bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distribution of the verrucomicrobial clade Spartobacteria along a salinity gradient in the Baltic Sea
Authors: Bergen Benjamin , Herlemann Daniel P. R. , Labrenz Matthias , Jürgens Klaus 
Published: May 2014

SummaryA recent pyrosequencing study along the whole Baltic Sea salinity transect identified members of the Verrucomicrobia class Spartobacteria as an important component of Baltic Sea bacterioplankton. In this study, catalysed reporter deposition‐fluorescence in situ hybridization was used for cellular quantification. The published probes VER47 and SPA714 were optimized for samples from the Baltic Sea and a new, specific probe (SPA476) was used to quantify the dominant spartobacterial lineage ‘LD29’. The results confirmed that in the brackish surface waters of the Baltic Sea Spartobacteria comprise an important component, constituting up to 12% of all bacteria. The positive correlation and physical association of Spartobacteria with phytoplankton suggest their involvement in the utilization of phytoplankton‐derived organic matter in the Baltic Sea.
A calibration study of SAPS II with Norwegian intensive care registry data
Authors: HAALAND Ø. A. , LINDEMARK F. , FLAATTEN H. , KVÅLE R. , JOHANSSON K. A. 
Published: May 2014

BackgroundMortality prediction is important in intensive care. The Simplified Acute Physiology Score (SAPS) II is a tool for predicting such mortality. However, the original SAPS II is poorly calibrated to current intensive care unit (ICU) populations because it draws on data, which is more than 20 years old. We aimed to improve the calibration of SAPS II using data from the Norwegian Intensive Care Registry (NIR). This is the first recalibration of SAPS II for Nordic data.MethodsA first‐level customization was applied to improve calibration of the original SAPS II model (Model A). NIR data used covered more than 90% of adult patients admitted to ICUs in Norway from 2008 to 2010 (n = 30712).ResultsThe modified SAPS II, Model B, outperformed the original Model A with respect to calibration. Model B gave more accurate predictions of mortality than Model A (Hosmer–Lemeshow's C: 22.01 vs. 689.07; Brier score: 0.120 vs. 0.131; Cox's calibration regression: α = −0.093 vs. −0.747, β = 0.921 vs. 0.735, (α|β = 1) = −0.009 vs. −0.630). The standardized mortality ratio was 0.73 [95% confidence interval (CI) of 0.70–0.76] for Model A and 0.99 (95% CI of 0.95–1.04) for Model B. Discrimination was good for both models (area under receiver operating characteristic curve = 0.83 for both models).ConclusionsAs expected, Model B is better calibrated than Model A, and both models have similar uniformity of fit and equal discrimination. Introducing Model B into Norwegian ICUs may improve precision in decision‐making. Units will have a more realistic benchmark for the assessment of ICU performance. Mortality risk estimates from Model B are better than previous SAPS II estimates have been.
Pentax Airway Scope® vs Macintosh laryngoscope for tracheal intubation in adult patients: a systematic review and meta‐analysis
Authors: Hoshijima H. , Kuratani N. , Hirabayashi Y. , Takeuchi R. , Shiga T. , Masaki E. 
Published: May 2014

SummaryThe Pentax Airway Scope® is a single‐use optical videolaryngoscope designed to assist with difficult tracheal intubation. We systematically reviewed the efficacy of the Pentax Airway Scope with that of a conventional laryngoscope for tracheal intubation in adults with ‘normal’ and ‘difficult’ airways. We included 17 randomised controlled trials with a total of 1801 participants. We used the DerSimonian and Laird random‐effects model to calculate pooled relative risk or weighted mean differences. The relative risk (95% CI) of a Cormack–Lehane grade‐1 laryngeal view was 2.40 (1.76–2.49) with the Pentax Airway Scope compared with the Macintosh laryngoscope, p < 0.00001. We found no other differences between the two laryngoscopes. Despite a superior laryngeal view, the Pentax Airway Scope provides little clinical benefit over the conventional laryngoscope.
L‐type calcium channels in sympathetic α3β2‐nAChR‐mediated cerebral nitrergic neurogenic vasodilation
Authors: Wu C. Y.‐C. , Lee R. H.‐C. , Chen P.‐Y. , Tsai A. P.‐Y. , Chen M.‐F. , Kuo J.‐S. , Lee T. J.‐F. 
Published: May 2014

AbstractAimNicotine stimulation of α3β2‐nicotinic acetylcholine receptors (α3β2‐nAChRs) located on sympathetic nerves innervating basilar arteries causes calcium‐dependent noradrenaline release, leading to activation of parasympathetic nitrergic nerves and dilation of basilar arteries. This study aimed to investigate the major subtype of calcium channels located on cerebral peri‐vascular sympathetic nerves, which is involved in nicotine‐induced α3β2‐nAChR‐mediated nitrergic vasodilation in basilar arteries.MethodsNicotine‐ and transmural nerve stimulation (TNS)‐induced dilation of isolated porcine basilar arteries was examined using in vitro tissue bath. Nicotine‐induced calcium influx, nicotine‐induced noradrenaline release and nicotine‐induced inward currents were evaluated in rat superior cervical ganglion (SCG) neurones, peri‐vascular sympathetic nerves of porcine basilar arteries and α3β2‐nAChRs‐expressing oocytes respectively. mRNA and protein expression of Cav1.2 and Cav1.3 channels were detected by RT‐PCR, Western blotting and immunohistochemistry.ResultsNicotine‐induced vasodilation was not affected by ω‐agatoxin TK (selective P/Q‐type calcium channel blocker) or ω‐conotoxin GVIA (N‐type calcium channel blocker). The vasodilation, however, was inhibited by nicardipine (L‐type calcium channel blocker) in concentrations which did not affect TNS‐induced vasodilation, suggesting the specific blockade. Nicardipine concentration‐dependently inhibited nicotine‐induced calcium influx in rat SCG neurones and reduced nicotine‐induced noradrenaline release from peri‐vascular sympathetic nerves of porcine basilar arteries. Nicardipine (10 μm), which significantly blocked nicotine‐induced vasorelaxation by 70%, did not appreciably affect nicotine‐induced inward currents in α3β2‐nAChRs‐expressing oocytes. Furthermore, the mRNAs and proteins of Cav1.2 and Cav1.3 channels were expressed in porcine SCG and peri‐vascular nerve terminals.ConclusionThe sympathetic neuronal calcium influx through L‐type calcium channels is modulated by α3β2‐nAChRs. This calcium influx causes noradrenaline release, initiating sympathetic–parasympathetic (axo‐axonal) interaction‐induced nitrergic dilation of porcine basilar arteries.
Single housing during early adolescence causes time‐, area‐ and peptide‐specific alterations in endogenous opioids of rat brain
Authors: Granholm L , Roman E , Nylander I 
Published: May 2014

Background and PurposeA number of experimental procedures require single housing to assess individual behaviour and physiological responses to pharmacological treatments. The endogenous opioids are closely linked to social interaction, especially early in life, and disturbance in the social environment may affect opioid peptides and thereby confound experimental outcome. The aim of the present study was to examine time‐dependent effects of single housing on opioid peptides in rats.Experimental ApproachEarly adolescent Sprague Dawley rats (post‐natal day 22) were subjected to either prolonged (7 days) or short (30 min) single housing. Several brain regions were dissected and immunoreactive levels of Met‐enkephalin‐Arg6Phe7 (MEAP), dynorphin B and nociception/orphanin FQ, as well as serum corticosterone were measured using RIA.Key ResultsProlonged single housing reduced immunoreactive MEAP in hypothalamus, cortical regions, amygdala, substantia nigra and periaqueductal grey. Short single housing resulted in an acute stress response as indicated by high levels of corticosterone, accompanied by elevated immunoreactive nociceptin/orphanin FQ in medial prefrontal cortex, nucleus accumbens and amygdala. Neither short nor prolonged single housing affected dynorphin B.Conclusions and ImplicationsDisruption in social environmental conditions of rats, through single housing during early adolescence, resulted in time‐, area‐ and peptide‐specific alterations in endogenous opioids in the brain. These results provide further evidence for an association between early life social environment and opioids. Furthermore, the results have implications for experimental design; in any pharmacological study involving opioid peptides, it is important to distinguish between effects induced by housing and treatment.Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Novel TAZ modulators enhance myogenic differentiation and muscle regeneration
Authors: Park Gun Hwa , Jeong Hana , Jeong Mi‐Gyeong , Jang Eun Jung , Bae Myung Ae , Lee Ye‐Lim , Kim Nak Jung , Hong Jeong‐Ho , Hwang Eun Sook 
Published: May 2014

Background and PurposeThe transcriptional co‐activator with PDZ‐binding motif (TAZ) is a key controller of mesenchymal stem cell differentiation through its nuclear localization and subsequent interaction with master transcription factors. In particular, TAZ directly associates with myoblast determining protein D (MyoD) and activates MyoD‐induced myogenic gene expression, thereby enhancing myogenic differentiation. Here, we have synthesized and characterized low MW compounds modulating myogenic differentiation via induction of TAZ nuclear localization.Experimental ApproachCOS7 cells stably transfected with GFP‐TAZ were used in a high content imaging screen for compounds specifically enhancing nuclear localization of TAZ. We then studied the effects of such TAZ modulators on myocyte differentiation of C2C12 cells and myogenic transdifferentiation of mouse embryonic fibroblast cells in vitro and muscle regeneration in vivo.Key ResultsWe identified two TAZ modulators, TM‐53, and its structural isomer, TM‐54. Each compound strongly enhanced nuclear localization of TAZ by reducing S89‐phosphorylation and dose‐dependently augmented myogenic differentiation and MyoD‐mediated myogenic transdifferentiation through an activation of MyoD–TAZ interaction. The myogenic stimulatory effects of TM‐53 and TM‐54 were impaired in the absence of TAZ, but retrieved by the restoration of TAZ. In addition, administration of TM‐53 and TM‐54 enhanced injury‐induced muscle regeneration in vivo and attenuated myofiber injury in vitro.Conclusions and ImplicationsThe novel TAZ modulators TM‐53 and TM‐54 accelerated myogenic differentiation and improved muscle regeneration and function after injury, demonstrating that low MW compounds targeting the nuclear localization of TAZ have beneficial effects in skeletal muscle regeneration and in recovery from muscle degenerative diseases.
Modulation of transglutaminase 2 activity in H9c2 cells by PKC and PKA signalling: a role for transglutaminase 2 in cytoprotection
Authors: Almami Ibtesam , Dickenson John M , Hargreaves Alan J , Bonner Philip L R 
Published: May 2014

Background and PurposeTissue transglutaminase (TG2) has been shown to mediate cell survival in many cell types. In this study, we investigated whether the role of TG2 in cytoprotection was mediated by the activation of PKA and PKC in cardiomyocyte‐like H9c2 cells.Experimental ApproachH9c2 cells were extracted following stimulation with phorbol‐12‐myristate‐13‐acetate (PMA) and forskolin. Transglutaminase activity was determined using an amine incorporating and a protein crosslinking assay. The presence of TG isoforms (TG1, 2, 3) was determined using Western blot analysis. The role of TG2 in PMA‐ and forskolin‐induced cytoprotection was investigated by monitoring H2O2‐induced oxidative stress in H9c2 cells.Key ResultsWestern blotting showed TG2 >> TG1 protein expression but no detectable TG3. The amine incorporating activity of TG2 in H9c2 cells increased in a time and concentration‐dependent manner following stimulation with PMA and forskolin. PMA and forskolin‐induced TG2 activity was blocked by PKC (Ro 31‐8220) and PKA (KT 5720 and Rp‐8‐Cl‐cAMPS) inhibitors respectively. The PMA‐ and forskolin‐induced increases in TG2 activity were attenuated by the TG2 inhibitors Z‐DON and R283. Immunocytochemistry revealed TG2‐mediated biotin‐X‐cadaverine incorporation into proteins and proteomic analysis identified known (β‐tubulin) and novel (α‐actinin) protein substrates for TG2. Pretreatment with PMA and forskolin reversed H2O2‐induced decrease in MTT reduction and release of LDH. TG2 inhibitors R283 and Z‐DON blocked PMA‐ and forskolin‐induced cytoprotection.Conclusions and ImplicationsTG2 activity was stimulated via PKA‐ and PKC‐dependent signalling pathways in H9c2 cells These results suggest a role for TG2 in cytoprotection induced by these kinases.
Pathway‐selective antagonism of proteinase activated receptor 2
Authors: Suen J Y , Cotterell A , Lohman R J , Lim J , Han A , Yau M K , Liu L , Cooper M A , Vesey D A , Fairlie D P 
Published: May 2014

Background and PurposeProteinase activated receptor 2 (PAR2) is a GPCR associated with inflammation, metabolism and disease. Clues to understanding how to block PAR2 signalling associated with disease without inhibiting PAR2 activation in normal physiology could be provided by studies of biased signalling.Experimental ApproachPAR2 ligand GB88 was profiled for PAR2 agonist and antagonist properties by several functional assays associated with intracellular G‐protein‐coupled signalling in vitro in three cell types and with PAR2‐induced rat paw oedema in vivo.Key ResultsIn HT29 cells, GB88 was a PAR2 antagonist in terms of Ca2+ mobilization and PKC phosphorylation, but a PAR2 agonist in attenuating forskolin‐induced cAMP accumulation, increasing ERK1/2 phosphorylation, RhoA activation, myosin phosphatase phosphorylation and actin filament rearrangement. In CHO‐hPAR2 cells, GB88 inhibited Ca2+ release, but activated Gi/o and increased ERK1/2 phosphorylation. In human kidney tubule cells, GB88 inhibited cytokine secretion (IL6, IL8, GM‐CSF, TNF‐α) mediated by PAR2. A rat paw oedema induced by PAR2 agonists was also inhibited by orally administered GB88 and compared with effects of locally administered inhibitors of G‐protein coupled pathways.Conclusions and ImplicationsGB88 is a biased antagonist of PAR2 that selectively inhibits PAR2/Gq/11/Ca2+/PKC signalling, leading to anti‐inflammatory activity in vivo, while being an agonist in activating three other PAR2‐activated pathways (cAMP, ERK, Rho) in human cells. These findings highlight opportunities to design drugs to block specific PAR2‐linked signalling pathways in disease, without blocking beneficial PAR2 signalling in normal physiology, and to dissect PAR2‐associated mechanisms of disease in vivo.
Palmitoylethanolamide normalizes intestinal motility in a model of post‐inflammatory accelerated transit: involvement of CB1 receptors and TRPV1 channels
Authors: Capasso Raffaele , Orlando Pierangelo , Pagano Ester , Aveta Teresa , Buono Lorena , Borrelli Francesca , Di Marzo Vincenzo , Izzo Angelo A 
Published: May 2014

Background and PurposePalmitoylethanolamide (PEA), a naturally occurring acylethanolamide chemically related to the endocannabinoid anandamide, interacts with targets that have been identified in peripheral nerves controlling gastrointestinal motility, such as cannabinoid CB1 and CB2 receptors, TRPV1 channels and PPARα. Here, we investigated the effect of PEA in a mouse model of functional accelerated transit which persists after the resolution of colonic inflammation (post‐inflammatory irritable bowel syndrome).Experimental ApproachIntestinal inflammation was induced by intracolonic administration of oil of mustard (OM). Mice were tested for motility and biochemical and molecular biology changes 4 weeks later. PEA, oleoylethanolamide and endocannabinoid levels were measured by liquid chromatography‐mass spectrometry and receptor and enzyme mRNA expression by qRT‐PCR.Key ResultsOM induced transient colitis and a functional post‐inflammatory increase in upper gastrointestinal transit, associated with increased intestinal anandamide (but not 2‐arachidonoylglycerol, PEA or oleoylethanolamide) levels and down‐regulation of mRNA for TRPV1 channels. Exogenous PEA inhibited the OM‐induced increase in transit and tended to increase anandamide levels. Palmitic acid had a weaker effect on transit. Inhibition of transit by PEA was blocked by rimonabant (CB1 receptor antagonist), further increased by 5′‐iodoresiniferatoxin (TRPV1 antagonist) and not significantly modified by the PPARα antagonist GW6471.Conclusions and ImplicationsIntestinal endocannabinoids and TRPV1 channel were dysregulated in a functional model of accelerated transit exhibiting aspects of post‐inflammatory irritable bowel syndrome. PEA counteracted the accelerated transit, the effect being mediated by CB1 receptors (possibly via increased anandamide levels) and modulated by TRPV1 channels.
Prolonged morphine treatment alters δ opioid receptor post‐internalization trafficking
Authors: Ong E W , Xue L , Olmstead M C , Cahill C M 
Published: May 2014

Background and PurposeThe δ opioid receptor (DOP receptor) undergoes internalization both constitutively and in response to agonists. Previous work has shown that DOP receptors traffic from intracellular compartments to neuronal cell membranes following prolonged morphine treatment. Here, we examined the effects of prolonged morphine treatment on the post‐internalization trafficking of DOP receptors.Experimental ApproachUsing primary cultures of dorsal root ganglia neurons, we measured the co‐localization of endogenous DOP receptors with post‐endocytic compartments following both prolonged and acute agonist treatments.Key ResultsA departure from the constitutive trafficking pathway was observed following acute DOP receptor agonist‐induced internalization by deltorphin II. That is, the DOP receptor underwent distinct agonist‐induced post‐endocytic sorting. Following prolonged morphine treatment, constitutive DOP receptor trafficking was augmented. SNC80 following prolonged morphine treatment also caused non‐constitutive DOP receptor agonist‐induced post‐endocytic sorting. The μ opioid receptor (MOP receptor) agonist DAMGO induced DOP receptor internalization and trafficking following prolonged morphine treatment. Finally, all of the alterations to DOP receptor trafficking induced by both DOP and MOP receptor agonists were inhibited or absent when those agonists were co‐administered with a DOP receptor antagonist, SDM‐25N.Conclusions and ImplicationsThe results support the hypothesis that prolonged morphine treatment induces the formation of MOP–DOP receptor interactions and subsequent augmentation of the available cell surface DOP receptors, at least some of which are in the form of a MOP/DOP receptor species. The pharmacology and trafficking of this species appear to be unique compared to those of its individual constituents.Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Comments on ‘A quantitative model of amphetamine action on the serotonin transporter’, by Sandtner et al., Br J Pharmacol 171: 1007–1018
Authors: De Felice Louis J , Cameron Krasnodara N 
Published: May 2014

Linked ArticlesThis article is a Commentary on Sandtner W, Schmid D, Schicker K, Gerstbrein K, Koenig X, Mayer FP, Boehm S, Freissmuth M and Sitte HH (2014). A quantitative model of amphetamine action on the 5‐HT transporter. Br J Pharmacol 171: 1007–1018. doi: 10.1111/bph.12520. The authors reply in Schmid et al., (2015). Br J Pharmacol 172: this issue. doi: 10.1111/bph.12766
A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis
Authors: Kao W , Gu R , Jia Y , Wei Xuemin , Fan H , Harris J , Zhang Zhiyi , Quinn J , Morand E F , Yang Y H 
Published: May 2014

Background and PurposeAnnexin A1 (AnxA1) is an endogenous anti‐inflammatory protein and agonist of the formyl peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune‐mediated disease has been little explored. We investigated the effects of a synthetic FPR agonist on joint disease in the K/BxN model of rheumatoid arthritis (RA) and RA fibroblast‐like synoviocytes (FLS).Experimental ApproachArthritis was induced by injection of K/BxN serum at day 0 and 2 in wild‐type (WT) or AnxA1−/− mice and clinical and histopathological manifestations measured 8–11 days later. WT mice were given the FPR agonist compound 43 (Cpd43) (6 or 30 mg·kg−1 i.p.) for 4 days. Effects of AnxA1 and Cpd43 on RANKL‐induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages.Key ResultsTreatment with Cpd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF‐α and osteoclast‐associated gene expression. Deletion of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL‐6 secretion by mouse macrophages. In human RA joint‐derived FLS and monocyte‐derived macrophages, Cpd43 treatment inhibited IL‐6 release, while blocking FPR2 or silencing AnxA1 increased this release.Conclusions and ImplicationsThe FPR agonist Cpd43 reduced osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti‐inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents capable of ameliorating inflammation and bone damage in RA.
Late, never or non‐existent: the inaccessibility of preclinical evidence for new drugs
Authors: Federico C A , Carlisle B , Kimmelman J , Fergusson D A 
Published: May 2014

Background and PurposeAnimal studies establish much of the evidence used to support clinical development of new drugs. Recent studies suggest that many preclinical investigations are withheld from publication, leading to exaggerated estimates of clinical utility. We sought to estimate the volume and properties of all published animal efficacy studies for a cohort of novel drugs.Experimental ApproachWe searched biomedical databases to identify 47 novel drugs whose first trials were reported between 2000 and 2003, inclusive. Next, we searched for all published animal studies testing the same drug, regardless of publication date. We then extracted items from titles and abstracts of eligible studies.Key ResultsWe identified 2462 efficacy studies, representing an average of 52 studies per drug. No published efficacy studies were available for three drugs in our sample. The volume of efficacy studies was related to how far the drug had progressed in clinical development (Spearman's correlation coefficient = 0.66, P < 0.0001). Most (87%) accessible animal efficacy studies were reported after publication of the first trial, and for 17% of the drugs in our sample, no efficacy studies were published before the first trial report. Disease indications used in trials often did not match those modelled in efficacy studies; for 35% of indications tested in trials, we were unable to identify any published efficacy studies in models of the same indication.Conclusions and ImplicationsThe volume of published efficacy studies is large, although numerous gaps reflect non‐publication, publication delay or non‐performance of efficacy studies supporting trials.