An overview of the CellML API and its implementation

<p>Abstract</p> <p>Background</p> <p>CellML is an XML based language for representing mathematical models, in a machine-independent form which is suitable for their exchange between different authors, and for archival in a model repository. Allowing for the exchange and archival of models in a computer readable form is a key strategic goal in bioinformatics, because of the associated improvements in scientific record accuracy, the faster iterative process of scientific development, and the ability to combine models into large integrative models.</p> <p>However, for CellML models to be useful, tools which can process them correctly are needed. Due to some of the more complex features present in CellML models, such as imports, developing code <it>ab initio </it>to correctly process models can be an onerous task. For this reason, there is a clear and pressing need for an application programming interface (API), and a good implementation of that API, upon which tools can base their support for CellML.</p> <p>Results</p> <p>We developed an API which allows the information in CellML models to be retrieved and/or modified. We also developed a series of optional extension APIs, for tasks such as simplifying the handling of connections between variables, dealing with physical units, validating models, and translating models into different procedural languages.</p> <p>We have also provided a Free/Open Source implementation of this application programming interface, optimised to achieve good performance.</p> <p>Conclusions</p> <p>Tools have been developed using the API which are mature enough for widespread use. The API has the potential to accelerate the development of additional tools capable of processing CellML, and ultimately lead to an increased level of sharing of mathematical model descriptions.</p

Revision history aware repositories of computational models of biological systems

<p>Abstract</p> <p>Background</p> <p>Building repositories of computational models of biological systems ensures that published models are available for both education and further research, and can provide a source of smaller, previously verified models to integrate into a larger model.</p> <p>One problem with earlier repositories has been the limitations in facilities to record the revision history of models. Often, these facilities are limited to a linear series of versions which were deposited in the repository. This is problematic for several reasons. Firstly, there are many instances in the history of biological systems modelling where an 'ancestral' model is modified by different groups to create many different models. With a linear series of versions, if the changes made to one model are merged into another model, the merge appears as a single item in the history. This hides useful revision history information, and also makes further merges much more difficult, as there is no record of which changes have or have not already been merged. In addition, a long series of individual changes made outside of the repository are also all merged into a single revision when they are put back into the repository, making it difficult to separate out individual changes. Furthermore, many earlier repositories only retain the revision history of individual files, rather than of a group of files. This is an important limitation to overcome, because some types of models, such as CellML 1.1 models, can be developed as a collection of modules, each in a separate file.</p> <p>The need for revision history is widely recognised for computer software, and a lot of work has gone into developing version control systems and distributed version control systems (DVCSs) for tracking the revision history. However, to date, there has been no published research on how DVCSs can be applied to repositories of computational models of biological systems.</p> <p>Results</p> <p>We have extended the Physiome Model Repository software to be fully revision history aware, by building it on top of Mercurial, an existing DVCS. We have demonstrated the utility of this approach, when used in conjunction with the model composition facilities in CellML, to build and understand more complex models. We have also demonstrated the ability of the repository software to present version history to casual users over the web, and to highlight specific versions which are likely to be useful to users.</p> <p>Conclusions</p> <p>Providing facilities for maintaining and using revision history information is an important part of building a useful repository of computational models, as this information is useful both for understanding the source of and justification for parts of a model, and to facilitate automated processes such as merges. The availability of fully revision history aware repositories, and associated tools, will therefore be of significant benefit to the community.</p

CellML metadata standards, associated tools and repositories

The development of standards for encoding mathematical models is an important component of model building and model sharing among scientists interested in understanding multi-scale physiological processes. CellML provides such a standard, particularly for models based on biophysical mechanisms, and a substantial number of models are now available in the CellML Model Repository. However, there is an urgent need to extend the current CellML metadata standard to provide biological and biophysical annotation of the models in order to facilitate model sharing, automated model reduction and connection to biological databases. This paper gives a broad overview of a number of new developments on CellML metadata and provides links to further methodological details available from the CellML website

Peptide Bβ15-42 Preserves Endothelial Barrier Function in Shock

Loss of vascular barrier function causes leak of fluid and proteins into tissues, extensive leak leads to shock and death. Barriers are largely formed by endothelial cell-cell contacts built up by VE-cadherin and are under the control of RhoGTPases. Here we show that a natural plasmin digest product of fibrin, peptide Bß15-42 (also called FX06), significantly reduces vascular leak and mortality in animal models for Dengue shock syndrome. The ability of Bß15-42 to preserve endothelial barriers is confirmed in rats i.v.-injected with LPS. In endothelial cells, Bß15-42 prevents thrombin-induced stress fiber formation, myosin light chain phosphorylation and RhoA activation. The molecular key for the protective effect of Bß15-42 is the src kinase Fyn, which associates with VE-cadherin-containing junctions. Following exposure to Bß15-42 Fyn dissociates from VE-cadherin and associates with p190RhoGAP, a known antagonists of RhoA activation. The role of Fyn in transducing effects of Bß15-42 is confirmed in Fyn−/− mice, where the peptide is unable to reduce LPS-induced lung edema, whereas in wild type littermates the peptide significantly reduces leak. Our results demonstrate a novel function for Bß15-42. Formerly mainly considered as a degradation product occurring after fibrin inactivation, it has now to be considered as a signaling molecule. It stabilizes endothelial barriers and thus could be an attractive adjuvant in the treatment of shock

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

Is close radiographic and clinical control after repair of acute type A aortic dissection really necessary for improved long-term survival?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether radiographic and clinical control after surgery for acute type A aortic dissection (AAD) is needed for improved long-term survival. Altogether, 118 relevant papers were identified using the reported search, of which seven represented the best evidence to answer the question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that most patients after surgery for AAD remain at risk for dissection-related aortic complications. Late aortic growth is often slow and linear, but the occurrence of major aortic events is unpredictable and can initially present more than a decade postoperatively. Risk factors for rapid late aortic enlargement and reoperations include patent or partially thrombosed false lumen, large aortic size, Marfan syndrome and younger age. Whether performing a more extensive first procedure (e.g. aortic arch replacement±elephant trunk) can be translated into improved outcome and a lower incidence of aorta-related reoperations remains to be elucidated. Aortic reoperation rates range between 10% and 120 mmHg), including ?-blocker therapy, seems to decrease late aortic dilatation and the incidence of aortic reoperations. Close and careful lifelong surveillance of patients after AAD repair including radiographic and clinical controls to evaluate the status of the remaining aorta, and thus to facilitate adaptations of medical therapy and planning of timely reprocedures seems mandatory for improved long-term survival. A suggested timeframe for computed tomographic (CT) imaging after surgery for AAD is before discharge, at six and 12 months postdissection and, if stable, annually thereafter. Patients with large aneurysms (aortic diameter?50 mm) should be maintained at radiographic intervals of six months or less. If the thoracic aneurysm is moderate in size and remains stable over time, magnetic resonance imaging instead of CT-scanning is reasonable to minimize the patient's radiation exposure

The CellML 1.1 Specification

This document specifies CellML 1.1, an XML-based language for describing and exchanging models of cellular and subcellular processes. MathML embedded in CellML documents is used to define the underlying mathematics of models. Models consist of a network of re- usable components, each with variables and equations manipulating those variables. Models may import other models to create systems of increasing complexity. Metadata may be embedded in CellML documents using RDF