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Summary: In the framework of quantitative feedback theory, this paper develops a new method to compute robust stability bounds. This is of special interest when stability is defined directly on the open‐loop function. Thus, ignorance of the plant gain and phase shift can be specifically and independently considered. Furthermore, upper and lower stability margins for both gain and phase can be chosen. However, classical quantitative feedback theory stability specifications are defined as constraining the peak magnitude of closed‐loop functions, which lack the said flexibility. Once the upper tolerance has been defined, all stability margins are determined. Moreover, confining the most restrictive stability margin may result in other excessive margins. However, the stability bounds of the new approach guard just the required distance from the open‐loop frequency response to the critical point. This allows maximization of the available feedback in the functional bandwidth and minimization of the cost of feedback beyond the crossover frequency, provided that the open‐loop frequency response is shaped to closely follow the stability bounds. It should be noted that the new bound computation algorithm performs few and simple arithmetic operations. This makes it far more efficient than traditional methods. The flight altitude control of an unmanned aerial vehicle is proposed as a practical example to show the new method's potential benefits. [ABSTRACT FROM AUTHOR]

Eosinophils are leukocytes characterized by their ability to release granule content that is highly rich in enzymes and proteins. Besides the antihelminthic, bactericidal, and antiviral properties of eosinophils and their secretory granules, these also play a prominent role in the pathophysiology of diseases such as asthma, eosinophilic esophagitis, and other hypereosinophilic conditions by causing tissue damage and airway hyperresponsiveness. Although this cell was first recognized mainly for its capacity to release granule content, nowadays other capabilities such as cytokine secretion have been linked to its physiology, and research has found that eosinophils are not only involved in innate immunity, but also as orchestrators of immune responses. Nearly 10 yr ago, eosinophil-derived extracellular vesicles (EVs) were first described; since then, the EV field has grown exponentially, revealing their vital roles in intracellular communication. In this review, we synthesize current knowledge on eosinophil-derived EVs, beginning with a description of what they are and what makes them important regulators of disease, followed by an account of the methodologies used to isolate and characterize EVs. We also summarize current understanding of eosinophil-derived vesicles functionality, especially in asthma, the disease in which eosinophil-derived EVs have been most widely studied, describing how they modulate the role of eosinophils themselves (through autocrine signaling) and the way they affect airway structural cells and airway remodeling. Deeper understanding of this cell type could lead to novel research in eosinophil biology, its role in other diseases, and possible use of eosinophil-derived EVs as therapeutic targets., Competing Interests: Conflict of interest statement. J.M.R.-M. reports receiving payments for lectures and educational events from AstraZeneca and GSK. V.d.P. has received honoraria (advisory board, speaker) and/or institutional grant/research support from AstraZeneca and GSK and unpaid Leadership or fiduciary role in committees of the EAACI. All other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Our objective was to evaluate changes in patient-reported outcome measures using the NEI-VFQ 25 questionnaire during a treat and extend regimen in naive neovascular Age-Related Macular Degeneration patients, and its correlation with anatomical and functional data. We conducted a prospective observational study. Patients underwent a treat and extend regimen with intravitreal ranibizumab for neovascular Age-Related Macular Degeneration. Initial response was evaluated at 4th month, and subsequently in every follow-up visit. If a clinical response was achieved, the injection interval was extended in two-week increments, up to a maximum of 12 weeks. Quality of life was assessed using the NEI-VFQ 25 questionnaire at baseline, 4th months, and 12th months. Patients were categorized as good or poor responders based on Best corrected visual acuity, central foveal thickness, intraretinal fluid, or subretinal fluid. Treatment with ranibizumab led to a significant improvement in quality of life, with a mean increase in NEI-VFQ 25 score of 4.27 points in the 12th month. No significant differences in improvement were observed between good and poor responders. Quality of life scores in neovascular Age-Related Macular Degeneration patients improved with intravitreal treatment regardless of the clinical response. The early response following the loading phase could indicate better quality of life after one year of treatment, with Best corrected visual acuity being the clinical parameter with the greatest influence on quality of life.

(1) Background: Eosinophilia has traditionally been linked to eosinophilic asthma, for which it is the gold-standard prognostic biomarker. However, the association between eosinophilia and the presence of other diseases and comorbidities is yet unclear. (2) Methods: For this retrospective study, we reviewed the electronic medical records of 49,909 subjects with blood eosinophilia to gather data on the presence of asthma, COPD, sleep apnea, tuberculosis, dyslipidemia, hypertension, and other cardiovascular diseases and severe CRSwNP among these subjects. Demographic features including age, sex, and smoking habits were collected, as well as the number of hospitalizations and emergency department visits. T-tests, ANOVA, Fisher test, and logistic regression models were used. (3) Results: For all age groups studied, eosinophilia was significantly more prevalent among asthmatic subjects than nonasthmatics, especially in patients also presenting CRSwNP, hypertension, and dyslipidemia. The likelihood of developing asthma, COPD, and CRSwNP, and hospitalization, was increased when BEC was above 600 eosinophils/μL. The association between asthma, CRSwNP, and BEC was corroborated by multiple logistic regressions models. (4) Conclusions: We demonstrated the association of having over 600 blood eosinophils/μL with a higher number of hospitalizations and comorbidities (CRSwNP and COPD), which proves that BEC is a highly useful parameter to consider in subjects who present blood eosinophilia.

Anti-vascular endothelial growth factor drugs keep being the main therapy for neovascular age-related macular degeneration (AMD). Possible predictive parameters (demographic, biochemical and/or inflammatory) could anticipate short-term treatment response with ranibizumab. 46 treatment-naive patients were included in a prospective observational study. They underwent three monthly injections of intravitreal ranibizumab for neovascular AMD and the clinical examination was made at baseline and one month after the third injection. Demographic characteristics, co-morbidities and concomitant treatments were recorded at the baseline visit. Biochemical parameters, complete blood count and inflammation biomarkers were also measured at these times. Uric Acid was found to be statistically significant with a one-point difference between good and poor responders in both basal and treated patients, but only in basal parameters was statistical significance reached ( p = 0.007 vs. p = 0.071 in treated patients). Cholesterol and inflammatory parameters such as white blood cell count and neutrophils were significantly reduced over time when treated with intravitreal ranibizumab. On the other hand, women seemed to have a worse prognosis for short-term response to intravitreal ranibizumab treatment. Uric acid may help identify possible non-responders before initial treatment with ranibizumab, and cholesterol and white blood cells could be good candidates to monitor short-term response to ranibizumab treatment.

Clarifying inflammatory processes and categorising asthma into phenotypes and endotypes improves asthma management. Obesity worsens severe asthma and reduces quality of life, although its specific molecular impact remains unclear. We previously demonstrated that hsa-miR-26a-1-3p and hsa-miR-376a-3p, biomarkers related to an inflammatory profile, discriminate eosinophilic from non-eosinophilic asthmatics. We aimed to study hsa-miR-26a-1-3p, hsa-miR-376a-3p, and their target genes in asthmatic subjects with or without obesity to find biomarkers and comprehend obese asthma mechanisms. Lung tissue samples were obtained from asthmatic patients (n = 16) and healthy subjects (n = 20). We measured miRNA expression using RT-qPCR and protein levels (IGF axis) by ELISA in confirmation samples from eosinophilic (n = 38) and non-eosinophilic (n = 39) obese (n = 26) and non-obese (n = 51) asthma patients. Asthmatic lungs showed higher hsa-miR-26a-1-3p and hsa-miR-376a-3p expression than healthy lungs. A study of seven genes regulated by these miRNAs revealed differential expression of IGFBP3 between asthma patients and healthy individuals. In obese asthma patients, we found higher hsa-miR-26a-1-3p and IGF-1R values and lower values for hsa-miR-376a-3p and IGFBP-3. Hsa-miR-26a-1-3p and IGFBP-3 were directly and inversely correlated with body mass index, respectively. Hsa-miR-26a-1-3p and hsa-miR-376a-3p could be used as biomarkers to phenotype patients with eosinophilic and non-eosinophilic asthma in relation to comorbid obesity.

Asthma is a heterogeneous inflammatory disease of the airways that causes breathing difficulties, episodes of cough and wheezing, and in more severe cases can greatly diminish quality of life. Epigenetic regulation, including post-transcriptional mediation of microRNAs (miRNAs), is one of the mechanisms behind the development of the range of asthma phenotypes and endotypes. As in every other immune-mediated disease, miRNAs regulate the behavior of cells that shape the airway structure as well as those in charge of the defense mechanisms in the bronchi and lungs, controlling cell survival, growth, proliferation, and the ability of cells to synthesize and secrete chemokines and immune mediators. More importantly, miRNAs are molecules with chemical and biological properties that make them appropriate biomarkers for disease, enabling stratification of patients for optimal drug selection and thereby simplifying clinical management and reducing both the economic burden and need for critical care associated with the disease. In this review, we summarize the roles of miRNAs in asthma and describe how they regulate the mechanisms of the disease. We further describe the current state of miRNAs as biomarkers for asthma phenotyping, endotyping, and treatment selection.

Nowadays, microRNAs (miRNAs) are increasingly used as biomarkers due to their potential contribution to the diagnosis and targeted treatment of a range of diseases. The aim of the study was to analyze the miRNA expression profiles in serum and lung tissue from patients with severe asthma treated with oral corticosteroids (OCS) and those without OCS treatment. For this purpose, serum and lung tissue miRNAs of OCS and non-OCS asthmatic individuals were evaluated by miRNAs-Seq, and subsequently miRNA validation was performed using RT-qPCR. Additionally, pathway enrichment analysis of deregulated miRNAs was conducted. We observed altered expression by the next-generation sequencing (NGS) of 11 miRNAs in serum, of which five (hsa-miR-148b-3p, hsa-miR-221-5p, hsa-miR-618, hsa-miR-941, and hsa-miR-769-5p) were validated by RT-qPCR, and three miRNAs in lung tissue (hsa-miR-144-3p, hsa-miR-144-5p, and hsa-miR-451a). The best multivariate logistic regression model to differentiate individuals with severe asthma, treated and untreated with OCS, was to combine the serum miRNAs hsa-miR-221-5p and hsa-miR-769-5p. Expression of hsa-miR-148b-3p and hsa-miR-221-5p correlated with FEV 1 /FVC (%) and these altered miRNAs act in key signaling pathways for asthma disease and the regulated expression of some genes ( FOXO3 , PTEN , and MAPK3 ) involved in these pathways. In conclusion, there are miRNA profiles differentially expressed in OCS-treated individuals with asthma and could be used as biomarkers of OCS treatment.

Respiratory viral infections (RVIs) are frequent in preterm infants possibly inducing long-term impact on respiratory morbidity. Immune response and respiratory barriers are key defense elements against viral insults in premature infants admitted to Neonatal Intensive Care Units (NICUs). Our main goals were to describe the local immune response in respiratory secretions of preterm infants with RVIs during NICU admission and to evaluate the expression and synthesis of lung barrier regulators, both in respiratory samples and in vitro models. Samples from preterm infants that went on to develop RVIs had lower filaggrin gene and protein levels at a cellular level were compared to never-infected neonates (controls). Filaggrin, MIP-1α/CCL3 and MCP-1 levels were higher in pre-infection supernatants compared to controls. Filaggrin, HIF-1α, VEGF, RANTES/CCL5, IL-17A, IL-1β, MIP-1α and MIP-1β/CCL5 levels were higher during and after infection. ROC curve and logistic regression analysis shows that these molecules could be used as infection risk biomarkers. Small airway epithelial cells stimulated by poly:IC presented reduced filaggrin gene expression and increased levels in supernatant. We conclude that filaggrin gene and protein dysregulation is a risk factor of RVI in newborns admitted at the NICU., (© 2022. The Author(s).)

Age-related macular degeneration (AMD) is a common ocular disease characterized by degeneration of the central area of the retina in the elderly population. Progression and response to treatment are influenced by genetic and non-genetic factors. Proteomics is a powerful tool to study, at the molecular level, the mechanisms underlying the progression of the disease, to identify new therapeutic targets and to establish biomarkers to monitor progression and treatment effectiveness. In this work, we systematically review the use of proteomics-based approaches for the study of the molecular mechanisms underlying the development of AMD, as well as the progression of the disease and on-treatment patient monitoring. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guidelines were followed. Proteomic approaches have identified key players in the onset of the disease, such as complement components and proteins involved in lipid metabolism and oxidative stress, but also in the progression to advanced stages, including factors related to extracellular matrix integrity and angiogenesis. Although anti-vascular endothelial growth factor (anti-VEGF)-based therapy has been crucial in the treatment of neovascular AMD, it is necessary to deepen our understanding of the underlying disease mechanisms to move forward to next-generation therapies for later-stage forms of this multifactorial disease.

Respiratory diseases such as bronchiolitis, and those with wheezing episodes, are highly important during infancy due to their potential chronicity. Immune response dysregulation is critical in perpetuating lung damage. Epigenetic modifications including microRNA (miRNA) post-transcriptional regulation are among the factors involved in alleviating inflammation. We evaluated the expression of miR-146a-5p, a previously described negative regulator of immunity, in infants with respiratory diseases, in order to study epigenetic regulation of the immune response. Nasopharyngeal aspirate (NPA) was obtained from infants with bronchiolitis (ongoing and post-disease) or with wheezing episodes in addition to healthy controls. Virus presence was determined by nested PCR, while miRNA and gene expression were studied in cells from NPAs using qPCR. Healthy small airway epithelial cells (SAECs) were used as an in vitro model. We observe a reduction in miR-146a-5p expression in infants with either of the two diseases compared to controls, suggesting the potential of this miRNA as a disease biomarker. Post-bronchiolitis, miR-146a-5p expression increases, though without reaching levels of healthy controls. MiR-146a-5p expression correlates inversely with the immune-related gene PTGS2 , while its expression correlates directly with TSLP . When heathy donor SAECs are stimulated by poly:IC, we observe an increase in miR-146a-5p, with wounds having a synergistic effect. In conclusion, infants with respiratory diseases present reduced miR-146a-5p expression, possibly affecting immune dysregulation.

MicroRNAs are non-coding molecules that act both as regulators of the epigenetic landscape and as biomarkers for diseases, including asthma. In the era of personalized medicine, there is a need for novel disease-associated biomarkers that can help in classifying diseases into phenotypes for treatment selection. Currently, severe eosinophilic asthma is one of the most widely studied phenotypes in clinical practice, as many patients require higher and higher doses of corticosteroids, which in some cases fail to achieve the desired outcome. Such patients may only benefit from alternative drugs such as biologics, for which novel biomarkers are necessary. The objective of the study was to study the expression of miR-144-3p in order to discover its possible use as a diagnostic biomarker for severe asthma. For this purpose, miR-144-3p was evaluated in airway biopsies and serum from asthmatics and healthy individuals. mRNA was studied in asthmatic biopsies and smooth muscle cells transfected with miR-144-3p mimic. An in silico regulation of miR-144-3p was performed using miRSystem, miRDB, STRING, and ShinyGO for pathway analysis. From our experimental procedures, we found that miR-144-3p is a biomarker associated with asthma severity and corticosteroid treatment. MiR-144-3p is increased in asthmatic lungs, and its presence correlates directly with blood eosinophilia and with the expression of genes involved in asthma pathophysiology in the airways. When studied in serum, this miRNA was increased in severe asthmatics and associated with higher doses of corticosteroids, thereby making it a potential biomarker for severe asthma previously treated with higher doses of corticosteroids. Thus, we can conclude that miR-144-3p is associated with severe diseases in both the airways and serum of asthmatics, and this association is related to corticosteroid treatment., Competing Interests: S.Q. reports personal fees from AstraZeneca, Novartis, Sanofi, Boehringer Ingelheim, Teva, ALK, Mundipharma, GSK, Chiesi, and personal fees from Leti, outside the submitted work. J.S. reports having served as a consultant to Thermofisher, MEDA, Novartis, Sanofi, Leti, Faes Farma, Mundipharma, and GSK; having been paid lecture fees by Novartis, GSK, Stallergenes, Leti, and Faes Pharma; as well as having received grant support for research from Thermofisher, Sanofi, and ALK. V.d.P reports having served as a consultant to Astra Zeneca and GSK and having been paid lecture fees by both. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rodrigo-Muñoz, Gil-Martínez, Lorente-Sorolla, García-Latorre, Valverde-Monge, Quirce, Sastre and del Pozo.)

Asthma is a chronic respiratory disease produced by an aberrant immune response that originates with breathing difficulties and cough, through airway remodeling. The above pathophysiological events of asthma emerge the regulators of effectors, like epigenetics, which include microRNAs (miRNAs) who perform post-transcriptional regulation, controlling diverse pathways in respiratory diseases. The objective of the study was to determine how miR-185-5p regulates the secretion of periostin by airway structural cells, and smooth muscle cells contraction, both related to airway remodeling in asthma. We used miR-185-5p mimic and inhibitors in bronchial smooth muscle cells (BSMCs) and small airway epithelial cells (SAECs) from healthy subjects. Gene expression and protein levels of periostin (POSTN), CDC42, and RHOA were analyzed by RT-PCR and ELISA/Western blot, respectively. BSMC contractility was analyzed using cell-embedded collagen gels and measurement of intracellular calcium was performed using Fura-2. Additionally, miR-185-5p and periostin expression were evaluated in sputum from healthy and asthmatics. From these experiments, we observed that miR-185-5p modulation regulates periostin mRNA and protein in BSMCs and SAECs. A tendency for diminished miR-185-5p expression and higher periostin levels was seen in sputum cells from asthmatics compared to healthy, with an inverse correlation observed between POSTN and miR-185-5p. Inhibition of miR-185-5p produced higher BSMCs contraction induced by histamine. Calcium mobilization was not modified by miR-185-5p, showing that miR-185-5p role in BSMC contractility is performed by regulating CDC42 and RhoA pro-contractile factors instead. In conclusion, miR-185-5p is a modulator of periostin secretion by airway structural cells and of smooth muscle contraction, which can be related to asthma pathophysiology, and thus, might be a promising therapeutic target., (© 2021 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Vitreo-retinal disorders constitute a significant portion of treatable ocular diseases. These pathologies often require vitreo-retinal surgery and, as a consequence, the use of vitreous substitutes. Nowadays, the vitreous substitutes that are used in clinical practice are mainly divided into gases (air, SF 6 , C 2 F 6 , C 3 F 8 ) and liquids (perfluorocarbon liquids, silicone oils, and heavy silicone oils). There are specific advantages and drawbacks to each of these, which determine their clinical indications. However, developing the ideal biomaterial for vitreous substitution continues to be one of the most important challenges in ophthalmology, and a multidisciplinary approach is required. In this sense, recent research has focused on the development of biocompatible, biodegradable, and injectable hydrogels (natural, synthetic, and smart), which also act as medium and long-term internal tamponade agents. This comprehensive review aims to cover the main characteristics and indications for use of the extensive range of vitreous substitutes that are currently used in clinical practice, before going on to describe the hydrogels that have been developed recently and which have emerged as promising biomaterials for vitreous substitution., (© 2021 The Authors. Macromolecular Bioscience published by Wiley-VCH GmbH.)

Eosinophils are complex granulocytes with the capacity to react upon diverse stimuli due to their numerous and variable surface receptors, which allows them to respond in very different manners. Traditionally believed to be only part of parasitic and allergic/asthmatic immune responses, as scientific studies arise, the paradigm about these cells is continuously changing, adding layers of complexity to their roles in homeostasis and disease. Developing principally in the bone marrow by the action of IL-5 and granulocyte macrophage colony-stimulating factor GM-CSF, eosinophils migrate from the blood to very different organs, performing multiple functions in tissue homeostasis as in the gastrointestinal tract, thymus, uterus, mammary glands, liver, and skeletal muscle. In organs such as the lungs and gastrointestinal tract, eosinophils are able to act as immune regulatory cells and also to perform direct actions against parasites, and bacteria, where novel mechanisms of immune defense as extracellular DNA traps are key factors. Besides, eosinophils, are of importance in an effective response against viral pathogens by their nuclease enzymatic activity and have been lately described as involved in severe acute respiratory syndrome coronavirus SARS-CoV-2 immunity. The pleiotropic role of eosinophils is sustained because eosinophils can be also detrimental to human physiology, for example, in diseases like allergies, asthma, and eosinophilic esophagitis, where exosomes can be significant pathophysiologic units. These eosinophilic pathologies, require specific treatments by eosinophils control, such as new monoclonal antibodies like mepolizumab, reslizumab, and benralizumab. In this review, we describe the roles of eosinophils as effectors and regulatory cells and their involvement in pathological disorders and treatment.

Severe eosinophilic asthma poses a serious health and economic problem, so new therapy approaches have been developed to control it, including biological drugs such as benralizumab, which is a monoclonal antibody that binds to IL-5 receptor alpha subunit and depletes peripheral blood eosinophils rapidly. Biomarkers that predict the response to this drug are needed so that microRNAs (miRNAs) can be useful tools. This study was performed with fifteen severe eosinophilic asthmatic patients treated with benralizumab, and serum miRNAs were evaluated before and after treatment by semi-quantitative PCR (qPCR). Patients showed a clinical improvement after benralizumab administration. Additionally, deregulation of miR-1246, miR-5100 and miR-338-3p was observed in severe asthmatic patients after eight weeks of therapy, and a correlation was found between miR-1246 and eosinophil counts, including a number of exacerbations per year in these severe asthmatics. In silico pathway analysis revealed that these three miRNAs are regulators of the MAPK signaling pathway, regulating target genes implicated in asthma such as NFKB2 , NFATC3 , DUSP1 , DUSP2 , DUSP5 and DUSP16 . In this study, we observed an altered expression of miR-1246, miR-5100 and miR-338-3p after eight weeks of benralizumab administration, which could be used as early response markers.

Asthma is a chronic disease of the airways that has an important inflammatory component. Multiple cells are implicated in asthma pathogenesis (lymphocytes, eosinophils, mast cells, basophils, neutrophils), releasing a wide variety of cytokines. These cells can exert their inflammatory functions throughout extracellular vesicles (EVs), which are small vesicles released by donor cells into the extracellular microenvironment that can be taken up by recipient cells. Depending on their size, EVs can be classified as microvesicles, exosomes, or apoptotic bodies. EVs are heterogeneous spherical structures secreted by almost all cell types. One of their main functions is to act as transporters of a wide range of molecules, such as proteins, lipids, and microRNAs (miRNAs), which are single-stranded RNAs of approximately 22 nucleotides in length. Therefore, exosomes could influence several physiological and pathological processes, including those involved in asthma. They can be detected in multiple cell types and biofluids, providing a wealth of information about the processes that take account in a pathological scenario. This review thus summarizes the most recent insights concerning the role of exosomes from different sources (several cell populations and biofluids) in one of the most prevalent respiratory diseases, asthma.