Severe asthma imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co‐morbidities, complexity in care pathways and ...differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of severe asthma, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include selection of a certain biological (as they all target overlapping disease phenotypes), the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home‐based) and its cost‐effectiveness. The EAACI Guidelines on the use of biologicals in severe asthma follow the GRADE approach in formulating recommendations for each biological and each outcome. In addition, a management algorithm for the use of biologicals in the clinic is proposed, together with future approaches and research priorities.
Five biologicals have been approved for severe eosinophilic asthma, a well‐recognized phenotype. Systematic reviews (SR) evaluated the efficacy and safety of benralizumab, dupilumab, mepolizumab, ...omalizumab and reslizumab (alphabetical order) compared to standard of care for severe eosinophilic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma‐related outcomes were evaluated for each of the biologicals. The risk of bias and the certainty of the evidence were assessed using GRADE. 19 RCTs (three RCTs for benralizumab, three RCTs for dupilumab, three RCTs for mepolizumab, five RCTs for omalizumab and five RCTs for reslizumab), including subjects 12 to 75 years old (except for omalizumab including also subjects 6‐11 years old), ranging from 12 to 56 weeks were evaluated. All biologicals reduce exacerbation rates with high certainty of evidence: benralizumab incidence rate ratio (IRR) 0.53 (95% CI 0.39 to 0.72), dupilumab (IRR) 0.43 (95% CI 0.32 to 0.59), mepolizumab IRR 0.49 (95% CI 0.38 to 0.66), omalizumab (IRR) 0.56 (95% CI 0.40 to 0.77) and reslizumab (IRR) 0.46 (95% CI 0.37 to 0.58). Benralizumab, dupilumab and mepolizumab reduce the daily dose of oral corticosteroids (OCS) with high certainty of evidence. All evaluated biologicals probably improve asthma control, QoL and FEV1, without reaching the minimal important difference (moderate certainty). Benralizumab, mepolizumab and reslizumab slightly increase drug‐related adverse events (AE) and drug‐related serious AE (low to very low certainty of evidence). The incremental cost‐effectiveness ratio per quality‐adjusted life year value is above the willingness to pay threshold for all biologicals (moderate certainty). Potential savings are driven by decrease in hospitalizations, emergency and primary care visits. There is high certainty that all approved biologicals reduce the rate of severe asthma exacerbations and for benralizumab, dupilumab and mepolizumab for reducing OCS. There is moderate certainty for improving asthma control, QoL, FEV1. More data on long‐term safety are needed together with more efficacy data in the paediatric population.
Diguanylate cyclase and phosphodiesterase enzymatic activities control c-di-GMP levels modulating planktonic versus sessile lifestyle behavior in bacteria. The PilZ domain is described as a sensor of ...c-di-GMP intracellular levels and the proteins containing a PilZ domain represent the best studied class of c-di-GMP receptors forming part of the c-di-GMP signaling cascade. In P. fluorescens F113 we have found two diguanylate cyclases (WspR, SadC) and one phosphodiesterase (BifA) implicated in regulation of swimming motility and biofilm formation. Here we identify a flgZ gene located in a flagellar operon encoding a protein that contains a PilZ domain. Moreover, we show that FlgZ subcellular localization depends on the c-di-GMP intracellular levels. The overexpression analysis of flgZ in P. fluorescens F113 and P. putida KT2440 backgrounds reveal a participation of FlgZ in Pseudomonas swimming motility regulation. Besides, the epistasis of flgZ over wspR and bifA clearly shows that c-di-GMP intracellular levels produced by the enzymatic activity of the diguanylate cyclase WspR and the phosphodiesterase BifA regulates biofilm formation through FlgZ.
Two new luminophore polymorphs of 4-bromo-7-(4-nonylphenyl)benzoc1,2,5thiadiazole (1α and 1β) exhibiting different color emissions, which switch into each other in response to shear force and ...solvent vapors, are presented and their X-ray structure is determined. Supramolecular organic framework topology (SOFT) studies on the two polymorphic structures led us to conclude that the mechanochromic phase transformation can be explained on the basis of modifications in their respective topological nets: mab and pcu for 1α and 1β, respectively, as a result of the breaking and restoration of a number of weak supramolecular interactions. The color changes accompanying this transformation have been rationalized with the help of time-dependent density functional theory. We firmly believe that our findings will inspire future research on the design of novel stimuli-responsive organic materials with switchable properties based on their supramolecular interactions by establishing clear SOFT-property relationships.
A selective palladium‐catalyzed C(sp) arylation/carbocyclization/iodonium migration reaction sequence has been accomplished. Novel 2‐iodo‐1‐aryl‐9H‐carbazoles are now easily available. As this result ...is contrary to the selectivity observed using gold catalysis, the formation of 2‐iodocarbazoles is noticeable, suggesting a metal‐controlled cyclization through chemo‐ and regioselective 1,2‐alkyl migration and 1,4‐iodonium migration.
Forest regrowth following farmland (agriculture and pasture) abandonment has been positively associated with a number of processes including the regulation of hydrological cycling, the enhancement of ...soil functioning and an increase in forest productivity and carbon (C) sequestration. Although these changes in ecosystem functioning post‐farmland abandonment have been observed in multiple locations and studies, the ecophysiological basis underpinning these patterns remains unclear. Here, we examine whether increased forest expansion following pastureland abandonment is associated with greater water‐use efficiency (WUE) and legacies from previous land use in terms of nitrogen (N) availability.
We thus explored differences in leaf traits and N availability between recently established (post‐1950) beech Fagus sylvatica (L.) forests on former pastureland and long‐established beech forests (pre‐1950). The investigated leaf traits were SLA, leaf N concentration (%N) and intrinsic WUE (iWUE, i.e. the ratio between photosynthesis and stomatal conductance); as well, leaf and soil stable N isotope composition (δ15N) and total %N were used to assess changes in N availability. Finally, we compared the correlation strength between the above‐mentioned parameters and those associated with tree productivity (wood density and basal area increment, BAI) and the richness of ectomycorrhizal fungi (ECM) in these two forest types.
Recent forests had greater iWUE than long‐established forests, which was associated more with lower SLA than leaf %N. Leaf and soil δ15N were more robust proxies than %N for detecting differences in N availability. Less negative leaf and soil δ15N values in recent versus long‐established forests suggest, on the one hand, greater N availability, probably due to higher historical N input originating from animal excreta on these former pasturelands, and, on the other hand, an increase in N loss pathways.
Our results point to greater correlations between leaf δ15N, tree iWUE and productivity in recent forests than in long‐established forests, thereby suggesting a close link between C and N cycles. Our findings also highlight different N dynamics between the two forest types, with recent forests showing ‘leaky’ N cycling wherever lower N retention by trees and associated ECM fungi occurs as a legacy of previous land use.
A free Plain Language Summary can be found within the Supporting Information of this article.
Resumen
La expansión de bosques secundarios después del abandono de tierras agrícolas se ha asociado positivamente con la regulación del ciclo hidrológico, la mejora del funcionamiento del suelo y un aumento de la productividad forestal y de la captura de carbono (C). Sin embargo la base ecofisiológica que sustenta estos patrones permanece inexplorada. En este estudio, examinamos si la expansión forestal sobre antiguos pastizales está asociada con una mayor eficiencia en el uso del agua (WUE) y con legados del uso anterior del suelo en la disponibilidad de nitrógeno (N).
Concretamente hemos analizado las diferencias en las características de las hojas y la disponibilidad de N entre hayedos Fagus sylvatica (L.) establecidos antes y después de 1950. Los rasgos foliares investigados fueron el área específica foliar (SLA), la concentración de N (%N) y eficiencia en el uso del agua intrínseca (iWUE, i.e. relación entre la fotosíntesis y la conductancia estomática). Asimismo, también, se analizó la composición de isótopos de N en las hojas y en el suelo (δ15N) y el % total de N, para valorar la disponibilidad de N. Finalmente, comparamos la correlación entre estos parámetros con indicadores de la productividad forestal (densidad de la madera e incremento del área basal) y la riqueza de ectomicorrizas en ambos tipos de bosques.
Los hayedos recientes mostraban una iWUE mayor que los bosques establecidos antes de 1950, lo que se asoció más con un menor SLA que del %N foliar. La δ15N foliar y del suelo fueron mejores que el %N para detectar diferencias en la disponibilidad de N. Valores de δ15N foliar y del suelo menos negativos en los hayedos recientes sugieren una mayor disponibilidad de N, probablemente debida a un mayor aporte histórico procedente de las heces del ganado en estos antiguos pastizales, y, asimismo, un aumento en las vías de pérdida de N.
Nuestros resultados apuntan a mayores correlaciones entre δ15N de hojas, iWUE y productividad en los bosques recientes, lo que sugiere un vínculo estrecho entre los ciclos de C y N. Asimismo, también resaltan diferentes dinámicas de N entre ambos tipos de bosques: i.e. los hayedos recientes muestran ciclos de N con "perdidas" por una menor retención de N por parte de los árboles y ectomicorrizas asociadas, por efecto del legado del uso anterior del suelo.
A free Plain Language Summary can be found within the Supporting Information of this article.
Pomegranate (Punica granatum L.) is a well-known source of bioactive phenolic compounds such as ellagitannins, anthocyanins, and flavanols. Punicalagin, one of the main constituents of pomegranate, ...needs to be biodegraded by bacteria to yield metabolites of medicinal interest. In this work, we tested 30 lactic acid bacteria (LAB) and their capacity to transform punicalagin from a punicalagin-rich pomegranate extract into smaller bioactive molecules, namely, ellagic acid and urolithins. These were identified and quantified by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS2). Further, we evaluated the molecular mechanism governing this transformation through label-free comparative MS-based proteomics. All tested LAB strains were capable of transforming punicalagin into ellagic acid, while the biosynthesis of urolithins was not observed. Proteomic analysis revealed an increase of generic transglycosylases that might have a hydrolytic role in the target phenolic molecule, coupled with an increase in the quantity of ATP-binding cassette (ABC) transporters, which might play a relevant role in transporting the resulting byproducts in and out of the cell.
The carboarylation reaction of biphenyl‐alkynes was successfully triggered by electrophilic attack of 1,1‐bis(triflyl)ethylene on the alkyne moiety to give polycyclic aromatic hydrocarbons (PAHs) ...decorated by superacidic carbon acid functionality. Neutralisation of thus obtained acids with NaHCO3 yielded the corresponding sodium salts, which showed improved solubility in both aqueous and organic solvents.
The reaction of biphenyl‐alkynes with in situ generated Tf2C=CH2 followed by neutralization gave polycyclic aromatic hydrocarbons (PAHs) decorated by a highly stabilized carbanionic functionality. Thus obtained PAHs showed improved solubility in both aqueous and organic solvents.
The Terrestrial Ecosystem Research Network (TERN), Australia's national land ecosystem monitoring programme, measures critical environmental attributes from local to continental scale and generates ...quality data for research and land management. Since 2011, TERN has performed standardised field surveys and sampling across a national plot network. At each plot, TERN records vegetation structure, composition and diversity, soil characteristics, and collects plant and soil samples for analysis. At the time of submission, TERN has established over 750 plots and performed over 1,000 plot surveys across Australia. Here we present ausplotsR, an R package for the R statistical computing environment that provides a user‐friendly interface to rapidly import, visualise, and analyse TERN plot data. Easy‐to‐use functions extract the data and compile data tables that can be incorporated into a variety of statistical analysis, most notably multivariate applications requiring plant community data with standardised relative abundances. ausplotsR includes functions to calculate useful vegetation metrics, such as species presence/absence, cover, and basal area. The package also provides information on TERN’s extensive soil and plant sample collection. We expect ausplotsR will help facilitate and advance ecological research and management throughout Australia and provide useful data for vegetation modellers globally.
The Terrestrial Ecosystem Research Network (TERN), Australia's national land ecosystem monitoring programme, has launched ausplotsR — an R package for live extraction, preparation, visualisation and analysis of TERN ecosystem monitoring data. Through ausplotsR, users can directly access plot‐based data on vegetation and soils across Australia from over 600 TERN monitoring sites, such as cover by species and physical sample barcode numbers.
“Torta del Casar” cheese is a high-quality cheese made with raw whole sheep's milk with quite broad commercialisation in Europe. This cheese, like other similar ones made with raw milk, are very ...susceptible to contamination by Listeria monocytogenes. In this work, the effect of two selected protective cultures of Lacticaseibacillus casei 116 and Lactococcus garvieae 151 on the reduction of L. monocytogenes throughout the processing of the traditional “Torta del Casar” was evaluated. Moisture content (%) and water activity (aw) decreased during ripening up to values around 35–38% and 0.93–0.94, respectively. The addition of the selected LAB did not affect physicochemical parameters. Both inoculated LAB strains provoked a relevant reduction in L. monocytogenes counts during the ripening of “Torta del Casar” cheese (up to 5 log CFU/g). Thus, the utilization of any of both strains, Lc. casei 116 and Lco. garvieae 151, as a protective culture in “Torta del Casar” or other similar cheese made with raw milk, could be of great interest to ensure the EU microbiological criteria for this RTE product before the food has left the immediate control of the food business operator, who has produced it, and products placed on the market during their shelf-life.
•LAB did not modify physicochemical characteristics of cheese during ripening.•“Torta del Casar” ripening control and even inhibit growth of L. monocytogenes.•Lc.casei 116 and Lco. garvieae 151 did not greatly affect the cheese microbial population.•Lc. casei 116 and Lco. garviae 151 provoked a relevant reduction in L. monocytogenes counts.•Lc. casei 116 and Lco. garviae 151 are proposed as protective cultures to keep cheese quality.
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