bluuebunny/crossref_metadata_2025_split huggingface dataset:
A reappraisal of the central effects of botulinum neurotoxin type A: by what mechanism?
Authors: Caleo Matteo , Antonucci Flavia , Restani Laura , Mazzocchio Riccardo 
Published: January 2009

AbstractBotulinum neurotoxin A (BoNT/A) is a metalloprotease that enters peripheral motor nerve terminals and blocks the release of acetylcholine via the specific cleavage of the synaptosomal‐associated protein of 25‐kDa. Localized injections of BoNT/A are widely employed in clinical neurology to treat several human diseases characterized by muscle hyperactivity. It is generally assumed that the effects of BoNT/A remain localized to the injection site. However, several neurophysiological studies have provided evidence for central effects of BoNT/A, raising the issue of how these actions arise. Here we review these data and discuss the possibility that retrograde axonal transport of catalytically active BoNT/A may explain at least some of its effects at the level of central circuits.
Different climatic envelopes among invasive populations may lead to underestimations of current and future biological invasions
Authors: Beaumont Linda J. , Gallagher Rachael V. , Thuiller Wilfried , Downey Paul O. , Leishman Michelle R. , Hughes Lesley 
Published: January 2009

ABSTRACTAim  We explore the impact of calibrating ecological niche models (ENMs) using (1) native range (NR) data versus (2) entire range (ER) data (native and invasive) on projections of current and future distributions of three Hieracium species.Location  H. aurantiacum, H. murorum and H. pilosella are native to Europe and invasive in Australia, New Zealand and North America.Methods  Differences among the native and invasive realized climatic niches of each species were quantified. Eight ENMs in BIOMOD were calibrated with (1) NR and (2) ER data. Current European, North American and Australian distributions were projected. Future Australian distributions were modelled using four climate change scenarios for 2030.Results  The invasive climatic niche of H. murorum is primarily a subset of that expressed in its native range. Invasive populations of H. aurantiacum and H. pilosella occupy different climatic niches to those realized in their native ranges. Furthermore, geographically separate invasive populations of these two species have distinct climatic niches. ENMs calibrated on the realized niche of native regions projected smaller distributions than models incorporating data from species’ entire ranges, and failed to correctly predict many known invasive populations. Under future climate scenarios, projected distributions decreased by similar percentages, regardless of the data used to calibrate ENMs; however, the overall sizes of projected distributions varied substantially.Main conclusions  This study provides quantitative evidence that invasive populations of Hieracium species can occur in areas with different climatic conditions than experienced in their native ranges. For these, and similar species, calibration of ENMs based on NR data only will misrepresent their potential invasive distribution. These errors will propagate when estimating climate change impacts. Thus, incorporating data from species’ entire distributions may result in a more thorough assessment of current and future ranges, and provides a closer approximation of the elusive fundamental niche.
Contrasting patterns of genetic variation and structure in plant invasions of mountains
Authors: Alexander Jake M. , Poll Myriam , Dietz Hansjörg , Edwards Peter J. 
Published: January 2009

ABSTRACTAim  To assess the population genetic consequences of the colonization of two species with contrasting mating systems, Solidago canadensis and Lactuca serriola, along altitudinal gradients in both their native and introduced ranges.Location  Allegheny Mountains, West Virginia and Wallowa Mountains, Oregon, USA; Valais, southern Switzerland.Methods  Leaf material was collected from populations along altitudinal gradients and genotyped at seven microsatellite loci for each species. Differences in variability between native and introduced areas and in relation to altitude were analysed using linear models. Differences in the genetic, geographical and altitudinal structure of populations between areas were analysed by AMOVA, cluster analysis and Mantel tests.Results  Genetic variation within and across populations of S. canadensis was significantly reduced, while populations of L. serriola were significantly more variable, in the introduced area. Genetic diversity decreased significantly with altitude for S. canadensis but not L. serriola. Genetic structure of S. canadensis was similar in both areas, and populations were isolated by geographical but not altitudinal distance. By contrast, population structure of L. serriola was much weaker in the introduced area, and populations were not isolated by distance in either area.Main conclusions  Solidago canadensis has experienced a strong genetic bottleneck on introduction to the Valais, but this has not prevented it from colonizing a wide altitudinal range. Variation in neutral markers is therefore not necessarily a good measure for judging the ecological behaviour of a species. By contrast, the greater variability of L. serriola in the introduced area, where it also occurs over a greater altitudinal range, can be explained by increased outcrossing among admixed populations. This suggests that the ecological amplitude of alien species might be enhanced after population admixture in the new range, especially for species with highly structured native populations. However, even genetically depauperate introduced populations can be expected to colonize the same environmental range that they occupy in the native area.
Incomplete dissociation of glibenclamide from wild‐type and mutant pancreatic KATPchannels limits their recovery from inhibition
Authors: Russ U , Kühner P , Prager R , Stephan D , Bryan J , Quast U 
Published: January 2009

Background and purpose: The antidiabetic sulphonylurea, glibenclamide, acts by inhibiting the pancreatic ATP‐sensitive K+(KATP) channel, a tetradimeric complex of KIR6.2 and sulphonylurea receptor 1 (KIR6.2/SUR1)4. At room temperature, recovery of channel activity following washout of glibenclamide is very slow and cannot be measured. This study investigates the relation between the recovery of channel activity from glibenclamide inhibition and the dissociation rate of [3H]‐glibenclamide from the channel at 37°C.Experimental approach: KIR6.2, KIR6.2ΔN5 or KIR6.2ΔN10 (the latter lacking amino‐terminal residues 2–5 or 2–10 respectively) were coexpressed with SUR1 in HEK cells. Dissociation of [3H]‐glibenclamide from the channel and recovery of channel activity from glibenclamide inhibition were determined at 37°C.Key results: The dissociation kinetics of [3H]‐glibenclamide from the wild‐type channel followed an exponential decay with a dissociation half‐time,t1/2(D) = 14 min; however, only limited and slow recovery of channel activity was observed.t1/2(D) for KIR6.2ΔN5/SUR1 channels was 5.3 min and recovery of channel activity exhibited a sluggish sigmoidal time course with a half‐time,t1/2(R) = 12 min.t1/2(D) for the ΔN10 channel was 2.3 min; recovery kinetics were again sigmoidal witht1/2(R) ∼4 min.Conclusions and implications: The dissociation of glibenclamide from the truncated channels is the rate‐limiting step of channel recovery. The sigmoidal recovery kinetics are in quantitative agreement with a model where glibenclamide must dissociate from all four (or at least three) sites before the channel reopens. It is argued that these conclusions hold also for the wild‐type (pancreatic) KATPchannel.
The effect of ‘two hit’ neonatal and young‐adult stress on dopaminergic modulation of prepulse inhibition and dopamine receptor density
Authors: Choy Kwok Ho Christopher , De Visser Yvonne P. , Van Den Buuse Maarten 
Published: January 2009

Background and purpose: A combination of early neurodevelopmental insult(s) and young‐adult stress exposure may be involved in the development of schizophrenia. We studied prepulse inhibition (PPI) regulation in rats after an early stress, maternal deprivation, combined with a later stress, simulated by chronic corticosterone treatment, and also determined whether changes in brain dopamine receptor density were involved.Experimental approach: Rats were subjected to either 24 h maternal deprivation on postnatal day 9, corticosterone treatment from 8 to 10 weeks of age, or both. At 12 weeks of age, the rats were injected with 0.1, 0.3 or 1.0 mg·kg−1of apomorphine or 0.5 or 2.5 mg·kg−1of amphetamine and PPI was determined using automated startle boxes. Dopamine D1and D2receptor levels were assessed in the nucleus accumbens and caudate nucleus using receptor autoradiography.Key results: Young‐adult treatment with corticosterone resulted in attenuated disruption of PPI by apomorphine and amphetamine. In some rats, maternal deprivation resulted in reduced baseline PPI which added to the effect of corticosterone treatment. There was no down‐regulation of dopamine D1or D2receptors.Conclusions and implications: These results confirm and extend our finding of an inhibitory interaction of developmental stress on dopaminergic regulation of PPI. No corresponding changes in dopamine receptor density were observed in brain regions with a major involvement in PPI regulation, suggesting long‐lasting desensitization of dopamine receptor signalling or indirect changes in PPI regulation.
Pharmacokinetic optimization of four soluble epoxide hydrolase inhibitors for use in a murine model of inflammation
Authors: Liu Jun‐Yan , Tsai Hsing‐Ju , Hwang Sung Hee , Jones Paul D , Morisseau Christophe , Hammock Bruce D 
Published: January 2009

Background and purpose:  Early soluble epoxide hydrolase inhibitors (sEHIs) such as 12‐(3‐adamantan‐1‐yl‐ureido)‐dodecanoic acid (AUDA) are effective anti‐hypertensive and anti‐inflammatory agents in various animal models. However, their poor metabolic stability and limited water solubility make them difficult to use pharmacologically. Here we present the evaluation of four sEHIs for improved pharmacokinetic properties and the anti‐inflammatory effects of one sEHI.Experimental approach:  The pharmacokinetic profiles of inhibitors were determined following p.o. (oral) administration and serial bleeding in mice. Subsequently the pharmacokinetics of trans‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)‐cyclohexyloxy]‐benzoic acid (t‐AUCB), the most promising inhibitor, was further studied following s.c. (subcutaneous), i.v. (intravenous) injections and administration in drinking water. Finally, the anti‐inflammatory effect of t‐AUCB was evaluated by using a lipopolysaccharide (LPS)‐treated murine model.Key results:  Better pharmacokinetic parameters (higher Cmax, longer t1/2 and greater AUC) were obtained from the tested inhibitors, compared with AUDA. Oral bioavailability of t‐AUCB (0.1 mg·kg−1) was 68 ± 22% (n = 4), and giving t‐AUCB in drinking water is recommended as a feasible, effective and easy route of administration for chronic studies. Finally, t‐AUCB (p.o.) reversed the decrease in plasma ratio of lipid epoxides to corresponding diols (a biomarker of soluble epoxide hydrolase inhibition) in lipopolysaccharide‐treated mice. The in vivo potency of 1 mg·kg−1 of t‐AUCB (p.o.) was better in this inflammatory model than that of 10 mg·kg−1 of AUDA‐butyl ester (p.o) at 6 h after treatment.Conclusions and implications:  t‐AUCB is a potent sEHI with improved pharmacokinetic properties. This compound will be a useful tool for pharmacological research and a promising starting point for drug development.
Selective noradrenaline reuptake inhibitor atomoxetine directly blocks hERG currents
Authors: Scherer Daniel , Hassel David , Bloehs Ramona , Zitron Edgar , Von Löwenstern Katharina , Seyler Claudia , Thomas Dierk , Konrad Franziska , Bürgers Heiner F. , Seemann Gunnar , Rottbauer Wolfgang , Katus Hugo A. , Karle Christoph A. , Scholz Eberhard P. 
Published: January 2009

Background and purpose:  Atomoxetine is a selective noradrenaline reuptake inhibitor, recently approved for the treatment of attention‐deficit/hyperactivity disorder. So far, atomoxetine has been shown to be well tolerated, and cardiovascular effects were found to be negligible. However, two independent cases of QT interval prolongation, associated with atomoxetine overdose, have been reported recently. We therefore analysed acute and subacute effects of atomoxetine on cloned human Ether‐à‐Go‐Go‐Related Gene (hERG) channels.Experimental approach:  hERG channels were heterologously expressed in Xenopus oocytes and in a human embryonic kidney cell line and hERG currents were measured using voltage clamp and patch clamp techniques. Action potential recordings were made in isolated guinea‐pig cardiomyocytes. Gene expression and channel surface expression were analysed using quantitative reverse transcriptase polymerase chain reaction, Western blot and the patch clamp techniques.Key results:  In human embryonic kidney cells, atomoxetine inhibited hERG current with an IC50 of 6.3 µmol·L−1. Development of block and washout were fast. Channel activation and inactivation were not affected. Inhibition was state‐dependent, suggesting an open channel block. No use‐dependence was observed. Inhibitory effects of atomoxetine were attenuated in the pore mutants Y652A and F656A. In guinea‐pig cardiomyocytes, atomoxetine lengthened action potential duration without inducing action potential triangulation. Overnight incubation with high atomoxetine concentrations resulted in a decrease of channel surface expression.Conclusions and implications:  Whereas subacute effects of atomoxetine seem negligible under therapeutically relevant concentrations, hERG channel block should be considered in cases of atomoxetine overdose and when administering atomoxetine to patients at increased risk for the development of acquired long‐QT syndrome.
P‐selectin glycoprotein‐ligand‐1 regulates pulmonary recruitment of neutrophils in a platelet‐independent manner in abdominal sepsis
Authors: Asaduzzaman Muhammad , Rahman Milladur , Jeppsson Bengt , Thorlacius Henrik 
Published: January 2009

Background and purpose:  Neutrophil‐mediated lung injury is an insidious feature in sepsis although the mechanisms regulating pulmonary recruitment of neutrophils remain elusive. Here, we investigated the role of P‐selectin glycoprotein‐ligand‐1 (PSGL‐1) in sepsis‐induced neutrophil recruitment and tissue injury in the lung.Experimental approach:  Bronchoalveolar infiltration of neutrophils, levels of myeloperoxidase, oedema formation and CXC chemokines were determined 24 h after caecal ligation and puncture (CLP) in mice. Animals were pretreated with a control antibody, monoclonal antibodies directed against PSGL‐1 and P‐selectin as well as a platelet‐depleting antibody directed against GP1bα.Key results:  CLP caused pulmonary damage characterized by oedema formation, neutrophil infiltration and increased levels of CXC chemokines in the lung. Immunoneutralization of PSGL‐1 or P‐selectin reduced CLP‐induced neutrophil recruitment in the bronchoalveolar space by more than 56% and lung myeloperoxidase activity by 62%. Notably, the inhibitory effect of the anti‐PSGL‐1 antibody on sepsis‐induced neutrophil infiltration was also observed in platelet‐depleted mice. Moreover, inhibition of PSGL‐1 and P‐selectin abolished CLP‐induced oedema formation and tissue damage in the lung. CLP‐induced formation of CXC chemokines was not changed in mice pretreated with the anti‐PSGL‐1 and anti‐P‐selectin antibodies.Conclusions and implications:  These data demonstrate that PSGL‐1 plays a key role in pulmonary infiltration of neutrophils as well as lung oedema associated with abdominal sepsis. Moreover, our findings suggest that PSGL‐1‐dependent neutrophil recruitment is independent of circulating platelets. Thus, these novel findings indicate that PSGL‐1 may be a useful target to protect against sepsis‐induced accumulation of neutrophils and tissue damage in the lung.
Levosimendan induces NO production through p38 MAPK, ERK and Akt in porcine coronary endothelial cells: role for mitochondrial KATPchannel
Authors: Grossini E , Molinari C , Caimmi PP , Uberti F , Vacca G 
Published: January 2009

Background and purpose: Levosimendan acts as a vasodilator through the opening of ATP‐sensitive K+channels (KATP) channels. Moreover, the coronary vasodilatation caused by levosimendan in anaesthetized pigs has recently been found to be abolished by the nitric oxide synthase (NOS) inhibitor Nω‐nitro‐L‐arginine methyl ester, indicating that nitric oxide (NO) has a role in the vascular effects of levosimendan. However, the intracellular pathway leading to NO production caused by levosimendan has not yet been investigated. Thus, the purpose of the present study was to examine the effects of levosimendan on NO production and to evaluate the intracellular signalling pathway involved.Experimental approach: In porcine coronary endothelial cells (CEC), the release of NO in response to levosimendan was examined in the presence and absence of Nω‐nitro‐L‐arginine methyl ester, an adenylyl cyclase inhibitor, KATPchannel agonists and antagonists, and inhibitors of intracellular protein kinases. In addition, the role of Akt, ERK, p38 and eNOS was investigated through Western blot analysis.Key results: Levosimendan caused a concentration‐dependent and K+‐related increase of NO production. This effect was amplified by the mitochondrial KATPchannel agonist, but not by the selective plasma membrane KATPchannel agonist. The response of CEC to levosimendan was prevented by the KATPchannel blockers, the adenylyl cyclase inhibitor and the Akt, ERK, p38 inhibitors. Western blot analysis showed that phosphorylation of the above kinases lead to eNOS activation.Conclusions and implications: In CEC levosimendan induced eNOS‐dependent NO production through Akt, ERK and p38. This intracellular pathway is associated with the opening of mitochondrial KATPchannels and involves cAMP.
Accelerated inactivation of cardiac L‐type calcium channels triggered by anaesthetic‐induced preconditioning
Authors: Tampo A , Hogan CS , Sedlic F , Bosnjak ZJ , Kwok WM 
Published: January 2009

Mandarin translation of abstractBackground and purpose:  Cardioprotection against ischaemia by anaesthetic‐induced preconditioning (APC) is well established. However, the mechanism underlying Ca2+ overload attenuation by APC is unknown. The effects of APC by isoflurane on the cardiac L‐type Ca channel were investigated.Experimental approach:  In a model of in vivo APC, Wistar rats were exposed to isoflurane (1.4%), delivered via a vaporizer in an enclosure, prior to thoracotomy. The Dahl S rats were similarly preconditioned to determine strain‐dependent effects. Whole‐cell patch clamp using cardiac ventricular myocytes was used to determine the L‐type Ca2+ current (ICa,L) characteristics and calmodulin (CaM) levels were determined by Western blot analysis. Cytosolic Ca2+ levels were monitored using fluo‐4‐AM. Action potential (AP) simulations examined the effects of APC.Key results:  In Wistar rats, APC significantly accelerated ICa,L inactivation kinetics. This was abolished when external Ca2+ was replaced with Ba2+, suggesting that Ca2+‐dependent inactivation of ICa,L was modulated by APC. Expression levels of CaM, a determinant of ICa,L inactivation, were not affected. Attenuation of cytosolic Ca2+ accumulation following oxidative stress was observed in the APC group. Simulations showed that the accelerated inactivation of ICa,L resulted in a shortening of the AP duration. The Dahl S rat strain was resistant to APC and changes in ICa,L inactivation were not observed in cardiomyocytes prepared from these rats.Conclusions and implications:  APC triggered persistent changes in the inactivation of cardiac L‐type Ca channels. This can potentially lead to a reduction in Ca2+ influx and attenuation of Ca2+ overload during ischaemia/reperfusion. Mandarin translation of abstract
Tachykinin receptor modulation of cyclooxygenase‐2 expression in human polymorphonuclear leucocytes
Authors: Gallicchio M , Benetti E , Rosa AC , Fantozzi R 
Published: January 2009

Mandarin translation of abstractBackground and purpose: We investigated the ability of natural and synthetic selective NK receptors agonists and antagonists to modulate cyclooxygenase‐2 (COX‐2) expression in human polymorphonuclear leucocytes (PMNs).Experimental approach: The presence of all three tachykinin in PMNs was assessed by Western blot and PCR techniques. Natural and synthetic ligands selective for the tachykinin receptors were used to modulate COX‐2 protein (measured with Western blotting) and activity [as prostaglandin E2(PGE2) output]. Effects of substance P (SP) on phosphorylation of mitogen‐activated protein kinases (MAPKs) and nuclear factor‐kappa B (NF‐κB) activation were studied to analyse the signalling pathway involved in COX‐2 up‐regulation mediated by SP.Key results: Stimulation of NK receptors with the natural ligands SP, neurokinin A (NKA) and neurokinin B, in the pmol·L−1‐µmol·L−1concentration range, modulated COX‐2 expression and PGE2release in a concentration‐ and time‐dependent manner. Experiments with synthetic selective agonists [Sar9, Met(O2)11]SP, [β‐Ala8] NKA(4‐10), senktide or selective antagonists L703,606, SR48,968 or SR142801, confirmed that COX‐2 up‐regulation was mediated by NK receptors. We found that mainly p38, p42 and p46 MAPKs were phosphorylated by SP and SB202190, PD98059 and SP600125, which are selective inhibitors of these kinases, blocked SP‐induced COX‐2 expression. SP also induced nuclear translocation of NF‐κB concentration‐dependently, with a maximum effect at 1 nmol·L−1.Conclusions and implications: Human PMNs possess functional NK1, NK2and NK3receptors, which mediate the induction of COX‐2 expression and NF‐κB activation by SP.Mandarin translation of abstract
Pharmacological characterization of recombinant NR1/NR2A NMDA receptors with truncated and deleted carboxy termini expressed inXenopus laevisoocytes
Authors: Puddifoot CA , Chen PE , Schoepfer R , Wyllie DJA 
Published: January 2009

Mandarin translation of abstractBackground and purpose: The carboxy terminal domain (CTD) of NR2N‐methyl‐d‐aspartate receptor (NMDAR) subunits interacts with numerous scaffolding and signal transduction proteins. Mutations of this region affect trafficking and downstream signalling of NMDARs. This study determines to what extent characteristic pharmacological properties of NR2A‐containing NMDARs are influenced by this key functional domain.Experimental approach: Using recombinant receptor expression inXenopus laevisoocytes and two electrode voltage clamp recordings we characterized pharmacological properties of rat NR1/NR2A NMDARs with altered CTDs. We assessed the effects of truncating [at residue Iso1098; NR2A(trunC)] and deleting [from residue Phe822; NR2A(delC)] the CTD of NR2A NMDAR subunits on agonist potencies, channel block by Mg2+and memantine and potentiation of NMDAR‐mediated responses by chelating contaminating divalent cations.Key results: Truncation or deletion of the CTD of NR2A NMDAR subunits did not affect glutamate potency [EC50 = 2.2 µmol·L−1, NR2A(trunC); 2.7 µmol·L−1, NR2A(delC) compared with 3.3 µmol·L−1, NR2A(WT)] but did significantly increase glycine potency [EC50 = 500 nmol·L−1, NR2A(trunC); 900 nmol·L−1, NR2A(delC) compared with 1.3 µmol·L−1, NR2A(WT)]. Voltage‐dependent Mg2+block of NR2A(WT)‐ and NR2A(trunC)‐containing NMDARs was similar but low concentrations of Mg2+(1 µmol·L−1) potentiated NR1/NR2A(delC) NMDARs. Memantine block was not affected by changes to the structure of the NR2A CTD. EDTA‐induced potentiation was similar at each of the three NMDAR constructs.Conclusions and implications: Of the parameters studied only minor influences of the CTD were observed; these are unlikely to compromise interpretation of studies that make use of CTD‐mutated recombinant receptors or transgenic mice in investigations of the role of the CTD in NMDAR signalling.Mandarin translation of abstract