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Abstract Patients with severe uncontrolled asthma have disproportionally high morbidity and healthcare utilization as compared with their peers with well-controlled disease. Although treatment options for these patients were previously limited, with unacceptable side effects, the emergence of biologic therapies for the treatment of asthma has provided promising targeted therapy for these patients. Biologic therapies target specific inflammatory pathways involved in the pathogenesis of asthma, particularly in patients with an endotype driven by type 2 (T2) inflammation. In addition to anti-IgE therapy that has improved outcomes in allergic asthma for more than a decade, three anti–IL-5 biologics and one anti–IL-4R biologic have recently emerged as promising treatments for T2 asthma. These targeted therapies have been shown to reduce asthma exacerbations, improve lung function, reduce oral corticosteroid use, and improve quality of life in appropriately selected patients. In addition to the currently approved biologic agents, several biologics targeting upstream inflammatory mediators are in clinical trials, with possible approval on the horizon. This article reviews the mechanism of action, indications, expected benefits, and side effects of each of the currently approved biologics for severe uncontrolled asthma and discusses promising therapeutic targets for the future.

Soil flooding creates composite and complex stress in plants known as either submergence or waterlogging stress depending on the depth of the water table. In nature, these stresses are important factors dictating the species composition of the ecosystem. On agricultural land, they cause economic damage associated with long-term social consequences. The understanding of the plant molecular responses to these two stresses has benefited from research studying individual components of the stress, in particular low-oxygen stress. To a lesser extent, other associated stresses and plant responses have been incorporated into the molecular framework, such as ion and ROS signaling, pathogen susceptibility, and organ-specific expression and development. In this review, we aim to highlight known or suspected components of submergence/waterlogging stress that have not yet been thoroughly studied at the molecular level in this context, such as miRNA and retrotransposon expression, the influence of light/dark cycles, protein isoforms, root architecture, sugar sensing and signaling, post-stress molecular events, heavy-metal and salinity stress, and mRNA dynamics (splicing, sequestering, and ribosome loading). Finally, we explore biotechnological strategies that have applied this molecular knowledge to develop cultivars resistant to flooding or to offer alternative uses of flooding-prone soils, like bioethanol and biomass production.

Phytoremediation is an attractive strategy for cleaning soils polluted with a wide spectrum of organic and inorganic toxic compounds. Among these pollutants, heavy metals have attracted global attention due to their negative effects on human health and terrestrial ecosystems. As a result of this, numerous studies have been carried out to elucidate the mechanisms involved in removal processes. These studies have employed many plant species that might be used for phytoremediation and the obtention of end bioproducts such as biofuels and biogas useful in combustion and heating. Phytotechnologies represent an attractive segment that is increasingly gaining attention worldwide due to their versatility, economic profitability, and environmental co-benefits such as erosion control and soil quality and functionality improvement. In this review, the process of valorizing biomass from phytoremediation is described; in addition, relevant experiments where polluted biomass is used as feedstock or bioenergy is produced via thermo- and biochemical conversion are analyzed. Besides, pretreatments of biomass to increase yields and treatments to control the transfer of metals to the environment are also mentioned. Finally, aspects related to the feasibility, benefits, risks, and gaps of converting toxic-metal-polluted biomass are discussed.

Successful mathematical modeling of biological processes relies on the expertise of the modeler to capture the essential mechanisms in the process at hand and on the ability to extract useful information from empirical data. A model is said to be structurally unidentifiable, if different quantitative sets of parameters provide the same observable outcome. This is typical (but not exclusive) of partially observed problems in which only a few variables can be experimentally measured. Most of the available methods to test the structural identifiability of a model are either too complex mathematically for the general practitioner to be applied, or require involved calculations or numerical computation for complex non-linear models. In this work, we present a new analytical method to test structural identifiability of models based on ordinary differential equations, based on the invariance of the equations under the scaling transformation of its parameters. The method is based on rigorous mathematical results but it is easy and quick to apply, even to test the identifiability of sophisticated highly non-linear models. We illustrate our method by example and compare its performance with other existing methods in the literature.

The search for efficient materials for cleaning water is still being explored today. With this objective, pure hydroxyapatite (HAp) was prepared in this work as a ceramic matrix doped with 1, 3 and 5% magnesium by a microwave-assisted hydrothermal method (MAH) aimed at photocatalytic application under sunlight irradiation. XRD and FTIR analyses showed that only HAp was obtained from all the samples, and Rietveld refinement indicated a reduced crystallite size and increased microstrain after Mg doping. Nanorod-like morphologies were observed after analysis by SEM-FEG, with a decrease in the length and width of the particles after inserting the dopant. The UV‒Vis results revealed that the HAp bandgap decreased to 3.75 eV after doping. The photoluminescence spectra showed that oxygen vacancies were generated in the presence of Mg, which also caused an increase in the specific surface area of HAp. Photocatalytic tests were conducted with mixtures of methylene blue, crystal violet and malachite green dyes. After 120 min of sunlight irradiation, the sample with 3% Mg obtained the best results, achieving up to 94% degradation of the dyes. Furthermore, reusability tests showed that there was a small reduction in photocatalytic efficiency after five cycles, without structural changes in the photocatalyst. Inhibition tests showed that superoxides and holes are the active radicals, and tests with inorganic anions revealed that carbonates, nitrates and sulphates promote degradation, while phosphates reduce photocatalytic performance. This work highlights the promising alternative application of hydroxyapatite for simultaneous efficient photodegradation of different pollutants using sustainable energy. Graphical abstract

Patients who used oral glucocorticoids for asthma were able to reduce the dose of treatment more successfully when dupilumab, a monoclonal antibody targeting signaling through the interleukin-4 and interleukin-13 receptor, was added to their regimen than when placebo was added.

In this work, heterostructures formed by carbon nitride (CN) and hydroxyapatite (HAp) were successfully synthesized by the microwave-assisted hydrothermal method, varying the addition of CN in mass percentages (25–50%). Structural and spectroscopic analyses showed the formation of the CN/HAp heterostructure free from impurities with the presence of both phases, and morphological analyses showed the HAp nanorods together with the CN nanosheets. The obtained heterostructures enabled absorption in the visible region, with a band gap reduction from 5.43 eV (HAp) to 3.07 eV. The photocatalytic activity of the nanoparticles was evaluated under sunlight irradiation on the degradation of organic methylene blue (MB) and methyl orange (MO) dyes, and a mixture (MIX) of both. The heterostructure with 50% CN had degradation efficiency of up to 99% of MB and up to 81% of MO after 20 min. The reusability of the photocatalysts was tested in three cycles and showed improved photocatalytic activity of the heterostructure, maintaining its structural stability in the photodegradation of the dyes by at least 75%. Tests with inhibitors indicated that superoxide (O2−) and hole (h+) are the active radicals, indicating that the obtained heterostructure is type I.

Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist, irrespective of baseline eosinophil count. We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per μL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16. 769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per μL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06–0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11–0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per μL subgroup (overall population: 200 mg every 2 weeks, p<0·0001; 300 mg every 2 weeks, p<0·0001; <300 eosinophils per μL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70–70·5%), the subgroup with at least 300 eosinophils per μL (71·2–80·7%), and the subgroup with fewer than 300 eosinophils per μL (59·9–67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33–41% vs 35%) and injection-site reactions (13–26% vs 13%). Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone. Sanofi-Genzyme and Regeneron Pharmaceuticals.

Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1β in asthma is uncertain. To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation. We measured sputum eDNA in induced sputum from 399 patients with asthma in the Severe Asthma Research Program-3 and in 94 healthy control subjects. We subdivided subjects with asthma into eDNA-low and -high subgroups to compare outcomes of asthma severity and of neutrophil and inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can be prevented by DNase. We found that 13% of the Severe Asthma Research Program-3 cohort is \"eDNA-high,\" as defined by sputum eDNA concentrations above the upper 95th percentile value in health. Compared with eDNA-low patients with asthma, eDNA-high patients had lower Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral corticosteroids for maintenance of asthma control (all values <0.05). Sputum eDNA in asthma was associated with airway neutrophilic inflammation, increases in soluble NET components, and increases in caspase 1 activity and IL-1β (all values <0.001). In studies, NETs caused cytotoxicity in airway epithelial cells that was prevented by disruption of NETs with DNase. High extracellular DNA concentrations in sputum mark a subset of patients with more severe asthma who have NETs and markers of inflammasome activation in their airways.

Abstract Rationale Eosinophilic asthma is a phenotype of asthma characterized by the persistence of eosinophils in the airways. IL-5 is involved in the activation and survival of eosinophils. Objectives To evaluate the effect of the antibody to IL-5, reslizumab, in patients with eosinophilic asthma that is poorly controlled with high-dose inhaled corticosteroid. Methods Patients were randomly assigned to receive infusions of reslizumab at 3.0 mg/kg (n = 53) or placebo (n = 53) at baseline and at Weeks 4, 8, and 12, with stratification by baseline Asthma Control Questionnaire (ACQ) score less than or equal to 2 or greater than 2. The primary efficacy measure was the difference between the reslizumab and placebo groups in the change in ACQ score from baseline to end of therapy (Week 15 or early withdrawal). Measurements and Main Results Mean changes from baseline to end of therapy in ACQ score were –0.7 in the reslizumab group and –0.3 in the placebo group (P = 0.054) and in FEV1 were 0.18 and –0.08 L, respectively (P = 0.002). In those patients with nasal polyps, the changes in ACQ score were –1.0 and –0.1, respectively (P = 0.012). Median percentage reductions from baseline in sputum eosinophils were 95.4 and 38.7%, respectively (P = 0.007). Eight percent of patients in the reslizumab group and 19% of patients in the placebo group had an asthma exacerbation (P = 0.083). The most common adverse events with reslizumab were nasopharyngitis, fatigue, and pharyngolaryngeal pain. Conclusions Patients receiving reslizumab showed significantly greater reductions in sputum eosinophils, improvements in airway function, and a trend toward greater asthma control than those receiving placebo. Reslizumab was generally well tolerated.