bluuebunny/crossref_metadata_2025 huggingface dataset:
Future innovations in anti‐platelet therapies
Authors: Barrett N E , Holbrook L , Jones S , Kaiser W J , Moraes L A , Rana R , Sage T , Stanley R G , Tucker K L , Wright B , Gibbins J M
Published: June 2008

Platelets have long been recognized to be of central importance in haemostasis, but their participation in pathological conditions such as thrombosis, atherosclerosis and inflammation is now also well established. The platelet has therefore become a key target in therapies to combat cardiovascular disease. Anti‐platelet therapies are used widely, but current approaches lack efficacy in a proportion of patients, and are associated with side effects including problem bleeding. In the last decade, substantial progress has been made in understanding the regulation of platelet function, including the characterization of new ligands, platelet‐specific receptors and cell signalling pathways. It is anticipated this progress will impact positively on the future innovations towards more effective and safer anti‐platelet agents. In this review, the mechanisms of platelet regulation and current anti‐platelet therapies are introduced, and strong, and some more speculative, potential candidate target molecules for future anti‐platelet drug development are discussed.

British Journal of Pharmacology (2008) 154, 918–939; doi:10.1038/bjp.2008.151; published online 21 April 2008
Arsenic trioxide and auranofin inhibit selenoprotein synthesis: implications for chemotherapy for acute promyelocytic leukaemia
Authors: Talbot S , Nelson R , Self W T
Published: June 2008

Background and purpose:

Arsenicals have been used medicinally for decades to treat both infectious disease and cancer. Arsenic trioxide (As2O3) is effective for treatment of acute promyelocytic leukaemia (APL), yet the mechanism of action of this drug is still widely debated. Recently, As2O3 was shown to inhibit the activity of the selenoenzyme thioredoxin reductase (TrxR). TrxR has been proposed to be required for selenium metabolism. The effect of inhibitors of TrxR on selenium metabolism has yet to be assessed. This study aims to determine whether chemotherapeutics that target selenocysteine within selenoenzymes may also affect the metabolism of selenium.

Experimental approach:

A lung cell line, A549, was used to assess the effect of TrxR inhibitors on selenium metabolism, using 75Se‐selenite. The level of mRNA encoding cytosolic TrxR (TrxR1) was determined using real‐time reverse transcriptase‐PCR. TrxR activity was determined in whole‐cell extracts.

Key results:

Exposure of cells to As2O3, arsenite or auranofin led to a concentration‐dependent reduction of selenium metabolism into selenoproteins. Knockdown of TrxR1, using small inhibitory RNA, did not affect selenium metabolism. Exposure of cells to monomethylarsonic acid, a potent inhibitor of TrxR, did not alter selenium metabolism but did inhibit enzyme activity.

Conclusions and implications:

As2O3 and auranofin block the metabolism of selenium in A549 cells. Because As2O3 is used to treat APL, our findings may reveal the mechanism of this therapeutic action and lead to further research targeting selenium metabolism to find novel chemotherapeutic agents for the treatment of APL.

British Journal of Pharmacology (2008) 154, 940–948; doi:10.1038/bjp.2008.161; published online 21 April 2008
Sites of action of hydrogen peroxide on ion transport across rat distal colon
Authors: Schultheiss G , Hennig B , Diener M
Published: June 2008

Background and purpose:

The aim of this study was the identification of the mechanism of oxidant‐induced intestinal secretion.

Experimental approach:

The action of H2O2 on ion transport across rat distal colon was evaluated in Ussing chambers. Changes in cytosolic Ca2+ concentration were measured using fura‐2.

Key results:

H2O2 concentration‐dependently induced an increase in short‐circuit current (Isc), which was due to a stimulation of Cl− secretion. The effect of H2O2 was dependent on the presence of serosal Ca2+. It was inhibited after emptying of intracellular Ca2+ stores by cyclopiazonic acid or blockade of ryanodine receptors by ruthenium red, whereas a blocker of inositol 1,4,5‐trisphosphate receptors was less effective. Fura 2‐experiments confirmed an increase in the cytosolic Ca2+ concentration in the presence of H2O2. Measurements of Cl− currents across the apical membrane at basolaterally depolarized epithelia revealed the activation of a glibenclamide‐sensitive, SITS‐resistant Cl− conductance by the oxidant. The activation of this conductance was inhibited after blockade of protein kinases with staurosporine. When the apical membrane was permeabilized with nystatin, two sites of action of H2O2 were identified at the basolateral membrane. The oxidant stimulated a basolateral tetrapentylammonium‐sensitive K+ conductance and increased the current generated by the Na+–K+ pump. Pretreatment of the tissues with H2O2 reduced the action of subsequently administered Ca2+‐, cAMP‐ and cGMP‐dependent secretagogues demonstrating a long‐term downregulation after the initial secretory response evoked by the oxidant.

Conclusions and implications:

H2O2 affects colonic anion secretion by action sites at both the apical, as well as the basolateral membrane.

British Journal of Pharmacology (2008) 154, 991–1000; doi:10.1038/bjp.2008.162; published online 21 April 2008
Pharmacological profile of the clonidine‐induced inhibition of vasodepressor sensory outflow in pithed rats: correlation with a2A/2C‐adrenoceptors
Authors: Villalón C M , Albarrán‐Juárez J A , Lozano‐Cuenca J , Pertz H H , Görnemann T , Centurión D
Published: June 2008

British Journal of Pharmacology (2008) 154, 1160; doi:10.1038/bjp.2008.250
Discovery and biological characterization of a novel series of androgen receptor modulators
Authors: Zhou C , Wu G , Feng Y , Li Q , Su H , Mais D E , Zhu Y , Li N , Deng Y , Yang D , Wang M‐W
Published: June 2008

British Journal of Pharmacology (2008) 154, 1161; doi:10.1038/bjp.2008.251
Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues
Authors: Behm D J , McAtee J J , Dodson J W , Neeb M J , Fries H E , Evans C A , Hernandez R R , Hoffman K D , Harrison S M , Lai J M , Wu C , Aiyar N V , Ohlstein E H , Douglas S A
Published: June 2008

Background and purpose:

The recent development of the UT ligand palosuran (1‐[2‐(4‐benzyl‐4‐hydroxy‐piperidin‐1‐yl)‐ethyl]‐3‐(2‐methyl‐ quinolin‐4‐yl)‐urea sulphate salt) has led to the proposition that urotensin‐II (U‐II) plays a significant pathological role in acute and chronic renal injury in the rat.

Experimental approach:

In the present study, the pharmacological properties of palosuran were investigated further using a series of radioligand binding and functional bioassays.

Key results:

Palosuran functioned as a ‘primate‐selective’ UT ligand in recombinant cell membranes (monkey and human UT Ki values of 4±1 and 5±1 nM), lacking appreciable affinity at other mammalian UT isoforms (rodent and feline Ki values >1 μM). Paradoxically, however, palosuran lost significant (10‐ to 54‐fold) affinity for native and recombinant human UT when radioligand binding was performed in intact cells (Ki values of 50±3 and 276±67 nM). In accordance, palosuran also exhibited diminished activity in hUT (human urotensin‐II receptor)‐CHO (Chinese hamster ovary) cells (IC50 323±67 nM) and isolated arteries (Kb>10 μM in rat aorta; Kb>8.5 μM in cat arteries; Kb>1.6 μM in monkey arteries; Kb 2.2±0.6 μM in hUT transgenic mouse aorta). Relative to recombinant binding Ki values, palosuran was subjected to a 392‐ to 690‐fold reduction in functional activity in monkey isolated arteries. Such phenomena were peculiar to palosuran and were not apparent with an alternative chemotype, SB‐657510 (2‐bromo‐N‐[4‐chloro‐3‐((R)‐1‐methyl‐ pyrrolidin‐3‐yloxy)‐phenyl]‐4,5‐dimethoxybenzenesulphonamide HCl).

Conclusions and implications:

Collectively, such findings suggest that caution should be taken when interpreting data generated using palosuran. The loss of UT affinity/activity observed in intact cells and tissues cf. membranes offers a potential explanation for the disappointing clinical efficacy reported with palosuran in diabetic nephropathy patients. As such, the (patho)physiological significance of U‐II in diabetic renal dysfunction remains uncertain.

British Journal of Pharmacology (2008) 155, 374–386; doi:10.1038/bjp.2008.266; published online 30 June 2008
Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea‐pig model
Authors: Yao X , Anderson D L , Ross S A , Lang D G , Desai B Z , Cooper D C , Wheelan P , McIntyre M S , Bergquist M L , MacKenzie K I , Becherer J D , Hashim M A
Published: June 2008

Background and purpose:

Drug‐induced prolongation of the QT interval can lead to torsade de pointes, a life‐threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans.

Experimental approach:

Sixteen marketed drugs from various pharmacological classes with a known incidence—or lack thereof—of QT prolongation in humans were examined in hERG (human ether a‐go‐go‐related gene) patch‐clamp assay and an anaesthetized guinea‐pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea‐pigs were determined using liquid chromatography‐mass spectrometry.

Key results:

Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea‐pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model.

Conclusions and implications:

Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea‐pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization.

British Journal of Pharmacology(2008)154, 1446–1456; doi:10.1038/bjp.2008.267; published online 30 June 2008
Somatostatin inhibits colon cancer cell growth through cyclooxygenase‐2 downregulation
Authors: Colucci R , Blandizzi C , Ghisu N , Florio T , Del Tacca M
Published: June 2008

Background and purpose:

Cyclooxygenase‐2 (COX‐2) is expressed in colonic neoplasms, where it supports cell proliferation via prostaglandin E2 (PGE2) production. This study investigated the effects of somatostatin‐14 on COX‐2 expression, PGE2 production and proliferation in colon cancer cells.

Experimental approach:

Human colon adenocarcinoma cell lines Caco‐2, HT‐29 and HCT116 were used. The following techniques were employed: colourimetric assay for cell growth; 5‐bromo‐2′‐deoxyuridine assay for DNA synthesis; enzyme immunoassay for PGE2; COX‐2 mRNA silencing; RT–PCR or Western blot for somatostatin receptor subtypes, cyclooxygenase isoforms, phosphorylated‐ERK‐1/ERK‐2 and phosphorylated‐Akt.

Key results:

HT‐29 and Caco‐2 cells expressed COX‐2 and somatostatin receptors (sst3/4/5 and sst3/5, respectively). HCT116 cells did express somatostatin receptors (sst2/3/5), but not COX‐2. Somatostatin‐14 inhibited basal COX‐2 expression, PGE2 production, DNA synthesis and growth in Caco‐2 cells and these effects were prevented by BN81658 (sst3 receptor antagonist). Basal proliferation of HT‐29, HCT116 and COX‐2‐silenced Caco‐2 cells was not affected by somatostatin‐14. Stimulation of HT‐29 cells with gastrin‐17 elicited increments of ERK‐1/ERK‐2 and Akt phosphorylation, COX‐2 expression, PGE2 production, DNA synthesis and cell growth, which were all counteracted by somatostatin‐14. Somatostatin‐14‐induced inhibition of COX‐2 expression, PGE2 production and DNA synthesis were blocked by BIM23056 (sst5 receptor antagonist).

Conclusions and implications:

Somatostatin decreases COX‐2 expression and function in colon cancer cells via activation of sst3 or sst5 receptors, and these effects contribute to the inhibitory action of somatostatin on cell proliferation. These findings can be relevant to the development of therapeutic strategies based on the modulation of the COX‐2 pathway.

British Journal of Pharmacology (2008) 155, 198–209; doi:10.1038/bjp.2008.268; published online 30 June 2008
Effect of oral organic nitrates on expression and activity of vascular soluble guanylyl cyclase
Authors: Oppermann M , Dao V T‐V , Suvorava T , Bas M , Kojda G
Published: June 2008

Background and purpose:

The regulation of vascular soluble guanylyl cyclase (sGC) expression by nitric oxide (NO) is still under discussion. In vitro, NO has been shown to downregulate the expression of sGC but it is unclear if this mechanism is operative in vivo and occurs during nitrate treatment.

Experimental approach:

We investigated whether high dose isosorbide mononitrate (ISMN) or pentaerythrityl tetranitrate (PETN) treatment changes vascular sGC expression and activity in vivo. New Zealand White rabbits received a standard diet, 2 or 200 mg ISMN kg−1 d−1 for 16 weeks, and C57BL/6 mice received a standard diet, 6, 60 or 300 mg PETN kg−1 d−1 for four weeks. Absorption was checked by measuring the plasma levels of the drug/metabolite.

Key results:

Western blots of rabbit aortic rings showed similar protein levels of sGC α1‐ (P=0.2790) and β1‐subunits (P=0.6900) in all groups. Likewise, ANOVA showed that there was no difference in the expression of sGC in lungs of PETN‐treated mice (P=0.0961 for α1 and P=0.3709 for β1). The activities of isolated sGC in response to SNAP (1 μM–1 mM) were identical in aortae of ISMN‐treated rabbits (P=0.0775) and lungs of PETN‐treated mice (P=0.6348). The aortic relaxation response to SNAP slightly decreased at high ISMN but not at high PETN.

Conclusions and implications:

These data refute the hypothesis that therapeutic treatment with long acting NO donors has a significant impact on the regulation of vascular sGC expression and activity in vivo.

British Journal of Pharmacology (2008) 155, 335–342; doi:10.1038/bjp.2008.269; published online 30 June 2008
Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice
Authors: Zarbock A , Allegretti M , Ley K
Published: June 2008

Background and purpose:

Acute lung injury (ALI) remains a major challenge in critical care medicine. Both neutrophils and chemokines have been proposed as key components in the development of ALI. The main chemokine receptor on neutrophils is CXCR2, which regulates neutrophil recruitment and vascular permeability, but no small molecule CXCR2 inhibitor has been demonstrated to be effective in ALI or animal models of ALI. To investigate the functional relevance of the CXCR2 inhibitor Reparixin in vivo, we determined its effects in two models of ALI, induced by either lipopolysaccharide (LPS) inhalation or acid instillation.

Experimental approach:

In two ALI models in mice, we measured vascular permeability by Evans blue and evaluated neutrophil recruitment into the lung vasculature, interstitium and airspace by flow cytometry.

Key results:

Pharmacological inhibition of CXCR2 by Reparixin reduced CXCL1‐induced leukocyte arrest in the microcirculation of the cremaster muscle, but did not influence arrest in response to leukotriene B4 (LTB4) demonstrating specificity. Reparixin (15 μg g−1) reduced neutrophil recruitment in the lung by approximately 50% in a model of LPS‐induced ALI. A higher dose did not provide additional reduction of neutrophil recruitment. This dose also reduced accumulation of neutrophils in the interstitial compartment and vascular permeability in LPS‐induced ALI. Furthermore, both prophylactic and therapeutic application of Reparixin improved gas exchange, and reduced neutrophil recruitment and vascular permeability in a clinically relevant model of acid‐induced ALI.

Conclusions and implications:

Reparixin, a non‐competitive allosteric CXCR2 inhibitor attenuates ALI by reducing neutrophil recruitment and vascular permeability.

British Journal of Pharmacology (2008) 155, 357–364; doi:10.1038/bjp.2008.270; published online 30 June 2008
Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt‐dependent mechanisms
Authors: Xia L , Wang X X , Hu X S , Guo X G , Shang Y P , Chen H J , Zeng C L , Zhang F R , Chen J Z
Published: June 2008

Background and purpose:

Recent studies have shown that resveratrol increased endothelial progenitor cells (EPCs) numbers and functional activity. However, the mechanisms remain to be determined. Previous studies have demonstrated that increased EPC numbers and activity were associated with the inhibition of EPC senescence, which involves activation of telomerase. Therefore, we investigated whether resveratrol inhibits the onset of EPC senescence through telomerase activation, leading to potentiation of cellular activity.

Experimental approach:

After prolonged in vitro cultivation, EPCs were incubated with or without resveratrol. The senescence of EPCs were determined by acidic β‐galactosidase staining. The bromo‐deoxyuridine incorporation assay or a modified Boyden chamber assay were employed to assess proliferative or migratory capacity, respectively. To further examine the underlying mechanisms of these effects, we measured telomerase activity and the phosphorylation of Akt by western blotting.

Key results:

Resveratrol dose dependently prevented the onset of EPCs senescence and increased the proliferation and migration of EPCs. The effect of resveratrol on senescence could not be abolished by eNOS inhibitor or by an oestrogenic receptor antagonist. Resveratrol significantly increased telomerase activity and Akt phosphorylation. Pre‐treatment with the PI3K inhibitor, LY294002, significantly attenuated resveratrol‐induced telomerase activity.

Conclusions and implications:

Resveratrol delayed the onset of EPC senescence and this effect was accompanied by activation of telomerase through the PI3K‐Akt signalling pathway. The inhibition of EPCs senescence by resveratrol might protect EPCs against dysfunction induced by pathological factors in vivo and improve EPC functional activities in a way that may be important for cell therapy.

British Journal of Pharmacology (2008) 155, 387–394; doi:10.1038/bjp.2008.272; published online 30 June 2008
CD8+ T‐cell attenuation of cutaneous herpes simplex virus infection reduces the average viral copy number of the ensuing latent infection
Authors: Wakim Linda M , Jones Claerwen M , Gebhardt Thomas , Preston Christopher M , Carbone Francis R
Published: July 2008

During an initial encounter with herpes simplex virus type 1 (HSV‐1) it takes several days for an adaptive immune response to develop and for herpes‐specific CD8+ T cells to infiltrate sites of infection. By this time the virus has firmly established itself within the innervating sensory nervous system where it then persists indefinitely. Preventing the establishment of viral latency would require blocking the skin to nervous system transmission of the virus. We wished to examine if CD8+ T cells present early during acute HSV‐1 infection could block this transmission. We show that effector CD8+ T cells failed to prevent the establishment of HSV latency even when present prior to infection. This lack of blocking likely reflects the delayed infiltration of the CD8+ T cells into the infected skin. Examination of the kinetics of HSV‐1 infection highlighted the rapidity at which the virus infects the sensory ganglia and singled out early viral replication within the skin as an important factor in determining the magnitude of the ensuing latent infection. Though unable to prevent the establishment of latency, CD8+ T cells could reduce the average viral copy number of the residual latent infection by dampening the skin infection and thus limiting the skin‐to‐nerve transmission of virus.
Dorsal Nucleus Raphé
Authors:   Allen Institute for Brain Science, Royall Josh , Ng Lydia , Morris John
Published: July 2008

This report contains a gene expression summary of the dorsal nucleus raphé (DR), derived from the Allen Brain Atlas (ABA) in-situ hybridization (ISH) mouse data set. The structure’s location and morphological characteristics in the mouse brain are described using the Nissl data found in the Allen Reference Atlas. Using an established algorithm, the expression values of the DR were compared to the values of the macro/parent-structure, in this case the midbrain, for the purpose of extracting regionally specific gene expression data. The highest ranking ratios were then manually curated and verified. The 50 Select Genes were compiled for expression characterization. The experimental data for each gene may be accessed via the links provided; complementary sagittal data may also be accessed using the ABA. Correlation between gene expression in the DR and the rest of the brain, across all genes in the coronal dataset (~4300 genes), were derived computationally and are presented below. A gene ontology table (derived from DAVID Bioinformatics Resources 2007) is also included, highlighting possible functions of these 50 Select Genes.
Decreased Scholastic Achievement in Overweight Middle School Students
Authors: Shore Stuart M. , Sachs Michael L. , Lidicker Jeffrey R. , Brett Stephanie N. , Wright Adam R. , Libonati Joseph R.
Published: June 2008

The purpose of this study was to investigate whether overweight students achieved a lower relative degree of scholastic achievement compared to nonoverweight students. Subjects consisted of 6th and 7th grade students enrolled in a large public middle school in a suburb of Philadelphia, Pennsylvania. We compared grade point averages (GPAs), nationally standardized reading scores, school detentions, school suspensions, school attendance, tardiness to school, physical fitness test scores, and participation on school athletic teams among nonoverweight, at risk for overweight, and overweight students. Overweight students achieved lower grades (P < 0.001) and lower physical fitness scores (P < 0.0001) than their nonoverweight peers. Overweight students demonstrated a 0.4 letter grade lower GPA (on a 4.00 scale) and 11% lower national percentile reading scores than their nonoverweight peers. The overweight students also demonstrated significantly more detentions, worsened school attendance, more tardiness to school, and less participation on school athletic teams than their nonoverweight peers. Our study suggests that body mass is an important indicator of scholastic achievement, attendance, behavior, and physical fitness among middle school students, reiterating the need for healthy lifestyle intervention and prevention measures.
Chromium(VI) inhibits mouse metallothionein-I gene transcription by preventing the zinc-dependent formation of an MTF-1–p300 complex
Authors: Kimura Tomoki , Li Yong , Okumura Fumika , Itoh Norio , Nakanishi Tsuyoshi , Sone Tomomichi , Isobe Masakazu , Andrews Glen K.
Published: July 2008

Mouse MT-I (metallothionein-I) transcription is regulated by MTF-1 (metal-response-element-binding transcription factor-1) which is recruited to the promoter in response to zinc. Cr(VI) [chromium(VI)] pretreatment blocks zinc-activation of the endogenous MT-I gene and attenuates zinc-activation of MT-I-promoter-driven luciferase reporter genes in transient transfection assays. Chromatin immunoprecipitation assays revealed that Cr(VI) only modestly reduces recruitment of MTF-1 to the MT-I promoter in response to zinc, but drastically reduces the recruitment of RNA polymerase II. These results suggest that Cr(VI) inhibits the ability of MTF-1 to transactivate this gene in response to zinc. Zinc has recently been shown to induce the formation of a co-activator complex containing MTF-1 and the histone acetyltransferase p300 which plays an essential role in the activation of MT-I transcription. In the present study, co-immunoprecipitation assays demonstrated that Cr(VI) pretreatment blocks the zinc-induced formation of this co-activator complex. Thus Cr(VI) inhibits mouse MT-I gene expression in response to zinc by interfering with the ability of MTF-1 to form a co-activator complex containing p300 and recruiting RNA polymerase II to the promoter.
Remarkable breakdown voltage enhancement in AlGaN channel high electron mobility transistors
Authors: Nanjo Takuma , Takeuchi Misaichi , Suita Muneyoshi , Oishi Toshiyuki , Abe Yuji , Tokuda Yasunori , Aoyagi Yoshinobu
Published: June 2008

The channel layer substitution of a wider bandgap AlGaN for a conventional GaN in high electron mobility transistors (HEMTs) is an effective method of enhancing the breakdown voltage. We demonstrated a remarkable breakdown voltage enhancement in these AlGaN channel HEMTs. The obtained maximum breakdown voltages were 463 and 1650V in the Al0.53Ga0.47N∕Al0.38Ga0.62N HEMT with the gate-drain distances of 3 and 10μm, respectively. This result is very promising for the further higher power operation of high-frequency HEMTs.
Efficient single layer solution-processed blue-emitting electrophosphorescent devices based on a small-molecule host
Authors: Hou Liudong , Duan Lian , Qiao Juan , Li Wei , Zhang Deqiang , Qiu Yong
Published: June 2008

We report highly efficient single layer solution-processed blue small-molecule electrophosphorescent organic light-emitting diodes with iridium (III) bis[2-(4,6-difluorophenyl)-pyridinato-N,C2′]picolinate (FIrpic) doped into a wide-gap 9,9-bis[4-(3 c6-di-tert-butylcarbazol-9-yl)phenyl]fluorene (TBCPF) as the emission layer. An optimized device with 1,3-bis[(4-tert-butylphenyl)-1,3,4-oxidiazolyl]phenylene as the electron-transporting component doped into the emission layer, with a blue electrophosphorescence peaked at 474nm from FIrpic, shows a maximum luminance efficiency of 12.7cd∕A at 190A∕m2 and brightness of 19900cd∕m2 at 20V. We attribute the high performance to the excellent film forming ability and high triplet energy of TBCPF.
Conversion electron Mössbauer spectroscopy of epitaxial Co2Cr0.6Fe0.4Al thin films
Authors: Ksenofontov Vadim , Herbort Christian , Jourdan Martin , Felser Claudia
Published: June 2008

Heusler half-metals are promising for spintronic applications. Epitaxial thin films of the exemplar compound Co2Cr0.6Fe0.4Al (CCFA) were investigated using conversion electron Mössbauer spectroscopy to clarify the factors influencing the spin polarization. CCFA films were deposited by rf magnetron sputtering on MgO substrates with and without an Fe buffer layer. Annealing improves their crystallographic order, causes the diffusion of Fe atoms from the Fe buffer layer into the CCFA, and favors the Co–Fe disorder. The listed factors are possible reasons for the increase and subsequent reduction of the tunneling magnetoresistance in CCFA thin films observable across the annealing temperature range.
Shear-strain-induced low symmetry phase and domain ordering in epitaxial La0.7Sr0.3MnO3 thin films
Authors: Jin S. W. , Gao G. Y. , Huang Z. , Yin Z. Z. , Zheng X. , Wu Wenbin
Published: June 2008

The domain structure in epitaxial La0.7Sr0.3MnO3 films grown on (LaAlO3)0.3(Sr2AlTaO6)0.7(001) substrates has been investigated by x-ray reciprocal space maps on (003), (103), (1¯03), (013), and (01¯3) reflections in the high-resolution scattering zone containing the c* axis, and the transmission electron microscopy. We revealed that at above 20nm, the films show clearly a low symmetry monoclinic phase, and the shear strain relaxation can induce a patterned domain structure and in-plane superlattice in the films. The domain width versus the film thickness and the shear strain effect on the Curie temperature of the films were also discussed.
Poisson’s Ratio and Intrinsic Plasticity of Metallic Glasses
Authors: Poon S. J. , Zhu Aiwu , Shiflet G. J.
Published: June 2008

Through a comparison of the activation barrier densities for plastic deformation and brittle fracture at the yield point, a condition for intrinsic plasticity versus brittleness of metallic glasses under shear loading is derived. The quantitative role of Poisson’s ratio ν on fracture is revealed and additional effects due to local shear modulus (G) fluctuations are pointed out. The findings account for the onset of plasticity near reported ν values, as well as the brittleness of some high-ν alloys. Structural relaxation increases G and reduces fluctuations, incurring dual adverse effects on ductility. Implications for designing ductile metallic glasses are discussed.
Extrinsic origin of ferromagnetism in single crystalline LaAlO3 substrates and oxide films
Authors: Golmar F. , Mudarra Navarro A. M. , Rodríguez Torres C. E. , Sánchez F. H. , Saccone F. D. , dos Santos Claro P. C. , Benítez G. A. , Schilardi P. L.
Published: June 2008

Commercial LaAlO3 substrates were thermally cycled simulating a procedure similar to those followed during TiO2 and SnO2 dilute magnetic semiconductors’ film pulsed laser deposition. Ferromagneticlike behavior was found in some substrates, in which metallic iron impurities were detected by x-ray photoelectron spectroscopy and total reflection x-ray fluorescence measurements. A thorough experimental investigation, using high resolution techniques, showed that these impurities were introduced by the procedure used to fix the substrates to the oven silicon holders. It is suggested that magnetism observed previously in nominally pure SnO2 films is of extrinsic origin.
The Dynamics of Land Development in Resort Communities: A Multiagent Simulation of Growth Regimes and Housing Choice
Authors: Muller Brian , Yin Li , Kim Yuseung , Alexandrescu Florin
Published: June 2008

Over the past thirty years, recreation communities in many parts of the globe have gone through cycles of diversification and integration into complex recreation regions. As resort communities mature, they face increasing pressures on scarce recreational resources, demands for economic diversification, and changing attitudes toward tourism on the part of local residents. A variety of land-use management practices and economic development initiatives has emerged in resort towns in response to resource congestion and other growth issues. In this paper we explore alternative growth strategies through a simulation of housing decisions by primary actors in resort land markets. We use a multiagent system to model the dynamics of growth regimes, assess the influence of recreational and town amenities, and evaluate the effect of alternative growth processes on long-term development patterns. Our case study area is Steamboat Springs and surrounding parts of Routt County, a four-season recreational region in northwestern Colorado.
Testing the Regional Restructuring Hypothesis in Western Germany
Authors: Bierens Herman J , Kontuly Thomas
Published: June 2008

In this paper we test the importance of the regional restructuring hypothesis by investigating whether the internal migration flows in western Germany can be explained by employment changes, on the basis of data of out-migration of employed workers and employment in seventy-five regions over the period 1982–97 for each year separately. Starting from a conditional probability model for the unobserved individual migration decisions, we derive mathematically a dynamic version of the Poisson gravity model for the total out-migration per region per year. Estimating this model for each year separately, we find partial confirmation of the regional restructuring hypothesis.
The Practice of Biosecurity in Canada: Public Health Legal Preparedness and Toronto's SARS Crisis
Authors: Van Wagner Estair
Published: June 2008

The experience of the 2003 Severe Acute Respiratory Syndrome outbreak in Toronto, Canada provides an important example for understanding how the relationship between national security and public health is being defined in the contemporary context of emerging infectious diseases and the globalization of public health. This paper argues that Canada's public health legal framework is a critical part of Canada's practice of ‘biosecurity’ through which an unpredictable and continually emergent ‘new reality’, is mobilized to justify an ongoing state of emergency. Norms about state power and human rights are suspended in the interest of global capitalism and at the expense of those most vulnerable to the short-term and long-term effects of infectious disease.
Affect Work and Infected Bodies: Biosecurity in an Age of Emerging Infectious Disease
Authors: Major Claire
Published: June 2008

The movement of viruses is, in part, enabled when frontline workers straddle the sites of where illness meets health or where mobile bodies meet those that are fixed. Using the 2003 SARS outbreak in Toronto as a lens, this paper explores the neoliberalisms and managerialism that render nurses and hotel housekeepers vulnerable, then turns attention to how their affective immaterial labour was simultaneously demanded and dismissed during the outbreak. I argue the affective labour of both nurses and hotel housekeepers is mobilized to perform unquantifiable but essential life-management and that they function as a frontline of the barrier in thwarting the mobility of SARS as an infectious disease. Thus, nurses and hotel housekeepers are precarious gatekeepers, in vulnerable positions as they perform tasks of biosecurity as they monitor borders of transmission.
The Spaces of Biosecurity: Prescribing and Negotiating Solutions to Bovine Tuberculosis
Authors: Enticott Gareth
Published: June 2008

Using the example of bovine tuberculosis, this paper explores the emergence, understanding, and rejection of new forms of biosecurity. The paper argues that debates over biosecurity can be conceptualised as arguments over the ability to regulate flows of disease and the constructions of space they adopt. Data from parliamentary inquiries and interviews are used to show how attempts to institutionalise forms of biosecurity emerge from a delicate balance of prescribed and negotiated spaces configured by a host of social, natural, and material agents. The interaction between these spaces provides a way of regulating the flows of disease and purifying agricultural space. This balance is resisted by farmers, whose practical knowledges of the constant struggle of managing the contingencies of agriculture lead them to suggest that only uniform versions of space can effectively regulate flows of disease. The author concludes by discussing the importance of recognising these differences for future biosecurity and animal health policy.
Securing Life: The Emerging Practices of Biosecurity
Authors: Hinchliffe Steve , Bingham Nick
Published: June 2008

In this paper we review recent social science work on the issue of biosecurity and suggest ways in which geographers and social scientists can approach and intervene in current biosecurity practices. Our argument is that it is both useful and necessary to locate and intervene at sites where the ordering of biomatters is open to doubt and/or contestation. We pitch discourses of biological immanence and emergence against forms of social science thinking which tend to trace overarching logics or seemingly unstoppable forces in matters of power and politics. While acknowledging the import of both literatures, our aim is to engage with the fraught empirical practicalities of making biomatters secure in order to bring to the fore the ways in which life matters are patterned by any number of processes and the ways in which these patterns are always conditional on sociomaterial contingencies.
Safe from the Wolf: Biosecurity, Biodiversity, and Competing Philosophies of Nature
Authors: Buller Henry
Published: June 2008

By using the example of the reintroduction of wolves to the southern French Alps, this paper explores the competing ‘philosophies of nature’ that are revealed when agendas of biodiversity enhancement and protection conflict with notions of biosecurity. Tracing the shifting status of wolves as threat and hazard to emblems of reconstituted naturality, I argue that the reintroduction of wolves disturbs notions of both biodiversity and biosecurity, making unified strategies of management increasingly difficult and problematic. More significantly, the reintroduction of these classically ‘wild’ predators into seminatural and domesticated spaces challenges otherwise simplistic classifications not only of wild and domestic but also of human and nonhuman.
Biosecurity after the Event: Risk Politics and Animal Disease
Authors: Donaldson Andrew
Published: June 2008

This paper examines the politics of agricultural biosecurity in the UK, following the 2001 epidemic of foot and mouth disease. Biosecurity politics epitomise the ‘risk politics’ of animal disease, which acts antipolitically by focusing on problem-solving mechanisms and shutting down spaces for debate and dissent. By following biosecurity through three sites, various inconsistencies of this politics are described. On farms, biosecurity is seen as a routine and regulated practice that is more novel discursively than it is materially. In parliamentary and policy discourse, biosecurity is caught between a prescriptive regulatory logic tied to on-farm practices and a more open rhetorical construction which links it to a wider range of affairs of state (such as security, the national border, the public interest). At the science–policy interface, biosecurity politics enacts divisions not only between the roles of science and politics, but also between types of science. An event-based appreciation of risk and contingency highlights the need to unlock the problem-making potential inherent in these various inconsistencies and connections, a role which should be undertaken by social scientists working with others. The aim of this problem making should be a better constructed biosecurity through good biosecurity science.
Signals Come and Go: Syndromic Surveillance and Styles of Biosecurity
Authors: Fearnley Lyle
Published: June 2008

This paper follows the development of a novel biosecurity technology known as ‘syndromic surveillance’. By monitoring new sources of nondiagnostic health information (911 calls, ER triage logs, pharmaceutical sales), syndromic surveillance produces new ‘territories of intelligibility’. But the implemention of syndromic systems—and the opening up of these new territories—poses a problem of interpretation. What is significant in nondiagnostic data flows? In fact, the development of a national syndromic system in the United States attracted criticism from local public health experts, who complained about the costs of ‘false positive’ or insignificant detections. This exposes a disjuncture between two interpretative frameworks, two styles of governing biosecurity: public health (a responsibility for maximal population health) and preparedness (a concern for disaster-scale events). At stake are new norms and forms of securing life.
Flexible Boundaries in Biosecurity: Accommodating Gorse in Aotearoa New Zealand
Authors: Barker Kezia
Published: June 2008

The context of biosecurity has been theorised through attention to borders, boundaries, and expert processes of categorisation. This emergent literature represents biosecurity governance as brittle, unreflexive, and unresponsive. In contrast, biosecurity practices in New Zealand produce a complexity of semipermeable boundaries of control that are beginning to incorporate flexibility and sensitivity to the spatiotemporal geographies of indeterminate entities, and to changing and competing human values. Gorse ( Ulex spp), a woody, perennial shrub, was imported to New Zealand during the early stages of European settlement, and has been the subject of shifting biosecurity-related management practices for close to 150 years. Classified as a ‘pest plant’, gorse is currently subject to the biosecurity rationalities of internal pest management. Cost–benefit analysis and the ‘infestation-curve model’ are drawn on in the placement of gorse in a hierarchy of control categories within regional pest management strategies. This classification and control is negotiated between institutional and public values and rationalities within a formalised consultation process, and through the diffuse impact of public opinion. Gorse also plays an active role in the decision-making process, as its extensive distribution informs the allocation of control responses, and through its controversial role as a ‘nurse plant’ for native species. This paper therefore presents a challenge to emergent critical social scientific approaches to biosecurity, suggesting that we can learn something from the socionatural subtlety of policy making and implementation practices in New Zealand.
Gene expression patterns in visual cortex during the critical period: Synaptic stabilization and reversal by visual deprivation
Authors: Lyckman Alvin W. , Horng Sam , Leamey Catherine A. , Tropea Daniela , Watakabe Akiya , Van Wart Audra , McCurry Cortina , Yamamori Tetsuo , Sur Mriganka
Published: July 2008

The mapping of eye-specific, geniculocortical inputs to primary visual cortex (V1) is highly sensitive to the balance of correlated activity between the two eyes during a restricted postnatal critical period for ocular dominance plasticity. This critical period is likely to have amplified expression of genes and proteins that mediate synaptic plasticity. DNA microarray analysis of transcription in mouse V1 before, during, and after the critical period identified 31 genes that were up-regulated and 22 that were down-regulated during the critical period. The highest-ranked up-regulated gene, cardiac troponin C, codes for a neuronal calcium-binding protein that regulates actin binding and whose expression is activity-dependent and relatively selective for layer-4 star pyramidal neurons. The highest-ranked down-regulated gene,
synCAM
, also has actin-based function. Actin-binding function, G protein signaling, transcription, and myelination are prominently represented in the critical period transcriptome. Monocular deprivation during the critical period reverses the expression of nearly all critical period genes. The profile of regulated genes suggests that synaptic stability is a principle driver of critical period gene expression and that alteration in visual activity drives homeostatic restoration of stability.
Long-term resistance to simulated climate change in an infertile grassland
Authors: Grime J. Philip , Fridley Jason D. , Askew Andrew P. , Thompson Ken , Hodgson John G. , Bennett Chris R.
Published: July 2008

Climate shifts over this century are widely expected to alter the structure and functioning of temperate plant communities. However, long-term climate experiments in natural vegetation are rare and largely confined to systems with the capacity for rapid compositional change. In unproductive, grazed grassland at Buxton in northern England (U.K.), one of the longest running experimental manipulations of temperature and rainfall reveals vegetation highly resistant to climate shifts maintained over 13 yr. Here we document this resistance in the form of: (
i
) constancy in the relative abundance of growth forms and maintained dominance by long-lived, slow-growing grasses, sedges, and small forbs; (
ii
) immediate but minor shifts in the abundance of several species that have remained stable over the course of the experiment; (
iii
) no change in productivity in response to climate treatments with the exception of reduction from chronic summer drought; and (
iv
) only minor species losses in response to drought and winter heating. Overall, compositional changes induced by 13-yr exposure to climate regime change were less than short-term fluctuations in species abundances driven by interannual climate fluctuations. The lack of progressive compositional change, coupled with the long-term historical persistence of unproductive grasslands in northern England, suggests the community at Buxton possesses a stabilizing capacity that leads to long-term persistence of dominant species. Unproductive ecosystems provide a refuge for many threatened plants and animals and perform a diversity of ecosystem services. Our results support the view that changing land use and overexploitation rather than climate change
per se
constitute the primary threats to these fragile ecosystems.
Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1
Authors: Cha Seung-Kuy , Ortega Bernardo , Kurosu Hiroshi , Rosenblatt Kevin P. , Kuro-o Makoto , Huang Chou-Long
Published: July 2008

Klotho is a mammalian senescence-suppression protein that has homology with glycosidases. The extracellular domain of Klotho is secreted into urine and blood and may function as a humoral factor. Klotho-deficient mice have accelerated aging and imbalance of ion homeostasis. Klotho treatment increases cell-surface abundance of the renal epithelial Ca
2+
channel TRPV5 by modifying its N-linked glycans. However, the precise sugar substrate and mechanism for regulation by Klotho is not known. Here, we report that the extracellular domain of Klotho activates plasma-membrane resident TRPV5 through removing terminal sialic acids from their glycan chains. Removal of sialic acids exposes underlying disaccharide galactose-
N
-acetylglucosamine, a ligand for a ubiquitous galactoside-binding lectin galectin-1. Binding to galectin-1 lattice at the extracellular surface leads to accumulation of functional TRPV5 on the plasma membrane. Knockdown of β-galactoside α2,6-sialyltransferase (ST6Gal-1) by RNA interference, but not other sialyltransferases, in a human cell line prevents the regulation by Klotho. Moreover, the regulation by Klotho is absent in a hamster cell line that lacks endogenous ST6Gal-1, but is restored by forced expression of recombinant ST6Gal-1. Thus, Klotho participates in specific removal of α2,6-linked sialic acids and regulates cell surface retention of TRPV5 through this activity. This action of Klotho represents a novel mechanism for regulation of the activity of cell-surface glycoproteins and likely contributes to maintenance of calcium balance by Klotho.
Greek “Heroes” in the Polish People's Republic and the Geopolitics of the Cold War, 1948–1956*
Authors: Fleming Michael
Published: June 2008

Over the last decade or so there has been renewed interest in the Greek civil war, with a number of important publications shifting the focus of research from the high plane of international relations and Cold War polemics to a critical history of the period, allowing unheard voices and perspectives to be heard and revealed. The volume edited by Mark Mazower, for example, places the experiences of the 1940s in thelongue duréeof Greek nation-state formation as well as in the wider context of war and post-war violence and resistance—the social character of which is emphasized. Yet the importance of the Greek civil war in the emergence of the Cold War cannot be underestimated as Gerolymatos makes clear. This paper, therefore, aims to demonstrate how the refugees from Greece who arrived in Poland constitute an important part of Cold War history and to show how their experience in Poland can shed light upon both the wider international context and the dynamics of nationality policy in Poland itself. I contend that the arrival of Greek refugees weakened the Polish state's drive to national homogeneity.