bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biological implications of low condition factor “axe handle” specimens of the Antarctic toothfish,Dissostichus mawsoni, from the Ross Sea
Authors: Fenaughty J.M. , Eastman Joseph T. , Sidell Bruce D. 
Published: June 2008

AbstractWe evaluated the condition factor (K), an index of weight per unit length, in a sample of 49 761 longline-caught specimens of Antarctic toothfish,Dissostichus mawsoni, from the Ross Sea. Our sample consisted of specimens from northern (60–70°S) and southern (70–78°S) regions. Fifty percent of the northern sample and 4.9% of the southern sample were large individuals with a low condition factor (Kah ≤ 1.0182) and displaying an “axe handle (ah)” morphology with a notably thinner trunk. In the northern sample 55.4% of the males and 43.2% of the females were less thanKah.In the southern region 5.3% of the males and 4.5% of the females were less thanKah. The axe handle morphology is attributable to the metabolic loss of muscular and subcutaneous lipid stores, and probably proteins, from white muscle. Our discussion considers energy metabolism as related to migration, feeding and reproduction. We suggest that migration, a life history trait of the phyletically basal notothenioid cladesPseudaphritisandEleginops, persists inD. mawsoni. The spawning migration from the southern shelf to ridges and seamounts in the north may reflect fidelity to historic spawning grounds. As evidenced by the axe handle specimens neutral buoyancy of largeD. mawsonimay be ephemeral, fluctuating over the course of adult life.
Advances in mouse models of prostate cancer
Authors: Ahmad Imran , Sansom Owen J. , Leung Hing Y. 
Published: June 2008

Advances in science and technology have allowed us to manipulate the mouse genome and analyse the effect of specific genetic alterations on the development of prostate cancer in vivo. We can now analyse the molecular basis of initiation, invasion and progression to metastatic disease. The current mouse models utilise knockout, knock-in or conditional regulation of expression using Cre–loxP technology. Genes that have been targeted include homeobox genes, tumour suppressors and oncogenes, growth factors (and their receptors), steroid hormones and cell-cycle regulators, as well as pro- and anti-apoptotic proteins. Bigenic models indicate that that two ‘hits’ are required for progression from intra-epithelial neoplasia (PIN) to invasion carcinoma, and two to five hits are needed for metastasis. Here, we discuss the numerous models that mimic various aspects of the disease process, such as PIN, locally invasive adenocarcinoma and metastatic disease. Currently the PB-Cre4 × PTENloxP/loxPmouse is the only model that spans the entire continuum from initiation to local invasion and metastasis. Such mouse models increase our understanding of the disease process and provide targets for novel therapeutic approaches. Hopefully, the transgenic models will become inducible and ultimately allow both temporal and spatial gene inactivation. Compound mutational models will also develop further, with double and triple knock-in or knockout systems adding to our knowledge of the interaction between different signalling cascades.
Interactions between commensal bacteria and the gut-associated immune system of the chicken
Authors: Brisbin Jennifer T. , Gong Joshua , Sharif Shayan 
Published: June 2008

AbstractThe chicken gut-associated lymphoid tissue is made up of a number of tissues and cells that are responsible for generating mucosal immune responses and maintaining intestinal homeostasis. The normal chicken microbiota also contributes to this via the ability to activate both innate defense mechanisms and adaptive immune responses. If left uncontrolled, immune activation in response to the normal microbiota would pose a risk of excessive inflammation and intestinal damage. Therefore, it is important that immune responses to the normal microbiota be under strict regulatory control. Through studies of mammals, it has been established that the mucosal immune system has specialized regulatory and anti-inflammatory mechanisms for eliminating or tolerating the normal microbiota. The mechanisms that exist in the chicken to control host responses to the normal microbiota, although assumed to be similar to that of mammals, have not yet been fully described. This review summarizes what is currently known about the host response to the intestinal microbiota, particularly in the chicken.
Genes and Ideologies
Authors: Charney Evan 
Published: June 2008

AbstractThere is a trend among behavioral scientists to view ever more complex attitudes or systems of belief as in some sense genetically determined (or “heritable”). Consistent with this trend is the recent article of Alford, Funk, and Hibbing titled “Are Political Orientations Genetically Transmitted?” in which the authors claim to have demonstrated that when it comes to the transmission of political ideologies, genes count for more than environment. Their article has received an enormous amount of attention among political scientists and in the popular press. I critically evaluate the research technique on the basis of which the authors' support their claims and argue that it suffers from significant methodological flaws. Such flaws notwithstanding, I demonstrate that the authors' data do not clearly support their conclusions. I then question the cogency, from an historical and theoretical perspective, of proposing the existence of “liberal” and “conservative” “phenotypes” and “genotypes.” My argument has implications beyond the findings of Alford, Funk, and Hibbing, and applies to all studies that claim to have demonstrated the heritability of complex and politically relevant attitudes.
Translocation of the insulin‐regulated aminopeptidase to the cell surface: detection by radioligand binding
Authors: Demaegdt H , Smitz L , De Backer J‐P , Le M T , Bauwens M , Szemenyei E , Tóth G , Michotte Y , Vanderheyden P , Vauquelin G 
Published: June 2008

Background and purpose:Insulin‐regulated aminopeptidase (IRAP) and the insulin‐dependent glucose transporter GLUT4 colocalize in specific intracellular vesicles (that is, GLUT4 vesicles). These vesicles move slowly to the cell surface, but their translocation is markedly enhanced by insulin, resulting in higher glucose uptake. Previous studies of the insulin‐mediated translocation of IRAP to the cell surface have been hampered by the laborious detection of IRAP at the cell surface. We aimed to develop a more direct and faster method to detect IRAP. To this end, we used model systems with well‐characterized IRAP: CHO‐K1 cells expressing endogenous IRAP and recombinant HEK293 cells expressing human IRAP. A more widespread application of the method was demonstrated by the use of 3T3‐L1 adipocytes.Experimental approach:After stimulation of the cells with insulin, internalization of IRAP was inhibited by the addition of phenyl arsine oxide (PAO). Then, cell‐surface IRAP was detected by the high‐affinity binding of radiolabelled angiotensin (Ang) IV (either125I or3H).Key Results:We monitored the time‐ and concentration dependence of insulin‐mediated translocation of IRAP in both cell lines and 3T3‐L1 adipocytes. A plateau was reached between 6 and 8 min, and 10−7 Minsulin led to the highest amount of IRAP at the cell surface.Conclusions and implications:Based on the capacity of the IRAP apoenzyme to display high affinity for radiolabelled Ang IV and on the ability of PAO to inhibit IRAP internalization, we developed a more direct and faster method to measure insulin‐mediated translocation of IRAP to the cell surface.British Journal of Pharmacology(2008)154, 872–881; doi:10.1038/bjp.2008.117; published online 21 April 2008
Characterization of (R,S)‐5,7‐di‐tert‐butyl‐3‐hydroxy‐3‐trifluoromethyl‐3H‐benzofuran‐2‐one as a positive allosteric modulator of GABABreceptors
Authors: Malherbe P , Masciadri R , Norcross R D , Knoflach F , Kratzeisen C , Zenner M‐T , Kolb Y , Marcuz A , Huwyler J , Nakagawa T , Porter R H P , Thomas A W , Wettstein J G , Sleight A J , Spooren W , Prinssen E P 
Published: June 2008

Background and purpose:As baclofen is active in patients with anxiety disorders, GABABreceptors have been implicated in the modulation of anxiety. To avoid the side effects of baclofen, allosteric enhancers of GABABreceptors have been studied to provide an alternative therapeutic avenue for modulation of GABABreceptors. The aim of this study was to characterize derivatives of (R,S)‐5,7‐di‐tert‐butyl‐3‐hydroxy‐3‐trifluoromethyl‐3H‐benzofuran‐2‐one (rac‐BHFF) as enhancers of GABABreceptors.Experimental approach:Enhancing properties ofrac‐BHFF were assessed in the Chinese hamster ovary (CHO)‐Gα16‐hGABAB(1a,2a)cells by Fluorometric Imaging Plate Reader and GTPγ[35S]‐binding assays, and in rat hippocampal slices by population spike (PS) recordings.In vivoactivities ofrac‐BHFF were assessed using the loss of righting reflex (LRR) and stress‐induced hyperthermia (SIH) models.Key results:In GTPγ[35S]‐binding assays, 0.3 μMrac‐BHFF or its pure enantiomer (+)‐BHFF shifted the GABA concentration–response curve to the left, an effect that resulted in a large increase in both GABA potency (by 15.3‐ and 87.3‐fold) and efficacy (149% and 181%), respectively. In hippocampal slices,rac‐BHFF enhanced baclofen‐induced inhibition of PS of CA1 pyramidal cells. In anin vivomechanism‐based model in mice,rac‐BHFF increased dose‐dependently the LRR induced by baclofen with a minimum effective dose of 3 mg kg−1p.o.rac‐BHFF (100 mg kg−1p.o.) tested alone had no effect on LRR nor on spontaneous locomotor activity, but exhibited anxiolytic‐like activity in the SIH model in mice.Conclusions and implications:rac‐BHFF derivatives may serve as valuable pharmacological tools to elucidate the pathophysiological roles played by GABABreceptors in the central and peripheral nervous systems.British Journal of Pharmacology(2008)154, 797–811; doi:10.1038/bjp.2008.135; published online 21 April 2008
Pattern recognition receptors and interleukin‐8 mediate effects of Gram‐positive and Gram‐negative bacteria on lung epithelial cell function
Authors: Sorrentino R , De Souza P M , Sriskandan S , Duffin C , Paul‐Clark M J , Mitchell J A 
Published: June 2008

Background and purpose:Lung epithelial cells express pattern recognition receptors, which react to bacteria. We have evaluated the effect of Gram‐positive and Gram‐negative bacteria on interleukin‐8 (CXCL8) release from epithelial cells and the integrity of the epithelial barrier.Experimental approach:Primary cultures of human airway epithelial cells and the epithelial cell line A549 were used, and CXCL8 release was measured after exposure to Gram‐negative or Gram‐positive bacteria. Epithelial barrier function was assessed in monolayer cultures of A549 cells.Results:Gram‐positive bacteria Staphylococcus aureus or Streptococcus pneumoniae, induced release of CXCL8 from human airway epithelial cells. These bacteria also disrupted barrier function in A549 cells, an effect mimicked by CXCL8 and blocked by specific binding antibodies to CXCL8. Gram–negative bacteria Escherichia coli or Pseudomonas aeruginosa induced greater release of CXCL8 than Gram‐positive bacteria. However, Gram‐negative bacteria did not affect epithelial barrier function directly, but prevented disruption induced by Gram‐positive bacteria. These effects of Gram‐negative bacteria on barrier function were mimicked by FK565, an agonist of the nucleotide‐binding oligomerization domain 1 (NOD1) receptor, but not by the Toll‐like receptor (TLR) 4 agonist bacterial lipopolysaccharide. Neither the Gram‐negative bacteria nor FK565 blocked CXCL8 release.Conclusions:These data show differential functional responses induced by Gram‐negative and Gram‐positive bacteria in human lung epithelial cells. The NOD1 receptors may have a role in preventing disruption of the epithelial barrier in lung, during inflammatory states.British Journal of Pharmacology (2008) 154, 864–871; doi:10.1038/bjp.2008.139; published online 21 April 2008
Examination of signalling pathways involved in muscarinic responses in bovine ciliary muscle using YM‐254890, an inhibitor of the Gq/11 protein
Authors: Yasui F , Miyazu M , Yoshida A , Naruse K , Takai A 
Published: June 2008

Background and purpose:In the ciliary muscle, the tonic component of the contraction produced by cholinergic agonists is highly dependent on Ca2+ provided by influx through non‐selective cation channels (NSCCs) opened by stimulation of M3 muscarinic receptors. We examined effects of YM‐254890 (YM), a Gq/11‐specific inhibitor, on contraction, NSCC currents and [Ca2+]i elevation induced by carbachol (CCh).Experimental approach:Isometric tension was recorded from ciliary muscle bundles excised from bovine eyes. In ciliary myocytes dispersed with collagenase and cultured for 1–5 days, whole‐cell currents were recorded by voltage clamp and the intracellular free Ca2+ concentration [Ca2+]i was monitored using the Fluo‐4 fluorophore. Existence and localization of M3 receptors and the α subunit of Gq/11 (Gαq/11) were examined by immunofluorescence microscopy using AlexaFluor‐conjugated antibodies.Key results:Both phasic and tonic components of contractions evoked by 2 μM CCh were inhibited by YM (3–10 μM) in a dose‐dependent manner. In the cultured cells, CCh (0.05–10 μM) evoked an NSCC current as well as an elevation of the [Ca2+]i. Both initial and sustained phases of these CCh‐evoked responses were abolished by YM (3–10 μM). Immunostaining of the cytoplasmic side of the plasma membrane of ciliary myocytes revealed a dense distribution of M3 receptors and Gαq/11.Conclusions and implications:The tonic as well as phasic component of the ciliary muscle contraction appears to be under control of signals conveyed by a Gq/11‐coupled pathway. YM is a useful tool to assess whether Gq/11 is involved in a signal transduction system.British Journal of Pharmacology (2008) 154, 890–900; doi:10.1038/bjp.2008.140; published online 21 April 2008
Vardenafil, but not sildenafil or tadalafil, has calcium‐channel blocking activity in rabbit isolated pulmonary artery and human washed platelets
Authors: Toque H A , Teixeira C E , Priviero F B M , Morganti R P , Antunes E , De Nucci G 
Published: June 2008

Background and purpose:Phosphodiesterase type‐5 (PDE5) inhibitors constitute a novel and important therapeutic option for the treatment of pulmonary hypertension. The effects of the PDE5 inhibitors sildenafil, tadalafil and vardenafil on rabbit isolated pulmonary artery ring preparations and on intracellular Ca2+ concentration of thrombin‐stimulated human platelets were investigated.Experimental approach:Rabbit pulmonary artery rings were mounted in 10 mL organ bath containing Krebs solution. Tissues were connected to force‐displacement transducers, and changes in isometric force were recorded. Ca2+ flux in human washed platelets was measured.Key results:Sildenafil, tadalafil and vardenafil (0.0001–10 μM) concentration‐dependently relaxed endothelium‐intact and endothelium‐denuded pulmonary artery rings. Endothelium denudation caused rightward shifts in the concentration–response curves to sildenafil, tadalafil and vardenafil (9‐, 12‐ and 123‐fold, respectively). Incubation with Nω‐nitro‐L‐arginine methyl ester (100 μM) or ODQ (1H‐[1,2,4] oxadiazolo [4,3,‐a]quinoxalin‐1‐one) (10 μM) caused similar reductions of PDE5‐induced vasorelaxations in intact rings. Sildenafil and tadalafil did not affect the phenylephrine‐induced contractions, whereas vardenafil reduced the maximal responses, and shifted the phenylephrine‐induced contraction curves to the right in endothelium‐denuded rings (5‐ and 19‐fold for 1 and 10 μM, respectively). Vardenafil (but neither sildenafil nor tadalafil) caused a marked rightward shift and a decrease of maximal contractile response to CaCl2. Vardenafil, but neither sildenafil nor tadalafil, significantly reduced the Ca2+ mobilization and Ca2+ influx in thrombin‐stimulated washed platelets.Conclusions and implications:Our results indicate that vardenafil, in contrast to sildenafil or tadalafil, also blocked Ca2+ fluxes, thus enhancing its vasorelaxation of the pulmonary artery.British Journal of Pharmacology (2008) 154, 787–796; doi:10.1038/bjp.2008.141; published online 21 April 2008
Pathology‐specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation
Authors: Christ T , Wettwer E , Voigt N , Hála O , Radicke S , Matschke K , Várro A , Dobrev D , Ravens U 
Published: June 2008

Background and purposeThis study was designed to establish the pathology‐specific inhibitory effects of the IKur/Ito/IK,ACh blocker AVE0118 on atrium‐selective channels and its corresponding effects on action potential shape and effective refractory period in patients with chronic AF (cAF).Experimental approachOutward K+‐currents of right atrial myocytes and action potentials of atrial trabeculae were measured with whole‐cell voltage clamp and microelectrode techniques, respectively. Outward currents were dissected by curve fitting.Key resultsFour components of outward K+‐currents and AF‐specific alterations in their properties were identified. Ito was smaller in cAF than in SR, and AVE0118 (10 μM) apparently accelerated its inactivation in both groups without reducing its amplitude. Amplitudes of rapidly and slowly inactivating components of IKur were lower in cAF than in SR. The former was abolished by AVE0118 in both groups, the latter was partially blocked in SR, but not in cAF, even though its inactivation was apparently accelerated in cAF. The large non‐inactivating current component was similar in magnitude in both groups, but decreased by AVE0118 only in SR. AVE0118 strongly suppressed AF‐related constitutively active IK,ACh and prolonged atrial action potential and effective refractory period exclusively in cAF.Conclusions and implicationsIn atrial myocytes of cAF patients, we detected reduced function of distinct IKur components that possessed decreased component‐specific sensitivity to AVE0118 most likely as a consequence of AF‐induced electrical remodelling. Inhibition of profibrillatory constitutively active IK,ACh may lead to pathology‐specific efficacy of AVE0118 that is likely to contribute to its ability to convert AF into SR.British Journal of Pharmacology (2008) 154, 1619–1630; doi: 10.1038/bjp.2008.209; published online 9 June 2008
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