Alterations in vasodilator-stimulated phosphoprotein (VASP) phosphorylation: associations with asthmatic phenotype, airway inflammation and β\u3csub\u3e2\u3c/sub\u3e-agonist use

Background Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this brake on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1) injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2) regular in vivo β2-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion. Methods Bronchial epithelium was obtained from asthmatic and non-asthmatic normal subjects before and after segmental allergen challenge, and after regularly inhaled albuterol, in three separate protocols. VASP phosphorylation was examined in Western blots of epithelial samples. DNA was obtained for β2-adrenergic receptor haplotype determination. Results Although VASP phosphorylation increased, it was not significantly greater after allergen challenge in asthmatics or normals. However, VASP phosphorylation in epithelium of nonasthmatic normal subjects was double that observed in asthmatic subjects, both at baseline and after challenge. Regularly inhaled albuterol significantly increased VASP phosphorylation in asthmatic subjects in both unchallenged and antigen challenged lung segment epithelium. There was also a significant increase in epithelial cells in the bronchoalveolar lavage of the unchallenged lung segment after regular inhalation of albuterol but not of placebo. The haplotypes of the β2-adrenergic receptor did not appear to associate with increased or decreased phosphorylation of VASP. Conclusion Decreased VASP phosphorylation was observed in epithelial cells of asthmatics compared to nonasthmatic normals, despite response to β-agonist. The decreased phosphorylation does not appear to be associated with a particular β2-adrenergic receptor haplotype. The observed decrease in VASP phosphorylation suggests greater inhibition of actin reorganization which is necessary for altering attachment and migration required during epithelial repair

A Bayesian Secondary Analysis in an Asthma Study

A recent study published in the New England Journal of Medicine by the Asthma Clinical Research Network (ACRN) compared three different treatments for their effectiveness in treating adults with uncontrolled asthma. This paper will describe the study design and its results, then detail the beginnings of a secondary analysis using Bayesian methods to estimate the parameters of interest. The methods will be explained, and the preliminary estimates given and contextualized. The paper will conclude with a discussion of the next steps and the goals for further analysis of the data in this study

The Kepler End-to-End Model: Creating High-Fidelity Simulations to Test Kepler Ground Processing

The Kepler mission is designed to detect the transit of Earth-like planets around Sun-like stars by observing 100,000 stellar targets. Developing and testing the Kepler ground-segment processing system, in particular the data analysis pipeline, requires high-fidelity simulated data. This simulated data is provided by the Kepler End-to-End Model (ETEM). ETEM simulates the astrophysics of planetary transits and other phenomena, properties of the Kepler spacecraft and the format of the downlinked data. Major challenges addressed by ETEM include the rapid production of large amounts of simulated data, extensibility and maintainability

Electrodialytic recovery of rare earth elements from coal ashes

Fundação para a Ciência e a Tecnologia, I.P., Portugal, UIDB/04085/2020 (Research unit CENSE “Center for Environmental and Sustainability Research”). Fundação para a Ciência e a Tecnologia is also acknowledged for N. Couto Contract established under Individual Call to Scientific Employment Stimulus (CEECIND/04210/2017).Rare earth elements (REE) are critical raw materials crucial for modern technologies and used in a variety of industries. There is a need of investment in REE recovery from secondary sources. The present work was designed to assess the potential of the electrodialytic process to recover REE from coal ash. The content of REE was evaluated in bituminous and anthracite ash. Anthracite presented higher REE concentration (447 ppm vs. 138 ppm) and a triple concentration of critical REE compared with bituminous ash. Anthracite ash was treated aiming to test the REE recover potential, including differences between light REE (LREE) and heavy REE (HREE) fractions as well as the specific recovery of REE with high criticality. A two-compartment electrodialytic cell was tested with the matrix placed in the anode compartment and a cation-exchange membrane separating the compartments. Experiments lasted a maximum of 7 days applying different current intensities and pH adjustment in the catholyte (≈ 2). Three main steps are observed in the removal process 1) REE solubilization - from the solid to the liquid phase (anolyte); 2) REE mobilization - movement from the anolyte towards the cathode end; 3) REE removal - presence in the catholyte. The extent of each step observed for the REE depends on their individual position in the periodic table with HREE removal being more regulated by step 1 and LREE by step 2. At the best tested conditions (50 mA, 3 days, pH adjustment), more than 70% of REE were extracted from the ash with the catholyte enclosing up to ≈ 50% of LREE and HREE. Combining the high criticality of neodymium with its high concentration in anthracite coal ash (65 ppm), the electrodialytic treatment is highly recommended to concentrate this REE in the catholyte. The results demonstrated the proof-of-concept for electro-assisted extraction of REE from anthracite coal ash, opening perspectives to a selective recovery of these elements from secondary sources.authorsversionpublishe

Overstating the evidence - double counting in meta-analysis and related problems

Background: The problem of missing studies in meta-analysis has received much attention. Less attention has been paid to the more serious problem of double counting of evidence. Methods: Various problems in overstating the precision of results from meta-analyses are described and illustrated with examples, including papers from leading medical journals. These problems include, but are not limited to, simple double-counting of the same studies, double counting of some aspects of the studies, inappropriate imputation of results, and assigning spurious precision to individual studies. Results: Some suggestions are made as to how the quality and reliability of meta-analysis can be improved. It is proposed that the key to quality in meta-analysis lies in the results being transparent and checkable. Conclusions: Existing quality check lists for meta-analysis do little to encourage an appropriate attitude to combining evidence and to statistical analysis. Journals and other relevant organisations should encourage authors to make data available and make methods explicit. They should also act promptly to withdraw meta-analyses when mistakes are found

Second-order phase transition at the phase boundary through the FeRh first-order metamagnetic phase transition

The phase coexistence present through first-order phase transitions implies the presence of phase boundary walls, which can be of finite size. Better understanding of the phase boundary wall properties will provide an insight into the dynamics of first-order phase transitions. Here, by combining x-ray photon correlation spectroscopy investigations with magnetometry measurements of magnetic relaxation through the thermally activated first-order metamagnetic phase transition present in the B2-ordered FeRh alloy, we are able to isolate the dynamic behaviour of the phase boundary wall present in this system. These investigations reveal a change in the nature of the dynamic behaviour and critical scaling of the relaxation time centred around the point of maximum phase coexistence within the phase transition. All of this behaviour can be attributed to the introduction of exchange coupling across the phase boundary wall and raises questions about the role of latent heat in dynamic behaviour of this region

General model with experimental validation of electrical resonant frequency tuning of electromagnetic vibration energy harvesters

This paper presents a general model and its experimental validation for electrically tunable electromagnetic energy harvesters. Electrical tuning relies on the adjustment of the electrical load so that the maximum output power of the energy harvester occurs at a frequency which is different from the mechanical resonant frequency of the energy harvester. Theoretical analysis shows that for this approach to be feasible the electromagnetic vibration energy harvester’s coupling factor must be maximized so that its resonant frequency can be tuned with the minimum decrease of output power. Two different-sized electromagnetic energy harvesters were built and tested to validate the model. Experimentally, the micro-scale energy harvester has a coupling factor of 0.0035 and an untuned resonant frequency of 70.05 Hz. When excited at 30 mg, it was tuned by 0.23 Hz by changing its capacitive load from 0 to 4000 nF; its effective tuning range is 0.15 Hz for a capacitive load variation from 0 to 1500 nF. The macro-scale energy harvester has a coupling factor of 552.25 and an untuned resonant frequency of 95.1 Hz and 95.5 Hz when excited at 10 mg and 25 mg, respectively. When excited at 10 mg, it was tuned by 3.8 Hz by changing its capacitive load from 0 to 1400 nF; it has an effective tuning range of 3.5 Hz for a capacitive load variation from 0 to 1200 nF. When excited at 25 mg, its resonant frequency was tuned by 4.2 Hz by changing its capacitive load from 0 to 1400 nF; it has an effective tuning range of about 5 Hz. Experimental results were found to agree with the theoretical analysis to within 10%

HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention