bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of satellite ozone profile retrievals using Beijing ozonesonde data
Authors: Bian Jianchun , Gettelman Andrew , Chen Hongbin , Pan Laura L.
Published: March 2007

Ozonesondes launched from Beijing, China, over a 3 year time period (September 2002 to July 2005) are used to evaluate the performance of ozone profile retrievals in the upper troposphere and lower stratosphere (UTLS) from two new spaceborne instruments, the Atmospheric Infrared Sounder (AIRS) on the NASA Aqua satellite and the Microwave Limb Sounder (MLS) on the NASA Aura satellite. Since the Global Positioning System ozone sensors (GPSO3) used in Beijing ozonesondes are new, comparisons with simultaneously launched Vaisala ECC sensors, and comparisons with an ozonesonde climatology from Sapporo, Japan, are presented. The results show that although the new GPSO3 sensor has a positive bias (about 20–30%) below 200 hPa and a negative bias (about 5–10%) above 60 hPa relative to known sensors, the measured ozone variability is consistent with Vaisala ECC ozonesondes, particularly in the UTLS region. The GPSO3 ozonesonde profiles over Beijing are then used to evaluate coincident ozone profiles from AIRS version 4 retrieval and MLS version 1.5 retrieval. Qualitatively, both satellite data sets can reproduce the gradients and variability of ozone in the UTLS region. Quantitatively, the agreement between the AIRS and ozonesonde ozone profiles is largely within 10% in the UTLS region (from 400 to 70 hPa). The statistical difference between the retrieval and ozonesonde data is minimum in the vicinity of the tropopause. The MLS ozone profiles also show good quality in the UTLS region with the best performance between 147 and 46 hPa.
Effects of mixing on evolution of hydrocarbon ratios in the troposphere
Authors: Parrish D. D. , Stohl A. , Forster C. , Atlas E. L. , Blake D. R. , Goldan P. D. , Kuster W. C. , de Gouw J. A.
Published: March 2007

Nonmethane hydrocarbon (NMHC) concentration ratios provide useful indicators of tropospheric oxidation and transport processes. However, the influences of both photochemical and mixing processes are inextricably linked in the evolution of these ratios. We present a model for investigating these influences by combining the transport treatment of the Lagrangian particle dispersion model FLEXPART with an ultrasimple (i.e., constant OH concentration) chemical treatment. Required model input includes NMHC emission ratios, but not ad hoc assumed background NMHC concentrations. The model results give NMHC relationships that can be directly compared, in a statistical manner, with measurements. The measured concentration ratios of the longest‐lived alkanes show strong deviations from purely kinetic behavior, which the model nicely reproduces. In contrast, some measured aromatic ratio relationships show even stronger deviations that are not well reproduced by the model for reasons that are not understood. The model‐measurement comparisons indicate that the interaction of mixing and photochemical processing prevent a simple interpretation of “photochemical age,” but that the average age of any particular NMHC can be well defined and can be approximated by a properly chosen and interpreted NMHC ratio. In summary, the relationships of NMHC concentration ratios not only yield useful measures of photochemical processing in the troposphere, but also provide useful test of the treatment of mixing and chemical processing in chemical transport models.
Evaluation of several PM2.5 forecast models using data collected during the ICARTT/NEAQS 2004 field study
Authors: McKeen S. , Chung S. H. , Wilczak J. , Grell G. , Djalalova I. , Peckham S. , Gong W. , Bouchet V. , Moffet R. , Tang Y. , Carmichael G. R. , Mathur R. , Yu S.
Published: March 2007

Real‐time forecasts of PM2.5 aerosol mass from seven air quality forecast models (AQFMs) are statistically evaluated against observations collected in the northeastern United States and southeastern Canada from two surface networks and aircraft data during the summer of 2004 International Consortium for Atmospheric Research on Transport and Transformation (ICARTT)/New England Air Quality Study (NEAQS) field campaign. The AIRNOW surface network is used to evaluate PM2.5 aerosol mass, the U.S. EPA STN network is used for PM2.5 aerosol composition comparisons, and aerosol size distribution and composition measured from the NOAA P‐3 aircraft are also compared. Statistics based on midday 8‐hour averages, as well as 24‐hour averages are evaluated against the AIRNOW surface network. When the 8‐hour average PM2.5 statistics are compared against equivalent ozone statistics for each model, the analysis shows that PM2.5 forecasts possess nearly equivalent correlation, less bias, and better skill relative to the corresponding ozone forecasts. An analysis of the diurnal variability shows that most models do not reproduce the observed diurnal cycle at urban and suburban monitor locations, particularly during the nighttime to early morning transition. While observations show median rural PM2.5 levels similar to urban and suburban values, the models display noticeably smaller rural/urban PM2.5 ratios. The ensemble PM2.5 forecast, created by combining six separate forecasts with equal weighting, is also evaluated and shown to yield the best possible forecast in terms of the statistical measures considered. The comparisons of PM2.5 composition with NOAA P‐3 aircraft data reveals two important features: (1) The organic component of PM2.5 is significantly underpredicted by all the AQFMs and (2) those models that include aqueous phase oxidation of SO2 to sulfate in clouds overpredict sulfate levels while those AQFMs that do not include this transformation mechanism underpredict sulfate. Errors in PM2.5 ammonium levels tend to correlate directly with errors in sulfate. Comparisons of PM2.5 composition with the U.S. EPA STN network for three of the AQFMs show that sulfate biases are consistently lower at the surface than aloft. Recommendations for further research and analysis to help improve PM2.5 forecasts are also provided.
Robustness of terrestrial carbon and water cycle simulations against variations in spatial resolution
Authors: Müller Christoph , Lucht Wolfgang
Published: March 2007

Dynamic Global Vegetation Models (DGVMs) of the terrestrial carbon and water cycle have been developed and validated at specific spatial resolutions (mostly 0.5°) but are increasingly being coupled to climate models at coarser spatial resolutions. Is this permissible? We ran the LPJ‐DGVM at different spatial resolutions (0.5 × 0.5° to 10.0 × 10.0° in 0.5° intervals) to assess the robustness of terrestrial carbon and water flux simulations to changes in spatial resolution. We show that global model results are robust with only small deviations in the single‐digit percent range from a benchmark run at 0.5°. The magnitude of the deviation increases with grid coarseness. Temporal dynamics are largely unaffected by grid cell size. The deviations from the benchmark are mostly spread evenly in space and are otherwise concentrated in areas with strong environmental gradients. We conclude that for coarse‐resolution model coupling (such as with climate models) as well as for specific global‐scale applications (such as global agroeconomic modeling or integrated assessment modeling) the spatial resolution of DGVMs can be reduced to coarser grids with little biogeochemical error.
Recent glaciation at high elevations on Arsia Mons, Mars: Implications for the formation and evolution of large tropical mountain glaciers
Authors: Shean David E. , Head James W. , Fastook James L. , Marchant David R.
Published: March 2007

The ∼166,000 km2fan‐shaped deposit at Arsia Mons contains three characteristic facies (ridged, knobby, and smooth), which are interpreted as the depositional remains of a cold‐based glacier that was present on the west–northwestern flanks in the Late Amazonian period of Mars history. Here, we consider several high‐elevation graben on the western flank of Arsia Mons that are interpreted as the source regions for late‐stage, cold‐based glaciers that overflowed graben walls, advanced tens to hundreds of kilometers downslope, experienced subsequent retreat, and left distinctive depositional features similar to those associated with cold‐based glaciers in the Dry Valleys of Antarctica. These new observations provide additional support for a cold‐based glacial interpretation of the Tharsis Montes fan‐shaped deposits. Morphological evidence suggests that the largest of these graben was the primary source region for the most proximal smooth facies lobes at Arsia Mons, and map‐plane ice sheet reconstructions are consistent with these observations. This relationship has significant implications for the relative ages of the individual facies within the fan‐shaped deposit, including the possibility that the smooth facies represents several distinct phases of glaciation. The high relief and large elevation differences between the upslope and downslope walls of these graben appear to be critical factors for ice accumulation and the generation/collection of rockfall within glacial accumulation zones. We suggest that rockfall was the dominant process responsible for debris‐cover formation on the glaciers sourced within these graben and consider the implications for the entire Arsia fan‐shaped deposit. New crater count data suggest that the fill material in the large Arsia graben formed within the past ∼100 Myr (model age of ∼65 Ma). Taken together, these new observations provide additional evidence for several periods of Late Amazonian climate change on Mars within the past few 100 Myr resulting in episodes of tropical mountain glaciation. Finally, MOLA topography reveals that several lobate features interpreted as remnant debris‐covered ice from the most recent phase of glaciation are presently hundreds of meters thick, suggesting the possibility of long‐term, near‐surface water ice survival in the equatorial regions of Mars.
Long‐term changes in stream bank soil pipes and the effects of afforestation
Authors: Jones J. A. A. , Cottrell C. I.
Published: March 2007

Natural soil pipes are now recognized as potentially significant elements in hillslope drainage systems, sometimes developing into open channel tributaries or contributing often substantial volumes of quick flow to streams. However, there has been no detailed, long‐term monitoring study of the evolution of pipe networks to indicate how permanent they are or how readily they may develop into open channels. This paper reports a resurvey of a section of stream bank in the English Peak District and compares it with the original survey 35 years previous. Comparison of the distribution, size, and shape of pipes on both banks of a 250 m stretch of the stream reveals significant changes. There were no cases of roof collapse forming new open channels. However, there has been a significant change in land use within the basin, with afforestation of the east bank. The resurvey shows a marked reduction in the number and size of pipes on the forested bank, but no significant change on the opposite bank that has remained moorland. The number of pipe outlets on the afforested bank halved over the period, and their mean diameter has reduced by 30%. In combination with the reduced number the smaller size resulted in a 71% reduction in the total area of stream bank occupied by pipe outlets on the forested bank. It is postulated that the change is primarily due to a change in the amount of throughflow beneath the forest caused by an increase in evapotranspiration.
Methods to assess natural and anthropogenic thaw lake drainage on the western Arctic coastal plain of northern Alaska
Authors: Hinkel Kenneth M. , Jones Benjamin M. , Eisner Wendy R. , Cuomo Chris J. , Beck Richard A. , Frohn Robert
Published: March 2007

Thousands of lakes are found on the Arctic Coastal Plain of northern Alaska and northwestern Canada. Developed atop continuous permafrost, these thaw lakes and associated drained thaw lake basins are the dominant landscape elements and together cover 46% of the 34,570 km2 western Arctic Coastal Plain (WACP). Lakes drain by a variety of episodic processes, including coastal erosion, stream meandering, and headward erosion, bank overtopping, and lake coalescence. Comparison of Landsat multispectral scanner (MSS) imagery from the mid‐1970s to Landsat 7 enhanced thematic mapper (ETM+) imagery from around 2000 shows that 50 lakes completely or partially drained over the approximately 25 year period, indicating landscape stability. The lake‐specific drainage mechanism can be inferred in some cases and is partially dependant on geographic settings conducive to active erosion such as riparian and coastal zones. In many cases, however, the cause of drainage is unknown. The availability of high‐resolution aerial photographs for the Barrow Peninsula extends the record back to circa 1950; mapping spatial time series illustrates the dynamic nature of lake expansion, coalescence, and drainage. Analysis of these historical images suggests that humans have intentionally or inadvertently triggered lake drainage near the village of Barrow. Efforts to understand landscape processes and identify events have been enhanced by interviewing Iñupiaq elders and others practicing traditional subsistence lifestyles. They can often identify the year and process by which individual lakes drained, thereby providing greater dating precision and accuracy in assessing the causal mechanism. Indigenous knowledge has provided insights into events, landforms, and processes not previously identified or considered.
F15063, a potential antipsychotic with D2/D3antagonist, 5‐HT1Aagonist and D4partial agonist properties: (I)in vitroreceptor affinity and efficacy profile
Authors: Newman‐Tancredi A , Assié M‐B , Martel J‐C , Cosi C , Slot L Bruins , Palmier C , Rauly‐Lestienne I , Colpaert F , Vacher B , Cussac D
Published: March 2007

Background and purpose:

Combining 5‐HT1Areceptor activation with dopamine D2/D3receptor blockade should improve negative symptoms and cognitive deficits in schizophrenia. We describe thein vitroprofile of F15063 (N‐[(2,2‐dimethyl‐2,3‐dihydro‐benzofuran‐7‐yloxy)ethyl]‐3‐(cyclopent‐1‐enyl)‐benzylamine).

Experimental approach:

F15063 was characterised in tests of binding affinity and in cellular models of signal transduction at monoamine receptors.

Key results:

Affinities (receptor and pKivalues) of F15063 were: rD29.38; hD2L9.44; hD2S9.25; hD38.95; hD48.81; h5‐HT1A8.37. F15063 had little affinity (40‐fold lower than D2) at other targets. F15063 antagonised dopamine‐activated G‐protein activation at hD2, rD2and hD3receptors with potency (pKbvalues 9.19, 8.29 and 8.74 in [35S]GTPγS binding experiments) similar to haloperidol. F15063 did not exhibit any hD2receptor agonism, even in tests of ERK1/2 phosphorylation and G‐protein activation in cells with high receptor expression. In contrast, like (±)8‐OH‐DPAT, F15063 efficaciously activated h5‐HT1A(Emax70%, pEC507.57) and r5‐HT1Areceptors (52%, 7.95) in tests of [35S]GTPγS binding, cAMP accumulation (90%, 7.12) and ERK1/2 phosphorylation (93%, 7.13). F15063 acted as a partial agonist for [35S]GTPγS binding at hD4(29%, 8.15) and h5‐HT1Dreceptors (35%, 7.68). In [35S]GTPγS autoradiography, F15063 activated G‐proteins in hippocampus, cortex and septum (regions enriched in 5‐HT1Areceptors), but antagonised quinelorane‐induced activation of D2/D3receptors in striatum.

Conclusions and implications:

F15063 antagonised dopamine D2/D3receptors, a property underlying its antipsychotic‐like activity, whereas activation of 5‐HT1Aand D4receptors mediated its actions in models of negative symptoms and cognitive deficits of schizophrenia (see companion papers).

British Journal of Pharmacology(2007)151, 237–252. doi:10.1038/sj.bjp.0707158
F15063, a compound with D2/D3antagonist, 5‐HT1Aagonist and D4partial agonist properties: (II) Activity in models of positive symptoms of schizophrenia
Authors: Depoortère R , Bardin L , Auclair A L , Kleven M S , Prinssen E , Colpaert F , Vacher B , Newman‐Tancredi A
Published: March 2007

Background and purpose:

F15063 is a high affinity D2/D3antagonist, D4partial agonist, and high efficacy 5‐HT1Aagonist, with little affinity (40‐fold lower than for D2receptors) at other central targets. Here, the profile of F15063 was evaluated in models of positive symptoms of schizophrenia and motor side‐effects.

Experimental approach:

Rodent behavioural tests were based on reversal of hyperactivity induced by psychostimulants and on measures of induction of catalepsy and ‘serotonin syndrome’.

Key results:

F15063 potently (ED50s: 0.23 to 1.10 mg kg−1i.p.) reversed methylphenidate‐induced stereotyped behaviors, blocked d‐amphetamine and ketamine hyperlocomotion, attenuated apomorphine‐induced prepulse inhibition (PPI) deficits, and was active in the conditioned avoidance test. In mice, it reversed apomorphine‐induced climbing (ED50= 0.30 mg kg−1i.p.). F15063, owing to its 5‐HT1Aagonism, did not produce (ED50> 40 mg kg−1i.p.) catalepsy in rats and mice, a behavior predictive of occurrence of extra‐pyramidal syndrome (EPS) in man. This absence of cataleptogenic activity was maintained upon sub‐chronic treatment of rats for 5 days at 40 mg kg−1p.o. Furthermore, F15063 did not induce the ‘serotonin syndrome’ in rats (flat body posture and forepaw treading: ED50>32 mg kg−1i.p.).

Conclusions and implications:

F15063 conformed to the profile of an atypical antipsychotic, with potent actions in models of hyperdopaminergic activity but without inducing catalepsy. These data suggest that F15063 may display potent antipsychotic actions with low EPS liability. This profile is complemented by a favourable profile in rodent models of negative symptoms and cognitive deficits of schizophrenia (companion paper).

British Journal of Pharmacology(2007)151, 253–265. doi:10.1038/sj.bjp.0707159
F15063, a compound with D2/D3antagonist, 5‐HT1Aagonist and D4partial agonist properties: (III) Activity in models of cognition and negative symptoms
Authors: Depoortère R , Auclair A L , Bardin L , Slot L Bruins , Kleven M S , Colpaert F , Vacher B , Newman‐Tancredi A
Published: March 2007

Background and purpose:

The D2/D3receptor antagonist, D4receptor partial agonist, and high efficacy 5‐HT1Areceptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the ‘serotonin syndrome’. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/cognitive deficits of schizophrenia.

Experimental approach:

F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems.

Key results:

Through 5‐HT1Aactivation, F15063 partially alleviated (MED: 0.04 mg kg−1) PCP‐induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mg kg−1, F15063 reduced interaction by itself. F15063 (0.16 mg kg−1) selectively re‐established PCP‐impaired ‘cognitive flexibility’ in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04–0.63 mg kg−1) also reversed scopolamine‐induced amnesia in a juvenile‐adult rat social recognition test, indicative of a pro‐cholinergic influence. Activity in this latter test is consistent with its D4partial agonism, as it was blocked by the D4antagonist L745,870. Finally, F15063 up to 40 mg kg−1did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating.

Conclusions and implications:

The balance of D2/D3, D4and 5‐HT1Areceptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia.

British Journal of Pharmacology(2007)151, 266–277. doi:10.1038/sj.bjp.0707160
Optimisation of anti‐psychotic therapeutics: a balancing act?
Authors: Lawrence A J
Published: March 2007

Schizophrenia is a complex and debilitating disorder. Although effective therapeutic strategies are available, these are not without problems and are not universally efficacious. In this issue of the British Journal of Pharmacology, a trio of papers describe the characterisation of a potential, novel anti‐psychotic medication, F15063. This compound combines antagonism of dopamine D2‐like receptors with agonism at 5‐HT1A receptors. Based on in vitro and in vivo profiles, the authors suggest that this compound approaches the ‘optimal balance’ for activity at these receptor systems.

British Journal of Pharmacology (2007) 151, 161–162. doi:10.1038/sj.bjp.0707164
Continuous infusion of the cannabinoid WIN 55,212–2 to the site of a peripheral nerve injury reduces mechanical and cold hypersensitivity
Authors: Lever I J , Pheby T M , Rice A S C
Published: March 2007

Background and purpose:

Cannabinoids have analgesic and anti‐inflammatory properties but their use is limited by psychotropic activity at CNS receptors. Restricting cannabinoid delivery to peripheral tissues at systemically inactive doses offers a potential solution to this problem.

Experimental approach:

WIN 55,212‐2 was continuously delivered to the site of a partial ligation injury to the sciatic nerve via a perineural catheter connected to a mini‐osmotic pump implanted at the time of injury. Bilateral reflex limb withdrawal behaviour was measured in adult male Wistar rats in response to mechanical and cooling stimulation of the hind paw.

Key results:

Compared with vehicle treatment, WIN 55,212‐2 (1.4μg μl−1 hr−1) reduced hypersensitivity to stimuli applied to the injured limb at 2, 4 and 6 days after injury. The effects of WIN 55,212‐2 (0.6‐2.8μg μl−1 hr−1) were dose‐dependent. Estimated EC50 values for reduction in mean responses to mechanical and cooling stimulation (day 4 post‐surgery) were 1.55 (95% C.I, [1.11‐2.16]) μg μl−1 hr−1 and 1.52 (95% C.I, [1.07‐2.18]) μg μl−1 hr−1, respectively. When delivered to the contralateral side to injury, WIN 55,212‐2 (1.4 or 2.8μg μl−1 hr−1) did not significantly affect nerve injury‐associated hypersensitivity. Co‐perineural application of a CB1 receptor antagonist SR141716a and WIN 55,212‐2 prevented the effects of WIN 55,212‐2 on hypersensitivity. Co‐application of CB2 receptor antagonist SR144528 reversed WIN 55,212‐2's effect on mechanical hypersensitivity on day 2 only.

Conclusions and implications:

These data support a peripheral antihyperalgesic effect of WIN 55,212‐2 when delivered directly to the site of a nerve injury at systemically inactive doses.

British Journal of Pharmacology (2007) 151, 292–302. doi:10.1038/sj.bjp.0707210
Oral administration of Ginkgo biloba extract, EGb‐761 inhibits thermal hyperalgesia in rodent models of inflammatory and post‐surgical pain
Authors: Biddlestone L , Corbett A D , Dolan S
Published: March 2007

Background and purpose:

Studies in vitro suggest that the standardised extract of Ginkgo biloba, EGb‐761 has anti‐inflammatory properties and modulatory effects on key pain‐related molecules. This study investigated the analgesic and anti‐inflammatory effects of EGb‐761 on carrageenan‐induced inflammatory and hindpaw incisional pain.

Experimental approach:

Adult male Wistar rats (n=6‐10/group; 250‐420 g) were injected intradermally with carrageenan into the left hindpaw or anaesthetised with isoflurane (2%) and a longitudinal 1 cm incision was made through the skin, fascia and plantaris muscle of the hindpaw. EGb‐761 (3, 10, 30, 100 or 300 mg kg−1), diclofenac (5 mg kg−1) or drug‐vehicle was administered 3 h post‐carrageenan/post‐surgery. Hindpaw withdrawal latency (in seconds) to thermal stimulation, response threshold (in grams) to mechanical stimulation and paw volume were measured.

Key results:

Carrageenan induced significant mechanical allodynia, thermal hyperalgesia and paw oedema at 6 h post‐carrageenan, while paw incision surgery induced significant mechanical allodynia and thermal hyperalgesia at 6 and 24 h post‐surgery. Administration of EGb‐761 dose‐dependently inhibited thermal hyperalgesia and was equally effective as diclofenac (5 mg kg−1) in both the carrageenan and hindpaw incision model. EGb‐761 had no effect on carrageenan‐ or incision‐induced mechanical allodynia or paw oedema. Diclofenac significantly reduced mechanical allodynia in both models and carrageenan‐induced paw oedema.

Conclusions and Implications:

EGb‐761 dose‐dependently alleviates acute inflammatory and surgically induced thermal hyperalgesia and is comparable to diclofenac, a commonly prescribed non‐steroidal anti‐inflammatory drug. This indicates that EGb‐761 has analgesic potential in acute inflammatory pain.

British Journal of Pharmacology (2007) 151, 285–291. doi:10.1038/sj.bjp.0707220
Characterization of the postjunctionalα2C‐adrenoceptor mediating vasoconstriction to UK14304 in porcine pulmonary veins
Authors: Görnemann T , von Wenckstern H , Kleuser B , Villalón C M , Centurión D , Jähnichen S , Pertz H H
Published: March 2007

Background and purpose:

In terms of postjunctional α2‐adrenoceptors in the pulmonary circulation, no evidence is available with regard to the receptor subtypes mediating vasoconstriction. Therefore, we characterized the α2‐adrenoceptor subtypes mediating contraction in isolated porcine pulmonary veins.

Experimental approach:

α‐adrenoceptor‐mediated vasoconstriction was studied using a tissue bath protocol. mRNA profile and relative quantification of α2‐adrenoceptor subtypes were determined in porcine pulmonary veins using reverse‐transcriptase polymerase chain reaction (RT‐PCR) and real‐time PCR.

Key results:

In porcine pulmonary veins, noradrenaline, phenylephrine (α1‐adrenoceptor agonist), UK14304 and clonidine (α2‐adrenoceptor agonists) caused concentration‐dependent contractions. The rank order of agonist potency was: NA≈UK14304≈clonidine > phenylephrine. UK14304 responses were antagonised by MK912 (noncompetitive antagonist parameter pD’2: 10.1), rauwolscine (pKB: 9.5), yohimbine (pKB: 9.1), WB4101 (pKB: 8.7), ARC239 (pKB: 7.5), prazosin (pKB: 7.1) and BRL44408 (pKB: 7.0). Antagonist potencies fitted best with radioligand binding data (pKi) at the human recombinant α2C‐adrenoceptor (r2= 0.96,P= 0.0001). Correlation with α2B‐adrenoceptors was lower (r2= 0.74,P> 0.01) and no correlation was obtained with α2A‐adrenoceptors. Moreover, RT‐PCR studies in porcine pulmonary veins showed mRNA signals for α2A‐ and α2C‐adrenoceptors, but not for α2B‐adrenoceptors, whilst real‐time PCR studies indicated a prominent expression of α2C‐adrenoceptor mRNA.

Conclusions and Implications:

Postjunctional α2C‐adrenoceptors mediated contraction in porcine pulmonary veins. α1‐Adrenoceptors also seem to be present in this tissue. Since α2‐adrenoceptor responsiveness is increased when pulmonary vascular tone is elevated, α2C‐adrenoceptor antagonists may be beneficial in diseases such as pulmonary hypertension or congestive heart failure.

British Journal of Pharmacology(2007)151, 186–194. doi:10.1038/sj.bjp.0707221
Melatonin inhibits nitric oxide production by microvascular endothelial cellsin vivoandin vitro
Authors: Silva C L M , Tamura E K , Macedo S M D , Cecon E , Bueno‐Alves L , Farsky S H P , Ferreira Z S , Markus R P
Published: March 2007

Background and purpose:

We have previously shown that melatonin inhibits bradykinin‐induced NO production by endothelial cellsin vitro.The purpose of this investigation was to extend this observation to anin vivocondition and to explore the mechanism of action of melatonin.

Experimental approach:

RT‐PCR assays were performed with rat cultured endothelial cells. The putative effect of melatonin upon arteriolar tone was investigated by intravital microscopy while NO production by endothelial cellsin vitrowas assayed by fluorimetry, and intracellular Ca2+measurements were assayed by confocal microscopy.

Key results:

No expression of the mRNA for the melatonin synthesizing enzymes, arylalkylamine N‐acetyltransferase and hydroxyindole‐O‐methyltransferase, or for the melatonin MT2receptor was detected in microvascular endothelial cells. Melatonin fully inhibitedL‐NAME‐sensitive bradykinin‐induced vasodilation and also inhibited NO production induced by histamine, carbachol and 2‐methylthio ATP, but did not inhibit NO production induced by ATP orα,β‐methylene ATP. None of its inhibitory effects was prevented by the melatonin receptor antagonist, luzindole. In nominally Ca2+‐free solution, melatonin reduced intracellular Ca2+mobilization induced by bradykinin (40%) and 2‐methylthio ATP (62%) but not Ca2+mobilization induced by ATP.

Conclusions and implications:

We have confirmed that melatonin inhibited NO production bothin vivoandin vitro. In addition, the melatonin effect was selective for some G protein‐coupled receptors and most probably reflects an inhibition of Ca2+mobilization from intracellular stores.

British Journal of Pharmacology(2007)151, 195–205. doi:10.1038/sj.bjp.0707225
Increased insulin sensitivity and reduced micro and macro vascular disease induced by 2‐deoxy‐D‐glucose during metabolic syndrome in obese JCR: LA‐cp rats
Authors: Russell J C , Proctor S D
Published: March 2007

Background and purpose:

The metabolic syndrome, characterized by obesity, insulin resistance and dyslipidemia, is a major cause of cardiovascular disease. The origins of the syndrome have been hypothesized to lie in continuous availability of energy dense foods in modern societies. In contrast, human physiology has evolved in an environment of sporadic food supply and frequent food deprivation. Intermittent food restriction in rats has previously been shown to lead to reduction of cardiovascular risk and a greater life span. The non‐metabolizable glucose analogue, 2‐deoxy‐D‐glucose (2‐DG) is taken up by cells and induces pharmacological inhibition of metabolism of glucose. We hypothesized that intermittent inhibition of glucose metabolism, a metabolic deprivation, may mimic intermittent food deprivation and ameliorate metabolic and pathophysiological aspects of the metabolic syndrome.

Experimental approach:

Insulin resistant, atherosclerosis‐prone JCR:LA‐cp rats were treated with 2‐DG (0.3% w/w in chow) on an intermittent schedule (2 days treated, one day non‐treated, two days treated and two days non‐treated) or continuously at a dose to give an equivalent averaged intake.

Key results:

Intermittent 2‐DG‐treatment improved insulin sensitivity, which correlated with increased adiponectin concentrations. Further, intermittent treatment (but not continuous treatment) reduced plasma levels of leptin and the inflammatory cytokine IL‐1β. Both 2‐DG treatments reduced micro‐vascular glomerular sclerosis, but only the intermittent schedule improved macro‐vascular dysfunction.

Conclusions and implications:

Our findings are consistent with reduction in severity of the metabolic syndrome and protection against end stage micro‐ and macro‐vascular disease through intermittent metabolic deprivation at a cellular level by inhibition of glucose oxidation with 2‐DG.

British Journal of Pharmacology (2007) 151, 216–225. doi:10.1038/sj.bjp.0707226
The bisphosphonate alendronate improves the damage associated with trinitrobenzenesulfonic acid‐induced colitis in rats
Authors: Ballester I , Daddaoua A , López‐Posadas R , Nieto A , Suárez M D , Zarzuelo A , Martínez‐Augustin O , de Medina F Sánchez
Published: March 2007

Background and purpose:

The nitrogen‐containing bisphosphonates are drugs used successfully in the treatment of osteoporosis. They act inhibiting farnesyl diphosphate synthase. This mechanism may also produce anti‐inflammatory effects. The therapeutic activity of alendronate was tested in vivo using a model of inflammatory bowel disease.

Experimental approach:

The trinitrobenzenesulfonic acid model of colitis in the rat was used. Rats were treated orally with alendronate and its efficacy compared with that of oral sulphasalazine or vehicle, starting 2 h after colitis induction. The status of the animals was assessed 5 days later.

Key results:

Alendronate treatment (25 or 75 mg kg‐1 day‐1) resulted in a decrease in the colonic damage score and loss of body weight (at 25 mg kg‐1 day‐1 only). This was associated to a dramatic reduction in the mRNA levels of interleukin 1β (IL‐1β), monocyte chemoattractant protein 1 (MCP‐1) and interleukin 1 receptor antagonist (IL‐1ra). The magnitude of the beneficial effect was comparable to that of sulphasalazine (at a 6‐20 fold higher dose). Thus sulphasalazine post‐treatment reduced the mRNA levels of IL‐1β/IL‐1ra and MCP‐1 to the same extent as alendronate and additionally lowered colonic alkaline phosphatase activity, but failed to affect body weight loss or colonic damage score. Alendronate failed to exert beneficial effects when administered intraperitoneally.

Conclusions and Implications:

Oral but not intraperitoneal alendronate significantly protected the colon in experimental rat colitis. Inflammatory bowel disease patients might benefit from exposure to oral alendronate.

British Journal of Pharmacology (2007) 151, 206–215. doi:10.1038/sj.bjp.0707227
Nasopharyngeal carcinoma‐associated Epstein–Barr virus‐encoded oncogene latent membrane protein 1 potentiates regulatory T‐cell function
Authors: Pai Saparna , O'Sullivan Brendan , Abdul‐Jabbar Ibtissam , Peng Judy , Connoly Geoff , Khanna Rajiv , Thomas Ranjeny
Published: March 2007

Sequence variation in the Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) oncogene structure may affect antigen‐presenting cell (APC) function of infected B cells and immune escape by EBV‐specific T cells and thus contribute to the development of malignancy. Normal B cell‐associated LMP1 (B‐LMP1) upregulates B cell APC function through activation of the necrosis factor (NF)‐κB subunit, RelB. We examined the ability of B‐LMP1 and a nasopharyngeal carcinoma‐associated LMP1 (NPC‐LMP1) to modulate B cell APC function and T‐cell responses. B lymphoma cells transfected with NPC‐LMP1 stimulated resting T cells in mixed lymphocyte reaction less efficiently than B‐LMP1 transfectants. Unexpectedly, antigen presentation to CD4+ T helper cells was reduced owing to potentiation of regulatory T‐cell function by NPC‐LMP1 transfectants, which produce increased levels of interleukin‐10, rendering CD4+ T cells hyporesponsive. Thus, after primary EBV infection, T cells may escape activation by NPC‐LMP1. These observations have important implications for the establishment of EBV‐associated malignancy in the context of infection with tumour‐associated EBV LMP1 variants.
Tracing the action of IL‐2 in tolerance to islet‐specific antigen
Authors: Liston Adrian , Siggs Owen M , Goodnow Christopher C
Published: March 2007

Genetic variants of interleukin 2 (IL‐2) and its receptor are associated with murine and human susceptibility to Type 1 diabetes, yet the role of IL‐2 in controlling pancreatic islet‐reactive T cells is unknown. Here, we develop a model where IL‐2 deficiency precipitates a breakdown of self‐tolerance and progression to diabetes, and its action upon diabetogenic islet‐specific CD4 T cells can be tracked. We find that IL‐2 is not required for Aire‐dependent thymic clonal deletion of high‐avidity diabetogenic clones, but is essential for thymic formation of islet‐specific Foxp3‐expressing CD4 T cells. The absence of IL‐2 results in the expansion of low‐avidity Foxp3− islet‐reactive CD4 T cells. The mechanism by which IL‐2 prevents diabetes is therefore through the establishment of a repertoire of islet‐reactive Foxp3+ T cells within the thymus, and limitation of the peripheral activation of low‐avidity islet‐reactive T cells that normally escape thymic negative selection.
Stem cells from umbilical cord blood differentiate into myotubes and express dystrophin in vitro only after exposure to in vivo muscle environment
Authors: Nunes Viviane A. , Cavaçana Natale , Canovas Martha , Strauss Bryan E. , Zatz Mayana
Published: March 2007

Background information. Duchenne muscular dystrophy is a disease characterized by progressive and irreversible muscle degeneration for which there is no therapy. HUCB (human umbilical cord blood) has been considered as an important source of haematopoietic and mesenchymal stem cells, each having been shown to differentiate into distinct cell types. However, it remains unclear if these cells are able to differentiate into muscle cells.

Results. We have showed that stem cells from HUCB did not differentiate into myotubes or express dystrophin when cultured in muscle‐conditioned medium or with human muscle cells. However, delivery of GFP (green fluorescent protein)‐transduced mononucleated cells from HUCB, which comprises both haematopoietic and mesenchymal populations, into quadriceps muscle of mdx (mouse dystrophy X‐chromosome linked) mice resulted in the expression of human myogenic markers. After recovery of these cells from mdx muscle and in vitro cultivation, they were able to fuse and form GFP‐positive myotubes that expressed dystrophin.

Conclusions. These results indicate that chemical factors and cell‐to‐cell contact provided by in vitro conditions were not enough to trigger the differentiation of stem cells into muscle cells. Nevertheless, we showed that the HUCB‐derived stem cells were capable of acquiring a muscle phenotype after exposure to an in vivo muscle environment, which was required to activate the differentiation programme.
A new in vitro wound model based on the co‐culture of human dermal microvascular endothelial cells and human dermal fibroblasts
Authors: Oberringer Martin , Meins Claudia , Bubel Monika , Pohlemann Tim
Published: March 2007

Background information. Different in vitro models, based on co‐culturing techniques, can be used to investigate the behaviour of cell types, which are relevant for human wound and soft‐tissue healing. Currently, no model exists to describe the behaviour of fibroblasts and microvascular endothelial cells under wound‐specific conditions. In order to develop a suitable in vitro model, we characterized co‐cultures comprising NHDFs (normal human dermal fibroblasts) and HDMECs (human dermal microvascular endothelial cells). The CCSWMA (co‐culture scratch wound migration assay) developed was supported by direct visualization techniques in order to investigate a broad spectrum of cellular parameters, such as migration and proliferation activity, the differentiation of NHDFs into MFs (myofibroblasts) and the expression of endothelin‐1 and ED‐A‐fibronectin (extra domain A fibronectin). The cellular response to hypoxia treatment, as one of the crucial conditions in wound healing, was monitored.

Results. The comparison of the HDMEC—NHDF co‐culture with the respective mono‐cultures revealed that HDMECs showed a lower proliferation activity when co‐cultured, but their number was stable throughout a period of 48 h. NHDFs in co‐culture were slightly slower at proliferating than in the mono‐culture. The MF population was stable for 48 h in the co‐culture, as well as in NHDF mono‐culture. Co‐cultures and HDMEC mono‐cultures were characterized by a slower migration rate than NHDF mono‐cultures. Hypoxia decreased both cell proliferation and migration in the mono‐cultures, as well as in the co‐cultures, indicating the general suitability of the assay. Exclusively, in co‐cultures well‐defined cell clusters comprising HDMECs and MFs formed at the edges of the in vitro wounds.

Conclusions. On the basis of these results, the CCSWMA developed using co‐cultures, including HDMECs, NHDFs and MFs, proved to be an effective tool to directly visualize cellular interaction. Therefore, it will serve in the future to evaluate the influence of wound‐healing‐related factors in vitro, as shown for hypoxia in the present study.
First step of the cell‐penetrating peptide mechanism involves Rac1 GTPase‐dependent actin‐network remodelling
Authors: Gerbal‐Chaloin Sabine , Gondeau Claire , Aldrian‐Herrada Gudrun , Heitz Frédéric , Gauthier‐Rouvière Cécile , Divita Gilles
Published: March 2007

Background information. Application of CPPs (cell‐penetrating peptides) constitutes a promising strategy for the intracellular delivery of therapeutic molecules. The non‐covalent approach based on the amphipathic peptide MPG has been successfully used to improve the delivery of biologically active macromolecules, both in cellulo and in vivo, through a mechanism independent of the endosomal pathway and mediated by the membrane potential.

Results. In the present study, we have investigated the first step of the cellular uptake mechanism of MPG and shown that both MPG and MPG—cargo complexes interact with the extracellular matrix through the negatively charged heparan sulfate proteoglycans. We demonstrated that initiation of cellular uptake constitutes a highly dynamic mechanism where the binding of MPG or the MPG—cargo to the extracellular matrix is rapidly followed by a remodelling of the actin network associated with the activation of the GTPase Rac1. We suggest that MPG‐induced clustering of the glycosaminoglycan platform constitutes the ‘onset’ of the cellular uptake mechanism, thereby increasing membrane dynamics and membrane fusion processes. This process favours cell entry of MPG or MPG—DNA complexes, which is further controlled by the ability of MPG to induce a local membrane destabilization.

Conclusions. Although CPPs are taken up through different pathways and mechanisms, the initial step involves electrostatic interactions with the glycosaminoglycan platform, and the dynamics of associated membrane microdomains can be generalized to most non‐viral delivery systems.
Historic Waterfronts as Tourism Precincts: An Experiential Perspective
Authors: Griffin Tony , Hayllar Bruce
Published: March 2007

Over the last few decades, urban waterfronts worldwide have become places of significant change. Many have essentially lost their working port functions and have been redeveloped for other purposes, often incorporating significant leisure and tourism functions. Others, however, have maintained a significant portion of their original commercial maritime activities, but have still become a focus for leisure and tourism pursuits. This paper explores two such waterfront precincts in major Australian cities: Fremantle in Perth and Williamstown in Melbourne, places with long histories in shipping but very recent histories in tourism. The focus of the paper is on understanding how tourists experience these places, and what it is about such precincts that contribute most to their touristic appeal. The basis for the research was a series of structured interviews with both domestic and international visitors to each precinct. Fifty-six individual interviews were conducted in Williamstown and 30 interviews involving 48 individuals were conducted in Fremantle. In both cases, the interviews were conducted over a two-day period. The results shed light on why and how such places appeal to tourists and also provide guidance on how to maintain their appeal. Relaxation and taking time out from the everyday city were important visitor motivations, and the waterfront setting contributed to these. Fremantle, however, provided more depth to the tourists' experiences because it offered greater opportunities to engage actively with the setting and others who occupied it, rather than simply experiencing it in a passive way as appeared to be the case in Williamstown. Significantly there was a strong feeling that the working port element was an important part of Fremantle's appeal, along with a very strong connection to history through a well-conserved physical fabric. The lack of depth in the Williamstown experience seemed to limit the visitors' ability to appreciate the precinct's history, with its most positive features relating to the pure physicality of its waterfront setting. More generally, the results provide some key insights into the functions that tourism precincts perform within the overall urban tourism experience and how significant precincts are to such experiences. They reinforce earlier findings of the previous studies conducted by the researchers that intimacy, authenticity and a strong sense of place are vital elements of the tourist experience in urban precincts, and precincts are at the core of the urban tourism experience.
Understanding Tourist Movement Patterns in a Destination: A GIS Approach
Authors: Lau Gigi , McKercher Bob
Published: March 2007

This paper presents preliminary findings of research examining the movement patterns of tourists within a destination. The study focuses on fully independent individual travellers visiting Hong Kong. Little research has been conducted looking at movements within a destination. Macro or inter-destination movement patterns may inform intra-destination movements. Factors affecting tourists' choices of itineraries give reasons to support the shaping of the patterns. These factors include human factors (type of individual, travel party, motivations, etc), physical factors (destination geomorphology), trip factors (main or secondary destination, first-time or repeat visitor, etc) and the time factor (length of stay in destination, total trip duration). Geographic Information System is used for documenting spatial—temporal movements of tourists through mapping.
Tourism and the Globalisation of Fear: Analysing the Politics of Risk and (in)Security in Global Travel
Authors: Bianchi Raoul
Published: March 2007

International tourism represents the apotheosis of consumer capitalism and Western modernity, based on an apparently seamless harmony between the free movement of people, merchandise and capital. However, as the growing insecurities engendered by the globalisation of terrorism and military interventionism, as well as targeted attacks on foreign tourists in certain parts of the world illustrate, the liberal calculus of unhindered mobility, political stability and the unfettered expansion of the market, which underpins the ‘right’ to travel, is, however, increasingly mediated by heightened concerns of risk and security. This paper will examine how the geopolitics of security and the neo-liberal expansion of the global market have begun to radically reshape the parameters of mobility and the environments in which tourism operates. In doing so, it analyses the manner in which international tourism has become intertwined with restricted notions of freedom associated with the intensification of market relations and consumerism upon which the expansion of contemporary tourist mobilities often depends.