Assessment of the systemic effects of budesonide inhaled from Easyhaler®and from Turbuhaler®in healthy male volunteers

AbstractThe main objective of this study was to show dose-dependent equivalence in the systemic activity of budesonide 800 μ g day−1and 1600 μ g day−1delivered from either Easyhaler®or Turbuhaler®in healthy male subjects.This single-centre study was carried out according to a randomized, double-blind, double-dummy, five-way cross-over design over a 9-week period. All subjects received 1 week of treatment with the following, in randomized order, with a washout week between each treatment: budesonide Easyhaler®800 μ g day−1plus placebo Turbuhaler®; budesonide Easyhaler®1600 μ g day−1plus placebo Turbuhaler®; placebo Easyhaler®plus Pulmicort®Turbuhaler®800 μ g day−1; placebo Easyhaler®plus Pulmicort®Turbuhaler®1600 μ g day−1; placebo Easyhaler®plus placebo Turbuhaler®. The final inhalation of study drug was performed at the study centre, where blood and urine samples were collected.Fifteen subjects were recruited and all completed the study. Mean serum cortisol AUC0–20values (the primary outcome variable) were comparable for each device at the two dose levels, and met the defined criteria for equivalence (90% CI 0·8–1·25 for between-treatment difference). Budesonide 800 μ g day−1caused minimal suppression of serum cortisol AUC0-20values. Budesonide 1600 μ g day−1statistically significantly suppressed serum cortisol AUC0–20values compared with placebo. Mean morning serum cortisol values were within the reference range in all treatment groups. At a budesonide dose of 800 μ g day−1mean urine cortisol/creatinine ratio was statistically significantly higher with Easyhaler®than with Turbuhaler®, but there was no significant difference between the devices at the 1600 μ g day−1dose. Serum budesonide concentrations were equivalent for each device at both dose levels. Adverse drug reactions were infrequent and mild in nature and there were no clinically significant changes in laboratory safety variables.In conclusion, in healthy male volunteers, budesonide 800μ g day−1and 1600 μ g day−1inhaled from Easyhaler®had comparable systemic effects to the same doses inhaled via Turbuhaler®

Viscothermal Losses in Double-Negative Acoustic Metamaterials

[EN] The influence of losses in double-negative metamaterial slabs recently introduced by Graciá-Salgado et al. [Phys. Rev. B 88, 224305 (2013)] is comprehensively studied. Viscous and thermal losses are considered in the linearized Navier-Stokes equations with no flow. Despite the extremely low thicknesses of boundary layers associated with each type of losses, the double-negative behavior is totally suppressed for the rigid structures under analysis. In other words, almost 100% of the energy transmitted into the slab is dissipated by viscothermal effects, in agreement with experimental data. Simulations undertaken for larger structures, using scale factors of up to 20 times, show that double-negative behavior is never recovered. The huge dissipation obtained by these structures leads us to propose them as interesting alternatives to conventional absorbers for specific situations, e.g., when treating low frequencies or when the excitation is narrow banded.V. M. G.-C. and J. S.-D. acknowledge the support from the Spanish Ministerio de Economia y Competitividad (MINECO), and the European Union Fondo Europeo de Desarrollo Regional (FEDER) through Project No. TEC 2014-53088-C3-1-R.Cutanda-Henriquez, V.; Garcia Chocano, VM.; Sánchez-Dehesa Moreno-Cid, J. (2017). Viscothermal Losses in Double-Negative Acoustic Metamaterials. Physical Review Applied. 8(1):014029-1-014029-12. doi:10.1103/PhysRevApplied.8.014029S014029-1014029-128

Exhaust emissions of non-road mobile machine : Real-world and laboratory studies with diesel and HVO fuels

Exhaust emissions emitted by a non-road mobile machine were studied chasing a tractor in real-world conditions and repeating the same transient tests with a similar engine on an engine dynamometer where additionally, non-road steady state tests were carried out. The engines were equipped with an oxidation catalyst (DOC) and a selective catalytic reduction (SCR)system, and they were fuelled by fossil diesel fuel with ultra-low sulphur content and hydrotreated vegetable oil (HVO). By substituting diesel fuel with HVO the on-road emissions of nitrogen oxides (NOx) reduced 20% and particle number 44%, the emission factors being EFNOx =1.62 +/- 0.04 g/kWh and EFN = (28.2 +/- 7.8) x 10(13) #/kWh. Similar trend was observed for NOx at laboratory although the emissions were somewhat smaller than on-road. In contrast to real-world, in the laboratory experiment the EFN was only 2% smaller with HVO than with diesel, and these emission factors were almost one order of magnitude smaller than observed on-road. The number size distribution and volatility measurements showed that in real-world experiments small nucleation mode particles were formed during uphill and during downhill in engine braking conditions. These were not observed at laboratory. However, nucleation mode particles were observed in the laboratory experiments at high load steady driving conditions. At steady state tests the emissions strongly depended on engine load and engine speed with both fuels. (C) 2017 Elsevier Ltd. All rights reserved.Peer reviewe

BCOR modulates transcriptional activity of a subset of glucocorticoid receptor target genes involved in cell growth and mobility

Glucocorticoid (GC) receptor (GR) is a key transcription factor (TF) that regulates vital metabolic and antiinflammatory processes. We have identified BCL6 corepressor (BCOR) as a dexamethasone-stimulated interaction partner of GR. BCOR is a component of non-canonical polycomb repressor complex 1.1 (ncPCR1.1) and linked to different developmental disorders and cancers, but the role of BCOR in GC signaling is poorly characterized. Here, using ChIP-seq we show that, GC induces genome-wide redistribution of BCOR chromatin binding towards GR-occupied enhancers in HEK293 cells. As assessed by RNA-seq, depletion of BCOR altered the expression of hundreds of GC-regulated genes, especially the ones linked to TNF signaling, GR signaling and cell migration pathways. Biotinylation-based proximity mapping revealed that GR and BCOR share several interacting partners, including nuclear receptor corepressor NCOR1. ChIP-seq showed that the NCOR1 co-occurs with both BCOR and GR on a subset of enhancers upon GC treatment. Simultaneous depletion of BCOR and NCOR1 influenced GR target gene expression in a combinatorial and gene-specific manner. Finally, we show using live cell imaging that the depletion of BCOR together with NCOR1 markedly enhances cell migration. Collectively, our data suggest BCOR as an important gene and pathway selective coregulator of GR transcriptional activity.Peer reviewe

Good-Practice Non-Radioactive Assays of Inorganic Pyrophosphatase Activities

Inorganic pyrophosphatase (PPase) is a ubiquitous enzyme that converts pyrophosphate (PPi) to phosphate and, in this way, controls numerous biosynthetic reactions that produce PPi as a byproduct. PPase activity is generally assayed by measuring the product of the hydrolysis reaction, phosphate. This reaction is reversible, allowing PPi synthesis measurements and making PPase an excellent model enzyme for the study of phosphoanhydride bond formation. Here we summarize our long-time experience in measuring PPase activity and overview three types of the assay that are found most useful for (a) low-substrate continuous monitoring of PPi hydrolysis, (b) continuous and fixed-time measurements of PPi synthesis, and (c) high-throughput procedure for screening purposes. The assays are based on the color reactions between phosphomolybdic acid and triphenylmethane dyes or use a coupled ATP sulfurylase/luciferase enzyme assay. We also provide procedures to estimate initial velocity from the product formation curve and calculate the assay medium's composition, whose components are involved in multiple equilibria

Quantifying the effect of ocean bed properties on ice sheet geometry over 40 000 years with a full-Stokes model

Simulations of ice sheet evolution over glacial cycles require integration of observational constraints using ensemble studies with fast ice sheet models. These include physical parameterisations with uncertainties, for example, relating to grounding-line migration. More complete ice dynamic models are slow and have thus far only be applied for  50 % under almost equal forcing. Grounding-line positions differ by up to 49 km, show significant hysteresis, and migrate non-steadily in both scenarios with long quiescent phases disrupted by leaps of rapid migration. The simulations quantify the evolution of two different ice sheet geometries (namely thick and slow vs. thin and fast), triggered by the variable grounding-line migration over the differing ocean beds. Our study extends the timescales of 3D full-Stokes by an order of magnitude compared to previous studies with the help of parallelisation. The extended time frame for full-Stokes models is a first step towards better understanding other processes such as erosion and sediment redistribution in the ice shelf cavity impacting the entire catchment geometry

Multiwavelength study of the high-latitude cloud L1642: chain of star formation

L1642 is one of the two high galactic latitude (|b| > 30deg) clouds confirmed to have active star formation. We examine the properties of this cloud, especially the large-scale structure, dust properties, and compact sources in different stages of star formation. We present high-resolution far-infrared and submm observations with the Herschel and AKARI satellites and mm observations with the AzTEC/ASTE telescope, which we combined with archive data from near- and mid-infrared (2MASS, WISE) to mm observations (Planck). The Herschel observations, combined with other data, show a sequence of objects from a cold clump to young stellar objects at different evolutionary stages. Source B-3 (2MASS J04351455-1414468) appears to be a YSO forming inside the L1642 cloud, instead of a foreground brown dwarf, as previously classified. Herschel data reveal striation in the diffuse dust emission around L1642. The western region shows striation towards NE and has a steeper column density gradient on its southern side. The densest central region has a bow-shock like structure showing compression from the west and a filamentary tail extending towards east. The differences suggest that these may be spatially distinct structures, aligned only in projection. We derive values of the dust emission cross-section per H nucleon for different regions of the cloud. Modified black-body fits to the spectral energy distribution of Herschel and Planck data give emissivity spectral index beta values 1.8-2.0 for the different regions. The compact sources have lower beta values and show an anticorrelation between T and beta. Markov chain Monte Carlo calculations demonstrate the strong anticorrelation between beta and T errors and the importance of mm Planck data in constraining the estimates. L1642 reveals a more complex structure and sequence of star formation than previously known.Comment: 22 pages, 18 figures, accepted to Astronomy & Astrophysics; abstract shortened and figures reduced for astrop

SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites

Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin occupancy and target gene expression of GR in a locus-selective manner, but the mechanism of regulation has remained elusive. Here, we identify the protein network around chromatin-bound GR by using selective isolation of chromatin-associated proteins and show that the network is affected by receptor SUMOylation, with several nuclear receptor coregulators and chromatin modifiers preferring interaction with SUMOylation-deficient GR and proteins implicated in transcriptional repression preferring interaction with SUMOylation-competent GR. This difference is reflected in our chromatin binding, chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in binding and opening chromatin at glucocorticoid-regulated enhancers and inducing expression of target loci. Blockage of SUMOylation by a SUMO-activating enzyme inhibitor (ML-792) phenocopied to a large extent the consequences of GR SUMOylation deficiency on chromatin binding and target gene expression. Our results thus show that SUMOylation modulates the specificity of GR by regulating its chromatin protein network and accessibility at GR-bound enhancers. We speculate that many other SUMOylated TFs utilize a similar regulatory mechanism.Peer reviewe