A practical guide to mechanistic systems modeling in biology using a logic-based approach

Mechanistic computational models enable the study of regulatory mechanisms implicated in various biological processes. These models provide a means to analyze the dynamics of the systems they describe, and to study and interrogate their properties, and provide insights about the emerging behavior of the system in the presence of single or combined perturbations. Aimed at those who are new to computational modeling, we present here a practical hands-on protocol breaking down the process of mechanistic modeling of biological systems in a succession of precise steps. The protocol provides a framework that includes defining the model scope, choosing validation criteria, selecting the appropriate modeling approach, constructing a model and simulating the model. To ensure broad accessibility of the protocol, we use a logical modeling framework, which presents a lower mathematical barrier of entry, and two easy-to-use and popular modeling software tools: Cell Collective and GINsim. The complete modeling workflow is applied to a well-studied and familiar biological process—the lac operon regulatory system. The protocol can be completed by users with little to no prior computational modeling experience approximately within 3 h

Logical modelling of cellular decision processes with GINsim

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Building digital twins of the human immune system: toward a roadmap

Digital twins, customized simulation models pioneered in industry, are beginning to be deployed in medicine and healthcare, with some major successes, for instance in cardiovascular diagnostics and in insulin pump control. Personalized computational models are also assisting in applications ranging from drug development to treatment optimization. More advanced medical digital twins will be essential to making precision medicine a reality. Because the immune system plays an important role in such a wide range of diseases and health conditions, from fighting pathogens to autoimmune disorders, digital twins of the immune system will have an especially high impact. However, their development presents major challenges, stemming from the inherent complexity of the immune system and the difficulty of measuring many aspects of a patient’s immune state in vivo. This perspective outlines a roadmap for meeting these challenges and building a prototype of an immune digital twin. It is structured as a four-stage process that proceeds from a specification of a concrete use case to model constructions, personalization, and continued improvement

Addressing barriers in comprehensiveness, accessibility, reusability, interoperability and reproducibility of computational models in systems biology

Computational models are often employed in systems biology to study the dynamic behaviours of complex systems. With the rise in the number of computational models, finding ways to improve the reusability of these models and their ability to reproduce virtual experiments becomes critical. Correct and effective model annotation in community-supported and standardised formats is necessary for this improvement. Here,we present recent efforts toward a common framework for annotated, accessible, reproducible and interoperable computational models in biology, and discuss key challenges of the field. Scientists from different systems biology fields have long been developing community-driven guidelines and best practices for annotation, interoperability and reusability of computational models in biology. However, the parallel work, grounded on shared needs and similar aims, of separate communities creates a need for exchange and alignment of the different efforts to harmonise best practices. Hence, members of the Consortium for Logical Models and Tools (CoLoMoTo, http://colomoto.org) and the Computational Modelling of Biological Systems community of the International Society for Computational Biology (SysMod, https:// sysmod.info/) organised aworkshop to discusscommunitydriven guidelines and efforts for the curation and annotation of computational models during [BC]2 2021. The workshop grew from a previous edition organised during [BC]2 2019 focused on logical modelling [1]. The second edition brought together scientists with various research backgrounds and from different working groups such as BioModels [2], a central repository of mathematical models of biological/biomedical processes; the Computational Modelling in Biology Network initiative (COMBINE) [3]; CoLoMoTo, [4]; SysMod, [5]; the Systems Biology Graphical Notation (SBGN) project [6]; the systems biology markup language (SBML) [7] and simulation experiment description markup language (SED-ML) [8], to exchange and expand on several key topics of common interest (Figure 1). While the modelling approaches across these communities differ, several critical points are shared, such as (i) the importance of annotations for reproducibility, (ii) the use of community standards for exchange and annotation encoding, (iii) the need to implement standards in tools and platforms to boost reusability and interoperability, (iv) the importance of transparency of modelling frameworks in publications and (v) the use of shared repositories to enhance model accessibility (Figure 2). We use the term annotation to describe ‘a computeraccessible metadata item that captures, entirely or in part, the meaning of a model, model component or data element’. We borrow this definition from [9] which is in accordance with its use in [1]. We discuss the identified needs in the following sections

Setting the basis of best practices and standards for curation and annotation of logical models in biology

International audienceThe fast accumulation of biological data calls for their integration, analysis and exploitation through more systematic approaches. The generation of novel, relevant hypotheses from this enormous quantity of data remains challenging. Logical models have long been used to answer a variety of questions regarding the dynamical behaviours of regulatory networks. As the number of published logical models increases, there is a pressing need for systematic model annotation, referencing and curation in community-supported and standardised formats. This article summarises the key topics and future directions of a meeting entitled ‘Annotation and curation of computational models in biology’, organised as part of the 2019 [BC]2 conference. The purpose of the meeting was to develop and drive forward a plan towards the standardised annotation of logical models, review and connect various ongoing projects of experts from different communities involved in the modelling and annotation of molecular biological entities, interactions, pathways and models. This article defines a roadmap towards the annotation and curation of logical models, including milestones for best practices and minimum standard requirements

COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.

Funder: Bundesministerium für Bildung und ForschungFunder: Bundesministerium für Bildung und Forschung (BMBF)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

Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches

IntroductionThe 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. MethodsExtensive 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.ResultsResults 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. DiscussionThe 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

Study of the soluble form of membrane type1 matrix metalloproteinase from periprosthetic tissues of loose arthroplasty endoprostheses: effect of protein and map kinases inhibitors on its production as well as on the production of other metalloproteinases in periprosthetic tissues

The knee or hip arthroplasty endoprostheses loosening is a result of periprosthetic osteolysis caused from various factors (cytokines, enzymes etc) which are secreted from the cells occurred in periprosthetic tissues because of foreign-body reaction evoked from the fragmentation and wear of the implanted materials. It is a non inflammatory disorder that resembles to osteoarthritis. Among the factors which are implicated in the endoprostheses loosening, the extracellular matrix metalloproteinases (MMPs) are included. MMPs play an important role in the degradation of extracellular matrix and basal membrane. They are involved in normal physiological processes, such as tissue remodeling and wound healing, as well as in pathological processes such as osteolysis, tumor metastasis, periodontitis, rheumatoid arthritis etc.In the present study, a soluble type of MT1-MMP (sΜΤ1-ΜΜΡ) was investigated, in periprosthetic tissues extracts and tissue extracts from patients with various lung diseases and nasal polyposis as well. Various methods such as, western blot analysis, ELISA, immunoprecipitation, gelatin zymography, fluorometric assay, immunohistochemical analysis, RT-PCR and Northern blot analysis, were used. sΜΤ1-ΜΜΡ (57 kDa) was detected in all samples tested. This soluble type cannot form complexes with α2-macroglobulin, carries the propeptide domain and TIMP-2 which is not bound to the active site of the enzyme. ΑΡΜΑ and urokinase were not able to remove the propeptide region of sΜΤ1-ΜΜΡ. This detectable sΜΤ1-ΜΜΡ cannot be ascribed to alternative splicing. The immunohistochemical analysis revealed that ΜΤ1-ΜΜΡ is expressed in an activated form on the cell surface only in fibroblasts, whereas in all other cell types such as inflammatory cells, epithelial, endothelial and giant cells is expressed in the proenzyme form, carrying the propeptide domain. The production process of sΜΤ1-ΜΜΡ as well as its biological role remains for investigation.Endoprostheses loosening usually observed 8-10 years after the primary arthroplasty operation. In this case the surgical revision of arthroplasty is needed, a painful operation for old individuals, the most of patients which have been subjected in arthroplasty Thus today, the retardation of arthroplasty endoprostheses loosening by a pharmacologic treatment is considered of important significance. The protein and MAP kinases are considered key enzymes in cellular signaling and activation of various transcription factors, and are implicated in several pathologic processes. Their inhibitors are currently used in clinical trials. In order to approach the question whether protein and MAP kinases inhibitors would contribute in the endoprostheses loosening retardation, periprosthetic tissues were cultured in the absence and presence of protein and MAP kinases inhibitors and in the culture conditioned medium, the levels of factors which play a significant role in endoprostheses loosening, such as metalloproteinases and their inhibitors (sΜΤ1-ΜΜΡ, MMP-1, ΜΜΡ-2, ΜΜΡ-9, MMP-13 & TIMP-1), IL-6 και PGE2 were determined. Western blot analysis, ELISA and gelatin zymography were used for the determinations. In general, the inhibitors caused a decrease in the levels of the factors that were studied or had no effect at all. In some cases, even an increase was observed. However, in order to state safe conclusions, in respect to the ability of such inhibitors to retard the endoprostheses loosening, more experiments are needed with a larger cohort of patients.Η χαλάρωση των τεχνητών προθέσεων αρθροπλαστικών γόνατος ή ισχίου, αποτέλεσμα περιπροσθετικής οστεόλυσης που προκαλείται από διάφορους παράγοντες (κυτταροκίνες, ένζυμα κ.ά) που εκκρίνονται από κύτταρα των περιπροσθετικών ιστών λόγω αντίδρασης ξένου σώματος με τα υλικά φθοράς των τεχνικών προθέσεων, είναι μία μη-φλεγμονώδης πάθηση που προσομοιάζει της οστεοαρθρίτιδας. Μεταξύ των παραγόντων που εμπλέκονται στη χαλάρωση των προθέσεων συγκαταλέγονται και οι μεταλλοπρωτεάσες του εξωκυττάριου χώρου (ΜΜΡs). Οι ΜΜΡs παίζουν σημαντικό ρόλο στην αποικοδόμηση του εξωκυττάριου υλικού και της βασικής μεμβράνης. Εμπλέκονται τόσο σε φυσιολογικές (ανάπλαση ιστών, επούλωση τραυμάτων) όσο και σε παθολογικές (οστεόλυση, μετάσταση καρκινικών κυττάρων, περιοδοντίτιδα, ρευματοειδή αρθρίτιδα, κ.ά.) διαδικασίες. Στην παρούσα διατριβή μελετήθηκε ένας διαλυτός τύπος της μεμβρανικής μεταλλοπρωτεάσης-1 (sΜΤ1-ΜΜΡ) σε εκχυλίσματα περιπροσθετικών ιστών, πνευμονικών ιστών από ασθενείς με διάφορες παθήσεις των πνευμόνων καθώς και σε εκχυλίσματα πολύποδα ασθενών με ρινική πολυποδίαση. Χρησιμοποιήθηκαν διάφορες μέθοδοι, όπως ανοσοαποτύπωση western, ELISA, ανοσοκατακρήμνιση, ζυμογράφημα ζελατίνης, φθορισμομετρία, ανασοϊστοχημεία, RT-PCR και αποτύπωση Northern. H sΜΤ1-ΜΜΡ (57 kDa) ανιχνεύθηκε σε όλα τα δείγματα που εξετάστηκαν. Ο διαλυτός αυτός τύπος δεν συμπλοκοποιείται με α2-μακροσφαιρίνη, φέρει την περιοχή του προπεπτιδίου αλλά και ΤΙΜΡ-2, ο οποίος όμως δεν είναι δεσμευμένος στο ενεργό κέντρο του ενζύμου. Τόσο το ΑΡΜΑ όσο και η ουροκινάση δεν είχαν την ικανότητα απομάκρυνσης του προπεπτιδίου της sΜΤ1-ΜΜΡ. Η ύπαρξη της sΜΤ1-ΜΜΡ δεν φαίνεται να οφείλεται σε εναλλακτικό μάτισμα. Η ανοσοϊστοχημική ανάλυση έδειξε ότι η μεμβρανική μεταλλοπρωτεάση ΜΤ1-ΜΜΡ εκφράζεται στην κυτταρική μεμβράνη ενεργοποιημένη μόνο στις ινοβλάστες, ενώ σε όλα τα υπόλοιπα κύτταρα, όπως φλεγμονώδη, επιθηλιακά, ενδοθηλιακά και γιγαντοκύτταρα εκφράζεται στη μορφή του προενζύμου με το προπεπτίδιο. Ο τρόπος παραγωγής της sΜΤ1-ΜΜΡ όπως και ο βιολογικός της ρόλος παραμένουν πρός διερεύνηση. Χαλάρωση των προθέσεων παρατηρείται συνήθως μετά από 8-10 χρόνια από την πρώτη αρθροπλαστική και τότε απαιτείται αναθεώρηση της αρθροπλαστικής, επέμβαση επώδυνη για άτομα μεγάλης ηλικίας που είναι η πλειονότητα αυτών που έχουν υποβληθεί σε αρθροπλαστική. Είναι λοιπόν σήμερα ζητούμενο η καθυστέρηση της χαλάρωσης και η παράταση της ζωής των προθέσεων με κάποια φαρμακευτική αγωγή. Οι πρωτεϊνικές και οι ΜΑΡ κινάσες θεωρούνται κομβικά ένζυμα στη κυτταρική σηματοδότηση και στην ενεργοποίηση ποικίλων μεταγραφικών παραγόντων, και εμπλέκονται σε διάφορες παθολογικές καταστάσεις. Αναστολείς των ενζύμων αυτών βρίσκονται σήμερα σε διάφορες κλινικές δοκιμές. Για την προσέγγιση του ερωτήματος κατά πόσο αναστολείς των πρωτεϊνικών και ΜΑΡ κινασών θα μπορούσαν να συμβάλλουν στην επιμήκηνση του χρόνου ζωής των προθέσεων αρθροπλαστικής, περιπροσθετικοί ιστοί καλλιεργήθηκαν παρουσία και απουσία αναστολέων των ενζύμων αυτών και στο μέσο καλλιέργειας προσδιορίσθηκαν τα επίπεδα παραγόντων με σημαντικό ρόλο στη χαλάρωση των προθέσεων, όπως μεταλλοπρωτεασών και των αναστολέων τους (sΜΤ1-ΜΜΡ, MMP-1, ΜΜΡ-2, ΜΜΡ-9, MMP-13 & TIMP-1), IL-6 και PGE2. Χρησιμοποιήθηκαν μέθοδοι όπως, ανοσοαποτύπωση western, ELISA, και ζυμογράφημα ζελατίνης. Τα πειράματα έδειξαν ότι σε γενικές γραμμές οι αναστολείς προκάλεσαν κυρίως μείωση ή δεν επηρέασαν την παραγωγή των παραγόντων που μελετήθηκαν σε κάποιες όμως περιπτώσεις προκάλεσαν και αύξηση της παραγωγής τους. Για τη διατύπωση όμως ασφαλών συμπερασμάτων σχετικά με το κατά πόσο τέτοιοι αναστολείς θα μπορούσαν να συμβάλλουν στην επιμήκυνση του χρόνου ζωής των προθέσεων, απαιτούνται περαιτέρω πειράματα με μεγαλύτερο αριθμό ασθενών

Data integration in logic-based models of biological mechanisms

International audienceDiscrete, logic-based models are increasingly used to describe biological mechanisms. Initially introduced to study gene regulation, these models evolved to cover various molecular mechanisms, such as signaling, transcription factor cooperativity, and even metabolic processes. The abstract nature and amenability of discrete models to robust mathematical analyses make them appropriate for addressing a wide range of complex biological problems. Recent technological breakthroughs have generated a wealth of high-throughput data. Novel, literature-based representations of biological processes and emerging algorithms offer new opportunities for model construction. Here, we review up-to-date efforts to address challenging biological questions by incorporating omic data into logic-based models and discuss critical difficulties in constructing and analyzing integrative, large-scale, logicbased models of biological mechanisms

Activating and Inhibitory Receptors on Mast Cells

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