bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects
Authors: Namour Florence , Galien René , Van Kaem Tim , Van der Aa Annegret , Vanhoutte Frédéric , Beetens Johan , van't Klooster Gerben 
Published: February 2016

AimsFree fatty acids (FFA) can act as direct signalling molecules through activation of several membrane‐bound G‐protein coupled receptors. The FFA2 receptor (known as GPR43) is activated by short chain fatty acids (SCFA) such as acetate and has been shown to play a major role in SCFA‐induced neutrophil activation and migration and to contribute in the development and control of inflammation. GLPG0974 is a potent and selective antagonist of the human FFA2. The main objectives of the two phase 1 trials were to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of GLPG0974.MethodsTwo consecutive randomized, double‐blind, placebo‐controlled, single centre trials in healthy subjects were performed. In the first, GLPG0974 was administered as single doses up to 250 mg and in the second, multiple daily doses up to 400 mg for 14 days were evaluated. Non‐compartmental analysis was used to determine GLPG0974 pharmacokinetics while target engagement was investigated through the inhibition of neutrophils in acetate‐simulated whole blood samples using surface expression of CD11b activated epitope as a marker of neutrophil activation.ResultsThe investigation of safety/tolerability and pharmacokinetics in the early development phase showed that GLPG0974 was safe and well tolerated up to a daily dose of 400 mg. GLPG0974 showed good and dose proportional exposure up to 400 mg daily as well as a substantial and sustained inhibition of acetate‐stimulated neutrophil activation.ConclusionBased on these results, a proof‐of‐concept study was initiated to evaluate the safety, tolerability and efficacy of GLPG0974 in patients with mild to moderate ulcerative colitis.
Limited information estimation of the diffusion‐based item response theory model for responses and response times
Authors: Ranger Jochen , Kuhn Jörg‐Tobias , Szardenings Carsten 
Published: February 2016

Psychological tests are usually analysed with item response models. Recently, some alternative measurement models have been proposed that were derived from cognitive process models developed in experimental psychology. These models consider the responses but also the response times of the test takers. Two such models are the Q‐diffusion model and the D‐diffusion model. Both models can be calibrated with the diffIRT package of the R statistical environment via marginal maximum likelihood (MML) estimation. In this manuscript, an alternative approach to model calibration is proposed. The approach is based on weighted least squares estimation and parallels the standard estimation approach in structural equation modelling. Estimates are determined by minimizing the discrepancy between the observed and the implied covariance matrix. The estimator is simple to implement, consistent, and asymptotically normally distributed. Least squares estimation also provides a test of model fit by comparing the observed and implied covariance matrix. The estimator and the test of model fit are evaluated in a simulation study. Although parameter recovery is good, the estimator is less efficient than the MML estimator.
Extracellular matrix degradation via enolase/plasminogen interaction: Evidence for a mechanism conserved in Metazoa
Authors: Grossi Gerarda , Grimaldi Annalisa , Cardone Rosa A. , Monné Magnus , Reshkin Stephan J. , Girardello Rossana , Greco Maria R. , Coviello Elena , Laurino Simona , Falabella Patrizia 
Published: February 2016

Background InformationWhile enolase is a ubiquitous metalloenzyme involved in the glycolytic pathway, it is also known as a multifunctional protein, since enolases anchored on the outer surface of the plasma membrane are involved in tissue invasion.ResultsWe have identified an extracellular enolase (Ae‐ENO) produced by the teratocytes, embryonic cells of the insect parasitoid Aphidius ervi. We demonstrate that Ae‐ENO, although lacking a signal peptide, accumulates in cytoplasmic vesicles oriented towards the cell membrane. Ae‐ENO binds to and activates a plasminogen‐like molecule inducing digestion of the host tissue and thereby ensuring successful parasitism.ConclusionsThese results support the hypothesis that plasminogen‐like proteins exist in invertebrates. Interestingly the activation of a plasminogen‐like protein is mediated by a mechanisms involving the surface enolase/fibrinolytic system considered, until now, exclusive of vertebrates, and that instead is conserved across species.SignificanceTo our knowledge, this is the first example of enolase mediated Plg‐like binding and activation in insect cells, demonstrating the existence of an ECM degradation process via a Plg‐like protein in invertebrates.
Protease‐activated receptor 4: from structure to function and back again
Authors: French Shauna L , Hamilton Justin R 
Published: February 2016

Protease‐activated receptors are a family of four GPCRs (PAR1–PAR4) with a number of unique attributes. Nearly two and a half decades after the discovery of the first PAR, an antagonist targeting this receptor has been approved for human use. The first‐in‐class PAR1 antagonist, vorapaxar, was approved for use in the USA in 2014 for the prevention of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. These recent developments indicate the clinical potential of manipulating PAR function. While much work has been aimed at uncovering the function of PAR1 and, to a lesser extent, PAR2, comparatively little is known regarding the pharmacology and physiology of PAR3 and PAR4. Recent studies have begun to develop the pharmacological and genetic tools required to study PAR4 function in detail, and there is now emerging evidence for the function of PAR4 in disease settings. In this review, we detail the discovery, structure, pharmacology, physiological significance and therapeutic potential of PAR4.Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of G Protein‐Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc
Understanding Delay in Developmental Disorders
Authors: Thomas Michael S. C. 
Published: February 2016

AbstractResearchers in developmental disorders frequently refer to abilities that are in line with mental age as simply delayed. The qualifier simply might imply an existing theory of developmental delay that is well understood and uninteresting (perhaps because it is an exaggerated form of individual differences, the responsibility of other researchers). In this article, I argue that the notion of delay can be separated into descriptive and explanatory versions. The descriptive version is often used too coarsely to be helpful. Instead, we need an approach based on developmental trajectories to separate types of descriptive delay, which may then have different underlying causes. The explanatory version is poorly articulated in developmental theory. One useful way to deepen our understanding of delay is by building computational models that simulate development in large populations of individuals and explicitly implementing factors that cause variations in development. Finally, I suggest that dividing research among separate investigators of typical development, individual differences, and developmental disorders may be counterproductive if the underlying mechanisms recognize no such distinction.
Atp13a2 Deficiency Aggravates Astrocyte‐Mediated Neuroinflammation via NLRP3 Inflammasome Activation
Authors: Qiao Chen , Yin Nuo , Gu Huan‐Yu , Zhu Jia‐Lei , Ding Jian‐Hua , Lu Ming , Hu Gang 
Published: February 2016

SummaryAimAtp13a2 (Park9) gene encodes a transmembrane lysosomal P5‐type ATPase (ATP13A2), and its missense or truncation mutations leads to lysosomal dysfunction and consequently results in neuronal death in the pathogenesis of Parkinson's disease (PD). Nevertheless, the roles of ATP13A2 in the biological features of astrocytes, especially in the regulation of PD‐related neuroinflammation, have not been investigated.MethodsWe cultured primary neurons and astrocytes from mouse midbrain to investigate the mechanisms for astrocyte ATP13A2‐regulated lysosomal function and neuroinflammation following 1‐methyl‐4‐phenylpyridinium (MPP+) treatment.ResultsWe found that astrocytes expressed considerable levels of ATP13A2 and deficiency of ATP13A2 in astrocyte‐induced intense inflammation, which exacerbated dopaminergic neuron damage after exposure to MPP+. Notably, lack of ATP13A2 increased lysosomal membrane permeabilization and cathepsin B release, which in turn exacerbated activation of nod‐like receptor protein 3 (NLRP3) inflammasome to produce excess IL‐1β from astrocytes. Furthermore, overexpression of ATP13A2 reversed MPP+‐induced cathepsin B release and NLRP3 inflammasome activation in astrocytes.ConclusionsOur results have revealed a novel role of ATP13A2 in modulating astrocyte‐mediated neuroinflammation via NLRP3 inflammasome activation, thus bringing to light of a direct link between astrocyte lysosome and neuroinflammation in the pathological model of PD.
Systematic review of evidence and consensus on perianal fistula: an analysis of national and international guidelines
Authors: de Groof E. J. , Cabral V. N. , Buskens C. J. , Morton D. G. , Hahnloser D. , Bemelman W. A. ,   the research committee of the European Society of Coloproctology
Published: February 2016

AbstractAimTreatment of perianal fistula has evolved with the introduction of new techniques and biologicals in Crohn's disease (CD). Several guidelines are available worldwide, but many recommendations are controversial or lack high‐quality evidence. The aim of this work was to provide an overview of the current available national and international guidelines for perianal fistula and to analyse areas of consensus and areas of conflicting recommendations, thereby identifying topics and questions for future research.MethodMEDLINE, EMBASE and PubMed were systematically searched for guidelines on perianal fistula. Inclusion was limited to papers in English less than 10 years old. The included topics were classified as having consensus (unanimous recommendations in at least two‐thirds of the guidelines) or controversy (fewer than three guidelines commenting on the topic or no consensus) between guidelines. The highest level of evidence was scored as sufficient (level 3a or higher of the Oxford Centre for Evidence‐based Medicine Levels of Evidence 2009, http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/) or insufficient.ResultsTwelve guidelines were included and topics with recommendations were compared. Overall, consensus was present in 15 topics, whereas six topics were rated as controversial. Evidence levels varied from strong to lack of evidence.ConclusionEvidence on the diagnosis and treatment of perianal fistulae (cryptoglandular or related to CD) ranged from nonexistent to strong, regardless of consensus. The most relevant research questions were identified and proposed as topics for future research.
A case of brucellosis presenting with pericardial and pleural effusion
Authors: Altas Meryem Hilal , Karli Arzu , Sensoy Gulnar , Koken Ozlem , Yurek Burak , Baysal Kemal 
Published: February 2016

AbstractBrucellosis is a worldwide zoonotic infection with a diverse clinical presentation. Pericardial and pleural involvement is rare in brucellosis. There is no presentation with pleural and pericardial effusion in childhood brusellosis. In endemic countries Brucellosis must thought as an unknown etiology of pericardial and pleural effusion.
Eurotransplant donor‐risk‐index and recipient factors: influence on long‐term outcome after liver transplantation – A large single‐center experience
Authors: Schoening Wenzel , Helbig Michael , Buescher Niklas , Andreou Andreas , Schmitz Volker , Bahra Marcus , Puhl Gero , Pascher Andreas , Pratschke Johann , Seehofer Daniel 
Published: February 2016

AbstractThe organ shortage has led to increased use of marginal organs. The Eurotransplant Donor‐Risk‐Index (ET‐DRI) was established to estimate outcome after Liver Transplantation (LT). Currently, data on impact of ET‐DRI on long‐term outcome for different indications and recipient conditions are missing. Retrospective, single‐center analysis of long‐term graft survival (GS) of 1767 adult primary LTs according to indication, labMELDcategory (1: ≤18; 2: >18–25; 3: >25–35; 4: >35), and ET‐DRI. Mean ET‐DRI in our cohort was 1.63 (±0.43). One‐, 10, and 15‐yr GS was 83.5%, 63.3%, and 54.8%. Long‐term GS was significantly influenced by ET‐DRI. Accordingly, four ET‐DRI categories were defined and analyzed with respect to underlying disease. Significant impact of these categories was observed for: Alcohol, cholestatic/autoimmune diseases (CD/AIH), and HCV, but not for HCC, HBV, cryptogenic cirrhosis, and acute liver failure. labMELD categories showed no significant influence on graft, but on patient survival. Matching ET‐DRI categories with labMELD revealed significant differences in long‐term GS for labMELDcategories 1, 2, and 3, but not 4. In multivariate analysis, HCV combined with ET‐DRI > 2 and labMELDcategory 3 combined with ET‐DRI > 2 emerged as negative predictors. To achieve excellent long‐term graft survival, higher risk organs (ET‐DRI > 1.4) should be used restrictively for patients with CD/AIH or HCV. Organs with ET‐DRI > 2 should be avoided in patients with a labMELD of >25–35.
Sustained efficacy of insulin pump therapy compared with multiple daily injections in type 2 diabetes: 12‐month data from the OpT2mise randomized trial
Authors: Aronson R. , Reznik Y. , Conget I. , Castañeda J. A. , Runzis S. , Lee S. W. , Cohen O. ,   for the OpT2mise Study Group
Published: February 2016

AimsTo compare insulin pump therapy and multiple daily injections (MDI) in patients with type 2 diabetes receiving basal and prandial insulin analogues.MethodsAfter a 2‐month dose‐optimization period, 331 patients with glycated haemoglobin (HbA1c) levels ≥8.0% and ≤12% were randomized to pump therapy or continued MDI for 6 months [randomization phase (RP)]. The MDI group was subsequently switched to pump therapy during a 6‐month continuation phase (CP). The primary endpoint was the between‐group difference in change in mean HbA1c from baseline to the end of the RP.ResultsThe mean HbA1c at baseline was 9% in both groups. At the end of the RP, the reduction in HbA1c was significantly greater with pump therapy than with MDI (−1.1 ± 1.2% vs −0.4 ± 1.1%; p < 0.001). The pump therapy group maintained this improvement to 12 months while the MDI group, which was switched to pump therapy, showed a 0.8% reduction: the final HbA1c level was identical in both arms. In the RP, total daily insulin dose (TDD) was 20.4% lower with pump therapy than with MDI and remained stable in the CP. The MDI–pump group showed a 19% decline in TDD, such that by 12 months TDD was equivalent in both groups. There were no differences in weight gain or ketoacidosis between groups. In the CP, one patient in each group experienced severe hypoglycaemia.ConclusionsPump therapy has a sustained durable effect on glycaemic control in uncontrolled type 2 diabetes.
Rapid selection and characterization of Cry1F resistance in a Brazilian strain of fall armyworm
Authors: Leite Natália A. , Mendes Simone M. , Santos‐Amaya Oscar F. , Santos Chritiane A. , Teixeira Thaís P. M. , Guedes Raul N. C. , Pereira Eliseu J. G. 
Published: February 2016

AbstractTransgenic maize (Zea mays L., Poaceae) event TC1507, producing the Cry1F protein of Bacillus thuringiensis Berliner, has been used for management of the fall armyworm, Spodoptera frugiperda (JE Smith) (Lepidoptera: Noctuidae), in Brazil since 2009. A strain of S. frugiperda, obtained from field collections of larvae in TC1507 maize in Minas Gerais state in 2010, was selected in the laboratory for resistance to Cry1F using leaves of TC1507 maize in two selection regimes. Continuous exposure of larvae to Cry1F was more effective than exposure for 6, 8, and 10 days in the selection of resistant S. frugiperda individuals. With only four generations of laboratory selection, a strain with high levels of resistance to Cry1F was obtained, as indicated by the survival of insects reared on leaves of TC1507 maize plants and by the more than 300‐fold resistance level measured in bioassays with the purified Cry1F protein. Importantly, reciprocal crosses between control and the Cry1F‐selected strains revealed that the resistance is autosomal and incompletely recessive, and the response obtained in the backcross of the F1 generation with the resistant strain was consistent with simple monogenic inheritance. Additionally, there were no apparent fitness costs associated with resistance either for survival or larval growth on non‐Bt maize leaves. Our findings provide experimental evidence for rapid evolution of Cry1F resistance in S. frugiperda in the laboratory and further reinforce the potential of this species to evolve field resistance to the TC1507 maize as previously reported. The resistant strain isolated in this study provides an opportunity to estimate the resistance allele frequency in the field and to determine the biochemical and molecular basis of the resistance, which should provide further information to assist in the resistance management of S. frugiperda on transgenic maize producing B. thuringiensis proteins.
Forest edges enhance mate‐finding in the invasive European gypsy moth, Lymantria dispar
Authors: Thompson Lily M. , Grayson Kristine L. , Johnson Derek M. 
Published: February 2016

AbstractHabitat type, fragmentation, and edge effects can play important roles in the mate‐finding abilities of many species. These effects can be particularly pronounced in low‐density populations, which are often found at the margins of species' ranges or at the leading edge of an invasion. The European gypsy moth, Lymantria dispar (L.) (Lepidoptera: Erebidae), is a non‐native insect defoliator in the USA and Canada, where flightless females attract male moths through pheromone production and local extirpation of low‐density populations can be due to mate‐finding failure. To assess the effects of habitat edges on the ability of gypsy moths to find mates, we conducted a release experiment with male gypsy moths using female‐baited trap arrays in fields, at forest edges, and in the forest interior. Reduced mate‐finding was expected in fields and near forest edges based on geographic variation in invasion rates, male flight behavior, and pheromone plume dynamics. However, we found that mate‐finding was highest at forest edges, reduced in fields, and lowest within the forest interior. Within an array, traps closest to the forest edge also had the highest mate‐finding, suggesting that habitat characteristics can influence male flight direction in addition to pheromone cues. These results suggest that a moderate level of forest fragmentation enhances mate‐finding ability in the gypsy moth. Understanding the relationship between habitat heterogeneity and mate‐finding success in invasive species can inform predictions of future spread and assist with management plans that target mating disruption.
Filling a blank on the map: 60 years of fisheries in Equatorial Guinea
Authors: Belhabib D. , Hellebrandt Da Silva D. , Allison E. H. , Zeller D. , Pauly D. 
Published: February 2016

AbstractDespite a scarcity of pertinent information, it has been possible to reconstruct time series of marine fisheries catches for Equatorial Guinea from 1950 to 2010 using per capita fish consumption and population numbers for small‐scale fisheries, catch rates and number of vessels for industrial fisheries and discard rates to estimate the discarded bycatch. Small‐scale fisheries, industrial large‐scale fisheries, domestic and legal and illegal foreign fisheries and their discards are all included. Total catches were estimated at 2.7 million tonnes over the time period considered, of which 653 000 t were caught domestically compared to 187 000 t reported byFAO. This shows that fisheries have more importance for Equatorial Guinea's food security than the official data suggest. In contrast to what is suggested by official figures, fisheries were shown to be strongly impacted by civil and political unrest; notably, they declined overall because of civil and political conflicts, socio‐demographic dynamics, and a growing role of the newly discovered oil resources, which directly and indirectly threaten the food security of the people of Equatorial Guinea.
From global to regional and back again: common climate stressors of marine ecosystems relevant for adaptation across five ocean warming hotspots
Authors: Popova Ekaterina , Yool Andrew , Byfield Valborg , Cochrane Kevern , Coward Andrew C. , Salim Shyam S. , Gasalla Maria A. , Henson Stephanie A. , Hobday Alistair J. , Pecl Gretta T. , Sauer Warwick H. , Roberts Michael J. 
Published: February 2016

AbstractOcean warming ‘hotspots’ are regions characterized by above‐average temperature increases over recent years, for which there are significant consequences for both living marine resources and the societies that depend on them. As such, they represent early warning systems for understanding the impacts of marine climate change, and test‐beds for developing adaptation options for coping with those impacts. Here, we examine five hotspots off the coasts of eastern Australia, South Africa, Madagascar, India and Brazil. These particular hotspots have underpinned a large international partnership that is working towards improving community adaptation by characterizing, assessing and projecting the likely future of coastal‐marine food resources through the provision and sharing of knowledge. To inform this effort, we employ a high‐resolution global ocean model forced by Representative Concentration Pathway 8.5 and simulated to year 2099. In addition to the sea surface temperature, we analyse projected stratification, nutrient supply, primary production, anthropogenic CO2‐driven ocean acidification, deoxygenation and ocean circulation. Our simulation finds that the temperature‐defined hotspots studied here will continue to experience warming but, with the exception of eastern Australia, may not remain the fastest warming ocean areas over the next century as the strongest warming is projected to occur in the subpolar and polar areas of the Northern Hemisphere. Additionally, we find that recent rapid change in SST is not necessarily an indicator that these areas are also hotspots of the other climatic stressors examined. However, a consistent facet of the hotspots studied here is that they are all strongly influenced by ocean circulation, which has already shown changes in the recent past and is projected to undergo further strong change into the future. In addition to the fast warming, change in local ocean circulation represents a distinct feature of present and future climate change impacting marine ecosystems in these areas.