 of 124±12 nM and maximum contractile response of 37±4%. The A1 adenosine receptor‐selective antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX 100 nM) blocked this effect. In the presence of DPCPX (100 nM), NECA (1 nM–10 μM) inhibited contractions elicited by a submaximal concentration of PE (10 μM), with an IC50 of 48±2 nM. The A2A adenosine receptor‐selective antagonist 4‐(2‐[7‐amino‐2‐{furyl}{1,2,4}triazolo{2,3‐α}{1,3,5,}triazin‐5‐yl amino]ethyl)phenol (Zm241385 100 nM) blocked this effect.

In BCECF‐AM (10 μM)‐loaded cells, both CPA (100 pM–1 μM) and NECA (100 pM–10 μM) elicited concentration‐dependent decreases in intracellular pH (pHi), with EC50 values of 3.1±0.3 and 6.0±0.3 nM, respectively. The response to NECA was blocked by Zm241385 (100 nM; apparent pKB of 9.4±0.4), but not by DPCPX (100 nM). The maximum response to CPA was blocked by DPCPX (100 nM), and unaffected by Zm241385 (100 nM).

NECA (10 nM–10 μM) alone did not increase [3H]‐cAMP in HCPSC. In the presence of DPCPX (100 nM), NECA (10 nM–10 μM) caused a concentration dependent increase in [3H]‐cAMP, with an EC50 of 1.2±0.1 μM. This response was inhibited by Zm241385 (100 nM). CPA (10 nM–10 μM) had no effect on cAMP, in the presence or absence of forskolin (1 μM).

These findings are consistent with a role for adenosine receptors in the modulation of adrenoceptor‐mediated contractility in human prostate‐derived cells.

British Journal of Pharmacology (2004) 141, 302–310. doi:10.1038/sj.bjp.0705535
Coupling of boswellic acid‐induced Ca2+ mobilisation and MAPK activation to lipid metabolism and peroxide formation in human leucocytes
Authors: Altmann Anja , Poeckel Daniel , Fischer Lutz , Schubert‐Zsilavecz Manfred , Steinhilber Dieter , Werz Oliver
Published: January 2004

We have previously shown that 11‐keto boswellic acids (11‐keto‐BAs), the active principles of Boswellia serrata gum resins, activate p38 MAPK and p42/44MAPK and stimulate Ca2+ mobilisation in human polymorphonuclear leucocytes (PMNL).

In this study, we attempted to connect the activation of MAPK and mobilisation of Ca2+ to functional responses of PMNL, including the formation of reactive oxygen species (ROS), release of arachidonic acid (AA), and leukotriene (LT) biosynthesis.

We found that, in PMNL, 11‐keto‐BAs stimulate the formation of ROS and cause release of AA as well as its transformation to LTs via 5‐lipoxygenase.

Based on inhibitor studies, 11‐keto‐BA‐induced ROS formation is Ca2+‐dependent and is mediated by NADPH oxidase involving PI 3‐K and p42/44MAPK signalling pathways. Also, the release of AA depends on Ca2+ and p42/44MAPK, whereas the pathways stimulating 5‐LO are not readily apparent.

Pertussis toxin, which inactivates Gi/0 protein subunits, prevents MAPK activation and Ca2+ mobilisation induced by 11‐keto‐BAs, implying the involvement of a Gi/0 protein in BA signalling.

Expanding studies on differentiated haematopoietic cell lines (HL60, Mono Mac 6, BL41‐E‐95‐A) demonstrate that the ability of BAs to activate MAPK and to mobilise Ca2+ may depend on the cell type or the differentiation status.

In summary, we conclude that BAs act via Gi/0 protein(s) stimulating signalling pathways that control functional leucocyte responses, in a similar way as chemoattractants, that is, N‐formyl‐methionyl‐leucyl‐phenylalanine or platelet‐activating factor.

British Journal of Pharmacology (2004) 141, 223–232. doi:10.1038/sj.bjp.0705604
Antitussive activity of sigma‐1 receptor agonists in the guinea‐pig
Authors: Brown Claire , Fezoui Malika , Selig William M , Schwartz Carl E , Ellis James L
Published: January 2004

Current antitussive medications have limited efficacy and often contain the opiate‐like agent dextromethorphan (DEX). The mechanism whereby DEX inhibits cough is ill defined. DEX displays affinity at both NMDA and sigma receptors, suggesting that the antitussive activity may involve central or peripheral activity at either of these receptors. This study examined and compared the antitussive activity of DEX and various putative sigma receptor agonists in the guinea‐pig citric‐acid cough model.

Intraperitoneal (i.p.) administration of DEX (30 mg kg−1) and the sigma‐1 agonists SKF‐10,047 (1–5 mg kg−1), Pre‐084 (5 mg kg−1), and carbetapentane (1–5 mg kg−1) inhibited citric‐acid‐induced cough in guinea‐pigs. Intraperitoneal administration of a sigma‐1 antagonist, BD 1047 (1–5 mg kg−1), reversed the inhibition of cough elicited by SKF‐10,047. In addition, two structurally dissimilar sigma agonists SKF‐10,047 (1 mg ml−1) and Pre‐084 (1 mg ml−1) inhibited cough when administered by aerosol.

Aerosolized BD 1047 (1 mg ml−1, 30 min) prevented the antitussive action of SKF‐10,047 (5 mg kg−1) or DEX (30 mg kg−1) given by i.p. administration and, likewise, i.p. administration of BD 1047 (5 mg kg−1) prevented the antitussive action of SKF‐10,047 given by aerosol (1 mg ml−1).

These results therefore support the argument that antitussive effects of DEX may be mediated via sigma receptors, since both systemic and aerosol administration of sigma‐1 receptor agonists inhibit citric‐acid‐induced cough in guinea‐pigs. While significant systemic exposure is possible with aerosol administration, the very low doses administered (estimated <0.3 mg kg−1) suggest that there may be a peripheral component to the antitussive effect.

British Journal of Pharmacology (2004) 141, 233–240. doi:10.1038/sj.bjp.0705605
Membrane type‐1 matrix metalloproteinase stimulates tumour cell‐induced platelet aggregation: role of receptor glycoproteins
Authors: Alonso‐Escolano David , Strongin Alex Y , Chung Ada W , Deryugina Elena I , Radomski Marek W
Published: January 2004

Matrix metalloproteinase‐2 (MMP‐2) plays a role in agonist‐ and tumour cell‐induced platelet aggregation (TCIPA).

MMP‐2 is synthesized as a proenzyme and is activated at the cell surface by membrane type‐1 matrix metalloproteinase (MT1‐MMP, MMP‐14).

The significance of tumour cell‐associated MT1‐MMP for TCIPA was investigated using human breast carcinoma MCF7 cells stably coexpressing the integrin αvβ3 with MT1‐MMP, cells expressing αvβ3 alone and mock‐transfected cells.

Western blot and zymography confirmed that αvβ3/MT1‐MMP cells expressed MT1‐MMP and efficiently processed proMMP‐2 to MMP‐2.

Aggregometry, phase‐contrast and transmission electron microscopy and flow cytometry were used to characterize TCIPA induced by MCF7 cell lines.

The aggregating potency of cells was: αvβ3/MT1‐MMP >αvβ3=mock cells, as shown by aggregometry and phase‐contrast microscopy.

Electron microscopy revealed close, membrane–membrane interactions between activated platelets and αvβ3/MT1‐MMP cells during TCIPA.

Inhibition of MMP‐2 with the neutralizing anti‐MMP‐2 antibody (5 μg ml−1) and o‐phenanthroline (100 μM) reduced aggregation induced by αvβ3/MT1‐MMP cells.

TCIPA induced by αvβ3/MT1‐MMP cells was also reduced by inhibiting the generation and actions of ADP with apyrase (250 μg ml−1) and 2‐methylthio‐AMP (2‐MeSAMP) (30 μM), but not N6‐methyl‐2′‐deoxyadenosine‐3′,5′‐bisphosphate (MRS2179) (30 μM).

Flow cytometry demonstrated that TCIPA enhanced expression of glycoprotein (GP) Ib and IIb/IIIa receptors not only on platelets but also on breast cancer cells.

Thus, (a) human breast carcinoma cell surface‐associated MT1‐MMP, via activating proMMP‐2, stimulates TCIPA; (b) ADP amplifies the effects of MMPs via stimulation of P2Y12 receptors and (c) both tumour‐ and platelet‐derived GPIb and GPIIb/IIIa are involved in the aggregatory effects of MT1‐MMP.

British Journal of Pharmacology (2004) 141, 241–252. doi:10.1038/sj.bjp.0705606
Calcineurin‐independent inhibition of mitochondrial Ca2+ uptake by cyclosporin A
Authors: Montero M , Lobatón C D , Gutierrez‐Fernández S , Moreno A , Alvarez J
Published: January 2004

Cyclosporin A (CsA) is a widely used compound because of its potent immunosupressive properties, derived mainly from the inhibition of calcineurin, and also because of its ability to block the mitochondrial permeability transition pore (PTP). This second effect has been involved in the protection against apoptosis mediated by release of mitochondrial factors. We show here that CsA (1–10μM) has an additional effect on Ca2+ homeostasis in mitochondria that cannot be attributed to inhibition of PTP.

By measuring specifically mitochondrial [Ca2+] with targeted aequorin, we show that CsA inhibited Ca2+ entry into mitochondria both in intact and in permeabilized cells, and this effect was stronger when Ca2+ entry was triggered by low cytosolic [Ca2+], below 5 μM.

Inhibition of mitochondrial Ca2+ uptake required micromolar concentrations of CsA and was not mimicked by other inhibitors of calcineurin such as FK‐506 or cypermethrin, nor by a different inhibitor of the PTP, bongkrekic acid.

CsA blocked the increase in mitochondrial Ca2+ uptake rate induced by the mitochondrial Ca2+ uniporter activator SB202190.

Our results suggest that CsA inhibits Ca2+ entry through the Ca2+ uniporter by a mechanism independent of the inhibition of PTP or calcineurin. This effect may contribute to reduce depolarization and Ca2+ overloading in mitochondria after cell stimulation, and thus cooperate with the direct inhibition of PTP to prevent apoptosis.

British Journal of Pharmacology (2004) 141, 263–268. doi:10.1038/sj.bjp.0705609
Characterisation of the binding of [3H]‐SB‐674042, a novel nonpeptide antagonist, to the human orexin‐1 receptor
Authors: Langmead Christopher J , Jerman Jeffrey C , Brough Stephen J , Scott Claire , Porter Rod A , Herdon Hugh J
Published: January 2004

This study characterises the binding of a novel nonpeptide antagonist radioligand, [3H]SB‐674042 (1‐(5‐(2‐fluoro‐phenyl)‐2‐methyl‐thiazol‐4‐yl)‐1‐((S)‐2‐(5‐phenyl‐(1,3,4)oxadiazol‐2‐ylmethyl)‐pyrrolidin‐1‐yl)‐methanone), to the human orexin‐1 (OX1) receptor stably expressed in Chinese hamster ovary (CHO) cells in both a whole cell assay and in a cell membrane‐based scintillation proximity assay (SPA) format.

Specific binding of [3H]SB‐674042 was saturable in both whole cell and membrane formats. Analyses suggested a single high‐affinity site, with Kd values of 3.76±0.45 and 5.03±0.31 nM, and corresponding Bmax values of 30.8±1.8 and 34.4±2.0 pmol mg protein−1, in whole cell and membrane formats, respectively. Kinetic studies yielded similar Kd values.

Competition studies in whole cells revealed that the native orexin peptides display a low affinity for the OX1 receptor, with orexin‐A displaying a ∼five‐fold higher affinity than orexin‐B (Ki values of 318±158 and 1516±597 nM, respectively).

SB‐334867, SB‐408124 (1‐(6,8‐difluoro‐2‐methyl‐quinolin‐4‐yl)‐3‐(4‐dimethylamino‐phenyl)‐urea) and SB‐410220 (1‐(5,8‐difluoro‐quinolin‐4‐yl)‐3‐(4‐dimethylamino‐phenyl)‐urea) all displayed high affinity for the OX1 receptor in both whole cell (Ki values 99±18, 57±8.3 and 19±4.5 nM, respectively) and membrane (Ki values 38±3.6, 27±4.1 and 4.5±0.2 nM, respectively) formats.

Calcium mobilisation studies showed that SB‐334867, SB‐408124 and SB‐410220 are all functional antagonists of the OX1 receptor, with potencies in line with their affinities, as measured in the radioligand binding assays, and with approximately 50‐fold selectivity over the orexin‐2 receptor.

These studies indicate that [3H]SB‐674042 is a specific, high‐affinity radioligand for the OX1 receptor. The availability of this radioligand will be a valuable tool with which to investigate the physiological functions of OX1 receptors.

British Journal of Pharmacology (2004) 141, 340–346. doi:10.1038/sj.bjp.0705610
Contribution of nitric oxide produced by inducible nitric oxide synthase to vascular responses of mesenteric arterioles in streptozotocin‐diabetic rats
Authors: Ishikawa Tomohisa , Kohno Fumika , Kawase Ryosuke , Yamamoto Yuri , Nakayama Koichi
Published: January 2004

The functional changes in mesenteric arterioles of streptozotocin‐induced diabetes were investigated by intravital microscopy. The mesentery was exteriorized from anesthetized rats, spread in a chamber, and superfused with Tyrode solution. All drugs tested were applied to the superfusing Tyrode solution.

Compared with age‐matched controls, the diabetic rats showed enhanced vascular sensitivity to phenylephrine, an α1‐adrenoceptor agonist. The preincubation of the mesentery with NG‐nitro‐L‐arginine (L‐NNA), a nitric oxide synthase (NOS) inhibitor, shifted the phenylephrine‐concentration–response curves to the left in both the diabetic and control rats. Even in the presence of L‐NNA, the sensitivity to phenylephrine was higher in the diabetic rats than in the control.

Acetylcholine relaxed the mesenteric arterioles in both groups, but to a significantly greater extent in the control than in the diabetic rats. However, the L‐NNA‐induced constriction of arterioles did not differ significantly between the groups. In contrast, the amplitude of the constrictions of mesenteric arterioles induced by S‐ethylisothiourea, an inducible NOS (iNOS) inhibitor, was significantly greater in the diabetic rats than in the control.

Immunostaining of the mesentery with a specific antibody for iNOS revealed iNOS in the microvessels of only the diabetic rats.

These results suggest that constrictor responses to α1‐adrenoceptor stimulation are sensitized in the mesenteric arterioles of STZ‐diabetic rats, and that iNOS expressed in the arteriolar smooth muscle plays a role in suppressing the basal tone and the reactivity of the arterioles in STZ‐diabetic rats.

British Journal of Pharmacology (2004) 141, 269–276. doi:10.1038/sj.bjp.0705611
Efficacy of preconditioning should be gauged by reduction of infarction
Authors: Cohen Michael V
Published: January 2004

British Journal of Pharmacology (2004) 141, 197–198. doi:10.1038/sj.bjp.0705612
Minoxidil opens mitochondrial KATP channels and confers cardioprotection
Authors: Sato Toshiaki , Li Yulong , Saito Tomoaki , Nakaya Haruaki
Published: January 2004

ATP‐sensitive potassium channel in the mitochondrial inner membrane (mitoKATP channel) rather than in the sarcolemma (sarcKATP channel) appears to play an important role in cardioprotection. We examined the effect of minoxidil, a potent antihypertensive agent and hair growth stimulator, on sarcKATP and mitoKATP channels in guinea‐pig ventricular myocytes.

Minoxidil activated a glybenclamide‐sensitive sarcKATP channel current in the whole‐cell recording mode with an EC50 of 182.6 μM. Minoxidil reversibly increased the flavoprotein oxidation, an index of mitoKATP channel activity, in a concentration‐dependent manner. The EC50 for mitoKATP channel activation was estimated to be 7.3 μM; this value was notably ∼25‐fold lower than that for sarcKATP channel activation.

Minoxidil (10 μM) significantly attenuated the ouabain‐induced increase of mitochondrial Ca2+ concentration, which was measured by loading cells with rhod‐2 fluorescence. Furthermore, pretreatment with minoxidil (10 μM) before 20‐min no‐flow ischaemia significantly improved the recovery of developed tension measured after 60 min of reperfusion in coronary perfused guinea‐pig ventricular muscles. These cardioprotective effects of minoxidil were completely abolished by the mitoKATP channel blocker 5‐hydroxydecanoate (500 μM).

Our results indicate that minoxidil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by the selective activation of mitoKATP channels.

British Journal of Pharmacology (2004) 141, 360–366. doi:10.1038/sj.bjp.0705613
Effects of chloride channel blockers on hypotonicity‐induced contractions of the rat trachea
Authors: Coelho Roberta R , Souza Emmanuel P , Soares Pedro M G , Meireles Ana Vaneska P , Santos Geam C M , Scarparo Henrique C , Assreuy Ana Maria S , Criddle David N
Published: January 2004

We have investigated the inhibitory effects of blockers of volume‐activated (Clvol) and calcium‐activated (ClCa) chloride channels on hypotonic solution (HS)‐induced contractions of rat trachea, comparing their effects with those of the voltage‐dependent calcium channel (VDCC) blocker nifedpine.

HS elicited large, stable contractions that were partially dependent on the cellular chloride gradient; a reduction to 41.45±7.71% of the control response was obtained when extracellular chloride was removed. In addition, HS‐induced responses were reduced to 26.8±5.6% of the control by 1 μM nifedipine, and abolished under calcium‐free conditions, indicating a substantial requirement for extracellular calcium entry, principally via VDCCs.

The established Clvol blockers tamoxifen (10 μM) and 4,4′‐diisothiocyanatostilbene‐2,2′‐disulphonic acid (1–100 μM), at concentrations previously reported to inhibit Clvol in smooth muscle, did not significantly inhibit HS‐induced contractions.

In contrast, the recognized ClCa blocker niflumic acid (NFA; 1–100 μM) produced a reversible, concentration‐dependent inhibition of HS responses, with a reduction to 36.6±6.4% of control contractions at the highest concentration. The mixed Clvol and ClCa blocker, 5‐nitro 2‐(3‐phenylpropylamine) benzoic acid (NPPB; 10–100 μM) also elicited concentration‐related inhibition of HS‐induced contractions, producing a decrease to 35.9±11.3% of the control at 100 μM.

Our results show that HS induces reversible, chloride‐dependent contractions of rat isolated trachea that were inhibited by NFA and NPPB, while exhibiting little sensitivity to recognized blockers of Clvol. The data support the possibility that opening of calcium‐activated chloride channels under hypotonic conditions in respiratory smooth muscle may ultimately lead to VDCC‐mediated calcium entry and contraction.

British Journal of Pharmacology (2004) 141, 367–373. doi:10.1038/sj.bjp.0705615
Involvement of ASK1 in Ca2+‐induced p38 MAP kinase activation
Authors: Takeda Kohsuke , Matsuzawa Atsushi , Nishitoh Hideki , Tobiume Kei , Kishida Satoshi , Ninomiya‐Tsuji Jun , Matsumoto Kunihiro , Ichijo Hidenori
Published: January 2004

The mammalian mitogen‐activated protein (MAP) kinase kinase kinase apoptosis signal‐regulating kinase 1 (ASK1) is a pivotal component in cytokine‐ and stress‐induced apoptosis. It also regulates cell differentiation and survival through p38 MAP kinase activation. Here we show that Ca2+ signalling regulates the ASK1–p38 MAP kinase cascade. Ca2+ influx evoked by membrane depolarization in primary neurons and synaptosomes induced activation of p38, which was impaired in those derived from ASK1‐deficient mice. Ca2+/calmodulin‐dependent protein kinase type II (CaMKII) activated ASK1 by phosphorylation. Moreover, p38 activation induced by the expression of constitutively active CaMKII required endogenous ASK1. Thus, ASK1 is a critical intermediate of Ca2+ signalling between CaMKII and p38 MAP kinase.
Parasite‐specific immune response in adult Drosophila melanogaster: a genomic study
Authors: Roxström‐Lindquist Katarina , Terenius Olle , Faye Ingrid
Published: January 2004

Insects of the order Diptera are vectors for parasitic diseases such as malaria, sleeping sickness and leishmania. In the search for genes encoding proteins involved in the antiparasitic response, we have used the protozoan parasite Octosporea muscaedomesticae for oral infections of adult Drosophila melanogaster. To identify parasite‐specific response molecules, other flies were exposed to virus, bacteria or fungi in parallel. Analysis of gene expression patterns after 24 h of microbial challenge, using Affymetrix oligonucleotide microarrays, revealed a high degree of microbe specificity. Many serine proteases, key intermediates in the induction of insect immune responses, were uniquely expressed following infection of the different organisms. Several lysozyme genes were induced in response to Octosporea infection, while in other treatments they were not induced or downregulated. This suggests that lysozymes are important in antiparasitic defence.
Analysis of Scc1‐deficient cells defines a key metaphase role of vertebrate cohesin in linking sister kinetochores
Authors: Vagnarelli Paola , Morrison Ciaran , Dodson Helen , Sonoda Eiichiro , Takeda Shunichi , Earnshaw William C
Published: January 2004

Cleavage of the cohesin subunit Scc1p/Mcd1p/Rad21 permits sister chromatid separation and is considered to trigger anaphase onset. It has also been suggested that the cohesin complex is essential for chromosome condensation and for assembling fully functional kinetochores. Here, we used vertebrate cells conditionally deficient in Scc1 to probe cohesin function in mitosis. Cells lacking cohesin arrest in prometaphase, with many chromosomes failing to align at a metaphase plate and high levels of the spindle assembly checkpoint protein, BubR1, at all kinetochores. We show that the structural integrity of chromosomes is normal in the absence of Scc1. Furthermore, specific inhibition of topoisomerase II, which is required for decatenation of replicated chromosomes, can bypass the cohesin requirement for metaphase chromosome alignment and spindle checkpoint silencing. Since the kinetochore effects of Scc1 deficiency can be compensated for by topoisomerase II inhibition, we conclude that Scc1 is not absolutely required for kinetochore assembly or function, and that its principal role in allowing the onset of anaphase is the establishment of sufficient inter‐sister tension to allow biorientation.