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Objective: Machine learning (ML) approaches have the potential to uncover regular patterns in multi-layered data. Here we applied self-organizing maps (SOMs) to detect such patterns with the aim to better predict in-stent restenosis (ISR) at surveillance angiography 6 to 8 months after percutaneous coronary intervention with stenting. Methods: In prospectively collected data from 10,004 patients receiving percutaneous coronary intervention (PCI) for 15,004 lesions, we applied SOMs to predict ISR angiographically 6–8 months after index procedure. SOM findings were compared with results of conventional uni- and multivariate analyses. The predictive value of both approaches was assessed after random splitting of patients into training and test sets (50:50). Results: Conventional multivariate analyses revealed 10, mostly known, predictors for restenosis after coronary stenting: balloon-to-vessel ratio, complex lesion morphology, diabetes mellitus, left main stenting, stent type (bare metal vs. first vs. second generation drug eluting stent), stent length, stenosis severity, vessel size reduction, and prior bypass surgery. The SOM approach identified all these and nine further predictors, including chronic vessel occlusion, lesion length, and prior PCI. Moreover, the SOM-based model performed well in predicting ISR (AUC under ROC: 0.728); however, there was no meaningful advantage in predicting ISR at surveillance angiography in comparison with the conventional multivariable model (0.726, p = 0.3). Conclusions: The agnostic SOM-based approach identified—without clinical knowledge—even more contributors to restenosis risk. In fact, SOMs applied to a large prospectively sampled cohort identified several novel predictors of restenosis after PCI. However, as compared with established covariates, ML technologies did not improve identification of patients at high risk for restenosis after PCI in a clinically relevant fashion. [ABSTRACT FROM AUTHOR]

Reliable prediction models of treatment outcome in Major Depressive Disorder (MDD) are currently lacking in clinical practice. Data-driven outcome definitions, combining data from multiple modalities and incorporating clinician expertise might improve predictions. We used unsupervised machine learning to identify treatment outcome classes in 1060 MDD inpatients. Subsequently, classification models were created on clinical and biological baseline information to predict treatment outcome classes and compared to the performance of two widely used classical outcome definitions. We also related the findings to results from an online survey that assessed which information clinicians use for outcome prognosis. Three and four outcome classes were identified by unsupervised learning. However, data-driven outcome classes did not result in more accurate prediction models. The best prediction model was targeting treatment response in its standard definition and reached accuracies of 63.9 % in the test sample, and 59.5 % and 56.9 % in the validation samples. Top predictors included sociodemographic and clinical characteristics, while biological parameters did not improve prediction accuracies. Treatment history, personality factors, prior course of the disorder, and patient attitude towards treatment were ranked as most important indicators by clinicians. Missing data limited the power to identify biological predictors of treatment outcome from certain modalities. So far, the inclusion of available biological measures in addition to psychometric and clinical information did not improve predictive value of the models, which was overall low. Optimized biomarkers, stratified predictions and the inclusion of clinical expertise may improve future prediction models. • Data-driven treatment outcome classes in depressed patients were created. • Outcome classes were not easier to predict than response/remission using baseline data. • Clinical and sociodemographic data were more predictive than biological measures. • Top predictors were compared to clinical expertise from an online survey. [ABSTRACT FROM AUTHOR]

Purpose: The prospective multicenter VARIANZ study aimed to identify resistance biomarkers for HER2-targeted treatment in advanced gastric and esophago-gastric junction cancer (GC, EGJC). HER2 test deviations were found in 90 (22.3%) of 404 cases (central versus local testing) and were associated with negative impact on survival for trastuzumab-treated patients. Here, we investigated methodological and biological variables that may promote deviating HER2 test results. Methods: We analyzed HER2 testing procedures and participation in quality assurance programs of 105 participating local pathology laboratories. Furthermore, tumor localization and histological subtypes were compared between patients with centrally confirmed (central HER2 + /local HER2 + , n = 68) and unconfirmed HER2 status (central HER2 −/local HER2 + , n = 68). Results: For central HER2 testing, concordance between in situ hybridization (ISH) and immunohistochemistry (IHC) was 98.3%, with IHC sensitivity of 93.3% (84 IHC + of 90 ISH +), specificity of 99.5% (389 IHC- of 391 ISH-), and a positive diagnosis rate of 97.7%. Central confirmation of the local HER2 IHC scores were seen for the majority of locally HER2- IHC 0/1 (172/178; 96.6%), but less frequently for locally IHC3 + (57/124; 46.0%) cases. Deviation rate was not associated with IHC antibody platform used in the local pathology institute neither with participation in quality-assuring tests. Regarding tumor characteristics, deviating test results were more frequently found in GC vs. EGJC (69.1% vs. 39.7%; p = 0.001) and in Laurén diffuse vs. intestinal subtype (23.5% vs. 5.9%, p = 0.004). Conclusion: Tumor localization and histological subtype have an impact on HER2 test deviation rates. Assessment of HER2 remains challenging for GC and EGJC. [ABSTRACT FROM AUTHOR]

Background: The standard treatment for patients with advanced HER2-positive gastric cancer is a combination of the antibody trastuzumab and platin-fluoropyrimidine chemotherapy. As some patients do not respond to trastuzumab therapy or develop resistance during treatment, the search for alternative treatment options and biomarkers to predict therapy response is the focus of research. We compared the efficacy of trastuzumab and other HER-targeting drugs such as cetuximab and afatinib. We also hypothesized that treatment-dependent regulation of a gene indicates its importance in response and that it can therefore be used as a biomarker for patient stratification.Methods: A selection of gastric cancer cell lines (Hs746T, MKN1, MKN7 and NCI-N87) was treated with EGF, cetuximab, trastuzumab or afatinib for a period of 4 or 24 h. The effects of treatment on gene expression were measured by RNA sequencing and the resulting biomarker candidates were tested in an available cohort of gastric cancer patients from the VARIANZ trial or functionally analyzed in vitro.Results: After treatment of the cell lines with afatinib, the highest number of regulated genes was observed, followed by cetuximab and trastuzumab. Although trastuzumab showed only relatively small effects on gene expression, BMF, HAS2 and SHB could be identified as candidate biomarkers for response to trastuzumab. Subsequent studies confirmed HAS2 and SHB as potential predictive markers for response to trastuzumab therapy in clinical samples from the VARIANZ trial. AREG, EREG and HBEGF were identified as candidate biomarkers for treatment with afatinib and cetuximab. Functional analysis confirmed that HBEGF is a resistance factor for cetuximab.Conclusion: By confirming HAS2, SHB and HBEGF as biomarkers for anti-HER therapies, we provide evidence that the regulation of gene expression after treatment can be used for biomarker discovery.Trial Registration: Clinical specimens of the VARIANZ study (NCT02305043) were used to test biomarker candidates. [ABSTRACT FROM AUTHOR]

Targeted cancer therapies are powerful alternatives to chemotherapies or can be used complementary to these. Yet, the response to targeted treatments depends on a variety of factors, including mutations and expression levels, and therefore their outcome is difficult to predict. Here, we develop a mechanistic model of gastric cancer to study response and resistance factors for cetuximab treatment. The model captures the EGFR, ERK and AKT signaling pathways in two gastric cancer cell lines with different mutation patterns. We train the model using a comprehensive selection of time and dose response measurements, and provide an assessment of parameter and prediction uncertainties. We demonstrate that the proposed model facilitates the identification of causal differences between the cell lines. Furthermore, our study shows that the model provides predictions for the responses to different perturbations, such as knockdown and knockout experiments. Among other results, the model predicted the effect of MET mutations on cetuximab sensitivity. These predictive capabilities render the model a basis for the assessment of gastric cancer signaling and possibly for the development and discovery of predictive biomarkers. Author summary: Unraveling the causal differences between drug responders and non-responders is an important challenge. The information can help to understand molecular mechanisms and to guide the selection and design of targeted therapies. Here, we approach this problem for cetuximab treatment for gastric cancer using mechanistic mathematical modeling. The proposed model describes responder and non-responder gastric cancer cell lines and can predict the response in several validation experiments. Our analysis provides a differentiated view on mutations and explains, for instance, the relevance of MET mutations and the insignificance of PIK3CA mutation in the considered cell lines. The model might potentially provide the basis for understanding the recent failure of several clinical studies. [ABSTRACT FROM AUTHOR]

Activation and repression of Notch target genes is mediated by transcription factor CSL, known as Suppressor of Hairless (Su(H)) in Drosophila and CBF1 or RBPJ in human. CSL associates either with co-activator Notch or with co-repressors such as Drosophila Hairless. The nuclear translocation of transcription factor CSL relies on co-factor association, both in mammals and in Drosophila. The Drosophila CSL orthologue Su(H) requires Hairless for repressor complex formation. Based on its role in transcriptional silencing, H protein would be expected to be strictly nuclear. However, H protein is also cytosolic, which may relate to its role in the stabilization and nuclear translocation of Su(H) protein. Here, we investigate the function of the predicted nuclear localization signals (NLS 1–3) and single nuclear export signal (NES) of co-repressor Hairless using GFP-fusion proteins, reporter assays and in vivo analyses using Hairless wild type and shuttling-defective Hairless mutants. We identify NLS3 and NES to be critical for Hairless function. In fact, H⁎NLS3 mutant flies match H null mutants, whereas H ⁎NLS3⁎NES double mutants display weaker phenotypes in agreement with a crucial role for NES in H export. As expected for a transcriptional repressor, Notch target genes are deregulated in H ⁎NLS3 mutant cells, demonstrating nuclear requirement for its activity. Importantly, we reveal that Su(H) protein strictly follows Hairless protein localization. Together, we propose that shuttling between the nucleo-cytoplasmic compartments provides the possibility to fine tune the regulation of Notch target gene expression by balancing of Su(H) protein availability for Notch activation. • Nuclear import of Hairless is mediated by NLS3 and nuclear export by NES. • Hairless activity requires nuclear localization signal NLS3. • Su(H) protein is dynamically imported and exported together with Hairless protein. • Su(H) protein stability is independent of subcellular localization. • Nucleo-cytoplasmic shuttling of Su(H) may help to fine-tune Notch signalling activity. [ABSTRACT FROM AUTHOR]

During development of higher animals, the Notch signalling pathway governs cell type specification by mediating appropriate gene expression responses. In the absence of signalling, Notch target genes are silenced by repressor complexes. In the model organism Drosophila melanogaster, the repressor complex includes the transcription factor Suppressor of Hairless [Su(H)] and Hairless (H) plus general co-repressors. Recent crystal structure analysis of the Drosophila Notch repressor revealed details of the Su(H)-H complex. They were confirmed by mutational analyses of either protein; however, only Su(H) mutants have been further studied in vivo. Here, we analyse three H variants predicted to affect Su(H) binding. To this end, amino acid replacements Phenylalanine 237, Leucines 245 and 247, as well as Tryptophan 258 to Alanine were introduced into the H protein. A cell-based reporter assay indicates substantial loss of Su(H) binding to the respective mutant proteins HFA, HLLAA and HWA. For in vivo analysis, UAS-lines HFA, HLLAA and HWA were generated to allow spatially restricted overexpression. In these assays, all three mutants resembled the HLD control, shown before to lack Su(H) binding, indicating a strong reduction of H activity. For example, the H variants were impaired in wing margin formation, but unexpectedly induced ectopic wing venation. Concurrent overexpression with Su(H), however, suggests that all mutant H protein isoforms are still able to bind Su(H) in vivo. We conclude that a weakening of the cohesion in the H-Su(H) repressor complex is sufficient for disrupting its in vivo functionality. [ABSTRACT FROM AUTHOR]

The Notch signaling pathway is highly conserved in all animal metazoa: upon Notch receptor activation, transcription of Notch target genes is turned on by an activator complex that centers on the transcription factor CSL. In the absence of signal, CSL assembles transcriptional repression complexes that display remarkable evolutionary diversity. The major antagonist of Notch signaling in insects named Hairless was originally identified in Drosophila melanogaster. It binds to the Drosophila CSL homologue Suppressor of Hairless [Su(H)] and recruits the two general co-repressors, Groucho and C-terminal binding protein. Whereas the majority of Notch signaling components is conserved between insects and vertebrates, Hairless is found only in insects. Here, we present the analysis of the Hairless gene from Daphnia pulex and, hence, for the first time from a crustacean. Daphnia and Drosophila Hairless protein sequences are highly diverged. Known functional domains, however, the Su(H), Groucho and the C-terminal binding protein interactions domains, are well conserved. Moreover, direct binding of the Daphnia Hairless protein and the respective Drosophila interaction partners was detected, demonstrating the conservation at the molecular level. In addition, interaction between Daphnia Hairless and Drosophila Su(H) was demonstrated in vivo, as co-overexpression of the respective genes during Drosophila development resulted in the expected downregulation of Notch activity in the fly. Structural models show that the Hairless-Su(H) repressor complexes from Daphnia and Drosophila are almost indistinguishable from one another. Amino acid residues in direct contact within the Hairless-Su(H) complex are at absolutely identical positions in the two homologues. [ABSTRACT FROM AUTHOR]

Overexpression of Hairless (H) causes a remarkable degree of tissue loss and apoptosis during imaginal development. H functions as antagonist in the Notch-signaling pathway in Drosophila, and the link to growth and apoptosis is poorly understood. To further our insight into H-mediated apoptosis, we performed two large-scale screens for modifiers of a small rough eye phenotype caused by H overexpression. Both loss- and gain-of-function screens revealed known and new genetic interactors representing diverse cellular functions. Many of them did not cause eye phenotypes on their own, emphasizing a specific genetic interaction with H. As expected, we also identified components of different signaling pathways supposed to be involved in the regulation of cell growth and cell death. Accordingly, some of them also acted as modifiers of proapoptotic genes, suggesting a more general involvement in the regulation of apoptosis. Overall, these screens highlight the importance of H and the Notch pathway in mediating cell death in response to developmental and environmental cues and emphasize their role in maintaining developmental cellular homeostasis. [ABSTRACT FROM AUTHOR]

• Uncertainty exists as to the role of air pollution on childhood respiratory health. • Data from five recent European birth cohorts were meta-analyzed. • No evidence found for role of air pollution on asthma and allergies up to 8 years. • Findings consistently null across all cohorts considered. Uncertainly continues to exist regarding the role of air pollution on pediatric asthma and allergic conditions, especially as air pollution levels have started to decrease in recent decades. We examined associations of long-term air pollution levels at the home address with pediatric eczema, rhinoconjunctivitis and asthma prevalences in five birth cohorts (BIB, EDEN, GASPII, RHEA and INMA) from seven areas in five European countries. Current eczema, rhinoconjunctivitis and asthma were assessed in children aged four (N = 6527) and eight years (N = 2489). A multi-morbidity outcome (≥2 conditions versus none) was also defined. Individual outdoor levels of nitrogen dioxide (NO 2), nitrogen oxides, mass of particulate matter with an aerodynamic diameter <10 μm (PM 10), 10–2.5 μm (PM coarse) and <2.5 μm (PM 2.5), and PM 2.5 absorbance were assigned to the birth, four- and eight-year home addresses using highly defined spatial air pollution exposure models. Cohort-specific cross-sectional associations were assessed using logistic regression models adjusted for demographic and environmental covariates and combined in a random effects meta-analysis. The overall prevalence of pediatric eczema, rhinoconjunctivitis and asthma at four years was 15.4%, 5.9% and 12.4%. We found no increase in the prevalence of these outcomes at four or eight years with increasing air pollution exposure. For example, the meta-analysis adjusted odds ratios (95% confidence intervals) for eczema, rhinoconjunctivitis and asthma at four years were 0.94 (0.81, 1.09), 0.90 (0.75, 1.09), and 0.91 (0.74, 1.11), respectively, per 10 μg/m3 increase in NO 2 at the birth address, and 1.00 (0.81, 1.23), 0.70 (0.49, 1.00) and 0.88 (0.54, 1.45), respectively, per 5 μg/m3 increase in PM 2.5 at the birth address. In this large meta-analysis of five birth cohorts, we found no indication of adverse effects of long-term air pollution exposure on the prevalence of current pediatric eczema, rhinoconjunctivitis or asthma. [ABSTRACT FROM AUTHOR]

Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing., Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors., Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19., Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies., Competing Interests: AN collaborates with SANOFI-AVENTIS R&D via a public–private partnership grant CIFRE contract, n° 2020/0766. DM and AB are employed at Labvantage-Biomax GmbH and will be affected by any effect of this publication on the commercial version of the AILANI software. JB and BG received consulting fees from Two Six Labs, LLC. TH has served as a shareholder and has consulted for Discovery Collective, Inc. RB and RS are founders and shareholders of MEGENO SA and ITTM SA. JS-R reports funding from GSK, Pfizer and Sanofi and fees/honoraria from Travere Therapeutics, Stadapharm, Astex, Owkin, Pfizer and Grunenthal. JP and LF are employees and shareholders of MedBioinformatics Solutions SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Niarakis, Ostaszewski, Mazein, Kuperstein, Kutmon, Gillespie, Funahashi, Acencio, Hemedan, Aichem, Klein, Czauderna, Burtscher, Yamada, Hiki, Hiroi, Hu, Pham, Ehrhart, Willighagen, Valdeolivas, Dugourd, Messina, Esteban-Medina, Peña-Chilet, Rian, Soliman, Aghamiri, Puniya, Naldi, Helikar, Singh, Fernández, Bermudez, Tsirvouli, Montagud, Noël, Ponce-de-Leon, Maier, Bauch, Gyori, Bachman, Luna, Piñero, Furlong, Balaur, Rougny, Jarosz, Overall, Phair, Perfetto, Matthews, Rex, Orlic-Milacic, Gomez, De Meulder, Ravel, Jassal, Satagopam, Wu, Golebiewski, Gawron, Calzone, Beckmann, Evelo, D’Eustachio, Schreiber, Saez-Rodriguez, Dopazo, Kuiper, Valencia, Wolkenhauer, Kitano, Barillot, Auffray, Balling, Schneider and the COVID-19 Disease Map Community.)

Cellular differentiation relies on the highly conserved Notch signaling pathway. Notch activity induces gene expression changes that are highly sensitive to chromatin landscape. We address Notch gene regulation using Drosophila as a model, focusing on the genetic and molecular interactions between the Notch antagonist Hairless and the histone chaperone Asf1. Earlier work implied that Asf1 promotes the silencing of Notch target genes via Hairless (H). Here, we generate a novel H Δ CT allele by genome engineering. Phenotypically, H Δ CT behaves as a Hairless gain of function allele in several developmental contexts, indicating that the conserved CT domain of H has an attenuator role under native biological contexts. Using several independent methods to assay protein-protein interactions, we define the sequences of the CT domain that are involved in Hairless-Asf1 binding. Based on previous models, where Asf1 promotes Notch repression via Hairless, a loss of Asf1 binding should reduce Hairless repressive activity. However, tissue-specific Asf1 overexpression phenotypes are increased, not rescued, in the H Δ CT background. Counterintuitively, Hairless protein binding mitigates the repressive activity of Asf1 in the context of eye development. These findings highlight the complex connections of Notch repressors and chromatin modulators during Notch target-gene regulation and open the avenue for further investigations.

Humans are involuntarily exposed to hundreds of chemicals that either contaminate our environment and food or are added intentionally to our daily products. These complex mixtures of chemicals may pose a risk to human health. One of the goals of the European Union's Green Deal and zero-pollution ambition for a toxic-free environment is to tackle the existent gaps in chemical mixture risk assessment by providing scientific grounds that support the implementation of adequate regulatory measures within the EU. We suggest dealing with this challenge by: (1) characterising 'real-life' chemical mixtures and determining to what extent they are transferred from the environment to humans via food and water, and from the mother to the foetus; (2) establishing a high-throughput whole-mixture-based in vitro strategy for screening of real-life complex mixtures of organic chemicals extracted from humans using integrated chemical profiling (suspect screening) together with effect-directed analysis; (3) evaluating which human blood levels of chemical mixtures might be of concern for children's development; and (4) developing a web-based, ready-to-use interface that integrates hazard and exposure data to enable component-based mixture risk estimation. These concepts form the basis of the Green Deal project PANORAMIX, whose ultimate goal is to progress mixture risk assessment of chemicals.

Rationale: It is difficult to predict the effects of long-acting bronchodilators (LABD) on lung function, exercise capacity and physical activity in patients with chronic obstructive pulmonary disease (COPD). Therefore, the multidimensional response to LABD was profiled in COPD patients participating in the ACTIVATE study and randomized to LABD., Methods: In the ACTIVATE study, patients were randomized to aclidinium bromide/formoterol fumarate (AB/FF) or placebo for four weeks. The primary outcomes included (1) lung function as measured by functional residual capacity (FRC), residual volume (RV), and spirometric outcomes; (2) exercise performance as measured by a constant work rate cycle ergometry test (CWRT); and (3) physical activity (PA) using an activity monitor. Self-organizing maps (SOMs) were used to create an ordered representation of the patients who were randomly assigned to four weeks of AB/FF and cluster them into different outcome groups., Results: A total of 250 patients were randomized to AB/FF (n = 126) or placebo (n = 124). Patients in the AB/FF group (39.6% women) had moderate-to-severe COPD, static hyperinflation (FRC: 151.4 (27.7)% predicted) and preserved exercise capacity. Six clusters with differential outcomes were identified. Patients in clusters 1 and 2 had significant improvements in lung function compared to the remaining AB/FF-treated patients. Patients in clusters 1 and 3 had significant improvements in CWRT time, and patients in clusters 2, 3 and 6 had significant improvements in PA compared to the remaining AB/FF-treated patients., Conclusion: Individual responses to 4 weeks of AB/FF-treatment in COPD are differential and the degree of change differs across domains of lung function, exercise capacity and PA. These results indicate that clinical response to LABD therapy is difficult to predict and is non-linear, and show doctors that it is important to look at multiple outcomes simultaneously when evaluating the clinical response to LABD therapy., Clinical Trial Registration: The original ACTIVATE study was registered on ClinicalTrials.gov, registration number NCT02424344., Competing Interests: Maud Koopman reports no real or perceived conflict of interest. Frits M.E. Franssen reports grants and personal fees from AstraZeneca and Novartis; personal fees from Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and TEVA, outside the submitted work. Swetlana Gaffron works at Viscovery. Viscovery provides analysis services to Ciro+. Henrik Watz reports personal fees from AZ, during the conduct of the study; grants and/or personal fees from AZ, GSK, Chiesi, Boehringer Ingelheim Novartis, and Menarini, outside the submitted work. Thierry Troosters reports personal fees from AstraZeneca, Boehringer Ingelheim, and Chiesi, outside the submitted work. Judith Garcia-Aymerich reports consulting and lecture fees from AstraZeneca (outside the submitted work) and lecture fees from Esteve and Chiesi (outside the submitted work). Pierluigi Paggiaro reports grants and/or personal fees from ALK, AstraZeneca, Chiesi, GSK, Novartis, Sanofi, Guidotti, Menarini, and Mundipharma, outside the submitted work. Eduard Molins, Miguel Moya, Lindy van Burk, and Esther Garcia Gil are AstraZeneca employees. Dieter Maier works at Biomax. Biomax provides data management and analysis services to CIRO+. Emiel F.M. Wouters reports no real or perceived conflict of interest. Lowie E.G.W. Vanfleteren reports grants and/or personal fees from AstraZeneca, Novartis, GSK, Chiesi, Menarini, Pulmonx, Fisher&Paykel, and Boehringer, outside the submitted work. Martijn A. Spruit reports grants from the Netherlands Lung Foundation, Stichting Astma Bestrijding, GSK, Boehringer Ingelheim, AstraZeneca, TEVA, and Chiesi, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Koopman et al.)

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: It remains unknown whether and to what extent members of online "long COVID" peer support groups remain symptomatic and limited over time. Therefore, we aimed to evaluate symptoms in members of online long COVID peer support groups up to 6 months after the onset of coronavirus disease 2019 (COVID-19)-related symptoms., Methods: Demographics, symptoms, health status, work productivity, functional status and health-related quality of life were assessed about 3 and 6 months after the onset of COVID-19-related symptoms in members of online long COVID peer support groups., Results: Data from 239 patients with a confirmed COVID-19 diagnosis (83% women; median (interquartile range) age 50 (39-56) years) were analysed. During the infection, a median (interquartile range) of 15 (11-18) symptoms was reported, which was significantly lower 3 and 6 months later: 6 (4-9) and 6 (3-8), respectively (p<0.05). From 3 to 6 months follow-up, the proportion of patients without symptoms increased from 1.3% to only 5.4% (p<0.001). Patients also reported a significantly improved work productivity (work absenteeism and presenteeism: 73% versus 52% and 66% versus 60%, respectively), self-reported good health (9.2% versus 16.7%), functional status (mean±sd Post-COVID-19 Functional Status scale: 2.4±0.9 versus 2.2±1.0) and health-related quality of life (all p<0.05)., Conclusion: Although patients with confirmed COVID-19, who were all members of online long COVID peer support groups, reported significant improvements in work productivity, functional status and quality of life between 3 and 6 months follow-up, these data clearly highlight the long-term impact of COVID-19, as approximately 6 months after the onset of COVID-19-related symptoms a large proportion still experienced persistent symptoms, a moderate-to-poor health, moderate-to-severe functional limitations, considerable loss in work productivity, and/or an impaired quality of life. Action is needed to improve the management and healthcare of these patients., Competing Interests: Conflict of interest: A.W. Vaes has nothing to disclose. Conflict of interest: Y.M.J. Goërtz has nothing to disclose. Conflict of interest: M. Van Herck has nothing to disclose. Conflict of interest: F.V.C. Machado has nothing to disclose. Conflict of interest: R. Meys has nothing to disclose. Conflict of interest: J.M. Delbressine has nothing to disclose. Conflict of interest: S. Houben-Wilke has nothing to disclose. Conflict of interest: S. Gaffron has nothing to disclose. Conflict of interest: D. Maier reports Biomax provides data management and analysis services to CIRO. Conflict of interest: C. Burtin has nothing to disclose. Conflict of interest: R. Posthuma has nothing to disclose. Conflict of interest: N.P.H. van Loon has nothing to disclose. Conflict of interest: F.M.E. Franssen reports grants and personal fees from AstraZeneca, and personal fees from Boehringer Ingelheim, Chiesi, GSK and TEVA, outside the submitted work. Conflict of interest: B. Hajian has nothing to disclose. Conflict of interest: S.O. Simons reports personal fees from AstraZeneca and grants from GSK, outside the submitted work. Conflict of interest: J.F.M. Van Boven has nothing to disclose. Conflict of interest: F.A. Klok reports grants from Bayer, Bristol Meyer Squibb, Boehringer Ingelheim, MSD, Daiichi-Sankyo, Actelion, the Dutch Thrombosis Association, the Dutch Heart Foundation, and the Netherlands Organisation for Health Research and Development, outside the submitted work. Conflict of interest: B. Spaetgens has nothing to disclose. Conflict of interest: C.M.H. Pinxt has nothing to disclose. Conflict of interest: L.Y.L. Liu has nothing to disclose. Conflict of interest: G. Wesseling has nothing to disclose. Conflict of interest: Y. Spies has nothing to disclose. Conflict of interest: H. Vijlbrief has nothing to disclose. Conflict of interest: A.J. Van ’t Hul has nothing to disclose. Conflict of interest: D.J.A. Janssen reports personal fees from AstraZeneca, Boehringer Ingelheim and Novartis, outside the submitted work. Conflict of interest: M.A. Spruit reports grants from Lung Foundation Netherlands and Stichting Astma Bestrijding, and grants and personal fees from AstraZeneca and Boehringer Ingelheim, outside the submitted work., (Copyright ©The authors 2021.)

Purpose: Trastuzumab is the only approved targeted drug for first-line treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic gastric cancer (mGC). However, not all patients respond and most eventually progress. The multicenter VARIANZ study aimed to investigate the background of response and resistance to trastuzumab in mGC., Methods: Patients receiving medical treatment for mGC were prospectively recruited in 35 German sites and followed for up to 48 months. HER2 status was assessed centrally by immunohistochemistry and chromogenic in situ hybridization. In addition, HER2 gene expression was assessed using qPCR., Results: Five hundred forty-eight patients were enrolled, and 77 had HER2+ mGC by central assessment (14.1%). A high deviation rate of 22.7% between central and local test results was seen. Patients who received trastuzumab for centrally confirmed HER2+ mGC (central HER2+/local HER2+) lived significantly longer as compared with patients who received trastuzumab for local HER2+ but central HER2- mGC (20.5 months, n = 60 v 10.9 months, n = 65; hazard ratio, 0.42; 95% CI, 8.2 to 14.4; P < .001). In the centrally confirmed cohort, significantly more tumor cells stained HER2+ than in the unconfirmed cohort, and the HER2 amplification ratio was significantly higher. A minimum of 40% HER2+ tumor cells and a HER2 amplification ratio of ≥ 3.0 were calculated as optimized thresholds for predicting benefit from trastuzumab., Conclusion: Significant discrepancies in HER2 assessment of mGC were found in tumor specimens with intermediate HER2 expression. Borderline HER2 positivity and heterogeneity of HER2 expression should be considered as resistance factors for HER2-targeting treatment of mGC. HER2 thresholds should be reconsidered. Detailed reports with quantification of HER2 expression and amplification levels may improve selection of patients for HER2-directed treatment., Competing Interests: Birgitta GeierOther Relationship: Biomax Informatics AG Dieter MaierOther Relationship: Biomax Informatics AG Albrecht KretzschmarHonoraria: Roche Pharma AG, Merck Serono, Shire, Amgen, Medac, SERVIER, Sanofi, MSD, Bristol-Myers Squibb, Bayer Schering Pharma, Aspen PharmaConsulting or Advisory Role: Roche Pharma AG, Shire, AmgenTravel, Accommodations, Expenses: PharmaMar, Merck Serono, Ipsen, Medac Ludwig Von WeikersthalHonoraria: Novartis, Roche Pharma AG, AstraZeneca, Pierre Fabre Gabriele SieglerHonoraria: Medizinwelten services GmbH, Shire, Eisai, Roche, Janssen-Cilag, Aurikamed, Deutsche RöntgengesellschaftConsulting or Advisory Role: Janssen-Cilag, AstraZenecaResearch Funding: Servier, Beigene, Roche/Genentech, Roche, Celgene, Isofol Medical, Nutricia, Novartis, MOLOGEN, SanofiTravel, Accommodations, Expenses: Lilly Thomas DeckerConsulting or Advisory Role: Novartis Florian LordickHonoraria: Lilly, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Elsevier, BioNTech AG, SERVIER, Infomedica, Merck KGaA, Roche, MedscapeConsulting or Advisory Role: Lilly, Merck Sharp and Dohme, Bristol-Myers Squibb, Astellas Pharma, SERVIER, Zymeworks, Amgen, BeigeneResearch Funding: Bristol-Myers SquibbTravel, Accommodations, Expenses: Bristol-Myers Squibb, LillyNo other potential conflicts of interest were reported.

CSL transcription factors are central to signal transduction in the highly conserved Notch signaling pathway. CSL acts as a molecular switch: depending on the cofactors recruited, CSL induces either activation or repression of Notch target genes. Unexpectedly, CSL depends on its cofactors for nuclear entry, despite its role as gene regulator. In Drosophila, the CSL homologue Suppressor of Hairless (Su(H)), recruits Hairless (H) for repressor complex assembly, and eventually for nuclear import. We recently found that Su(H) is subjected to a dynamic nucleo-cytoplasmic shuttling, thereby strictly following H subcellular distribution. Hence, regulation of nuclear availability of Su(H) by H may represent a new layer of control of Notch signaling activity. Here we extended this work on the murine CSL homologue RBPJ. Using a 'murinized' fly model bearing RBPJ wt in place of Su(H) at the endogenous locus we demonstrate that RBPJ protein likewise follows H subcellular distribution. For example, overexpression of a H *NLS3 protein variant defective of nuclear import resulted in a cytosolic localization of RBPJ protein, whereas the overexpression of a H *NES protein variant defective in the nuclear export signal caused the accumulation of RBPJ protein in the nucleus. Evidently, RBPJ is exported from the nucleus as well. Overall these data demonstrate that in our fly model, RBPJ is subjected to H-mediated nucleo-cytoplasmic shuttling as is Su(H). These data raise the possibility that nuclear availability of mammalian CSL proteins is likewise restricted by cofactors, and may hence present a more general mode of regulating Notch signaling activity.

The response of pathophysiological research to emerging epidemics often occurs after the epidemic and, as a consequence, has little to no impact on improving patient outcomes or on developing high-quality evidence to inform clinical management strategies during the epidemic. Rapid and informed guidance of epidemic (research) responses to severe infectious disease outbreaks requires quick compilation and integration of existing pathophysiological knowledge. As a case study we chose the Zika virus (ZIKV) outbreak that started in 2015 to develop a proof-of-concept knowledge repository. To extract data from available sources and build a computationally tractable and comprehensive molecular interaction map we applied generic knowledge management software for literature mining, expert knowledge curation, data integration, reporting and visualization. A multi-disciplinary team of experts, including clinicians, virologists, bioinformaticians and knowledge management specialists, followed a pre-defined workflow for rapid integration and evaluation of available evidence. While conventional approaches usually require months to comb through the existing literature, the initial ZIKV KnowledgeBase (ZIKA KB) was completed within a few weeks. Recently we updated the ZIKA KB with additional curated data from the large amount of literature published since 2016 and made it publicly available through a web interface together with a step-by-step guide to ensure reproducibility of the described use case. In addition, a detailed online user manual is provided to enable the ZIKV research community to generate hypotheses, share knowledge, identify knowledge gaps, and interactively explore and interpret data. A workflow for rapid response during outbreaks was generated, validated and refined and is also made available. The process described here can be used for timely structuring of pathophysiological knowledge for future threats. The resulting structured biological knowledge is a helpful tool for computational data analysis and generation of predictive models and opens new avenues for infectious disease research. ZIKV Knowledgebase is available at www.zikaknowledgebase.eu., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Nanotechnology has enabled the discovery of a multitude of novel materials exhibiting unique physicochemical (PChem) properties compared to their bulk analogues. These properties have led to a rapidly increasing range of commercial applications; this, however, may come at a cost, if an association to long-term health and environmental risks is discovered or even just perceived. Many nanomaterials (NMs) have not yet had their potential adverse biological effects fully assessed, due to costs and time constraints associated with the experimental assessment, frequently involving animals. Here, the available NM libraries are analyzed for their suitability for integration with novel nanoinformatics approaches and for the development of NM specific Integrated Approaches to Testing and Assessment (IATA) for human and environmental risk assessment, all within the NanoSolveIT cloud-platform. These established and well-characterized NM libraries (e.g. NanoMILE, NanoSolutions, NANoREG, NanoFASE, caLIBRAte, NanoTEST and the Nanomaterial Registry (>2000 NMs)) contain physicochemical characterization data as well as data for several relevant biological endpoints, assessed in part using harmonized Organisation for Economic Co-operation and Development (OECD) methods and test guidelines. Integration of such extensive NM information sources with the latest nanoinformatics methods will allow NanoSolveIT to model the relationships between NM structure (morphology), properties and their adverse effects and to predict the effects of other NMs for which less data is available. The project specifically addresses the needs of regulatory agencies and industry to effectively and rapidly evaluate the exposure, NM hazard and risk from nanomaterials and nano-enabled products, enabling implementation of computational 'safe-by-design' approaches to facilitate NM commercialization., (© 2020 The Authors.)

Background: In Drosophila, the development of the fly eye involves the activity of several, interconnected pathways that first define the presumptive eye field within the eye anlagen, followed by establishment of the dorso-ventral boundary, and the regulation of growth and apoptosis. In Lobe (L) mutant flies, parts of the eye or even the complete eye are absent because the eye field has not been properly defined. Manifold genetic interactions indicate that L influences the activity of several signalling pathways, resulting in a conversion of eye tissue into epidermis, and in the induction of apoptosis. As information on the molecular nature of the L mutation is lacking, the underlying molecular mechanisms are still an enigma., Results: We have identified Protein Kinase D (PKD) as a strong modifier of the L mutant phenotype. PKD belongs to the PKC/CAMK class of Ser/Thr kinases that have been involved in diverse cellular processes including stress resistance and growth. Despite the many roles of PKD, Drosophila PKD null mutants are without apparent phenotype apart from sensitivity to oxidative stress. Here we report an involvement of PKD in eye development in the sensitized genetic background of Lobe . Absence of PKD strongly enhanced the dominant eye defects of heterozygous L 2 flies, and decreased their viability. Moreover, eye-specific overexpression of an activated isoform of PKD considerably ameliorated the dominant L 2 phenotype. This genetic interaction was not allele specific but similarly seen with three additional, weaker L alleles ( L 1 , L 5 , L G ), demonstrating its specificity., Conclusions: We propose that PKD-mediated phosphorylation is involved in underlying processes causing the L phenotype, i.e. in the regulation of growth, the epidermal transformation of eye tissue and apoptosis, respectively., Competing Interests: Competing interestsThe author declares that there are no competing financial, personal, or professional interests., (© The Author(s) 2019.)

Multi-omics approaches use a diversity of high-throughput technologies to profile the different molecular layers of living cells. Ideally, the integration of this information should result in comprehensive systems models of cellular physiology and regulation. However, most multi-omics projects still include a limited number of molecular assays and there have been very few multi-omic studies that evaluate dynamic processes such as cellular growth, development and adaptation. Hence, we lack formal analysis methods and comprehensive multi-omics datasets that can be leveraged to develop true multi-layered models for dynamic cellular systems. Here we present the STATegra multi-omics dataset that combines measurements from up to 10 different omics technologies applied to the same biological system, namely the well-studied mouse pre-B-cell differentiation. STATegra includes high-throughput measurements of chromatin structure, gene expression, proteomics and metabolomics, and it is complemented with single-cell data. To our knowledge, the STATegra collection is the most diverse multi-omics dataset describing a dynamic biological system.

Introduction: To understand the puberty-related sex shift in the prevalence of asthma and rhinitis as single entities and as respiratory multimorbidities, we investigated if there is also a sex-specific and puberty-related pattern of their incidences., Methods: We used harmonised questionnaire data from 18 451 participants in five prospective observational European birth cohorts within the collaborative MeDALL (Mechanisms of the Development of Allergy) project. Outcome definitions for IgE-associated and non-IgE-associated asthma, rhinitis and respiratory multimorbidity (first occurrence of coexisting asthma and rhinitis) were based on questionnaires and the presence of specific antibodies (IgE) against common allergens in serum. For each outcome, we used proportional hazard models with sex-puberty interaction terms and conducted a one-stage individual participant data meta-analysis., Results: Girls had a lower risk of incident asthma (adjusted HR 0.67, 95% CI 0.61 to 0.74), rhinitis (0.73, 0.69 to 0.78) and respiratory multimorbidity (0.58, 0.51 to 0.66) before puberty compared with boys. After puberty onset, these incidences became more balanced across the sexes (asthma 0.84, 0.64 to 1.10; rhinitis 0.90, 0.80 to 1.02; respiratory multimorbidity 0.84, 0.63 to 1.13). The incidence sex shift was slightly more distinct for non-IgE-associated respiratory diseases (asthma 0.74, 0.63 to 0.87 before vs 1.23, 0.75 to 2.00 after puberty onset; rhinitis 0.88, 0.79 to 0.98 vs 1.20, 0.98 to 1.47; respiratory multimorbidity 0.66, 0.49 to 0.88 vs 0.96, 0.54 to 1.71) than for IgE-associated respiratory diseases., Discussion: We found an incidence 'sex shift' in chronic respiratory diseases from a male predominance before puberty to a more sex-balanced incidence after puberty onset, which may partly explain the previously reported sex shift in prevalence. These differences need to be considered in public health to enable effective diagnoses and timely treatment in adolescent girls., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic airflow limitation is the common denominator of patients with chronic obstructive pulmonary disease (COPD). However, it is not possible to predict morbidity and mortality of individual patients based on the degree of lung function impairment, nor does the degree of airflow limitation allow guidance regarding therapies. Over the last decades, understanding of the factors contributing to the heterogeneity of disease trajectories, clinical presentation, and response to existing therapies has greatly advanced. Indeed, diagnostic assessment and treatment algorithms for COPD have become more personalized. In addition to the pulmonary abnormalities and inhaler therapies, extra-pulmonary features and comorbidities have been studied and are considered essential components of comprehensive disease management, including lifestyle interventions. Despite these advances, predicting and/or modifying the course of the disease remains currently impossible, and selection of patients with a beneficial response to specific interventions is unsatisfactory. Consequently, non-response to pharmacologic and non-pharmacologic treatments is common, and many patients have refractory symptoms. Thus, there is an ongoing urgency for a more targeted and holistic management of the disease, incorporating the basic principles of P4 medicine (predictive, preventive, personalized, and participatory). This review describes the current status and unmet needs regarding personalized medicine for patients with COPD. Also, it proposes a systems medicine approach, integrating genetic, environmental, (micro)biological, and clinical factors in experimental and computational models in order to decipher the multilevel complexity of COPD. Ultimately, the acquired insights will enable the development of clinical decision support systems and advance personalized medicine for patients with COPD., Competing Interests: FMEF received personal fees for lectures and consultancies from AstraZeneca, Boehringer Ingelheim, Chiesi, TEVA, GlaxoSmithKline, and Novartis, outside of this work. He also received research grants from Novartis and MedImmune. BS received research funding from GlaxoSmithKline. SI reports grants from Austrian Science Fund FWF, during the conduct of the study. DM reports grants from Austrian Science Fund FWF, during the conduct of the study. MM reports grants from German Ministry for Education and Research (BMBF), during the conduct of the study. CFV reports grants and personal fees from AstraZeneca Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Menarini, Mundipharma, Novartis, TEVA, Cipla, Bayer Schering, MSD, and Pfizer, outside the submitted work. BS reports grants from BMBF and GlaxoSmithKline, during the conduct of the study. The authors report no other conflicts of interest in this work.

Pharmacists are trusted health care professionals. Many patients use over-the-counter (OTC) medications and are seen by pharmacists who are the initial point of contact for allergic rhinitis management in most countries. The role of pharmacists in integrated care pathways (ICPs) for allergic diseases is important. This paper builds on existing studies and provides tools intended to help pharmacists provide optimal advice/interventions/strategies to patients with rhinitis. The Allergic Rhinitis and its Impact on Asthma (ARIA)-pharmacy ICP includes a diagnostic questionnaire specifically focusing attention on key symptoms and markers of the disease, a systematic Diagnosis Guide (including differential diagnoses), and a simple flowchart with proposed treatment for rhinitis and asthma multimorbidity. Key prompts for referral within the ICP are included. The use of technology is critical to enhance the management of allergic rhinitis. However, the ARIA-pharmacy ICP should be adapted to local healthcare environments/situations as regional (national) differences exist in pharmacy care., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The numbers of international collaborations among birth cohort studies designed to better understand asthma and allergies have increased in the last several years. However, differences in definitions and methods preclude direct pooling of original data on individual participants. As part of the Mechanisms of the Development of Allergy (MeDALL) Project, we harmonized data from 14 birth cohort studies (each with 3-20 follow-up periods) carried out in 9 European countries during 1990-1998 or 2003-2009. The harmonization process followed 6 steps: 1) organization of the harmonization panel; 2) identification of variables relevant to MeDALL objectives (candidate variables); 3) proposal of a definition for each candidate variable (reference definition); 4) assessment of the compatibility of each cohort variable with its reference definition (inferential equivalence) and classification of this inferential equivalence as complete, partial, or impossible; 5) convocation of a workshop to agree on the reference definitions and classifications of inferential equivalence; and 6) preparation and delivery of data through a knowledge management portal. We agreed on 137 reference definitions. The inferential equivalence of 3,551 cohort variables to their corresponding reference definitions was classified as complete, partial, and impossible for 70%, 15%, and 15% of the variables, respectively. A harmonized database was delivered to MeDALL investigators. In asthma and allergy birth cohorts, the harmonization of data for pooled analyses is feasible, and high inferential comparability may be achieved. The MeDALL harmonization approach can be used in other collaborative projects.

While there is evidence for variations in prevalence rates of childhood wheeze and asthma between countries, longitudinal, individual-level data are needed to understand these differences. The aim of this study was to examine variations in prevalence rates of childhood asthma, wheeze and wheeze with asthma in Europe. We analysed datasets from 10 MeDALL (Mechanisms of the Development of ALLergy) cohorts in eight countries, representing 26 663 children, to calculate prevalence rates of wheeze and asthma by child age and wheeze with asthma at age 4 years. Harmonised variables included outcomes parent-reported wheeze and parent-reported doctor-diagnosed asthma, and covariates maternal education, parental smoking, pets, parental asthma, doctor-diagnosed allergic rhinitis, doctor-diagnosed eczema and wheeze severity. At age 4 years, asthma prevalence varied from 1.72% in Germany to 13.48% in England and the prevalence of wheeze varied from 9.82% in Greece to 55.37% in Spain. Adjusted estimates of the proportion of 4-year-old children with wheeze diagnosed with asthma remained highest in England (38.14%, 95% CI 31.38-44.90%) and lowest in Spain (15.94%, 95% CI 6.16-25.71%). The large differences in prevalence rates of asthma, wheeze and wheeze with asthma at age 4 years between European cohorts may indicate that childhood asthma is more readily diagnosed in some countries while going unrecognised elsewhere., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at openres.ersjournals.com

Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non-IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including in vivo and in vitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20 years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. A microarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), and transcriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4 years and 11,080 children aged 8 years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Previous published analyses have focused on the effect of air pollution on asthma and rhinoconjunctivitis throughout early and middle childhood. However, the role of exposure to air pollution in the development of childhood and adolescent asthma and rhinoconjunctivitis remains unclear. We aimed to assess the longitudinal associations between exposure to air pollution and development of asthma and rhinoconjunctivitis throughout childhood and adolescence., Methods: We did a population-based birth cohort study of 14 126 participants from four prospective birth cohort studies from Germany, Sweden, and the Netherlands with 14–16 years of follow-up. We linked repeated questionnaire reports of asthma and rhinoconjunctivitis with annual average air pollution concentrations (nitrogen dioxide [NO2], particulate matter [PM] with a diameter of less than 2·5 μm [PM2·5], less than 10 μm [PM10], and between 2·5 μm and 10 μm [PMcoarse], and PM2·5 absorbance [indicator of soot]) at the participants' home addresses. We analysed longitudinal associations of air pollution exposure at participants' birth addresses and addresses at the time of follow-up with asthma and rhinoconjunctivitis incidence and prevalence in cohort-specific analyses, with subsequent meta-analysis and pooled analyses., Findings: Overall, the risk of incident asthma up to age 14–16 years increased with increasing exposure to NO2 (adjusted meta-analysis odds ratio [OR] 1·13 per 10 μg/m3 [95% CI 1·02–1·25]) and PM2·5 absorbance (1·29 per 1 unit [1·00–1·66]) at the birth address. A similar, albeit non-significant, trend was shown for PM2·5 and incident asthma (meta-analysis OR 1·25 per 5 μg/m3 [95% CI 0·94–1·66]). These associations with asthma were more consistent after age 4 years than before that age. There was no indication of an adverse effect of air pollution on rhinoconjunctivitis., Interpretation: Exposure to air pollution early in life might contribute to the development of asthma throughout childhood and adolescence, particularly after age 4 years, when asthma can be more reliably diagnosed. Reductions in levels of air pollution could help to prevent the development of asthma in children., Funding: The European Union.

Mechanisms of the Development of Allergy (MeDALL), a Seventh Framework Program European Union project, aims to generate novel knowledge on the mechanisms of initiation of allergy. Precise phenotypes of IgE-mediated allergic diseases will be defined in MeDALL. As part of MeDALL, a scientific seminar was held on January 24, 2011, to review current knowledge on the IgE-related phenotypes and to explore how a multidisciplinary effort could result in a new integrative translational approach. This article provides a summary of the meeting. It develops challenges in IgE-related phenotypes and new clinical and epidemiologic approaches to the investigation of allergic phenotypes, including cluster analysis, scale-free models, candidate biomarkers, and IgE microarrays; the particular case of severe asthma was reviewed. Then novel approaches to the IgE-associated phenotypes are reviewed from the individual mechanisms to the systems, including epigenetics, human in vitro immunology, systems biology, and animal models. The last chapter deals with the understanding of the population-based IgE-associated phenotypes in children and adolescents, including age effect in terms of maturation, observed effects of early-life exposures and shift of focus from early life to pregnancy, gene-environment interactions, cohort effects, and time trends in patients with allergic diseases. This review helps to define phenotypes of allergic diseases in MeDALL., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

By using mass spectrometry, we have identified Ser 402 as a new phosphorylation site within the catalytic domain of human slingshot 1 (SSH1). Phosphorylation at this site inhibits substrate binding and, thus, phosphatase activity in vitro, resulting in enrichment of phosphorylated cofilin in monolayer cell culture. We further demonstrate that protein kinase D (PKD) is upstream from Ser 402 phosphorylation. Accordingly, expression of active PKD in Drosophila phenotypically mimics the loss of SSH activity by inducing accumulation of phosphorylated cofilin and filamentous actin. We thus identify a universal mechanism by which PKD controls SSH1 phosphatase activity.

Motivation: Childhood B-precursor lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Despite the fact that 80% of ALL patients respond to anti-cancer drugs, the patho-physiology of this disease is still not fully understood. mRNA expression-profiling studies that have been performed have not yet provided novel insights into the mechanisms behind cellular response to DNA damage. More powerful data analysis techniques may be required for identifying novel functional pathways involved in the cellular responses to DNA damage., Results: In order to explore the possibility that unforeseen biological processes may be involved in the response to DNA damage, we have developed and applied a novel procedure for the identification of functional modules in ALL cells. We have discovered that the overall activity of functional modules integrating protein degradation and mRNA processing is predictive of response to DNA damage., Availability: Supplementary material including R code, additional results, experimental datasets, as well as a detailed description of the methodology are available at http://www.bip.bham.ac.uk/vivo/fumo.html., Supplementary Information: Supplementary data are available at Bioinformatics online.

In this paper, we present the Functional Catalogue (FunCat), a hierarchically structured, organism-independent, flexible and scalable controlled classification system enabling the functional description of proteins from any organism. FunCat has been applied for the manual annotation of prokaryotes, fungi, plants and animals. We describe how FunCat is implemented as a highly efficient and robust tool for the manual and automatic annotation of genomic sequences. Owing to its hierarchical architecture, FunCat has also proved to be useful for many subsequent downstream bioinformatic applications. This is illustrated by the analysis of large-scale experiments from various investigations in transcriptomics and proteomics, where FunCat was used to project experimental data into functional units, as 'gold standard' for functional classification methods, and also served to compare the significance of different experimental methods. Over the last decade, the FunCat has been established as a robust and stable annotation scheme that offers both, meaningful and manageable functional classification as well as ease of perception.