bluuebunny/crossref_metadata_2025 huggingface dataset:
Root‐selective expression of AtCAX4 and AtCAX2 results in reduced lamina cadmium in field‐grown Nicotiana tabacum L.
Authors: Korenkov Victor , King Brian , Hirschi Kendal , Wagner George J.
Published: January 2009

To assess the impact of enhanced root vacuole cadmium (Cd) sequestration on leaf Cd accumulation under a low Cd dose, as generally occurs in agriculture, leaf Cd accumulation was examined in field‐grown tobacco plants expressing genes encoding the high‐capacity‐Cd, tonoplast‐localized, divalent cation/H antiporters AtCAX4 and AtCAX2 (AtCAX, Arabidopsis cation exchanger). It has been shown previously that root tonoplast vesicles isolated from plants expressing these genes, directed by root‐selective promoters, show enhanced Cd transport activity, and young plants show enhanced root Cd accumulation when grown in solution culture containing 0.02 µm Cd, a moderate Cd dose. In this article, we present results which show that the lower leaves of mature plants expressing AtCAX2 or AtCAX4, under the control of two different root‐selective promoters, accumulate 15%–25% less lamina Cd than control plants when grown in the field (3 years, three different collection methods). Reciprocal grafting experiments of AtCAX2 shoots onto control roots (and vice versa), grown in solution culture with 0.005 µm Cd, indicated that the root controls Cd translocation and accumulation in the shoot in control and AtCAX2 and AtCAX4 tobacco plants exposed to low Cd concentration. The results are consistent with a model in which supplementation of Cd/H antiporter activity in root cell tonoplasts enhances root Cd sequestration, resulting in decreased translocation of Cd to the shoot of field‐grown plants. These results suggest that human Cd intake from food and tobacco use could be reduced via the enhancement of root vacuolar sequestration of this pollutant.
e‐Assessment and the student learning experience: A survey of student perceptions of e‐assessment
Authors: Dermo John
Published: January 2009

This paper describes a piece of research carried out at the University of Bradford into student perceptions of e‐assessment. An online questionnaire was delivered to 130 undergraduates who had taken part in online assessment (either formative or summative) during the academic year 2007–2008. The survey looked at six main dimensions: (1) affective factors, (2) validity, (3) practical issues, (4) reliability, (5) security, and (6) learning and teaching. The aim of the survey was to identify possible risks in planning e‐assessments, as well as to gauge student opinion. The findings of the survey indicated a range of opinions across the student body, with greatest concern about the fairness of item banking. It was also found that the most positive aspect of e‐assessment in the eyes of students concerned the benefits that it can bring to teaching and learning. In addition, the paper concludes that age and gender did not significantly affect student responses in any of the areas studied.
Does regular online testing enhance student learning in the numerical sciences? Robust evidence from a large data set
Authors: Angus Simon D. , Watson Judith
Published: January 2009

While a number of studies have been conducted on the impact of online assessment and teaching methods on student learning, the field does not seem settled around the promised benefits of such approaches. It is argued that the reason for this state of affairs is that few studies have been able to control for a number of confounding factors in student performance. We report on the introduction of a regular (every 3 weeks) low‐mark online assessment tool in a large, first‐year business mathematics course at the University of New South Wales, a major Australian university. Using a retrospective regression methodology together with a very large and rich data set, we test the proposition that exposure to the online assessment instrument enhances student learning. Significantly, we are able to control for prior student aptitude, in‐course mastery, gender and even effort via a voluntary class attendance proxy. Furthermore, the study incorporates two large, and statistically diverse cohorts as well as manipulations in the model tested to robustly examine the outcomes. Our central result is that higher exposure to the online instrument robustly leads to higher student learning, all else being equal. Various implications for online assessment design, implementation and targeting are also discussed.
The Cutest Little Baby Face
Authors: Sprengelmeyer R. , Perrett D.I. , Fagan E.C. , Cornwell R.E. , Lobmaier J.S. , Sprengelmeyer A. , Aasheim H.B.M. , Black I.M. , Cameron L.M. , Crow S. , Milne N. , Rhodes E.C. , Young A.W.
Published: January 2009

We used computer image manipulation to develop a test of perception of subtle gradations in cuteness between infant faces. We found that young women (19–26 years old) were more sensitive to differences in infant cuteness than were men (19–26 and 53–60 years old). Women aged 45 to 51 years performed at the level of the young women, whereas cuteness sensitivity in women aged 53 to 60 years was not different from that of men (19–26 and 53–60 years old). Because average age at menopause is 51 years in Britain, these findings suggest the possible involvement of reproductive hormones in cuteness sensitivity. Therefore, we compared cuteness discrimination in pre- and postmenopausal women matched for age and in women taking and not taking oral contraceptives (progestogen and estrogen). Premenopausal women and young women taking oral contraceptives (which raise hormone levels artificially) were more sensitive to variations of cuteness than their respective comparison groups. We suggest that cuteness sensitivity is modulated by female reproductive hormones.
Who Participates, How and Why in Urban Regeneration Projects? The Case of the New ‘City’ of East Manchester
Authors: Blakeley Georgina , Evans Brendan
Published: January 2009

Participation is advocated by political leaders as crucial for enhancing social responsibility, building social capital, improving public services, qualifying for full citizenship and for enabling local democratic participation. Despite this increased commitment to encouraging public participation, however, there remains a lack of understanding of what motivates individuals to become community activists. This analysis of urban regeneration confirms that participation is a minority sport reflecting the reluctance and/or inability of the majority of community members to engage. The motives for that minority of local people who do engage are, therefore, important for policy‐makers and academics to understand. This research project in east Manchester reveals that the motives of activists are varied and more nuanced than is proposed by existing social science theories such as rational choice, social network theory or the application of such concepts as citizen‐consumers. A hybridized model which privileges social network theory without, however, entirely excluding ideas of the consumer‐citizen and rational choice is advocated as a more effective way of explaining both community activism and also the varying levels and durability of individual participation. If participation is to increase, however, it is vital that the nuanced motives of participants are better appreciated.
From blog to bebo and beyond: text, risk, participation
Authors: Carrington Victoria
Published: January 2009

This paper broadly explores the notion that text is an artefact that encodes and displays the tensions, resistances, positioning and affinities of its producer and, further, that many of these drivers have their source in quite significant shifts in the broad contours of contemporary Western culture. Against this background, two different artefacts are analysed in this paper: a blog and a bebo page. The blog has been produced by an adult female academic and the bebo page by an early adolescent girl. These text producers and users are positioned quite differently in terms of geography, education, life experience, identity, social class and interests. They also have differential access to and experience of digital technologies. However, they both make use of the affordances of technologies, in particular Internet‐connected laptops and desktops, to create and disseminate these texts to do ‘work’ on their behalf in particular social domains.
How Much Does Investor Sentiment Really Matter for Equity Issuance Activity?
Authors: Derrien François , Kecskés Ambrus
Published: January 2009

We study the extent to which investor sentiment matters for aggregate equity issuance activity. We focus on firms that are susceptible to investor sentiment and for which accurate measures of economic fundamentals are available. While sentiment on its own matters for equity issuance, it matters relatively little once we control for accurately measured fundamentals. Collectively, proxies for sentiment explain roughly 10 percentage points of the time‐series variation of equity issuance beyond the roughly 40% explained by fundamentals. We conclude that investor sentiment does not seem to matter very much for aggregate equity issuance activity.
Multiple sclerosis patients with anti‐lipid oligoclonal IgM show early favourable response to immunomodulatory treatment
Authors: García‐Barragán N. , Villar L. M. , Espiño M. , Sádaba M. C. , González‐Porqué P. , Álvarez‐Cermeño J. C.
Published: January 2009

Background and purpose:  Interferon beta and Glatiramer acetate are safe immunomodulatory treatments (IT) for multiple sclerosis (MS), but not always effective. New drugs are available, although they show more side‐effects and unknown long‐term safety profile. Anti‐lipid oligoclonal IgM bands (OCMB) distinguish MS patients with early aggressive course. We prospectively studied if IT are effective in these patients or if they are candidates for more aggressive drugs as first therapeutic option.

Methods:  Seventy‐five clinically isolated syndrome patients were studied. OCMB and conversion to MS were assessed. Patients suffering at least two demyelinating events within 3 years were considered eligible to start IT.

Results:  Eighteen patients showed OCMB (M+) and 57 lacked them (M−). All M+ patients and only 25 M− patients were treated. The other 32 M− patients suffered less MS attacks than those required to initiate treatment. IT similarly reduced relapse rate in both treated groups (P < 0.0001) and reduced Expanded Disability Status Scale (EDSS) progression in M+ patients, whose EDSS score had significantly increased before treatment. EDSS did not change in M− patients during follow‐up, regardless if they were treated or not.

Conclusions:  Oligoclonal IgM bands identify MS patients who are candidates for early immunomodulatory treatment as IT improves their initial aggressive disease course.
Cerebral autoregulation in patients with obstructive sleep apnea syndrome during wakefulness
Authors: Nasr N. , Traon A. Pavy‐Le , Czosnyka M. , Tiberge M. , Schmidt E. , Larrue V.
Published: January 2009

Background and purpose:  Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for stroke. Impairment of cerebral autoregulation may play a potential role in the pre‐disposition to stroke of OSAS patients. In this study, we aimed to assess dynamic cerebral autoregulation (DCA) during wakefulness in OSAS patients and a group of matched controls.

Methods:  Patients and controls were examined in the morning after an overnight complete polysomnography. Mean cerebral blood flow velocity (CBFV) in the middle cerebral artery and mean arterial blood pressure (ABP) were continuously recorded using transcranial Doppler and Finapres. DCA was assessed using the Mx autoregulatory index. Mx is a moving correlation coefficient between mean CBFV and mean ABP. More positive value of Mx indicates worse autoregulation.

Results:  Eleven OSAS patients (mean age ± SD; 52.6 ± 7.9) and 9 controls (mean age ± SD; 49.1 ± 5.3) were enrolled. The mean apnea–hypopnea index (AHI) in the OSAS group was of 22.7 ± 11.6. No significant difference was found between the two groups as for age, body mass index, mean ABP and endtidal CO2 pressure. Cerebral autoregulation was impaired in OSAS patients compared with controls (Mx index: 0.414 ± 0.138 vs. 0.233 ± 0.100; P = 0.009). The severity of autoregulation impairment correlated to the severity of the sleep respiratory disturbance measured by the AHI (P = 0.003).

Conclusion:  Cerebral autoregulation is impaired in patients with OSAS during wakefulness. Impairment of cerebral autoregulation is correlated with the severity of OSAS.
The Mercian Connection, Harold Godwineson's Ambitions, Diplomacy and Channel‐crossing, 1056–1066
Authors: VAN KEMPEN AD F. J.
Published: January 2009

It is supposed that the Vita Ædwardi contains some information about Harold's dealings with William of Normandy in 1064. This article links these covert references with William of Poitiers’ statements about Harold's diplomatic activities in France. The combination turns out to be fruitful. Harold's Channel‐crossing was meant as a tour of diplomacy to win support for his candidacy for the throne of the English. This statement has implications for the sequence of events. Harold's expedition was a mere continuation of his diplomacy in the Midlands earlier in 1064, when he concluded a cunning deal with the rulers of Mercia. Part of the secret arrangement was the acquisition of Northumbria, so far ruled by his self‐willed brother Tostig. Harold's unintended landfall in Ponthieu and captivity in Normandy set many things in motion. His explaining‐away of his presence on the continent and his fabrications about a state mission revived William's latent interest in the English succession. After his return to England, Harold's extenuation of his inglorious, illegitimate promises to William did raise suspicion about the true nature of his Channel‐crossing. Eventually, the full facts of his Mercian connection were revealed, resulting in Queen Edith's and Tostig's desperate moves to prevent the take‐over in Northumbria.
Counselling the Prince: Advice and Counsel in Thirteenth‐Century Welsh Society
Authors: HURLOCK KATHRYN
Published: January 2009

In thirteenth‐century Gwynedd, advice and counsel were sought through a variety of means. Whilst some of them, such as consultation of leading magnates and prelates, were common to much of Europe, the princes of Gwynedd still relied on traditional methods of counsel, most notably the advice given by court poets through their works. This article demonstrates how this very public method of advice was employed, the reaction of the princes to it, and its role as part of the machinery of the court. It then considers how the advice of the poets contributed to, and reflected, the move away from confederate consultation with the other princes of Wales to the use of a body of ‘counsellors’ drawn from Gwynedd as the thirteenth century progressed, a style of leadership which brought Gwynedd into line with wider European methods of governance.
Exiles and the Politics of Reintegration in the Dutch Revolt
Authors: JANSSEN GEERT H.
Published: January 2009

The civil war in the sixteenth‐century Low Countries, generally known as the Dutch revolt, generated dramatic streams of refugees. Whereas scholars in the past have devoted much attention to the exile experience of Protestants in particular, the circumstances surrounding the return of these refugees to the Netherlands have remained largely unexplored. This article focuses on the repatriation and reintegration of Protestant exiles in the province of Holland in the years 1572–80. It seeks to assess what strategies returning exiles developed to regain their possessions and respectability in local communities and shows how they adopted rituals of cleansing to reinforce their social rehabilitation. It can be demonstrated that the exiles consciously used the houses and properties of their Catholic enemies to mark their re‐entry in Holland society. By appropriating possessions of escaped Catholic citizens, the former ‘victims’ of the Habsburg regime sought material compensation and styled themselves as members of a new civic elite. In this way two contrasting streams of refugees became symbolically connected because it was fugitive Catholics who provided returning Protestants with the tools to turn themselves from outlaws into the icons of the nascent Dutch Republic.
Speculations on the molecular structure of eumelanin
Authors: Swift J. A.
Published: January 2009

Synopsis

Eumelanin is the polymeric black pigment commonly found in hair and skin. Its chemical intractability, to all but vigorous oxidizing agents, has hindered satisfactory understanding of its molecular structure. It is well‐established that the immediate precursor to polymerization, indole‐5,6‐quinone (IQ), is biosynthesized from the amino acid tyrosine. Current views are that the polymer consists of single bond connections between random indole and degraded indole units. In this paper, an alternative chemical scheme for the polymerization of IQ is proposed based upon the original suggestion by Horner in 1949 that a Diels‐Alder (D–A) reaction might be involved. The proposed basic chemical scheme for eumelanin formation is that D–A addition occurs specifically between the 2‐ and 3‐positions of one IQ molecule and the 7‐ and 4‐ positions respectively of a second IQ molecule, that the ensuing diketo bridge is oxidized to carboxyl groups and that, by decarboxylation and aromatization, a fused indole dimer is produced. It is envisaged that, by further D–A addition of more IQ molecules, oligomers of greater molecular mass are produced. Calculations based on published bond lengths and angles for the indole nucleus show that oligomeric units containing a total of up to 11 fused indoles could be packed into a flat circular disc of 20 Å diameter. The discs of the extensively conjugated polymer are envisaged to be stacked above each other by π–π interaction and with a spacing of 3.4 Å to produce cylindrical units, the mass density of which is calculated to be 1.54 gm cm−3; approximating with actual physical measurements. The size and shape of the predicted cylinders are in concordance with those observed in atomic force microscope investigations of eumelanin proto‐particles. The model is also in agreement with published experimental data that 2/3rds of the carbon dioxide liberated during eumelanin formation derives from positions 5‐ and 6‐ of the IQ molecule.
Platelet Dopamine: D2 Receptor Binding in Patients with Migraine
Authors: Shukla R , Khanna VK , Vinod P , Sankhwar ML , Yadav RS
Published: January 2009

Clinical, genetic and pharmacological evidences suggest an abnormality of the dopaminergic system in the pathogenesis of migraine. Direct evidence of an abnormal metabolism of dopamine in migraine, however, is lacking. Platelets are a useful model to understand brain dopaminergic mechanisms. The present study has been undertaken to study the status of platelet dopamine receptor binding by carrying out radioligand receptor binding assay. Binding of 3H-spiperone to platelet membranes, known to label dopamine (DA)—D2 receptors, was conducted in 20 patients with migraine and an equal number of healthy controls. The equilibrium dissociation constant (Kd) in patients with migraine (1.71 ± 0.19 nM) was found to be significantly lower ( P < 0.001) as compared with controls (3.14 ± 0.33 nM). However, no significant change was observed in the maximal number of binding sites (Bmax) in patients with migraine. No relationship of Kd with type of migraine, presence of vomiting, family history, frequency of attack, duration of illness and menstrual migraine was observed. The findings of the present study provide support for the involvement of the dopaminergic system in migraine.
An emerging view of presynaptic structure from electron microscopic studies
Authors: Siksou Léa , Triller Antoine , Marty Serge
Published: January 2009

In response to calcium influx, some of the synaptic vesicles in presynaptic terminals fuse rapidly with the presynaptic membrane, allowing fast synaptic transmission. The regulated recycling of synaptic vesicles at the terminals is required for a sustained release of neurotransmitters. Localization of ‘ready to be released’ vesicles in close vicinities to voltage‐gated calcium channels enables the rapid release of neurotransmitters. Thus, recycling vesicles must translocate from the sites of endocytosis to these release sites. However, the sub‐cellular organization that supports this local vesicular traffic remains poorly understood. We will review the results of various electron microscopy studies, which have begun to unveil the structure of presynaptic terminals.
Spatial congruence between ecotones and range‐restricted species: implications for conservation biogeography at the sub‐continental scale
Authors: Van Rensburg Berndt J. , Levin Noam , Kark Salit
Published: January 2009

Aim  To examine whether at a sub‐continental scale range‐limited species tend to occur close to areas of transition between vegetation boundaries more often than expected by chance.

Location  South Africa and Lesotho.

Methods  We examined the relationship between the distance of a grid square to ecological transition areas between vegetation types and both avian and frog range‐limited species richness in the quadrat. We used quadrats at a spatial resolution of quarter degree (15′ × 15′≈ 676 km2). Spatial congruence between areas representing range‐restricted species and those representing ecological transition zones was assessed using a random draw technique.

Results  Species richness and range size rarity are generally negatively correlated with distance to transition areas between vegetation communities when analysed for the whole region for both groups. Although this relationship becomes weaker after controlling for environmental energy and topographical heterogeneity, the explanatory power of distance to transition areas remains significant, and compared to the different biomes examined, accounts for most of the variation in bird richness (20%), frog richness (18%), range‐restricted bird species (17%) and range‐restricted frog species (16%) in the savanna biome. The random draw technique indicated that areas representing range‐restricted species were situated significantly closer in space to those areas representing transition areas between vegetation communities than expected by chance.

Main conclusions  We find that at the sub‐continental scale, when examined for South Africa, areas of transition between vegetation communities hold concentrations of range‐limited species in both birds and frogs. We find that South African endemic/range‐limited birds and frogs are located closer to ecological transition zones than endemics and non‐endemics combined. This has important implications for ongoing conservation planning in a biogeographical context.
Detection of a colonizing, aquatic, non‐indigenous species
Authors: Harvey Chad T. , Qureshi Samir A. , MacIsaac Hugh J.
Published: January 2009

Detecting the presence of rare species has interested ecologists and conservation biologists for many years. A particularly daunting application of this problem pertains to the detection of non‐indigenous species (NIS) as they colonize new ecosystems. Ethical issues prevent experimental additions of NIS to most natural systems to explore the relationship between sampling intensity and the detection probability of a colonizing NIS. Here we examine this question using a recently introduced water flea, Cercopagis pengoi, in Lake Ontario. The species has biphasic population development, with sexually‐produced ‘spring morphs’ developing prior to parthenogenetically‐produced ‘typical’ morphs. Thus, this biphasic morphology allows distinction between new colonists (spring morphs) from subsequent generations. We repeatedly sampled Hamilton Harbour, Lake Ontario for the presence of both spring and typical morphs. Probability of detection was positively related to both the number of samples taken and animal density in the lake; however, even highly intensive sampling (100 samples) failed to detect the species in early spring when densities were very low. Spatial variation was greatest when densities of Cercopagis were intermediate to low. Sub‐sampling, which increased space between adjacent samples, significantly decreased the number of samples required to reach greater, calculated detection probabilities on these dates. Typical sampling protocols for zooplankton have a low probability (< 0.2) of detecting the species unless population density is high. Results of this study suggest that early detection of colonizing, aquatic NIS may be optimized through use of a risk‐based sampling design, combined with high sampling intensity in areas deemed most vulnerable to invasion, rather than less intensive sampling at a wider array of sites.
Habitat heterogeneity as a driver of ungulate diversity and distribution patterns: interaction of body mass and digestive strategy
Authors: Cromsigt Joris P. G. M. , Prins Herbert H. T. , Olff Han
Published: January 2009

Aim Classic island biogeographical theory predicts that reserves have to be large to conserve high biodiversity. Recent literature, however, suggests that habitat heterogeneity can counterbalance the effect of small reserve size. For savanna ungulates, body mass is said to drive habitat selection and facilitate species coexistence, where large species use a higher proportion of the landscape than smaller species, because a wider food quality tolerance allows them to use a higher diversity of habitat types. In this case, high habitat heterogeneity would facilitate diverse assemblages of different‐sized ungulates. Digestive physiology should further modify this relationship, because non‐ruminants have a wider diet tolerance than ruminants. We tested this hypothesis with an empirical dataset on distribution and habitat preference of different‐sized African grazers.

Location Hluhluwe‐iMfolozi Park, Republic of South Africa.

Methods We recorded herbivore dung and habitat type on 24 line transects varying between 4 and 11 km with a total length of 190 km to determine habitat selection and landscape distribution of six grazer species, three ruminants and three non‐ruminants.

Results Larger ruminant grazers were more evenly distributed than smaller ruminants, had a more diverse use of habitats and used more low quality habitat. In contrast, non‐ruminant grazers were more evenly distributed than similar‐sized ruminants and body mass did not clearly influence diversity of habitat use and use of low quality habitat.

Main conclusions  We confirm that body mass influences diversity of habitat use of large herbivores but digestive strategy potentially modifies this relationship. Hence, habitat heterogeneity might facilitate herbivore diversity in savanna ecosystems and high heterogeneity might counterbalance the effects of fragmentation and declining reserve size. Concluding, processes that homogenize the landscape, such as fire (mis)management and artificial waterholes, might be as threatening to biodiversity as landscape fragmentation, especially for smaller ruminant herbivores.
Effect of nebivolol on blood oxygen transport indices and endothelial dysfunction in patients with arterial hypertension
Authors: Pronko T. P. , Zinchuk V. V.
Published: January 2009

Endothelial dysfunction, which is characterized by impairment of nitric oxide (NO) bioavailability, plays an important role in the development of arterial hypertension. The L‐arginine‐NO pathway is closely related to oxygen transport to tissue. Endothelial dysfunction in patients with arterial hypertension can affect haemoglobin‐oxygen affinity and tissue oxygen supply. Alterations in blood oxygen transport indices may play role in the pathogenesis of arterial hypertension. The aim of the present study was to investigate the effect of the beta‐selective adrenoblocker nebilet (nebivolol) on blood oxygen transport indices and on endothelial dysfunction in patients with arterial hypertension. The study population included 52 patients with grade II and grade III arterial hypertension. The results of our studies indicate that endothelial dysfunction in hypertensive patients significantly changes blood oxygen indices. The endothelium can be involved in formation of these impairments because only NO synthesized in sufficient amounts can maintain normal blood flow and oxygen transport to tissues. Endothelial dysfunction impairs formation of different haemoglobin NO‐derivatives, that influence not only on the release of NO at different sites of the vascular bed, but also on haemoglobin‐oxygen affinity, and accordingly, on optimal blood oxygenation in capillaries of pulmonary circulation and its deoxygenation in capillaries of systemic circulation. Treatment of hypertensive patients with nebivolol corrects the blood oxygen transport indices, stimulates NO production and improves endothelium‐dependent dilatation. Normalization of blood oxygen transport indices may regulate the activity of the L‐arginine‐NO pathway. Thus, nebivolol may improve efficiency of the treatment of hypertension.
Comparison of mechanical and electrical activity and interstitial cells of Cajal in urinary bladders from wild‐type and W/Wv mice
Authors: McCloskey KD , Anderson UA , Davidson RA , Bayguinov YR , Sanders KM , Ward SM
Published: January 2009

Background and purpose:  W/Wv and wild‐type murine bladders were studied to determine whether the W/Wv phenotype, which causes a reduction in, but not abolition of, tyrosine kinase activity, is a useful tool to study the function of bladder interstitial cells of Cajal (ICC).

Experimental approach:  Immunohistochemistry, tension recordings and microelectrode recordings of membrane potential were performed on wild‐type and mutant bladders.

Key results:  Wild‐type and W/Wv detrusors contained c‐Kit‐ and vimentin‐immunopositive cells in comparable quantities, distribution and morphology. Electrical field stimulation evoked tetrodotoxin‐sensitive contractions in wild‐type and W/Wv detrusor strips. Atropine reduced wild‐type responses by 50% whereas a 25% reduction occurred in W/Wv strips. The atropine‐insensitive component was blocked by pyridoxal‐5‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid in both tissue types. Wild‐type and W/Wv detrusors had similar resting membrane potentials of −48 mV. Spontaneous electrical activity in both tissue types comprised action potentials and unitary potentials. Action potentials were nifedipine‐sensitive whereas unitary potentials were not. Excitatory junction potentials were evoked by single pulses in both tissues. These were reduced by atropine in wild‐type tissues but not in W/Wv preparations. The atropine‐insensitive component was abolished by pyridoxal‐5‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid in both preparations.

Conclusions and implications:  Bladders from W/Wv mice contain c‐Kit‐ and vimentin‐immunopositive ICC. There are similarities in the electrical and contractile properties of W/Wv and wild‐type detrusors. However, significant differences were found in the pharmacology of the responses to neurogenic stimulation with an apparent up‐regulation of the purinergic component. These findings indicate that the W/Wv strain may not be the best model to study ICC function in the bladder.
Selective desensitization of the 5‐HT4receptor‐mediated response in pig atrium but not in stomach
Authors: De Maeyer JH , Schuurkes JAJ , Lefebvre RA
Published: January 2009

Background and purpose: The time dependency of the effect of 5‐HT4receptor agonists depends on many specific regulatory mechanisms, which vary between tissues. This has important implications with regard to the effects of endogenous 5‐HT, as well as to the clinical use of 5‐HT4receptor agonists, and might contribute to tissue selectivity of agonists.

Experimental approach: The progression and desensitization of 5‐HT4receptor‐mediated responses were evaluated in an organ bath set‐up using two, clinically relevant, porcinein vitromodels: gastric cholinergic neurotransmission and atrial contractility.

Key results: Exposure of gastric tissue to 5‐HT or to the selective 5‐HT4receptor agonists prucalopride and M0003 results in a sustained non‐transient effect during exposure; after washout, the response to a subsequent challenge with 5‐HT shows no clear desensitization. Incubation of left atrial tissue with 5‐HT resulted in a transient response, leading after washout to a marked desensitization of the subsequent response to 5‐HT. The selective 5‐HT4receptor agonists prucalopride and M0003 induce only very weak atrial responses whereas they are very effective in desensitizing the atrial response to 5‐HT. The observations also suggest that the properties of prucalopride and M0003 to bind to and/or activate the 5‐HT4receptor differ from those of 5‐HT. This difference might have contributed to the observed desensitization.

Conclusions and implications: The high potency of prucalopride and M0003 in desensitizing the response to 5‐HT together with their low efficacy in the atrium emphasizes the cardiac safety of this class of 5‐HT4receptor agonists.
Inhibitory actions of the phosphatidylinositol 3‐kinase inhibitor LY294002 on the human Kv1.5 channel
Authors: Wu J , Ding W‐G , Matsuura H , Tsuji K , Zang W‐J , Horie M
Published: January 2009

Background and purpose: Kv1.5 channels conduct the ultra‐rapid delayed rectifier potassium current (IKur), and in humans, Kv1.5 channels are highly expressed in cardiac atria but are scarce in ventricles. Pharmacological blockade of human Kv1.5 (hKv1.5) has been regarded as effective for prevention and treatment of re‐entry‐based atrial tachyarrhythmias. Here we examined blockade of hKv1.5 channels by LY294002, a well‐known inhibitor of phosphatidylinositol 3‐kinase (PI3K).

Experimental approach: hKv1.5 channels were heterologously expressed in Chinese hamster ovary cells. Effects of LY294002 on wild‐type and mutant (T462C, H463C, T480A, R487V, A501V, I502A, I508A, L510A and V516A) hKv1.5 channels were examined by using the whole‐cell patch‐clamp method.

Key results: LY294002 rapidly and reversibly inhibited hKv1.5 current in a concentration‐dependent manner (IC50of 7.9 µmol·L−1). In contrast, wortmannin, a structurally distinct inhibitor of PI3K, had little inhibitory effect on hKv1.5 current. LY294002 block of hKv1.5 current developed with time during depolarizing voltage‐clamp steps, and this blockade was also voltage‐dependent with a steep increase over the voltage range for channel openings. The apparent binding (k+1) and unbinding (k−1) rate constants were calculated to be 1.6 µmol·L−1−1·s−1and 5.7 s−1respectively. Inhibition by LY294002 was significantly reduced in several hKv1.5 mutant channels: T480A, R487V, I502A, I508A, L510A and V516A.

Conclusions and implications: LY294002 acts directly on hKv1.5 currents as an open channel blocker, independently of its effects on PI3K activity. Amino acid residues located in the pore region (Thr480, Arg487) and the S6 segment (Ile502, Ile508, Leu510, Val516) appear to constitute potential binding sites for LY294002.
Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin‐induced lung injury
Authors: Cortijo J , Iranzo A , Milara X , Mata M , Cerdá‐Nicolás M , Ruiz‐Saurí A , Tenor H , Hatzelmann A , Morcillo EJ
Published: January 2009

Mandarin translation of abstract

Background and purpose: The effects of a phosphodiesterase 4 (PDE4) inhibitor, roflumilast, on bleomycin‐induced lung injury were explored in ‘preventive’ and ‘therapeutic’ protocols and compared with glucocorticoids.

Experimental approach: Roflumilast (1 and 5 mg·kg−1·d−1, p.o.) or dexamethasone (2.5 mg·kg−1·d−1, p.o.) was given to C57Bl/6J mice from day 1 to 14 (preventive) or day 7 to 21 (therapeutic) after intratracheal bleomycin (3.75 U·kg−1). In Wistar rats, roflumilast (1 mg·kg−1·d−1, p.o.) was compared with methylprednisolone (10 mg·kg−1·d−1, p.o.) from day 1 to 21 (preventive) or from day 10 to 21 (therapeutic), following intratracheal instillation of bleomycin (7.5 U·kg−1). Analyses were performed at the end of the treatment periods.

Key results: Preventive. Roflumilast reduced bleomycin‐induced lung hydroxyproline, lung fibrosis and right ventricular hypertrophy; muscularization of intraacinar pulmonary vessels was also attenuated. The PDE4 inhibitor diminished bleomycin‐induced transcripts for tumour necrosis factor (TNFα), transforming growth factor (TGFβ), connective tissue growth factor, αI(I)collagen, endothelin‐1 and the mucin, Muc5ac, in lung, and reduced bronchoalveolar lavage fluid levels of TNFα, interleukin‐13, TGFβ, Muc5ac, lipid hydroperoxides and inflammatory cell counts.Therapeutic. In mice, roflumilast but not dexamethasone reduced bleomycin‐induced lung αI(I)collagen transcripts, fibrosis and right ventricular hypertrophy. Similar results were found in the rat.

Conclusions and implications: Roflumilast prevented the development of bleomycin‐induced lung injury, and alleviated the lung fibrotic and vascular remodeling response to bleomycin in atherapeuticprotocol, the latter being resistant to glucocorticoids.

Mandarin translation of abstract
Complex adrenergic and inflammatory mechanisms contribute to phase 2 ventricular arrhythmias in anaesthetized rats
Authors: Clements‐Jewery Hugh , Andrag Ellen , Hearse David J , Curtis Michael J
Published: January 2009

Mandarin translation of abstract

Background and purpose: The mechanisms responsible for phase 2 (infarct‐related) ventricular arrhythmias remain unclear. We have investigated the role of α1and β1adrenoceptor activation and the interaction of this with infarct neutrophil accumulation, in anaesthetized rats.

Experimental approach: Neutrophil‐replete Sprague‐Dawley rats (n = 8–9 per group) were anaesthetized and randomized to receive vehicle, prazosin (0.5 mg·kg−1i.v.), atenolol (4 mg·kg−1i.v.) or their combination prior to left main coronary artery occlusion. A further group was depleted of neutrophils and received both atenolol and prazosin. Coronary ligation in all groups was maintained for 240 min.

Key results: Atenolol and prazosin treatment lowered heart rates and blood pressures respectively, but neither agent given alone affected the incidence of phase 2 ventricular tachycardia or fibrillation. However, co‐administration of atenolol with prazosin reduced phase 2 ventricular premature beats (log10‐transformed totals were 1.25 ± 0.26 vs. 2.43 ± 0.18 in controls;P < 0.05). Neutrophil depletion attenuated this antiarrhythmic effect (log10‐transformed total ventricular premature beats were 1.66 ± 0.35;P > 0.05 vs. controls).

Conclusions and implications: Phase 2 arrhythmias appear to depend in part on a complex interaction between catecholamines and neutrophils. A model of this interaction is proposed.

Mandarin translation of abstract
Relative contribution of ecto‐ATPase and ecto‐ATPDase pathways to the biphasic effect of ATP on acetylcholine release from myenteric motoneurons
Authors: Duarte‐Araújo M , Nascimento C , Timóteo MA , Magalhães‐Cardoso MT , Correia‐de‐Sá P
Published: January 2009

Mandarin translation of abstract

Background and purpose: The relative contribution of distinct ecto‐nucleotidases to the modulation of purinergic signalling may depend on differential tissue distribution and substrate preference.

Experimental approach: Extracellular ATP catabolism (assessed by high‐performance liquid chromatography) and its influence on [3H]acetylcholine ([3H]ACh) release were investigated in the myenteric plexus of rat ileumin vitro.

Key results: ATP was primarily metabolized via ecto‐ATPDase (adenosine 5′‐triphosphate diphosphohydrolase) into AMP, which was then dephosphorylated into adenosine by ecto‐5′‐nucleotidase. Alternative conversion of ATP into ADP by ecto‐ATPase (adenosine 5′‐triphosphatase) was more relevant at high ATP concentrations. ATP transiently increased basal [3H]ACh outflow in a 2′,3′‐O‐(2,4,6‐trinitrophenyl)adenosine‐5′‐triphosphate (TNP‐ATP)‐dependent, tetrodotoxin‐independent manner. ATP and ATPγS (adenosine 5′‐[γ‐thio]triphosphate), but not α,β‐methyleneATP, decreased [3H]ACh release induced by electrical stimulation. ADP and ADPβS (adenosine 5′[β‐thio]diphosphate) only decreased evoked [3H]ACh release. Inhibition by ADPβS was prevented by MRS 2179 (2′‐deoxy‐N6‐methyl adenosine 3′,5′‐diphosphate diammonium salt, a selective P2Y1antagonist); blockade of ADP inhibition required co‐application of MRS 2179 plus adenosine deaminase (which inactivates endogenous adenosine). Blockade of adenosine A1receptors with 1,3‐dipropyl‐8‐cyclopentyl xanthine enhanced ADPβS inhibition, indicating that P2Y1stimulation is cut short by tonic adenosine A1receptor activation. MRS 2179 facilitated evoked [3H]ACh release, an effect reversed by the ecto‐ATPase inhibitor, ARL67156, which delayed ATP conversion into ADP without affecting adenosine levels.

Conclusions and implications: ATP transiently facilitated [3H]ACh release from non‐stimulated nerve terminals via prejunctional P2X (probably P2X2) receptors. Hydrolysis of ATP directly into AMP by ecto‐ATPDase and subsequent formation of adenosine by ecto‐5′‐nucleotidase reduced [3H]ACh release via inhibitory adenosine A1receptors. Stimulation of inhibitory P2Y1receptors by ADP generated alternatively via ecto‐ATPase might be relevant in restraining ACh exocytosis when ATP saturates ecto‐ATPDase activity.

Mandarin translation of abstract
Eicosapentaenoic acid inhibits voltage‐gated sodium channels and invasiveness in prostate cancer cells
Authors: Nakajima T , Kubota N , Tsutsumi T , Oguri A , Imuta H , Jo T , Oonuma H , Soma M , Meguro K , Takano H , Nagase T , Nagata T
Published: January 2009

Mandarin translation of abstract

Background and purpose:  The voltage‐gated Na+ channels (Nav) and their corresponding current (INa) are involved in several cellular processes, crucial to metastasis of cancer cells. We investigated the effects of eicosapentaenoic (EPA), an omega‐3 polyunsaturated fatty acid, on INa and metastatic functions (cell proliferation, endocytosis and invasion) in human and rat prostate cancer cell lines (PC‐3 and Mat‐LyLu cells).

Experimental approach:  The whole‐cell voltage clamp technique and conventional/quantitative real‐time reverse transcriptase polymerase chain reaction analysis were used. The presence of Nav proteins was shown by immunohistochemical methods. Alterations in the fatty acid composition of phospholipids after treatment with EPA and metastatic functions were also examined.

Key results:  A transient inward Na+ current (INa), highly sensitive to tetrodotoxin, and NaV proteins were found in these cells. Expression of NaV1.6 and NaV1.7 transcripts (SCN8A and SCN9A) was predominant in PC‐3 cells, while NaV1.7 transcript (SCN9A) was the major component in Mat‐LyLu cells. Tetrodotoxin or synthetic small interfering RNA targeted for SCN8A and SCN9A inhibited metastatic functions (endocytosis and invasion), but failed to inhibit proliferation in PC‐3 cells. Exposure to EPA produced a rapid and concentration‐dependent suppression of INa. In cells chronically treated (up to 72h) with EPA, the EPA content of cell lipids increased time‐dependently, while arachidonic acid content decreased. Treatment of PC‐3 cells with EPA decreased levels of mRNA for SCN9A and SCN8A, cell proliferation, invasion and endocytosis.

Conclusion and implications:  Treatment with EPA inhibited INa directly and also indirectly, by down‐regulation of Nav mRNA expression in prostate cancer cells, thus inhibiting their metastatic potential.

Mandarin translation of abstract
Mechanism of asynchronous Ca2+waves underlying agonist‐induced contraction in the rat basilar artery
Authors: Syyong HT , Yang HHC , Trinh G , Cheung C , Kuo KH , Van Breemen C
Published: January 2009

Background and purpose: Uridine 5'‐triphosphate (UTP) is a potent vasoconstrictor of cerebral arteries and induces Ca2+waves in vascular smooth muscle cells (VSMCs). This study aimed to determine the mechanisms underlying UTP‐induced Ca2+waves in VSMCs of the rat basilar artery.

Experimental approach: Isometric force and intracellular Ca2+([Ca2+]i) were measured in endothelium‐denuded rat basilar artery using wire myography and confocal microscopy respectively.

Key results: Uridine 5'‐triphosphate (0.1–1000 µmol·L−1) concentration‐dependently induced tonic contraction (pEC50 = 4.34 ± 0.13), associated with sustained repetitive oscillations in [Ca2+]ipropagating along the length of the VSMCs as asynchronized Ca2+waves. Inhibition of Ca2+reuptake in sarcoplasmic reticulum (SR) by cyclopiazonic acid abolished the Ca2+waves and resulted in a dramatic drop in tonic contraction. Nifedipine reduced the frequency of Ca2+waves by 40% and tonic contraction by 52%, and the nifedipine‐insensitive component was abolished by SKF‐96365, an inhibitor of receptor‐ and store‐operated channels, and KB‐R7943, an inhibitor of reverse‐mode Na+/Ca2+exchange. Ongoing Ca2+waves and tonic contraction were also abolished after blockade of inositol‐1,4,5‐triphosphate‐sensitive receptors by 2‐aminoethoxydiphenylborate, but not by high concentrations of ryanodine or tetracaine. However, depletion of ryanodine‐sensitive SR Ca2+stores prior to UTP stimulation prevented Ca2+waves.

Conclusions and implications: Uridine 5'‐triphosphate‐induced Ca2+waves may underlie tonic contraction and appear to be produced by repetitive cycles of regenerative Ca2+release from the SR through inositol‐1,4,5‐triphosphate‐sensitive receptors. Maintenance of Ca2+waves requires SR Ca2+reuptake from Ca2+entry across the plasma membrane via L‐type Ca2+channels, receptor‐ and store‐operated channels, and reverse‐mode Na+/Ca2+exchange.

Mandarin translation of abstract
A novel diketopiperazine improves functional recovery given after the onset of 6‐OHDA‐induced motor deficit in rats
Authors: Krishnamurthi RVM , Mathai S , Kim AH , Zhang R , Guan J
Published: January 2009

Background and purpose:  Cyclo‐L‐glycyl‐L‐2‐allylproline (NNZ‐2591), a modified diketopiperazine, is neuroprotective and improves long‐term function after hypoxic‐ischaemic brain injury in rats. The present studies were designed to examine both the neuroprotective and neurotrophic actions of NNZ‐2591 on neurochemical and behavioural changes in a rat model of Parkinson's disease.

Experimental approach:  To examine its protective effect, either NNZ‐2591 (20 ng·day−1) or saline was given intracerebroventricularly for 3 days starting 2 h after 6‐hydroxydopamine (6‐OHDA) induced unilateral striatal lesion. In a subsequent experiment either NNZ‐2591 (0.2, 1 and 5 mg·day−1, s.c.) or saline was administered daily for 14 days starting 2 weeks after the lesion. Behavioural and neurochemical outcomes were examined using the adjusting step test and immunohistochemical staining.

Key results:  Cyclo‐L‐glycyl‐L‐2‐allylproline given 2 h after the lesion reduced the degree of motor deficit compared with the saline‐treated group. Delayed treatment with NNZ‐2591, initiated after the onset of motor deficit, significantly improved motor function from week 7 onwards compared with the saline‐treated group. Neither treatment regime altered nigrostriatal dopamine depletion. NNZ‐2591 significantly enhanced the expression of doublecortin‐positive neuroblasts in the sub‐ventricular zone.

Conclusions and implications:  These studies reveal that early treatment with NNZ‐2591 protects against the motor deficit induced by 6‐OHDA and that treatment initiated after the establishment of motor impairment significantly improves long‐term motor function. These effects of NNZ‐2591 on functional recovery were independent of dopamine depletion and also appeared not to be symptomatic as the improved motor function was long‐lasting. NNZ‐2591 has potential as a therapeutic agent for neurodegenerative disorders.

Mandarin translation of abstract