bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal variation in the demography of the clonal epiphyte Tillandsia brachycaulos (Bromeliaceae) in the Yucatán Peninsula, Mexico
Authors: Mondragón Demetria , Durán Rafael , Ramírez Ivón , Valverde Teresa
Published: March 2004

Epiphytes are one of the most ubiquitous elements of tropical forest canopies, including seasonally dry tropical forests. Given the temporal variation in weather conditions in the latter, epiphyte populations may be subject to wide temporal variation in seedling recruitment, reproductive success, vegetative propagation and mortality rate. In this study, we use a 3-y demographic data set for Tillandsia brachycaulos to project its long-term population dynamics through the use of average and periodic matrices, as well as stochastic simulations. The results show that demographic behaviour varied over the 3 years of study, apparently in relation to rainfall. The first 2 years yielded a low λ value (0.79 and 0.80 – although only the former was significantly lower than unity), while the third year resulted in a λ = 1.08 (not significantly different from 1.0). When incorporating this demographic variation in an average matrix, a periodic matrix and stochastic simulations, the resulting overall λ was below unity in all three cases. The projections of the stochastic simulations suggest that the population would be able to persist in the long run only if the frequency of “good” years (defined here as those with an August rainfall above 200 mm) was above 0.6, which appears unlikely given that global warming might result in a lower frequency of rainy years in tropical dry forests.
Pathways of genetic influences on
psychopathology
Authors: RUTTER MICHAEL
Published: March 2004

Quantitative genetics, using data from twin and adoptee studies, has shown substantial genetic influences on all forms of psychiatric disorder; however, with just a few exceptions, the evidence indicates that the disorders are multifactorial, with influences that are both genetic and environmental. In recent years, molecular genetics has begun to identify individual susceptibility genes; examples are given for schizophrenia, attention deficit/hyperactivity disorder, and Alzheimer's disease. Both quantitative and molecular genetics have shown the importance of gene-environment interplay with respect to the commoner disorders of emotions and behaviour. In particular, it has been found that genetic influences moderate people's vulnerability to environmental risks. Five main alternative routes by which genes indirectly (via their effects on proteins) lead to multifactorial psychiatric disorders are described. Four main research issues are highlighted: the fuller delineation of the mechanisms involved in nature–nurture interplay and its role in aetiology; determination of how genes play a role in the neural underpinning of psychiatric disorders; identification of the ways in which genes suggest a dissection of disorders; and an understanding of the role of risk dimensions and disorder dimensions.
Planet Earth – our oasis in space
Authors: BAUER SIEGFRIED J.
Published: March 2004

Planet Earth is unique in our solar system as an abode of life. In contrast to its planetary neighbours, the presence of liquid water, a benign atmospheric environment, a solid surface and an internal structure providing a protective magnetic field make it a suitable habitat for man. While natural forces have shaped the Earth over millennia, man through his technological prowess may become a threat to this oasis of life in the solar system.
Interannual variability of the carbon dioxide system in the southern Indian Ocean (20°S–60°S): The impact of a warm anomaly in austral summer 1998
Authors: Jabaud‐Jan A. , Metzl N. , Brunet C. , Poisson A. , Schauer B.
Published: March 2004

The interannual variations of the carbon dioxide system and air‐sea CO2 fluxes are analyzed in the southwestern Indian Ocean from both in situ (Océan Indien Service d'Observations cruises in 1998 and 2000) and simulated oceanic CO2 fugacity dissolved inorganic carbon, total alkalinity, and nutrients. During austral summer of 1998, the ocean was warmer from 20°S to 60°S. In the Subtropical Zone (20°S–37°S), the warming, associated with the subtropical dipole pattern, creates an oceanic CO2 source around 2 mmol m−2 d−1 in January 1998 where all previous observations, included in 2000, indicated that this region was a small sink in summer. In the Sub‐Antarctic and Polar Front Zones (37°S–50°S), the interannual signal is not clearly detected because of the complex coupling between the horizontal and vertical dynamics and the biological activity that creates very high mesoscale variability in each summer. For the austral region, south of the Polar Front, we observe large variability in the CO2 sources and sinks between summer 1998 and 2000. In the Seasonal Ice Zone (south of 58°S) the interannual variation of the CO2 flux was mainly controlled by a warmer ocean, from 1.1°C, in summer 1998 (CO2 source of 3.2 mmol m−2 d−1) and an enhanced primary production occurring during summer 2000 (CO2 sink of −3.8 mmol m−2 d−1). In the Permanent Open Ocean Zone (POOZ, latitude 50°S–57°S), despite the half‐degree warmer sea surface in 1998, we observe lower (−15 μatm (1 atm = 105 × 1.01325 N m−2) on average) during this period, and consequently, we estimate a double of the oceanic CO2 sink in this region in 1998 than 2000, from −3.2 mmol m−2 d−1 in 1998 to −1.3 mmol m−2 d−1 in 2000. The strong oceanic CO2 sink in 1998 is associated with a dramatic decrease of nutrients (silicates less than 2 μmol kg−1). The enhanced biological activity in summer 1998, probably diatoms bloom, is also apparent in Sea‐viewing Wide Field‐of‐view Sensor (SeaWiFS) chlorophyll a estimates. Using a one‐dimensional biogeochemical model applied in the POOZ and SeaWIFS time series, we predict a stronger oceanic sink during summer season than the winter, which is contrary to previous studies. The model suggests that biological activity controls most of the sink anomaly in summer 1998 (for about 70%) and dominates the warming effect.
Polynya Dynamics: a Review of Observations and Modeling
Authors: Morales Maqueda M. A. , Willmott A. J. , Biggs N. R. T.
Published: March 2004

Polynyas are nonlinear‐shaped openings within the ice cover, ranging in size from 10 to 105 km2. Polynyas play an important climatic role. First, winter polynyas tend to warm the atmosphere, thus affecting atmospheric mesoscale motions. Second, ocean surface cooling and brine rejection during sea ice growth in polynyas lead to vertical mixing and convection, contributing to the transformation of intermediate and deep waters in the global ocean and the maintenance of the oceanic overturning circulation. Since 1990, there has been an upsurge in polynya observations and theoretical models for polynya formation and their impact on the biogeochemistry of the polar seas. This article reviews polynya research carried out in the last 2 decades, focusing on presenting a state‐of‐the‐art picture of the physical interactions between polynyas and the atmosphere‐sea ice‐ocean system. Observational and modeling studies, the surface heat budget, and water mass transformation within these features are addressed.
Estimating photosynthetic 13C discrimination in terrestrial CO2 exchange from canopy to regional scales
Authors: Lai Chun‐Ta , Ehleringer James R. , Tans Pieter , Wofsy Steven C. , Urbanski Shawn P. , Hollinger David Y.
Published: March 2004

We determined δ13C values associated with canopy gross and net CO2 fluxes from four U.S. sites sampled between 2001 and 2002. Annual mean, flux‐weighted δ13C values of net ecosystem CO2 exchange (NEE) were estimated for four contrasting ecosystems (three forests and one grassland) by analyzing daytime flask measurements collected at the top of canopies. Combining δ13C values associated with respiratory and net (respiration minus photosynthesis) fluxes, we demonstrate a method for estimating whole‐canopy photosynthetic discrimination against 13C (ΔA) in terrestrial ecosystems directly from field measurements. This experimental approach offers the possibility of examining interannual variability in ΔA from ecosystem δ13C measurements. Our estimated δ13C values associated with photosynthetic fluxes are in agreement with those measured from foliar organic matter for C3 forests, and are within the range bounded by C3 and C4 grasses in a tallgrass prairie. The δ13C associated with NEE fluxes at our C3 forest sites ranges between −27.1 ± 2.7 and −28.3 ± 2.5‰, and is −22.6 ± 4.0‰ at the prairie site. These estimates differ from a previous study, particularly for C3 ecosystems at comparable latitudes. Sensitivity analyses indicate that our estimates of δ13C values of net CO2 fluxes are robust with respect to measurement errors, but can vary depending on the selection of background atmospheric values. Other factors (e.g., drought and sampling footprint) that might have influenced our δ13C measurements and calculations of ΔA are also discussed. Our measurement‐based analyses are particularly useful when both latitudinal and longitudinal variations in ΔA are to be considered in the global inversion modeling studies.
Real‐time monitoring of South American smoke particle emissions and transport using a coupled remote sensing/box‐model approach
Authors: Reid Jeffrey S. , Prins Elaine M. , Westphal Douglas L. , Schmidt Christopher C. , Richardson Kim A. , Christopher Sundar A. , Eck Thomas F. , Reid Elizabeth A. , Curtis Cynthia A. , Hoffman Jay P.
Published: March 2004

Since August 2000, the Wild fire Automated Biomass Burning Algorithm (WF_ABBA) has been generating half‐hourly fire hot spot analyses for the Western Hemisphere using GOES satellites to provide the Naval Research Laboratory (NRL) Aerosol Analysis and Prediction System (NAAPS) with near‐real‐time fire products. These are used to generate smoke particle fluxes for aerosol transport forecasting to benefit the scientific, weather, and regulatory communities. In South America, fire hot‐spot analysis is shown to be adequate for generating real‐time smoke source functions for aerosol forecast models. We present smoke coverage and flux estimates based on the WF_ABBA and NAAPS products. Modeled fluxes of emissions for 2001–2002 are ∼25 + 10 Tg yr−1, similar to previous estimates. Correlations of optical depth with MODIS and AERONET show good agreement with observations. Comparisons of NAAPS aerosol fields with MODIS also show potential clear sky and other biases as smoke is transported into the Atlantic Ocean and the ITCZ.
Detection of arbitrarily large dynamic ground motions with a dense high‐rate GPS network
Authors: Bock Yehuda , Prawirodirdjo Linette , Melbourne Timothy I.
Published: March 2004

We describe the detection of teleseismic surface waves from the 3 November 2002 Mw 7.9 Denali fault earthquake in Alaska with a dense network of 1 Hz GPS stations in southern California, about 3900 km from the event. Relative horizontal displacements with amplitudes in excess of 15 mm and duration of 700 seconds agree with integrated velocities recorded by nearby broadband seismometers with an rms difference of 2–3 mm. The displacements are derived from independent 1 Hz instantaneous positions demonstrating that a GPS network can provide direct measurements of arbitrarily large dynamic and static ground horizontal displacements at periods longer than 1 s and amplitudes above 2 mm, with an inherent precision (signal to noise) that improves indefinitely with amplitude without clipping and in real time. High‐rate, real‐time GPS networks can enhance earthquake detection and seismic risk mitigation and support other applications such as intelligent transportation and civil infrastructure monitoring.
A ‘low‐level’ explanation for the recent large warming trend over the western Antarctic Peninsula involving blocked winds and changes in zonal circulation
Authors: Orr A. , Cresswell D. , Marshall G. J. , Hunt J. C. R. , Sommeria J. , Wang C. G. , Light M.
Published: March 2004

We demonstrate a mechanism whereby the impact of stronger circumpolar westerly winds on the mountains of the Antarctic Peninsula contributes significantly to the enhanced warming trend observed over its western side in the last 50 years. Numerical and laboratory meteorological modelling demonstrate how, when westerly winds impinge on this side, warm air below the height (1.5–2.0 km) of the Peninsula is advected in a southerly direction. The strength of the annual mean westerly winds has increased by about 15–20% since the 1960s, while the modelling results indicate that contemporaneously the air advected to its western side originates from an increasingly northerly (and warmer) location. This gives rise to increased northerlies and a greater transport of warm air into this region. Consequently there is a reduction in the sea‐ice extent, further amplifying the local warming. This ‘low‐level’, orographic mechanism for the local climate trend is supported by observational evidence.
How deep can we find the traces of Alpine subduction?
Authors: Piromallo Claudia , Faccenna Claudio
Published: March 2004

Slab‐like seismic velocity heterogeneities below the Alpine chain, interpreted as subducted lithosphere, are imaged by tomographic studies down to only about 300 km depth. A non‐negligible discrepancy therefore exists between tomographic and geological data, the latter indicating at least 500 km of Tertiary convergence at trench. Yet a recently published tomographic study detects a pronounced high velocity anomaly at the bottom of the upper mantle right below the Alpine area. Combining tomographic images of the mantle, geological findings and plate system kinematics, we investigate how the presence of this feature in the transition zone below the Alps can be traced back to the Tertiary Alpine subduction and possibly explain the observed discrepancy. We propose that a part of the fast velocity body now residing just above the 660 km discontinuity once belonged to the Alpine slab, torn off by an event occurred at about 30–35 Ma.
Periodic emergence of multicomposition cold ions modulated by geomagnetic field line oscillations in the near‐Earth magnetosphere
Authors: Hirahara M. , Seki K. , Saito Y. , Mukai T.
Published: March 2004

In the equatorial magnetosphere during perigee passing, the Geotail spacecraft sometimes observes periodic enhancements of cold ion flux embedded in the energetic ion component. In particular, the dawnside and duskside regions, the periodic signatures indicate not only oscillating bulk motions of both energetic and cold ion components in the inner magnetosphere but also the existence of multiple ion components at thermal energies, namely, singly‐charged hydrogen, helium, and oxygen of ionospheric origin. Although these cold components would usually be invisible due to the low energy limit of the instrument and the positive potential of the spacecraft, the excitation of Pc 5 pulsations often causes the periodic emergence of the hidden cold ions after their escape from the ionosphere without further significant energization. The distinctive multicomponent ion signatures can be seen frequently from 1999 to 2002, near solar maximum, but not earlier in the Geotail mission, in 1995–1998 in the early rising phase of the solar cycle. It is probable that outflow processes of the ionospheric ions are active at times of high solar activity. A significant fraction of the near‐Earth magnetospheric ion population is dominated by ionospheric ions, as shown in the density calculations for the separate ion species.
Relativistic electrons in the outer radiation belt: Differentiating between acceleration mechanisms
Authors: Green Janet C. , Kivelson M. G.
Published: March 2004

Many theoretical models have been developed to explain the rapid acceleration to relativistic energies of electrons that form the Earth's radiation belts. However, after decades of research, none of these models has been unambiguously confirmed by comparison to observations. Proposed models can be separated into two types: internal and external source acceleration mechanisms. Internal source acceleration mechanisms accelerate electrons already present in the inner magnetosphere (L < 6.6), while external source acceleration mechanisms transport and accelerate a source population of electrons from the outer to the inner magnetosphere. In principle, the two types of acceleration mechanisms can be differentiated because they imply that different radial gradients of electron phase space density expressed as a function of the three adiabatic invariants will develop. Model predictions can be tested by transforming measured electron flux (given as a function of pitch angle, energy, and position) to phase space density as a function of the three invariants, μ, K, and Φ. The transformation requires adoption of a magnetic field model. Phase space density estimates have, in the past, produced contradictory results because of limited measurements and field model errors. In this study we greatly reduce the uncertainties of previous work and account for the contradictions. We use data principally from the Polar High Sensitivity Telescope energetic detector on the Polar spacecraft and the Tsyganenko and Stern [1996] field model to obtain phase space density. We show how imperfect magnetic field models produce phase space density errors and explore how those errors modify interpretations. On the basis of the analysis we conclude that the data are best explained by models that require acceleration of an internal source of electrons near L* ∼ 5. We also suggest that outward radial diffusion from a phase space density peak near L* ∼ 5 can explain the observed correspondence between flux enhancements at geostationary orbit and increases in ULF wave power.
Downward accelerated ions: Ion source for the potential layer
Authors: Hultqvist Bengt
Published: March 2004

The main purpose of this report is to present a solution to the problem of how the observed quasi‐stationary downward flow of ions through a potential difference between the magnetosphere and the ionosphere, ions which originate below the potential difference, can be understood. First, a summary of the observations of downward accelerated ions with keV or sub‐keV energies at altitudes of ∼1700 km is given and the mechanism causing the accelerating quasi‐static potential difference is described. Thereafter it is shown that the ionospheric ions may be transported upward through the potential region in a process sometimes called the “pressure‐cooker” mechanism involving wave turbulence within the region. The turbulence also gives rise to pitch‐angle scattering of the ions so that a fraction of them are precipitated into the altitude range where they are observed by the satellite. This process gives the observed spectral characteristics of the accelerated ions.
Modeling the field‐scale relationship between dielectric constant and water content in heterogeneous systems
Authors: Moysey Stephen , Knight Rosemary
Published: March 2004

Ground‐penetrating radar (GPR) can be used to obtain information about the variation in the dielectric constant of the subsurface. The sensitivity of a soil's dielectric constant to the presence of water therefore makes water content estimation by GPR possible. The dielectric constant derived from GPR data, however, is also influenced by the geometric distribution of water in the subsurface. We show that this causes the relationship between the dielectric constant and water content to become scale dependent in complex geologic systems. We have derived dielectric constant‐water content relationships that account for subsurface geometries in spatially correlated random media that can be characterized using geostatistics. From these relationships we illustrate that the importance of scale effects are strongly dependent on the variance and the anisotropy of the water content in the subsurface; in some cases, ignoring scale effects will not significantly impact the estimation of water content, while in other cases, large biases can occur. This work provides a conceptual framework for the predictive modeling of field‐scale dielectric constant‐water content relationships.
Study calls for improvements to U.S. visa process for students, scholars
Authors: Showstack Randy
Published: March 2004

U.S. federal agencies are implementing some measures to reduce delays in providing foreign scientists and students with non‐immigrant visas, although additional steps could help to improve the cumbersome process, according to a government study released on 25 February by the U.S. General Accounting Office (GAO).

The study, which was requested by the House of Representatives Science Committee, reviewed the issuance of F‐l and J‐1 visas in light of national security measures put in place after September 11, 2001. The committee has expressed concerns about whether new security measures are detrimental to scientific research by unnecessarily delaying the issuance of visas to foreign students and scholars.
Sun unleashes Halloween storm
Authors: Lopez Ramon E. , Baker Daniel N. , Allen Joe
Published: March 2004

It is supposed to be a quiet time on the Sun, as we head toward solar minimum. At the beginning of October, it looked that way, as only a few small sunspots were visible. Then, sunspot group 484 came around the limb of the Sun on 18 October. By 23 October, when 484 was located right on the Earth‐Sun line, this huge group covered 1.7% of the solar disk. At the far edge of the Sun, another massive sunspot group, 486, was just coming into the field of view. And late on the 26th, a third group, 488, emerged from the interior of the Sun just to the north of 486 (Figure 1).
Effects of GW274150, a novel and selective inhibitor of iNOS activity, in acute lung inflammation
Authors: Dugo Laura , Marzocco Stefania , Mazzon Emanuela , Paola Rosanna Di , Genovese Tiziana , Caputi Achille P , Cuzzocrea Salvatore
Published: March 2004

The aim of this study was to investigate the effect of GW274150, a novel, potent and selective inhibitor of inducible nitric oxide synthase (iNOS) activity in a model of lung injury induced by carrageenan administration in the rats.

Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by: fluid accumulation in the pleural cavity which contained a large number of polymorphonuclear cells (PMNs) as well as an infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), tumour necrosis factor α (TNF‐α) and interleukin‐1β (IL‐1β).

All parameters of inflammation were attenuated in a dose‐dependent manner by GW274150 (2.5, 5 and 10 mg kg−1 injected i.p. 5 min before carrageenan).

Carrageenan induced an upregulation of the intracellular adhesion molecules‐1 (ICAM‐1), as well as nitrotyrosine and poly (ADP‐ribose) (PAR) as determined by immunohistochemical analysis of lung tissues.

The degree of staining for the ICAM‐1, nitrotyrosine and PAR was reduced by GW274150. These results clearly confirm that NO from iNOS plays a role in the development of the inflammatory response by altering key components of the inflammatory cascade.

GW274150 may offer a novel therapeutic approach for the management of various inflammatory diseases where NO and related radicals have been postulated to play a role.

British Journal of Pharmacology (2004) 141, 979–987. doi:10.1038/sj.bjp.0705683
Carbamoylating chemoresistance induced by cobalt pretreatment in C6 glioma cells: putative roles of hypoxia‐inducible factor‐1
Authors: Yang Ding‐I , Chen Shang‐Der , Yang Ya‐Ting , Ju Tzyh‐Chwen , Xu Jin‐Ming , Hsu Chung Y
Published: March 2004

We tested whether pretreatment of reagents known to induce hypoxia‐inducible factor‐1 (HIF‐1) may confer chemoresistance against cytotoxicity of 1,3‐bis(2‐chloroethyl)‐1‐nitrosourea (BCNU) to rat C6 glioma cells. We also studied which cytotoxic mechanism(s) of chloroethylnitrosoureas could be neutralized by cobalt preconditioning.

Preconditioning of rat C6 glioma cells with cobalt chloride (300 μM, 2 h) induced HIF‐1 binding activity based on electrophoretic mobility shift assay (EMSA). Results from Western blotting confirmed a heightened HIF‐1α level upon cobalt chloride exposure (300–400 μM, 2 h). Cobalt chloride (300 μM) pretreatment for 2 h substantially neutralized BCNU toxicity, leading to increases in glioma cell survival based on MTT assay. In addition, pre‐exposure of C6 cells with desferrioxamine (DFO; 400 μM, 3 h), an iron chelator known to activate HIF‐1, also induced HIF‐1 binding and rendered the glioma cells resistant to cytotoxicity of BCNU.

Pre‐incubation with cobalt chloride abolished the cytotoxicity of several carbamoylating agents including 2‐chloroethyl isocyanate and cyclohexyl isocyanate, the respective carbamoylating metabolites of BCNU and 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea. The protective effect of cobalt exposure, however, was not observed when cells were challenged with alkylating agents including temozolomide.

Cadmium chloride (50 μM) effectively reversed cobalt‐induced HIF‐1 activation. Correspondingly, cadmium chloride suppressed carbamoylating chemoresistance mediated by cobalt chloride pretreatment. Furthermore, both double‐stranded oligodeoxynucleotide (ODN) decoy with HIF‐1 cognate sequence and antisense phosphorothioate ODNs against HIF‐1α partially abolished the carbamoylating chemoresistance associated with cobalt preconditioning.

Our results suggest that cobalt‐ or DFO‐preconditioning may enhance glioma carbamoylating chemoresistance that is dependent, at least in part, on induction of HIF‐1.

British Journal of Pharmacology (2004) 141, 988–996. doi:10.1038/sj.bjp.0705687
Neuroprotective effects of resveratrol against β‐amyloid‐induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C
Authors: Han Ying‐Shan , Zheng Wen‐Hua , Bastianetto Stéphane , Chabot Jean‐Guy , Quirion Rémi
Published: March 2004

Resveratrol, an active ingredient of red wine extracts, has been shown to exhibit neuroprotective effects in several experimental models.

The present study evaluated the neuroprotective effects of resveratrol against amyloid β(Aβ)‐induced toxicity in cultured rat hippocampal cells and examined the role of the protein kinase C (PKC) pathway in this effect.

Pre‐, co‐ and post‐treatment with resveratrol significantly attenuated Aβ‐induced cell death in a concentration‐dependent manner, with a concentration of 25 μM being maximally effective.

Pretreatment (1 h) of hippocampal cells with phorbol‐12‐myristate‐13‐acetate, a PKC activator, at increasing concentrations (1–100 ng ml−1), resulted in a dose‐dependent reduction in Aβ‐induced toxicity, whereas the inactive 4α‐phorbol had no effect.

Pretreatment (30 min) of hippocampal cells with GF 109203X (1 μM), a general PKC inhibitor, significantly attenuated the neuroprotective effect of resveratrol against Aβ‐induced cell death.

Treatment of hippocampal cells with resveratrol (20 μM) also induced the phosphorylation of various isoforms of PKC leading to activation.

Taken together, the present results indicate that PKC is involved in the neuroprotective action of resveratrol against Aβ‐induced toxicity.

British Journal of Pharmacology (2004) 141, 997–1005. doi:10.1038/sj.bjp.0705688
Binding of the prototypical adenosine A2A receptor agonist CGS 21680 to the cerebral cortex of adenosine A1 and A2A receptor knockout mice
Authors: Lopes Luísa V , Halldner Linda , Rebola Nelson , Johansson Björn , Ledent Catherine , Chen Jian Fan , Fredholm Bertil B , Cunha Rodrigo A
Published: March 2004

2‐p‐(2‐carboxyethylphenethylamino‐5′‐ethylcarboxamidoadenosine) (CGS 21680) is considered the reference compound to study adenosine A2A receptors. However, CGS 21680 binding in the cerebral cortex, where adenosine A1 receptors are predominant, displays a mixed A2A/A1 receptor pharmacology. We now use adenosine A1 and A2A receptor knockout mice to investigate the characteristics of cortical [3H]CGS 21680 binding.

[3H]CGS 21680 binding to the cerebral cortex was strongly reduced in adenosine A1 receptor knockout mice, but only slightly reduced in A2A receptor knockout mice compared with the corresponding wild‐type littermates.

Another selective A2A receptor ligand, [3H]‐5‐amino‐7‐(2‐phenylethyl)‐2‐(2‐furyl)‐pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine ([3H]SCH 58261), displayed a saturable binding to mouse cortical membranes, albeit with a binding density 20 times lower than that of striatal membranes, and this [3H]SCH58261 binding was abolished in both striatal and cortical membranes of A2A receptor knockout mice and unchanged in A1 receptor knockout mice.

The presence of A2A receptors in cortical neurons was further confirmed by Western blot in mouse cortical nerve terminal membranes.

It is concluded that, although A2A receptors are present in the cerebral cortex, the purportedly selective A2A receptor agonist [3H]CGS 21680 binds in the cerebral cortex to an entity that requires the presence of adenosine A1 receptors. Thus, CGS 21680 should be used with care in all preparations where adenosine A1 receptors out‐number A2A receptors.

British Journal of Pharmacology (2004) 141, 1006–1014. doi:10.1038/sj.bjp.0705692
Selectivity of 3H‐MADAM binding to 5‐hydroxytryptamine transporters in vitro and in vivo in mice; correlation with behavioural effects
Authors: Larsen A K , Brennum L T , Egebjerg J , Sánchez C , Halldin C , Andersen P H
Published: March 2004

Binding of the novel radioligand 3H‐2‐(2‐dimethylaminomethyl‐phenylsulphanyl)‐5‐methyl‐phenylamine (3H‐MADAM) to the serotonin transporter (SERT) was used to characterise a range of selective serotonin re‐uptake inhibitors (SSRIs) in vitro and in vivo.

3H‐MADAM bound with high affinity in a saturable manner to both human SERT expressed in CHO cells (Kd=0.20 nM (pKd=9.74±0.12), Bmax=35±4 fmol mg−1 protein) and mouse cerebral cortex membranes (Kd=0.21 nM (pKd=9.66±0.10), Bmax=50±24 fmol mg−1 protein).

Binding of 3H‐MADAM was highly selective for SERT in vitro as demonstrated by the in vitro profile of MADAM tested at 75 different receptors, ion channels and transporters. This was further substantiated by the pharmacological profile of the binding. Hence, the binding of 3H‐MADAM was potently inhibited by SSRIs but not by selective inhibitors of noradrenaline transport and dopamine transport. Likewise, a 5‐HT2A/2C receptor antagonist did not inhibit 3H‐MADAM binding.

3H‐MADAM binding in vivo was inhibited only by compounds which also inhibited the binding of 3H‐MADAM in vitro (the SSRIs, mixed SERT/noradrenaline transport inhibitors and clomipramine), confirming the selectivity of 3H‐MADAM for SERT also in vivo. Moreover, compounds effective in inhibiting 3H‐MADAM binding were the only ones found to be active in the mouse 5‐HTP potentiation test confirming the model as a behavioural correlate to in vivo 5‐HT uptake.

Finally, it was found that a SERT occupancy of 85–95% was necessary to produce 50% of the maximum behavioural response (ED50).

British Journal of Pharmacology (2004) 141, 1015–1023. doi:10.1038/sj.bjp.0705693
Dual effects of adenosine on acetylcholine release from myenteric motoneurons are mediated by junctional facilitatory A2A and extrajunctional inhibitory A1 receptors
Authors: Duarte‐Araújo Margarida , Nascimento Carlos , Alexandrina Timóteo M , Magalhães‐Cardoso Teresa , Correia‐de‐Sá Paulo
Published: March 2004

The coexistence of both inhibitory A1 and facilitatory A2 adenosine receptors in the rat myenteric plexus prompted the question of how adenosine activates each receptor subtype to regulate cholinergic neurotransmission.

Exogenously applied adenosine (0.3–300 μM) decreased electrically evoked [3H]acetylcholine ([3H]ACh) release. Blocking A1 receptors with 1,3‐dipropyl‐8‐cyclopentylxanthine (10 nM) transformed the inhibitory action of adenosine into a facilitatory effect. Adenosine‐induced inhibition was mimicked by the A1 receptor agonist R‐N6‐phenylisopropyladenosine (0.3 μM), but the A2A agonist CGS 21680C (0.003 μM) produced a contrasting facilitatory effect.

Increasing endogenous adenosine levels, by the addition of (1) the adenosine precursor AMP (30–100 μM), (2) the adenosine kinase inhibitor 5′‐iodotubercidin (10 μM) or (3) inhibitors of adenosine uptake (dipyridamole, 0.5 μM) and of deamination (erythro‐9(2‐hydroxy‐3‐nonyl)adenine, 50 μM), enhanced electrically evoked [3H]ACh release (5 Hz for 40 s). Release facilitation was prevented by adenosine deaminase (ADA, 0.5 U ml−1) and by the A2A receptor antagonist ZM 241385 (50 nM); these compounds decreased [3H]ACh release by 31±6% (n=7) and 37±10% (n=6), respectively.

Although inhibition of ecto‐5′‐nucleotidase by α,β‐methylene ADP (200 μM) or by concanavalin A (0.1 mg ml−1) attenuated endogenous adenosine formation from AMP, analysed by HPLC, the corresponding reduction in [3H]ACh release only became evident when stimulation of the myenteric plexus was prolonged to over 250 s.

In summary, we found that endogenously generated adenosine plays a predominantly tonic facilitatory effect mediated by prejunctional A2A receptors. Extracellular deamination and cellular uptake may restrict endogenous adenosine actions to the neuro‐effector region near the release/production sites.

British Journal of Pharmacology (2004) 141, 925–934. doi:10.1038/sj.bjp.141-0705697
Endothelium‐dependent smooth muscle hyperpolarization: do gap junctions provide a unifying hypothesis?
Authors: Griffith Tudor M
Published: March 2004

An endothelium‐derived hyperpolarizing factor (EDHF) that is distinct from nitric oxide (NO) and prostanoids has been widely hypothesized to hyperpolarize and relax vascular smooth muscle following stimulation of the endothelium by agonists. Candidates as diverse as K+ ions, eicosanoids, hydrogen peroxide and C‐type natriuretic peptide have been implicated as the putative mediator, but none has emerged as a ‘universal EDHF’. An alternative explanation for the EDHF phenomenon is that direct intercellular communication via gap junctions allows passive spread of agonist‐induced endothelial hyperpolarization through the vessel wall. In some arteries, eicosanoids and K+ ions may themselves initiate a conducted endothelial hyperpolarization, thus suggesting that electrotonic signalling may represent a general mechanism through which the endothelium participates in the regulation of vascular tone.

British Journal of Pharmacology (2004) 141, 881–903. doi:10.1038/sj.bjp.0705698
NPY presynaptic actions are reduced in the hypothalamic mpPVN of obese (fa/fa), but not lean, Zucker rats in vitro
Authors: Pronchuk Nina , Colmers William F
Published: March 2004

Neuropeptide Y (NPY) profoundly enhances feeding when injected intracerebroventricularly, or directly into hypothalamic nuclei, such as the paraventricular nucleus (PVN). Paradoxically, NPY has a reduced action on feeding in obese Zucker rats relative to lean Zucker rats, although the obese rats have much higher levels of hypothalamic NPY expression. GABAergic inputs to a subpopulation of medial parvocellular PVN (mpPVN) neurons are sensitive to NPY. Here, we tested the hypothesis that the blunted eating response to NPY observed in obese Zucker rats will be reflected in a reduced NPY action at mpPVN GABAergic synapses.

‘Blind’ whole‐cell patch‐clamp recordings made from mpPVN neurons in acute brain slices of lean and obese Zucker rats revealed GABAergic inhibitory postsynaptic currents (IPSC) responses which were inhibited by NPY. While the maximum response in the obese Zucker rats was significantly less than in lean Zucker or Sprague–Dawley rats, there was no difference in the EC50.

Experiments using blocking concentrations of Y1‐ or Y5‐receptor antagonists revealed no differences between lean and obese Zucker rats in the contributions of either of these receptors to the total NPY response in mpPVN.

NPY is less effective at the mpPVN GABA synapse in obese than in lean Zucker rats. This is not associated with a change in the proportion of Y1 or Y5 receptors mediating the NPY response, and is consistent with the downregulation of NPY receptors or a reduction in receptor–effector coupling, and with the reduced sensitivity of obese rats to NPY.

British Journal of Pharmacology (2004) 141, 1032–1036. doi:10.1038/sj.bjp.0705699
The anti‐inflammatory carbazole, LCY‐2‐CHO, inhibits lipopolysaccharide‐induced inflammatory mediator expression through inhibition of the p38 mitogen‐activated protein kinase signaling pathway in macrophages
Authors: Ho Feng‐Ming , Lai Chih‐Chang , Huang Li‐Jiau , Kuo Tsun Cheng , Chao Chien M , Lin Wan‐Wan
Published: March 2004

The present study was undertaken to investigate the anti‐inflammatory effects of a synthetic compound, LCY‐2‐CHO, on the expression of inducible nitric oxide synthase (iNOS), COX‐2, and TNF‐α in murine RAW264.7 macrophages.

Within 1–30 μM, LCY‐2‐CHO concentration‐dependently inhibited lipopolysaccharide (LPS)‐induced nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor‐α (TNF‐α) formation, with IC50 values of 2.3, 1, and 0.8 μM, respectively. Accompanying inhibition of LPS‐induced iNOS, cyclooxygenase‐2 (COX‐2), and pro‐TNF‐α proteins was observed.

Reverse transcription‐polymerase chain reaction (RT–PCR) and promoter analyses indicated that iNOS expression was inhibited at the transcriptional level (IC50=2.3 μM), that inhibition of COX‐2 expression only partially depended on gene transcription (IC50=7.6 μM), and that TNF‐α transcription was unaffected.

Transcriptional assays revealed that activation of AP‐1, but not NF‐κB, was concomitantly blocked by LCY‐2‐CHO. Our results showed that LCY‐2‐CHO was capable of interfering with post‐transcriptional regulation, altering the stability of COX‐2 and TNF‐α mRNAs.

Since the 3′‐untranslated region (3′ UTR) of both COX‐2 and TNF‐α mRNA contains a p38 mitogen‐activated protein kinase (MAPK)‐regulated element involved in mRNA stability, we assessed the effect of LCY‐2‐CHO on p38 MAPK. Our data clearly indicated an inhibition (IC50=1.7 μM) of LPS‐mediated p38 MAPK activity, but not of extracellular signal‐regulated kinase (ERK) or c‐Jun N‐terminal kinase (JNK) activity. However, kinase assays ruled out a direct inhibition of p38 MAPK action. The selective p38 MAPK inhibitor, SB203580, inhibited the promoter activities of iNOS and COX‐2 rather than that of TNF‐α.

In conclusion, LCY‐2‐CHO downregulates inflammatory iNOS, COX‐2, and TNF‐α gene expression in macrophages through interfering with p38 MAPK and AP‐1 activation.

British Journal of Pharmacology (2004) 141, 1037–1047. doi:10.1038/sj.bjp.0705700
Pharmacological activation of plasma‐membrane KATP channels reduces reoxygenation‐induced Ca2+ overload in cardiac myocytes via modulation of the diastolic membrane potential
Authors: Baczkó István , Giles Wayne R , Light Peter E
Published: March 2004

The opening of cardiac plasma‐membrane ATP‐sensitive K+ channels (pmKATP) can protect the heart against ischaemia/reperfusion injury. We recently demonstrated that the resting membrane potential (Em) of ventricular myocytes strongly modulates reoxygenation‐induced Ca2+ overload. This led to the hypothesis that activation of pmKATP can influence the extent of chemically induced hypoxia (CIH)/reoxygenation Ca2+ overload via hyperpolarization of the diastolic membrane potential of ventricular myocytes.

The membrane potential (Em) of isolated rat myocytes was determined using the perforated patch‐clamp technique and DiBac4(3) imaging. Intracellular Ca2+ ([Ca2+]i) was monitored using FURA‐2 imaging.

CIH/reoxygenation caused a significant depolarization of Em and a substantial increase in [Ca2+]i. The KATP opener pinacidil (100 μM) and the pmKATP opener P‐1075 (100 μM) hyperpolarized the Em of normoxic myocytes. Pinacidil (100 μM) and P‐1075 (10 and 100 μM), applied during reoxygenation, hyperpolarized Em and prevented reoxygenation‐induced increases in [Ca2+]i.

Myocyte hypercontracture and death increased in parallel with an Em depolarization of 10–15 mV and increases in [Ca2+]i. Under these conditions, the selective pmKATP channel inhibitor HMR 1098 further depolarized myocyte membrane potential and increased hypercontracture.

In conclusion, activation of pmKATP channels can prevent CIH/reoxygenation‐induced Ca2+ overload via a mechanism that is dependent on hyperpolarization of diastolic membrane potential. Hyperpolarization toward normal resting membrane potential favours the Ca2+ extrusion mode of Na+/Ca2+ exchange.

British Journal of Pharmacology (2004) 141, 1059–1067. doi:10.1038/sj.bjp.0705702
Differential modulation of ATP‐induced calcium signalling by A1 and A2 adenosine receptors in cultured cortical astrocytes
Authors: Alloisio Susanna , Cugnoli Carlo , Ferroni Stefano , Nobile Mario
Published: March 2004

Despite the accumulating evidence that under various pathological conditions the extracellular elevation of adenine‐based nucleotides and nucleosides plays a key role in the control of astroglial reactivity, how these signalling molecules interact in the regulation of astrocyte function is still largely elusive.

The action of the nucleoside adenosine in the modulation of the intracellular calcium signalling ([Ca2+]i) elicited by adenosine 5′‐triphosphate (ATP)‐induced activation of P2 purinoceptors was investigated on neocortical type‐1 astrocytes in primary culture by using single‐cell microfluorimetry.

Astrocyte challenge with ATP (1–10 μM) elicited biphasic [Ca2+]i responses consisting of an initial peak followed by a sustained elevation. The stable adenosine analogue 2‐chloroadenosine (2‐ClA) potentiated the transient [Ca2+]i rise induced by activation of metabotropic P2Y receptors. Among the various P1 receptor agonists tested, the nonselective agonist 5′‐N‐ethylcarboxamidoadenosine (NECA) mimicked the 2‐ClA action, whereas the selective A1 R(−) N6‐(2‐phenylisopropyl)‐adenosine (R‐PIA), the A2A 2‐[4‐(2‐carboxyethyl)phenethylamino]‐5′‐N‐ethylcarboxamidoadenosine (CGS‐21680) and A3 1‐deoxy‐1‐(6‐[([3‐lodophenyl]methyl)‐amino]‐9H‐purin‐9‐yl)‐N‐methyl‐β‐D‐ribofuranuronamide (IB‐MECA) agonists were ineffective.

Application of R‐PIA>NECA2‐ClA depressed the [Ca2+]i plateau reversibly. Moreover, in the presence of R‐PIA or 2‐ClA, the prolonged [Ca2+]i signal was maintained by application of the A1 antagonist 1,3‐diethyl‐8‐phenylxanthine (DPX). Finally, preincubation of the astrocytes with pertussis toxin abrogated the 2‐ClA inhibition of the ATP‐elicited sustained [Ca2+]i rise without affecting the transient [Ca2+]i potentiation.

Taken together, these findings indicate that stimulation of A1 and A2 adenosine receptors mediates a differential modulation of [Ca2+]i signalling elicited by P2 purinoceptors. Since variations in [Ca2+]i dynamics also affect cell proliferation and differentiation, our data suggest that tuning of the extracellular levels of adenosine may be relevant for the control of astrogliosis mediated by adenine nucleotides.

British Journal of Pharmacology (2004) 141, 935–942. doi:10.1038/sj.bjp.0705707
Differential involvement of N‐type calcium channels in transmitter release from vasoconstrictor and vasodilator neurons
Authors: Morris Judy L , Ozols Daina I , Lewis Richard J , Gibbins Ian L , Jobling Phillip
Published: March 2004

The effects of calcium channel blockers on co‐transmission from different populations of autonomic vasomotor neurons were studied on isolated segments of uterine artery and vena cava from guinea‐pigs.

Sympathetic, noradrenergic contractions of the uterine artery (produced by 200 pulses at 1 or 10 Hz; 600 pulses at 20 Hz) were abolished by the N‐type calcium channel blocker ω‐conotoxin (CTX) GVIA at 1–10 nM.

Biphasic sympathetic contractions of the vena cava (600 pulses at 20 Hz) mediated by noradrenaline and neuropeptide Y were abolished by 10 nM CTX GVIA.

Neurogenic relaxations of the uterine artery (200 pulses at 10 Hz) mediated by neuronal nitric oxide and neuropeptides were reduced <50% by CTX GVIA 10–100 nM.

Capsaicin (3 μM) did not affect the CTX GVIA‐sensitive or CTX GVIA‐resistant neurogenic relaxations of the uterine artery.

The novel N‐type blocker CTX CVID (100–300 nM), P/Q‐type blockers agatoxin IVA (10–100 nM) or CTX CVIB (100 nM), the L‐type blocker nifedipine (10 μM) or the ‘R‐type’ blocker SNX‐482 (100 nM), all failed to reduce CTX GVIA‐resistant relaxations. The T‐type channel blocker NiCl2 (100–300 μM) reduced but did not abolish the remaining neurogenic dilations.

Release of different neurotransmitters from the same autonomic vasomotor axon depends on similar subtypes of calcium channels. N‐type channels are responsible for transmitter release from vasoconstrictor neurons innervating a muscular artery and capacitance vein, but only partly mediate release of nitric oxide and neuropeptides from pelvic vasodilator neurons.

British Journal of Pharmacology (2004) 141, 961–970. doi:10.1038/sj.bjp.0705712
The fibrinolytic system attenuates vascular tone: effects of tissue plasminogen activator (tPA) and aminocaproic acid on renal microcirculation
Authors: Heyman Samuel N , Hanna Zohair , Nassar Taher , Shina Ahuva , Akkawi Sa'ed , Goldfarb Marina , Rosen Seymour , Higazi Abd‐Al Roof
Published: March 2004

The renal medulla is a major source of plasminogen activators (PA), recently shown to induce vasodilation in vitro. Treatment with PA inhibitors has been associated with renal dysfunction, suggesting compromised renal microvasculature. We investigated the impact of the PA inhibitor epsilon amino‐caproic acid (EACA) upon vascular tone in vitro, and studied the effect of both tPA and EACA upon intrarenal hemodynamics in vivo.

In vitro experiments were carried out in isolated aortic rings and with cultured vascular smooth muscle cells. Studies of renal microcirculation and morphology were conducted in anesthetized Sprague–Dawley rats.

In isolated aortic rings, EACA (but not the other inhibitors of the fibrinolytic system PAI‐1 or α‐2 antiplasmin) reduced the half‐maximal effective concentration of phenylephrine (PE) required to induce contraction (from 32 nM in control solution to 2 and 0.1 nM at EACA concentrations of 1 and 10 μM, respectively). Using reteplase (retavase) in the same model, we also provide evidence that the vasoactivity of tPA is in part kringle‐dependent. In cultured vascular smooth muscle cells, Ca2+ internalization following PE was enhanced by EACA, and retarded by tPA.

In anesthetized rats, EACA (150 mg kg−1) did not affect systemic blood pressure, total renal or cortical blood flow. However, the outer medullary blood flow declined 12±2% below the baseline (P<0.03). By contrast, tPA (2 mg kg−1), transiently increased outer medullary blood flow by 8±5% (P<0.02). Fibrin microthrombi were not found within the renal microvasculature in EACA‐treated animals.

In conclusion, both fibrinolytic and antifibrinolytic agents modulate medullary renal blood flow with reciprocal effects of vasodilation (PA) and vasoconstriction (EACA). In vitro studies suggest that these hemodynamic responses are related to direct modulation of the vascular tone.

British Journal of Pharmacology (2004) 141, 971–978. doi:10.1038/sj.bjp.0705714
Superfluidity of a Fermi liquid from the viewpoint of a hierarchy of equations for reduced density matrices
Authors: Golovko V. A.
Published: March 2004

The hierarchy of equations for reduced density matrices relevant to thermodynamic equilibrium with account taken of the spin obtained earlier is modified in order to describe the state of a Fermi system with a condensate. Although the procedure is to some extent analogous with the one carried out by the author earlier for a Bose liquid peculiarities relevant to Fermi statistics complicate considerably the treatment. As in the case of the Bose liquid the condensate phase can be superfluid as well as nonsuperfluid, the physical causes of superfluidity being identical. A new mechanism of fermion pairing that acts even in the case of a purely repulsive Hamiltonian is pointed out. Special attention is given to the thermodynamics of a superfluid Fermi system. The example of a hard-sphere system is used to find out the form of phase diagrams, the character of the phase transition to a condensate phase and the properties of the last. Noticeable dissimilarities from a Bose system with the same Hamiltonian are revealed. Application of the present approach to superconductivity is discussed as well.