Localization of Neuropeptide Gene Expression in Larvae of an Echinoderm, the Starfish Asterias rubens

This study was supported by a European Molecular Biology Organization fellowship awarded to TM (ASTF 168-2014), Russian Foundation for Basic Research (grant 15-04-04298 awarded to TM), BBSRC (grant BB/M001644/1), the Leverhulme Trust (grant RGP-2013-351), the China Scholarship Council and the Society for Experimental Biology

Executable specifications are in planning of databases

Предложена постановка задачи реализации подхода к проектированию компонентов программного обеспечения, известного как a priori reasoning в применении к базам данных. Основная идея этого подхода заключается в явном использовании спецификации как инструкции к сборке компонента. Рассмотрены проблемы, возникающие на практике, преимущества возможной реализации идеи, подходы к синтезу (генерации) проектного решения. Перечислены задачи для дальнейшей работы.Запропонована постановка задачі реалізації підходу до проектування компонентів програмного забезпечення, відомого як а priori reasoning в застосуванні до баз даних. Основна ідея цього підходу полягає в явному використанні специфікації як інструкції до збірки компоненту. Розглянуті проблеми, що виникають на практиці, переваги можливої реалізації ідеї, підходи до синтезу (генерації) проектного рішення. Перераховані завдання для подальшої роботи.Raising of task of realization of approach is offered to planning of components of software, known as and priori reasoning in application to the bases of information. The basic idea of this approach consists in the obvious use of specification as instruction to assembling of component. Problems, arising up in practice, advantages of possible realization of idea, approaches to the synthesis (generations) of project decision, are considered. Tasks are transferred for further work

Executable specifications are in planning of databases

Предложена постановка задачи реализации подхода к проектированию компонентов программного обеспечения, известного как a priori reasoning в применении к базам данных. Основная идея этого подхода заключается в явном использовании спецификации как инструкции к сборке компонента. Рассмотрены проблемы, возникающие на практике, преимущества возможной реализации идеи, подходы к синтезу (генерации) проектного решения. Перечислены задачи для дальнейшей работы.Запропонована постановка задачі реалізації підходу до проектування компонентів програмного забезпечення, відомого як а priori reasoning в застосуванні до баз даних. Основна ідея цього підходу полягає в явному використанні специфікації як інструкції до збірки компоненту. Розглянуті проблеми, що виникають на практиці, переваги можливої реалізації ідеї, підходи до синтезу (генерації) проектного рішення. Перераховані завдання для подальшої роботи.Raising of task of realization of approach is offered to planning of components of software, known as and priori reasoning in application to the bases of information. The basic idea of this approach consists in the obvious use of specification as instruction to assembling of component. Problems, arising up in practice, advantages of possible realization of idea, approaches to the synthesis (generations) of project decision, are considered. Tasks are transferred for further work

IL1RAP expression and the enrichment of IL-33 activation signatures in severe neutrophilic asthma.

Background Interleukin (IL)-33 is an upstream regulator of type 2 (T2) eosinophilic inflammation and has been proposed as a key driver of some asthma phenotypes. Objective To derive gene signatures from in vitro studies of IL-33-stimulated cells and use these to determine IL-33-associated enrichment patterns in asthma. Methods Signatures downstream of IL-33 stimulation were derived from our in vitro study of human mast cells and from public datasets of in vitro stimulated human basophils, type 2 innate lymphoid cells (ILC2), regulatory T cells (Treg) and endothelial cells. Gene Set Variation Analysis (GSVA) was used to probe U-BIOPRED and ADEPT sputum transcriptomics to determine enrichment scores (ES) for each signature according to asthma severity, sputum granulocyte status and previously defined molecular phenotypes. Results IL-33-activated gene signatures were cell-specific with little gene overlap. Individual signatures, however, were associated with similar signalling pathways (TNF, NF-κB, IL-17 and JAK/STAT signalling) and immune cell differentiation pathways (Th17, Th1 and Th2 differentiation). ES for IL-33-activated gene signatures were significantly enriched in asthmatic sputum, particularly in patients with neutrophilic and mixed granulocytic phenotypes. IL-33 mRNA expression was not elevated in asthma whereas the expression of mRNA for IL1RL1, the IL-33 receptor, was up-regulated in the sputum of severe eosinophilic asthma. The mRNA expression for IL1RAP, the IL1RL1 co-receptor, was greatest in severe neutrophilic and mixed granulocytic asthma. Conclusions IL-33-activated gene signatures are elevated in neutrophilic and mixed granulocytic asthma corresponding with IL1RAP co-receptor expression. This suggests incorporating T2-low asthma in anti-IL-33 trials.</p

Mapping atopic dermatitis and anti-IL-22 response signatures to Type 2-low severe neutrophilic asthma

BACKGROUND: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.OBJECTIVE: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma.METHODS: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.RESULTS: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, T H2, and T H17/T H22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P &lt; .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P &lt; .05) and particularly in neutrophilic and mixed granulocytic sputum (P &lt; .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with T H22/IL-22 pathways. CONCLUSIONS: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.</p

Correction to: Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma (Respiratory Research, (2021), 22, 1, (10), 10.1186/s12931-020-01605-8)

An amendment to this paper has been published and can be accessed via the original article.</p

Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma

Background: Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells. Methods: We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels. Results: ACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes. Conclusion: Levels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.</p

Mapping atopic dermatitis and anti-IL-22 response signatures to Type 2-low severe neutrophilic asthma.

BACKGROUND Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases. OBJECTIVE To determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma (SA) and whether a transcriptomic signature for AD patients who respond clinically to anti-IL-22 (Fezakinumab, FZ) is enriched in SA. METHODS An AD disease signature was obtained from analysis of differentially expressed genes (DEGs) between AD lesional and non-lesional skin biopsies. DEGs from lesional skin from therapeutic super-responders before and after 12 weeks FZ treatment defined the FZ-response signature. Gene Set Variation Analysis (GSVA) was used to produce enrichment scores (ES) of AD and FZ-response signatures in the U-BIOPRED asthma cohort. RESULTS The AD disease signature (112 up-regulated genes) encompassing inflammatory, T-cell, Th2 and Th17/Th22 pathways was enriched in the blood and sputum of asthmatics with increasing severity. Asthmatics with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (p<0.05). The FZ-response signature (296 down-regulated genes) was enriched in asthmatic blood (p<0.05) and particularly in neutrophilic and mixed granulocytic sputum (p<0.05). These data were confirmed in sputum of the ADEPT (Airway Disease Endotyping for Personalized Therapeutics) cohort. IL-22 mRNA across tissues did not correlate with FZ-response ES, but this response signature correlated with Th22/IL-22 pathways. CONCLUSIONS The FZ-response signature in AD identifies severe neutrophilic asthmatics as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases

Association of differential mast cell activation with granulocytic inflammation in severe asthma

Rationale: mast cells (MCs) play a role in inflammation and both innate and adaptive immunity, but their involvement in severe asthma (SA) remains undefined. Objectives: we investigated the phenotypic characteristics of the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) asthma cohort by applying published MC activation signatures to the sputum cell transcriptome. Methods: eighty-four participants with SA, 20 with mild/moderate asthma (MMA), and 16 healthy participants without asthma were studied. We calculated enrichment scores (ESs) for nine MC activation signatures by asthma severity, sputum granulocyte status, and three previously defined sputum molecular phenotypes or transcriptome-associated clusters (TACs) 1, 2, and 3 using gene set variation analysis. Measurements and Main Results: MC signatures except unstimulated, repeated FceR1-stimulated and IFN-g–stimulated signatures were enriched in SA. A FceR1-IgE–stimulated and a single-cell signature from asthmatic bronchial biopsies were highly enriched in eosinophilic asthma and in the TAC1 molecular phenotype. Subjects with a high ES for these signatures had elevated sputum amounts of similar genes and pathways. IL-33– and LPS-stimulated MC signatures had greater ES in neutrophilic and mixed granulocytic asthma and in the TAC2 molecular phenotype. These subjects exhibited neutrophil, NF-kB (nuclear factor-kB), and IL-1b/TNF-a (tumor necrosis factor-a) pathway activation. The IFN-g–stimulated signature had the greatest ES in TAC2 and TAC3 that was associated with responses to viral infection. Similar results were obtained in an independent ADEPT (Airway Disease Endotyping for Personalized Therapeutics) asthma cohort. Conclusions: gene signatures of MC activation allow the detection of SA phenotypes and indicate that MCs can be induced to take on distinct transcriptional phenotypes associated with specific clinical phenotypes. IL-33–stimulated MC signature was associated with severe neutrophilic asthma, whereas IgE-activated MC was associated with an eosinophilic phenotype.</p