bluuebunny/crossref_metadata_2025 huggingface dataset:
The relevance of kinin B1receptor upregulation in a mouse model of colitis
Authors: Hara D B , Leite D F P , Fernandes E S , Passos G F , Guimarães A O , Pesquero J B , Campos M M , Calixto J B
Published: June 2008

Background and purpose:

Kinins are implicated in many pathophysiological conditions, and recent evidence has suggested their involvement in colitis. This study assessed the role of the kinin B1receptors in a mouse model of colitis.

Experimental approach:

Colitis was induced in mice by 2,4,6‐trinitrobenzene sulphonic acid (TNBS), and tissue damage and myeloperoxidase activity were assessed. B1receptor induction was analysed by organ bath studies, binding assay and reverse transcription PCR.

Key results:

TNBS‐induced colitis was associated with tissue damage, neutrophil infiltration and time‐dependent increase of colon B1receptor‐mediated contraction, with the maximal response observed at 72 h. The upregulation of the B1receptor at this time point was also confirmed by means of binding studies. B1receptor mRNA levels were elevated as early as 6 h after colitis induction and remained high for up to 48 h. TNBS‐evoked tissue damage and neutrophil influx were reduced by the selective B1receptor antagonist SSR240612, and in B1receptor knockout mice.In vivotreatment with inhibitors of protein synthesis, nuclear factor‐κB activation, inducible nitric oxide synthase (iNOS) or tumour necrosis factor α (TNFα) significantly reduced B1receptor agonist‐induced contraction. Similar results were observed in iNOS and TNF receptor 1‐knockout mice.

Conclusions and implications:

These results provide convincing evidence on the role of B1receptors in the pathogenesis of colitis. Therefore, the blockade of kinin B1receptors might represent a new therapeutic option for treating inflammatory bowel diseases.

British Journal of Pharmacology(2008)154, 1276–1286; doi:fn1; published online 9 June 2008
CO‐MP4, a polyethylene glycol‐conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats
Authors: Vandegriff K D , Young M A , Lohman J , Bellelli A , Samaja M , Malavalli A , Winslow R M
Published: June 2008

Background and purpose:

MP4 (Hemospan) is a Hb‐based oxygen therapeutic agent, based on polyethylene‐glycol (PEG) conjugation to Hb, undergoing clinical trials as an oxygen carrier. This study describes the functional interaction between MP4 and carbon monoxide (CO), as a CO delivery agent, and the effects of CO‐MP4 on myocardial infarct size following ischaemia and reperfusion in rats.

Experimental approach:

Kinetic measurements of CO‐MP4 binding were used to evaluate the effects of PEG modification on Hb subunit structure/function and to calculate CO‐MP4 equilibrium constants. CO transport by CO‐MP4 was shown by ligand (O2/CO) partitioning between MP4 and red blood cell (RBC)‐Hb. Pharmacological effects of CO‐MP4 were studied on myocardial infarction in rats.

Key results:

CO binding kinetics show primary structural/functional effects on β chains in MP4, with α chains maintaining the ability to undergo tertiary conformational transition. CO confers long‐term, room‐temperature stability and is able to rapidly re‐equilibrate between MP4 and RBCs. In a rat model of myocardial infarct, in contrast to oxy‐MP4, CO‐MP4 reduced infarct size when administered prior to the induction of ischaemia.

Conclusions and implications:

MP4 PEGylation chemistry modifies the individual function of Hb subunits, but results in an overall CO equilibrium constant similar to that for unmodified Hb. CO‐MP4 is able to deliver CO to the circulation and reduces ischaemia/reperfusion injury in rats, providing the first evidence for this drug as a CO therapeutic agent.

British Journal of Pharmacology (2008) 154, 1649–1661; doi:10.1038/bjp.2008.219; published online 9 June 2008
Involvement of the BLT2 receptor in the itch‐associated scratching induced by 12‐(S)‐lipoxygenase products in ICR mice
Authors: Kim H J , Kim D K , Kim H , Koh J Y , Kim K M , Noh M S , Lee S , Kim S , Park S H , Kim J J , Kim S Y , Lee C H
Published: June 2008

Background and purpose:

Recently, we reported that 12(S)‐HPETE (12(S)‐hydroperoxyeicosa‐5Z,8Z,10E,14Z‐tetraenoic acid) induces scratching in ICR mice. We hypothesized that 12(S)‐HPETE might act as an agonist of the low‐affinity leukotriene B4 receptor BLT2. To confirm the involvement of the BLT2 receptor in 12(S)‐HPETE‐induced scratching, we studied the scratch response using the BLT2 receptor agonists compound A (4′‐{[pentanoyl (phenyl) amino]methyl}‐1,1′‐biphenyl‐2‐carboxylic acid) and 12(S)‐HETE (12(S)‐hydroxyeicosa‐5Z,8Z,10E,14Z‐tetraenoic acid).

Experimental approach:

A video recording was used to determine whether the BLT2 receptor agonists caused itch‐associated scratching in ICR mice. Selective antagonists and several chemicals were used.

Key results:

Both 12(S)‐HETE and compound A dose dependently induced scratching in the ICR mice. The dose–response curve for compound A showed peaks at around 0.005–0.015 nmol per site. Compound A‐ and 12(S)‐HETE‐induced scratching was suppressed by capsaicin and naltrexon. We examined the suppressive effects of U75302 (6‐[6‐(3‐hydroxy‐1E,5Z‐undecadienyl)‐2‐pyridinyl]‐1,5‐hexanediol, the BLT1 receptor antagonist) and LY255283 (1‐[5‐ethyl‐2‐hydroxy‐4‐[[6‐methyl‐6‐(1H‐tetrazol‐5‐yl)heptyl]oxy]phenyl]‐ethanone, the BLT2 receptor antagonist) on the BLT2 agonist‐induced scratching. LY255283 suppressed compound A‐ and 12(S)‐HETE‐induced scratching, but U75302 did not. LY255283 required a higher dose to suppress the compound A‐induced scratching than it did to suppress the 12(S)‐HETE‐induced scratching. One of the BLT2 receptor agonists, 12(R)‐HETE (12(R)‐hydroxyeicosa‐5Z,8Z,10E,14Z‐tetraenoic acid), also induced scratching in the ICR mice.

Conclusions and implications:

Our present results corroborate the hypothesis that the BLT2 receptor is involved in 12(S)‐lipoxygenase‐product‐induced scratching in ICR mice. We also confirmed that this animal model could be a valuable means of evaluating the effects of BLT2 receptor antagonists.

British Journal of Pharmacology (2008) 154, 1073–1078; doi:10.1038/bjp.2008.220; published online 9 June 2008
Key clinical considerations for demonstrating the utility of preclinical models to predict clinical drug‐induced torsades de pointes
Authors: Sager P T
Published: June 2008

While the QT/QTc interval is currently the best available clinical surrogate for the development of drug‐induced torsades de pointes, it is overall an imperfect biomarker. In addition to low specificity for predicting arrhythmias, other issues relevant to using QT as a biomarker include (1) an apparent dissociation, for some drugs (for example, amiodarone, sodium pentobarbital, ranolazine) between QT/QTc interval prolongation and TdP risk, (2) Lack of clarity regarding what determines the relationship between QTc prolongation and TdP risk for an individual drug, (3) QT measurement issues, including effects of heart rate and autonomic perturbations, (4) the significant circadian changes to the QT/QTc interval and (5) concerns that the development, regulatory and commercial implications of finding even a mild QT prolongation effect during clinical development has significant impact the pharmaceutical discovery pipeline. These issues would be significantly reduced, clinical development simplified and marketing approval for some drugs might be accelerated if there were a battery of preclinical tests that could reliably predict a drug's propensity to cause TdP in humans, even in the presence of QTc interval prolongation. This approach is challenging and for it to be acceptable to pharmaceutical developers, the scientific community and regulators, it would need to be scientifically well validated. A very high‐negative predictive value demonstrated in a wide range of drugs with different ionic effects would be critical. This manuscript explores the issues surrounding the use of QT as a clinical biomarker and potential approaches for validating preclinical assays for this purpose against clinical data sets.

British Journal of Pharmacology (2008) 154, 1544–1549; doi:fn1; published online 9 June 2008
Anti‐inflammatory actions of aprotinin provide dose‐dependent cardioprotection from reperfusion injury
Authors: Carter J M , Buerke U , Rössner E , Russ M , Schubert S , Schmidt H , Ebelt H , Pruefer D , Schlitt A , Werdan K , Buerke M
Published: June 2008

Background and purpose:

Myocardial injury following ischaemia and reperfusion has been attributed to activation and transmigration of polymorphonuclear leukocytes (PMNs) with release of mediators including oxygen‐derived radicals and proteases causing damage.

Experimental approach:

We studied the serine protease inhibitor aprotinin in an in vivo rabbit model of 1 h of myocardial ischaemia followed by 3 h of reperfusion (MI+R). Aprotinin (10 000 Ukg−1) or its vehicle were injected 5 min prior to the start of reperfusion.

Key results:

Myocardial injury was significantly reduced with aprotinin treatment as indicated by a reduced necrotic area (11±2.7% necrosis as percentage of area at risk after aprotinin; 24±3.1% after vehicle; P<0.05) and plasma creatine kinase activity (12.2±1.5 and 17.3±2.3 IU g−1 protein in aprotinin and vehicle groups, respectively, P<0.05). PMN infiltration (assessed by myeloperoxidase activity) was significantly decreased in aprotinin‐treated animals compared to vehicle (P<0.01). Histological analysis also revealed a substantial increase in PMN infiltration following MI+R and this was significantly reduced by aprotinin therapy (44±15 vs 102±2 PMN mm2 in aprotinin vs vehicle‐treated animals, P<0.05). In parallel in vitro experiments, aprotinin inhibited neutrophil‐endothelium interaction by reducing PMN adhesion on isolated, activated aortic endothelium. Finally, immunohistochemical analysis illustrated aprotinin significantly reduced myocardial apoptosis following MI+R.

Conclusions and implications:

Inhibition of serine proteases by aprotinin inhibits an inflammatory cascade initiated by MI+R. The cardioprotective effect appears to be at least partly due to reduced PMN adhesion and infiltration with subsequently reduced myocardial necrosis and apoptosis.

British Journal of Pharmacology (2008) 155, 93–102; doi:10.1038/bjp.2008.223; published online 9 June 2008
The PKs PKA and ERK 1/2 are involved in phosphorylation of TH at Serine 40 and 31 during morphine withdrawal in rat hearts
Authors: Almela P , Milanés M V , Laorden M L
Published: June 2008

Background and purpose:

Our previous studies have shown that morphine withdrawal induced hyperactivity of cardiac noradrenergic pathways. The purpose of the present study was to evaluate the effects of morphine withdrawal on site‐specific phosphorylation of TH in the heart.

Experimental approach:

Dependence on morphine was induced by a 7‐day s.c. implantation of morphine pellets in rats. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (2 mg kg−1). TH phosphorylation was determined by quantitative blot immunolabelling using phosphorylation state‐specific antibodies.

Key results:

Naloxone‐induced morphine withdrawal induced phosphorylation of TH at serine (Ser)40 and Ser31 in the right ventricle, associated with both an increase in total TH levels and an enhancement of TH activity. When HA‐1004 (PK A inhibitor) was infused, concomitantly with morphine, it diminished the increase in noradrenaline turnover, total TH levels and TH phosphorylation at Ser40 in morphine‐withdrawn rats. In contrast, the infusion of calphostin C (PKC inhibitor), did not modify the morphine withdrawal‐induced increase in noradrenaline turnover and total TH levels. In addition, we show that the ability of morphine withdrawal to stimulate phosphorylation at Ser31 was reduced by SL327, an inhibitor of ERK 1/2 activation.

Conclusions and implications:

The present findings demonstrate that the enhancement of total TH levels and the increased phosphorylation state of TH during morphine withdrawal were dependent on PKA and ERK activities and suggest that these transduction pathways might contribute to the activation of the cardiac catecholaminergic neurons in response to morphine withdrawal.

British Journal of Pharmacology(2008)155, 73–83; doi:10.1038/bjp.2008.224; published online 9 June 2008
Antiepileptic effects of two Rho‐kinase inhibitors, Y‐27632 and fasudil, in mice
Authors: İnan S Y , Büyükafşar K
Published: June 2008

Background and purpose:

Rho/Rho‐kinase signalling is involved in many cellular events, including some in the CNS. However, the role of this pathway in epilepsy has not yet been assessed. Therefore, we determined the effects of two Rho‐kinase inhibitors, Y‐27632 and fasudil, on seizures induced by pentylenetetrazole (PTZ) or maximal electroconvulsive shock (MES).

Experimental approach:

Effects of Y‐27632 (5–10 mg kg−1) and fasudil (5–25 mg kg−1) on duration of myoclonic jerks, clonic and tonic convulsions, tonic hindlimb extensions and percentage of tonic convulsion index, as well as recovery latency for righting reflex were investigated in mice stimulated with PTZ (65 mg kg−1) or MES (50 Hz, 50 mA and 0.4 s). These inhibitors were also tested on a model of kindling induced by PTZ (35 mg kg−1, for 11 days). Membrane and cytosolic levels of RhoA protein were measured in brain homogenates from kindled mice.

Key results:

Y‐27632 and fasudil diminished onset of myoclonic jerks, clonic convulsions and tonic hindlimb extensions in mice given PTZ. These inhibitors suppressed the percentage of tonic convulsion index and recovery latency for righting reflex in the mice excited with MES. Western blotting demonstrated that Rho translocation to plasma membrane increased in the brain homogenates obtained from PTZ‐kindled mice. However, the Rho‐kinase inhibitors at the given doses did not change motor coordination of the mice.

Conclusions and implications:

Rho/Rho‐kinase signalling may play a role in epilepsy induced by PTZ and MES. Furthermore, Rho‐kinase inhibitors could be novel important antiepileptic agents.

British Journal of Pharmacology (2008) 155, 44–51; doi:10.1038/bjp.2008.225; published online 9 June 2008
Blockade of adenosine A2B receptors ameliorates murine colitis
Authors: Kolachala V L , Ruble B K , Vijay‐Kumar M , Wang L , Mwangi S , Figler H E , Figler R A , Srinivasan S , Gewirtz A T , Linden J , Merlin D , Sitaraman S V
Published: June 2008

Background and purpose:

The adenosine 2B (A2B) receptor is the predominant adenosine receptor expressed in the colon. Acting through the A2B receptor, adenosine mediates chloride secretion, as well as fibronectin and interleukin (IL)‐6 synthesis and secretion in intestinal epithelial cells. A2B receptor mRNA and protein expression are increased during human and murine colitis. However, the effect of the A2B receptor in the activation of the intestinal inflammatory response is not known. In this study, we examined the effect of A2B receptor antagonism on murine colitis.

Experimental approach:

Dextran sodium sulphate (DSS)‐treated mice and piroxicam‐treated IL‐10−/− mice were used as animal models of colitis. The A2B receptor‐selective antagonist, ATL‐801, was given in the diet.

Key results:

Mice fed ATL‐801 along with DSS showed a significantly lower extent and severity of colitis than mice treated with DSS alone, as shown by reduced clinical symptoms, histological scores, IL‐6 levels and proliferation indices. The administration of ATL‐801 prevented weight loss, suppressed the inflammatory infiltrate into colonic mucosa and decreased epithelial hyperplasia in piroxicam‐treated IL‐10−/− mice. IL‐6 and keratinocyte‐derived chemokine (KC) concentrations in the supernatants of colonic organ cultures from colitic mice were significantly reduced by ATL‐801 administration.

Conclusions and implications:

Taken together, these data demonstrate that the intestinal epithelial A2B receptor is an important mediator of pro‐inflammatory responses in the intestine and that A2B receptor blockade may be an effective therapeutic strategy to treat inflammatory bowel disease.

British Journal of Pharmacology (2008) 155, 127–137; doi:10.1038/bjp.2008.227; published online 9 June 2008
Differential modulation of AP‐1‐ and CRE‐driven transcription by cannabinoid agonists emphasizes functional selectivity at the CB1receptor
Authors: Bosier B , Hermans E , Lambert D M
Published: June 2008

Background and purpose:

Long‐term adaptations to pharmacological stimuli frequently originate from modulation of complex intracellular signalling pathways. We previously reported that HU210 and CP55940, two CB1cannabinoid receptor agonists, induced opposite effects on TH expression. Herein, we characterized their influence on cAMP response element (CRE) and activator protein 1 (AP‐1)‐mediated regulation of gene transcription.

Experimental approach:

The activity of the agonists was examined on transfected N1E‐115 cells in which expression of the luciferase reporter gene was controlled by transcription promoters consisting of repeats of either CRE or AP‐1 elements. In addition, the implication of classical signalling pathways was investigated using a variety of kinase inhibitors.

Key results:

Consistent with the CB1‐mediated reduction of cAMP accumulation, both ligands decreased CRE‐driven luciferase expression with similar potencies. HU210 also exhibited a concentration‐dependent reduction of luciferase activity in cells engineered to examine AP‐1‐controlled transcription, whereas such response was not obtained with CP55940. Responses were all inhibited by SR141716A and were modified inPertussistoxin‐treated cells, suggesting agonist‐selective regulations of distinct Gi/o‐dependent mechanisms through CB1receptor activation. Finally, PKC inhibitors efficiently inhibited the paradoxical effect of HU210 on AP‐1‐mediated transcription, indicating selective regulation of PKC‐dependent responses.

Conclusions and implications:

Together, our results demonstrate that two cannabinoid ligands, commonly used as reference agonists acting on the same receptor with similar affinities, differentially modulate gene transcription through distinct controls of AP‐1. This could reflect activation of distinct subsets of Gi/o‐proteins, supporting the concept of functional selectivity at CB1receptors.

British Journal of Pharmacology(2008)155, 24–33; doi:10.1038/bjp.2008.230; published online 9 June 2008
Bimodal effects of the Kv7 channel activator retigabine on vascular K+currents
Authors: Yeung S Y M , Schwake M , Pucovský V , Greenwood I A
Published: June 2008

Background and purpose:

This study investigated the functional and electrophysiological effects of the Kv7 channel activator, retigabine, on murine portal vein smooth muscle.

Experimental approach:

KCNQ gene expression was determined by reverse transcriptase polymerase chain reaction (RT‐PCR) and immunocytochemical experiments. Whole cell voltage clamp and current clamp were performed on isolated myocytes from murine portal vein. Isometric tension recordings were performed on whole portal veins. K+currents generated by KCNQ4 and KCNQ5 expression were recorded by two‐electrode voltage clamp inXenopusoocytes.

Key results:

KCNQ1, 4 and 5 were expressed in mRNA derived from murine portal vein, either as whole tissue or isolated myocytes. Kv7.1 and Kv7.4 proteins were identified in the cell membranes of myocytes by immunocytochemistry. Retigabine (2–20 μM) suppressed spontaneous contractions in whole portal veins, hyperpolarized the membrane potential and augmented potassium currents at −20 mV. At more depolarized potentials, retigabine and flupirtine, decreased potassium currents. Both effects of retigabine were prevented by prior application of the Kv7 blocker XE991 (10 μM). Recombinant KCNQ 4 or 5 channels were only activated by retigabine or flupirtine.

Conclusions and implications:

The Kv7 channel activators retigabine and flupirtine have bimodal effects on vascular potassium currents, which are not seen with recombinant KCNQ channels. These results provide support for KCNQ4‐ or KCNQ5‐encoded channels having an important functional impact in the vasculature.

British Journal of Pharmacology(2008)155, 62–72; doi:10.1038/bjp.2008.231; published online 9 June 2008
Therapeutic options in inflammatory bowel disease: experimental evidence of a beneficial effect of kinin B1 receptor blockade
Authors: Marceau F , Regoli D
Published: June 2008

A surprising proportion of patients with inflammatory bowel disease (IBD) remain refractory to all classes of drugs presently in clinical use. Kinins are inflammatory mediators of potential relevance in IBD, because at least the kinin B1 receptor subtype is upregulated in human or animal intestinal inflammation and also both B1 and B2 receptors for kinins support inflammation and epithelial electrogenic ion transport that leads to secretory diarrhoea. In this issue of the BJP, Hara et al. report the therapeutic effect of a modern and selective nonpeptide kinin B1 receptor antagonist, SSR240612 ((2R)‐2‐(((3R)‐3‐(1,3‐benzodioxol‐5‐yl)‐3‐(((6‐ methoxy‐2‐naphthyl)sulphonyl)amino)propanoyl)amino)‐3‐(4‐((2R,6S)‐ 2,6‐dimethylpiperidinyl)methyl)phenyl)‐N‐isopropyl‐N‐ methylpropanamide hydrochloride), with benefits such as decreased neutrophil influx and improved macroscopic tissue scoring. The results were corroborated using kinin B1 receptor gene‐knockout mice. Further, kinin B1 receptor upregulation in this inflammatory model is partially dependent on TNF‐α, a recognized target for IBD pharmacotherapy. More work is warranted to evaluate the value of the kinin B1 receptor antagonists as a novel anti‐inflammatory therapeutic option for IBD.

British Journal of Pharmacology (2008) 154, 1163–1165; doi:fn1; published online 9 June 2008
On the fitting of binding data when receptor dimerization is suspected
Authors: Giraldo J
Published: June 2008

Mechanistic and empirical modelling are compared in context of dimeric receptors. In particular, the supposed advantages of the two‐state dimer model for fitting of binding data with respect to classical approaches such as the two‐independent sites model are investigated. The two models are revisited from both the mechanistic and empirical point of views. The problem of overparameterized models and the benefits of the concurrent use of mechanistic and empirical models for mechanism analysis are discussed. The pros and cons of mathematical models are examined with special emphasis given to the interpretation of the connection between the shapes of the curves and receptor cooperativity. It is shown that a given pharmacological phenotype (curve shape) can be obtained from different receptor genotypes (as, for instance, non‐interconvertible monomeric receptor species, receptor‐G protein interactions and dimeric receptors), though values of the Hill coefficient greater than one are indicative of receptor oligomerization. The existence of a relationship between the recently defined dimer cooperativity index and the more familiar Hill coefficient is proven.

British Journal of Pharmacology(2008)155, 17–23; doi:10.1038/bjp.2008.234; published online 9 June 2008
Anthracycline toxicity to cardiomyocytes or cancer cells is differently affected by iron chelation with salicylaldehyde isonicotinoyl hydrazone
Authors: Šimůnek T , Štěrba M , Popelová O , Kaiserová H , Adamcová M , Hroch M , Hašková P , Poňka P , Geršl V
Published: June 2008

Background and purpose:

The clinical utility of anthracycline antineoplastic drugs is limited by the risk of cardiotoxicity, which has been traditionally attributed to iron‐mediated production of reactive oxygen species (ROS).

Experimental approach:

The aims of this study were to examine the strongly lipophilic iron chelator, salicylaldehyde isonicotinoyl hydrazone (SIH), for its ability to protect rat isolated cardiomyocytes against the toxicity of daunorubicin (DAU) and to investigate the effects of SIH on DAU‐induced inhibition of proliferation in a leukaemic cell line. Cell toxicity was measured by release of lactate dehydrogenase and staining with Hoechst 33342 or propidium iodide and lipid peroxidation by malonaldehyde formation.

Key results:

SIH fully protected cardiomyocytes against model oxidative injury induced by hydrogen peroxide exposure. SIH also significantly but only partially and with no apparent dose‐dependency, reduced DAU‐induced cardiomyocyte death. However, the observed protection was not accompanied by decreased lipid peroxidation. In the HL‐60 acute promyelocytic leukaemia cell line, SIH did not blunt the antiproliferative efficacy of DAU. Instead, at concentrations that reduced DAU toxicity to cardiomyocytes, SIH enhanced the tumoricidal action of DAU.

Conclusions and implications:

This study demonstrates that iron is most likely involved in anthracycline cardiotoxicity and that iron chelation has protective potential, but apparently through mechanism(s) other than by inhibition of ROS‐induced injury. In addition to cardioprotection, iron chelation may have considerable potential to improve the therapeutic action of anthracyclines by enhancing their anticancer efficiency and this potential warrants further investigation.

British Journal of Pharmacology (2008) 155, 138–148; doi:10.1038/bjp.2008.236; published online 9 June 2008
Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension
Authors: Oka M , Fagan K A , Jones P L , McMurtry I F
Published: June 2008

A burgeoning body of evidence suggests that RhoA/Rho kinase (ROCK) signalling plays an important role in the pathogenesis of various experimental models of pulmonary hypertension (PH), including chronic hypoxia‐, monocrotaline‐, bleomycin‐, shunt‐ and vascular endothelial growth factor receptor inhibition plus chronic hypoxia‐induced PH. ROCK has been incriminated in pathophysiologic events ranging from mediation of sustained abnormal vasoconstriction to promotion of vascular inflammation and remodelling. In addition, the 3‐hydoxy‐3‐methylglutaryl CoA reductase inhibitors, statins, which inhibit activation of RhoA by preventing post‐translational isoprenylation of the protein and its translocation to the plasma membrane ameliorate PH in several different rat models, and may also be effective in PH patients. Also, phosphorylation of RhoA and prevention of its translocation to the plasma membrane are involved in the protective effect of the type 5‐PDE inhibitor, sildenafil, against hypoxia‐ and bleomycin‐induced PH. Collectively, these and other observations indicate that independent of the cause of PH, activation of the RhoA/ROCK pathway serves as a point of convergence of various signalling cascades in the pathogenesis of the disease. We propose that ROCK inhibitors and other drugs that inhibit this pathway might be useful in the treatment of various forms of PH.

British Journal of Pharmacology (2008) 155, 444–454; doi:10.1038/bjp.2008.239; published online 9 June 2008
Pulmonary hypertension: therapeutic targets within the serotonin system
Authors: Dempsie Y , MacLean M R
Published: June 2008

Pulmonary arterial hypertension (PAH) is characterized by a sustained and progressive elevation in pulmonary arterial pressure and pulmonary vascular remodelling leading to right heart failure and death. Prognosis is poor and novel therapeutic approaches are needed. The serotonin hypothesis of PAH originated in the 1960s after an outbreak of the disease was reported among patients taking the anorexigenic drugs aminorex and fenfluramine. These are indirect serotinergic agonists and serotonin transporter substrates. Since then many advances have been made in our understanding of the role of serotonin in the pathobiology of PAH. The rate‐limiting enzyme in the synthesis of serotonin is tryprophan hydroxylase (Tph). Serotonin is synthesized, through Tph1, in the endothelial cells of the pulmonary artery and can then act on underlying pulmonary arterial smooth muscle cells and pulmonary arterial fibroblasts in a paracrine fashion causing constriction and remodelling. These effects of serotonin can be mediated through both the serotonin transporter and serotonin receptors. This review will discuss our current understanding of ‘the serotonin hypothesis’ of PAH and highlight possible therapeutic targets within the serotonin system.

British Journal of Pharmacology(2008)155, 455–462; doi:10.1038/bjp.2008.241; published online 9 June 2008
The failure of torcetrapib: what have we learned?
Authors: Joy T R , Hegele R A
Published: June 2008

The failure of the cholesterol ester transfer protein (CETP) inhibitor, torcetrapib, has led to questions regarding whether the molecule itself or the mechanism of CETP inhibition was responsible for the adverse cardiovascular outcomes. Given the association with increases in blood pressure and plasma aldosterone levels, torcetrapib has been postulated to have adverse ‘off‐target’ effects. In this issue of British Journal of Pharmacology, Forrest and co‐workers have elegantly investigated these effects, demonstrating two salient points—(1) the pressor effect of torcetrapib is independent of CETP inhibition and (2) although associated with hyperaldosteronism, the pressor effect is likely not mediated by hyperaldosteronism. Anacetrapib, by contrast, did not demonstrate any pressor or off‐target effects. Despite these findings, it remains to be proven whether the adverse cardiovascular outcomes from torcetrapib were indeed related to the pressor effects and whether CETP inhibition by other agents will result in beneficial clinical outcomes. Yet, the studies of Forrest and co‐workers do bring us closer to unravelling the reasons behind the failure of torcetrapib.

British Journal of Pharmacology (2008) 154, 1379–1381; doi:fn1; published online 9 June 2008
Lattice model of equilibrium polymerization. VII. Understanding the role of “cooperativity” in self-assembly
Authors: Douglas Jack F. , Dudowicz Jacek , Freed Karl F.
Published: June 2008

Cooperativity is an emergent many-body phenomenon related to the degree to which elementary entities (particles, molecules, organisms) collectively interact to form larger scale structures. From the standpoint of a formal mean field description of chemical reactions, the cooperativity index m, describing the number of elements involved in this structural self-organization, is the order of the reaction. Thus, m for molecular self-assembly is the number of molecules in the final organized structure, e.g., spherical micelles. Although cooperativity is crucial for regulating the thermodynamics and dynamics of self-assembly, there is a limited understanding of this aspect of self-assembly. We analyze the cooperativity by calculating essential thermodynamic properties of the classical mth order reaction model of self-assembly (FAm model), including universal scaling functions describing the temperature and concentration dependence of the order parameter and average cluster size. The competition between self-assembly and phase separation is also described. We demonstrate that a sequential model of thermally activated equilibrium polymerization can quantitatively be related to the FAm model. Our analysis indicates that the essential requirement for “cooperative” self-assembly is the introduction of constraints (often nonlocal) acting on the individual assembly events to regulate the thermodynamic free energy landscape and, thus, the thermodynamic sharpness of the assembly transition. An effective value of m is defined for general self-assembly transitions, and we find a general tendency for self-assembly to become a true phase transition as m→∞. Finally, various quantitative measures of self-assembly cooperativity are discussed in order to identify experimental signatures of cooperativity in self-assembling systems and to provide a reliable metric for the degree of transition cooperativity.
Thermodynamic properties of benzene under shock conditions
Authors: Maillet Jean-Bernard , Pineau Nicolas
Published: June 2008

We present in this paper a thermodynamic analysis of benzene properties under shock conditions as given by molecular dynamics (MD) simulations. Reactive MD simulations of benzene predict a decomposition threshold corresponding to the flection point on the experimental Hugoniot curve. A polymerlike carbonated structure is observed for pressures above this threshold, but the calculated Hugoniot curve is in disagreement with the experimental one at high pressure. On the contrary, a system consisting of a diamond cluster in hydrogen gas leads to a correct prediction of the pressure on the Hugoniot curves. The central question is then linked to the kinetics of the transition between the polymerlike structure and the diamond cluster.
Betatron radiation from density tailored plasmas
Authors: Ta Phuoc K. , Esarey E. , Leurent V. , Cormier-Michel E. , Geddes C. G. R. , Schroeder C. B. , Rousse A. , Leemans W. P.
Published: June 2008

In laser wakefield accelerators, electron motion is driven by intense forces that depend on the plasma density. Transverse oscillations in the accelerated electron orbits produce betatron radiation. The electron motion and the resulting betatron radiation spectrum can therefore be controlled by shaping the plasma density along the orbit of the electrons. Here, a method based on the use of a plasma with a longitudinal density variation (density depression or step) is proposed to increase the transverse oscillation amplitude and the energy of the electrons accelerated in a wakefield cavity. For fixed laser parameters, by appropriately tailoring the plasma profile, the betatron radiation emitted by these electrons is significantly increased in both flux and energy.
Magnetic resonance–coupled fluorescence tomography scanner for molecular imaging of tissue
Authors: Davis Scott C. , Pogue Brian W. , Springett Roger , Leussler Christoph , Mazurkewitz Peter , Tuttle Stephen B. , Gibbs-Strauss Summer L. , Jiang Shudong S. , Dehghani Hamid , Paulsen Keith D.
Published: June 2008

A multichannel spectrally resolved optical tomography system to image molecular targets in small animals from within a clinical MRI is described. Long source/detector fibers operate in contact mode and couple light from the tissue surface in the magnet bore to 16 spectrometers, each containing two optical gratings optimized for the near infrared wavelength range. High sensitivity, cooled charge coupled devices connected to each spectrograph provide detection of the spectrally resolved signal, with exposure times that are automated for acquisition at each fiber. The design allows spectral fitting of the remission light, thereby separating the fluorescence signal from the nonspecific background, which improves the accuracy and sensitivity when imaging low fluorophore concentrations. Images of fluorescence yield are recovered using a nonlinear reconstruction approach based on the diffusion approximation of photon propagation in tissue. The tissue morphology derived from the MR images serves as an imaging template to guide the optical reconstruction algorithm. Sensitivity studies show that recovered values of indocyanine green fluorescence yield are linear to concentrations of 1nM in a 70mm diameter homogeneous phantom, and detection is feasible to near 10pM. Phantom data also demonstrate imaging capabilities of imperfect fluorophore uptake in tissue volumes of clinically relevant sizes. A unique rodent MR coil provides optical fiber access for simultaneous optical and MR data acquisition of small animals. A pilot murine study using an orthotopic glioma tumor model demonstrates optical-MRI imaging of an epidermal growth factor receptor targeted fluorescent probe in vivo.
Nonlinear current filamentation via magnetically trapped particles
Authors: Jovanović D. , Simić A.
Published: June 2008

The nonlinear kinetic theory of the saturated state of collisionless reconnection with a guide magnetic field is presented, associated with kinetic Alfvén waves. Using the drift-kinetic description of electrons, the effects of particle resonances are studied in details, in the presence of self-consistent nonlinear perturbations in the form of moving magnetic islands. The new type of magnetic resonance in velocity space is found. The corresponding magnetically trapped electrons are confined in the real space to the interior of the magnetic islands and at their edge, giving rise to a surface current in the vicinity of the magnetic separatrix. It is shown that the fast reconnection, associated with the near-singularities of the current, can be stabilized by this new nonlinear current.
Implosion and core heating requirements in subignition experiments FIREX-I
Authors: Johzaki Tomoyuki , Nakao Yasuyuki , Mima Kunioki
Published: June 2008

In the fast ignition realization experiment project phase-I (FIREX-I) [H. Azechi and the FIREX Project, Plasma Phys. Control. Fusion 48, B267 (2006)], core heating up to an ion temperature of 5keV is expected for subignition-class carbon-deuterium (CD) and deuterium-tritium (DT) fuels. The dependence of the achieved ion temperature on heating pulse parameters, and core density is investigated using two-dimensional simulations. Since the core size in FIREX-I is insufficient for self-ignition, and the confinement time is comparable to the heating duration (∼10ps), the temperature relaxation between the bulk electrons and ions is important for efficient ion heating. High compression (a core density of ρ>200g∕cm3) is required for pure DT fuel to shorten the relaxation time. In this case, a heating energy of Eh>2kJ and a duration of τh<10ps are required to achieve an ion temperature of 5keV. For CD and DT+foam fuels, the requirement for implosion is relaxed since the relaxation is fast, due to a large effective charge; 5keV ion heating is achieved at ρ⩾50g∕cm3 with Eh>2kJ and τh∼10ps.
Photoluminescence and photoreflectance study of annealing effects on GaAs0.909Sb0.07N0.021 layer grown by gas-source molecular beam epitaxy
Authors: Hsu Hung-Pin , Huang Yen-Neng , Huang Ying-Sheng , Lin Yang-Ting , Ma Ta-Chun , Lin Hao-Hsiung , Tiong Kwong-Kau , Sitarek Piotr , Misiewicz Jan
Published: June 2008

Thermal annealing effects of a GaAs0.909Sb0.07N0.021 film grown on GaAs substrate via gas-source molecular beam epitaxy have been characterized by photoluminescence (PL) and photoreflectance (PR) techniques. PL measurements show the evolution of luminescence feature with the thermal annealing treatment. The conduction to heavy-hole (HH) band and conduction to light-hole (LH) band transitions originated from the strained induced valence band splitting in GaAs0.909Sb0.07N0.021 layer have been observed by the PR measurements. The near band edge transition energies are slightly blueshifted, and the splitting of HH and LH bands is reduced with rising annealing temperature. The temperature dependences of near band edge transition energies are analyzed using Varshni and Bose–Einstein expressions in the temperature range from 15to300K. The parameters that describe the temperature variations of the near band edge transition energies are evaluated and discussed.
The Rouse–Mooney model for coherent quasielastic neutron scatterings of single chains well entangled in polymer melts
Authors: Lin Y.-H. , Huang C.-F.
Published: June 2008

The dynamic structure factor (DSF) for single (labeled) chains well entangled in polymer melts has been developed based on the Rouse–Mooney picture; the DSF functions derived from the Langevin equations of the model in both discrete and continuous forms are given. It is shown that for all practical purposes, it is sufficient to use the continuous form to analyze experimental results in the “safe” q region (q being the magnitude of the scattering wave vector q) where the Rouse-segment-based theories are applicable. The DSF form reduces to the same limiting form as that of the free Rouse chain as q2a2 or q2R2→∞ (a and R being the entanglement distance and the root mean square end-to-end distance, respectively), confirming what has been expected physically. The natural reduction to the limiting form allows the full range of DSF curves to be displayed in terms of the reduced Rouse variable q2(Zdt)0.5 in a unified way. The displayed full range represents a framework or “map,” with respect to which effects occurring in different regions of the DSF may be located and studied in a consistent manner. One effect is the significant or noticeable deviations of the theoretical DSF curves from the limiting curve in the region ∼4>q2(Zdt)0.5>∼0.1 (a time region where t<τ1e) to the faster side as qa is in the range 1–5. This is supported by the comparison of the experimental results of an entangled poly(vinylethylene) sample with the theoretical curves. The DSF functional forms predict plateaus with heights depending on the value of q—q-split plateaus—as can be experimentally observed in the time region greater than the relaxation time τ1e of the lowest Rouse–Mooney mode, when qa falls between ∼1 and ∼7. High sensitivity of the distribution of the q-split plateaus to a enables its value to be extracted from matching the calculated with the experimental results. The thus obtained a value for a well-entangled poly(ethylene-co-butene) polymer is in close agreement with the rheological result. It is shown that the fixed-end boundary conditions in the Rouse–Mooney model are responsible for the correct prediction of the distribution of the q-split plateaus.
The effect of collisional dissipation on the radial profiles of current driven by the lower-hybrid waves
Authors: Li Dehui , Kuang Guangli , Wang Shaojie
Published: June 2008

A simulation of the collisional dissipation of fast electrons has been conducted in lower-hybrid-current drive (LHCD) tokamak plasmas. The simulation results show that the dissipation of fast electrons will counteract the effect of radial diffusion to some extent, thereby making the LHCD current profile closer to the power deposition profile. It seems that the dissipation is helpful to maintain a steady state “hole current profile” in LHCD plasmas; thereby, the desired reversed magnetic shear should be maintained.
Nonparaxial theory of cross-focusing of two laser beams and its effects on plasma wave excitation and particle acceleration: Relativistic case
Authors: Sharma R. P. , Chauhan P. K.
Published: June 2008

Cross-focusing of two propagating ultrahigh power laser beams in homogeneous plasma (laser intensity IL>016W∕cm2) has been studied in the nonparaxial region. By expanding the eikonal and other relevant quantities up to the fourth power of r (radial distance), we observed that the focusing of the laser beams becomes fast in the nonparaxial region. The difference in focusing/defocusing of the axial and off-axial rays leads to the formation of a splitted profile of laser beams in the plasma. A remarkable change is also observed in the amplitude of plasma wave excitation and particle acceleration in the nonparaxial region in comparison to the paraxial region.
Validation in fusion research: Towards guidelines and best practices
Authors: Terry P. W. , Greenwald M. , Leboeuf J.-N. , McKee G. R. , Mikkelsen D. R. , Nevins W. M. , Newman D. E. , Stotler D. P. ,   Task Group on Verification and Validation,   U.S. Burning Plasma Organization,   U.S. Transport Task Force
Published: June 2008

Because experiment/model comparisons in magnetic confinement fusion have not yet satisfied the requirements for validation as understood broadly, approaches to validating mathematical models and numerical algorithms are recommended as good practices. Previously identified procedures, such as, verification, qualification, and analysis of errors from uncertainties and deficiencies, remain important. However, particular challenges intrinsic to fusion plasmas and physical measurement therein lead to identification of new or less familiar concepts that are also critical in validation. These include the primacy hierarchy, which tracks the integration of measurable quantities, and sensitivity analysis, which assesses how model output is apportioned to different sources of variation. The use of validation metrics for individual measurements is extended to multiple measurements, with provisions for the primacy hierarchy and sensitivity. This composite validation metric is essential for quantitatively evaluating comparisons with experiments. To mount successful and credible validation in magnetic fusion, a new culture of validation is envisaged.
Forces between nanorods with end-adsorbed chains in a homopolymer melt
Authors: Frischknecht Amalie L.
Published: June 2008

Adsorbed or grafted polymers are often used to provide steric stabilization of colloidal particles. When the particle size approaches the nanoscale, the curvature of the particles becomes relevant. To investigate this effect for the case of cylindrical symmetry, I use a classical fluids density functional theory applied to a coarse-grained model to study the polymer-mediated interactions between two nanorods. The rods are coated with end-adsorbing chains and immersed in a polymer melt of chemically identical, nonadsorbing chains. The force between the nanorods is found to be nonmonotonic, with an attractive well when the two brushes come into contact with each other, followed by a steep repulsion at shorter distances. The attraction is due to the entropic phenomenon of autophobic dewetting, in which there is a surface tension between the brush and the matrix chains. These results are similar to previous results for planar and spherical polymer brushes in melts of the same polymer. The depth of the attractive well increases with matrix chain molecular weight and with the surface coverage. The attraction is very weak when the matrix chain molecular weight is similar to or smaller than the brush molecular weight, but for longer matrix chains the magnitude of the attraction can become large enough to cause aggregation of the nanorods.
Ion- and electron-acoustic solitons in two-electron temperature space plasmas
Authors: Lakhina G. S. , Kakad A. P. , Singh S. V. , Verheest F.
Published: June 2008

Properties of ion- and electron-acoustic solitons are investigated in an unmagnetized multicomponent plasma system consisting of cold and hot electrons and hot ions using the Sagdeev pseudopotential technique. The analysis is based on fluid equations and the Poisson equation. Solitary wave solutions are found when the Mach numbers exceed some critical values. The critical Mach numbers for the ion-acoustic solitons are found to be smaller than those for electron-acoustic solitons for a given set of plasma parameters. The critical Mach numbers of ion-acoustic solitons increase with the increase of hot electron temperature and the decrease of cold electron density. On the other hand, the critical Mach numbers of electron-acoustic solitons increase with the increase of the cold electron density as well as the hot electron temperature. The ion-acoustic solitons have positive potentials for the parameters considered. However, the electron-acoustic solitons have positive or negative potentials depending whether the fractional cold electron density with respect to the ion density is greater or less than a certain critical value. Further, the amplitudes of both the ion- and electron-acoustic solitons increase with the increase of the hot electron temperature. Possible application of this model to electrostatic solitary waves observed on the auroral field lines by the Viking spacecraft is discussed.
Blowup of certain analytic solutions of the Hall magnetohydrodynamic equations
Authors: Núñez Manuel , Álvarez Jorge , Rojo Jesús
Published: June 2008

A recent analytic solution of the Hall magnetohydrodynamics equations is analyzed. It is shown that its evolution in time depends upon a certain set of inequalities upon the initial values of the velocity and the magnetic field. For most of the cases, both magnitudes will blow up in a finite time. This shows that for keeping the original structure of the solution, energy must be introduced into the system until eventually it cannot hold any longer.