Utilising a simulation platform to understand the effect of domain model assumptions

© The Author(s) 2014. This article is published with open access at Springerlink.com. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Computational and mathematical modelling approaches are increasingly being adopted in attempts to further our understanding of complex biological systems. This approach can be subjected to strong criticism as substantial aspects of the biological system being captured are not currently known, meaning assumptions need to be made that could have a critical impact on simulation response. We have utilised the CoSMoS process in the development of an agent-based simulation of the formation of Peyer's patches (PP), gut-associated lymphoid organs that have a key role in the initiation of adaptive immune responses to infection. Although the use of genetic tools, imaging technologies and ex vivo culture systems has provided significant insight into the cellular components and associated pathways involved in PP development, interesting questions remain that cannot be addressed using these approaches, and as such well justified assumptions have been introduced into our model to counter this. Here we focus not on the development of the model itself, but instead demonstrate how the resultant simulation can be used to assess how these assumptions impact the simulation response. For example, we consider the impact of our assumption that the migration rate of lymphoid tissue cells into the gut remains constant throughout PP development. We demonstrate that an analysis of the assumptions made in the construction of the domain model may either increase confidence in the model as a representation of the biological system it captures, or may suggest areas where further biological experimentation is required.This work was funded by the Wellcome Trust [ref:097829] through the Centre for Chronic Diseases and Disorders (C2D2) at the University of York. Paul Andrews is funded by EPSRC grant EP/I005943/1 “Resilient Futures.” Henrique Veiga-Fernandes is funded by Fundação para a Ciência e Tecnologia (PTDC/SAU-MII/100016/2008), Portugal, European Molecular Biology Organisation (Project 1648) and European Research Council (Project 207057). Jon Timmis is part funded by the Royal Society and the Royal Academy of Engineering. Funding for Mark Coles comes from grants from the Human Frontiers Science Program (RGP0006/2009) and the Medical Research Council (G0601156).info:eu-repo/semantics/publishedVersio

O VOTO E A DECISÃO DO VOTO EM SANTO ANTÔNIO DO PARAÍSO (PR)

VOTE AND DECISION OF THE VOTE IN SANTO ANTÔNIO DO PARAÍSO (PR)VOTO Y DECISIÓN DE VOTO EN SANTO ANTÔNIO DO PARAÍSO (PR)RESUMOA decisão do voto e as conjunturas que influenciam essa decisão são de fundamental relevância na escolha dos candidatos nas eleições municipais e, por conseguinte, no futuro da sociedade local, sobretudo quanto às políticas públicas. Sendo assim, este trabalho tem como objetivo compreender a Geografia Eleitoral e do Voto no município de Santo Antônio do Paraíso, no Norte do Estado do Paraná, particularmente, por meio do entendimento e da análise da decisão do voto dos eleitores. Diante disso, foram utilizados como procedimentos metodológicos: levantamento bibliográfico sobre o tema; levantamento de dados, principalmente de eleitores do município; aplicação de questionários nos habitantes locais; elaboração de material cartográfico, como figuras, mapas, tabelas e gráficos; e, por fim, sistematização das informações na redação final do artigo. Os resultados demonstram que os respondentes reconhecem a importância da decisão do voto e pesquisam sobre a vida do candidato e sobre as suas propostas para o município. Além disso, a maioria dos respondentes considerou que o principal critério que buscam no candidato é a honestidade para exercer esse tipo de cargo público.Palavras chave: Geografia Política; Geografia Eleitoral; Geografia do Voto; Norte do Paraná.ABSTRACTThe decision of the vote and the conjunctures that influence this decision are of fundamental relevance in the choice of candidates in municipal elections and, therefore, in the future of local society, especially about public policies. Thus, this study aims to comprehend the Electoral and Vote Geography in Santo Antônio do Paraíso, north of the state of Paraná, particularly, through the understanding and analysis the voters' voting decision. The following methodological procedures: bibliographic survey about the subject; data collection, mainly of voters, in the municipality; application of questionnaires in the local inhabitants; elaboration of cartographic material, such as figures, maps, tables and graphs; and systematization of information in the final writing of this paper. The results show that the respondents of the local population recognize the importance of the decision of the vote, being that they investigate the life of the candidate and his proposals for the municipality. In addition, most respondents considered that the main criterion they seek in a candidate is honesty to exercise an elected public office.Keywords: Political Geography; Electoral Geography; Vote Geography; North of Paraná.RESUMENLa decisión de votar y las circunstancias que influyen en esta decisión son de fundamental importancia en la elección de candidatos en las elecciones municipales y, por tanto, en el futuro de la sociedad local, especialmente en materia de políticas públicas. Así, este trabajo tiene como objetivo comprender la Geografía Electoral y del Voto en el municipio de Santo Antônio do Paraíso, en el Norte del Estado de Paraná, en particular, a través de la comprensión y análisis de la decisión de voto de los votantes. Por tanto, se utilizaron los siguientes procedimientos metodológicos: levantamiento bibliográfico sobre el tema; recolección de datos, principalmente de votantes del municipio; aplicación de cuestionarios a los habitantes locales; elaboración de material cartográfico, como figuras, mapas, tablas y gráficos; y, finalmente, sistematización de la información en la redacción final del artículo. Los resultados demuestran que los encuestados reconocen la importancia de la decisión del voto e investigan la vida del candidato y sus propuestas para el municipio. Además, la mayoría de los encuestados consideró que el principal criterio que buscan en el candidato es la honestidad para ejercer este tipo de cargos públicos.Palabras clave: Geografía política; Geografía electoral; Geografía del Voto; Norte de Paraná

IL-9 expression by invariant NKT cells is not imprinted during thymic development

Copyright © 2015 by The American Association of Immunologists, Inc. All rights reservedInvariant NKT (iNKT) cell thymic development can lead to distinct committed effector lineages, namely NKT1, NKT2, and NKT17. However, following identification of IL-9-producing iNKT cells involved in mucosal inflammation, their development remains unaddressed. In this study, we report that although thymic iNKT cells from naive mice do not express IL-9, iNKT cell activation in the presence of TGF-β and IL-4 induces IL-9 secretion in murine and human iNKT cells. Acquisition of IL-9 production was observed in different iNKT subsets defined by CD4, NK1.1, and neuropilin-1, indicating that distinct functional subpopulations are receptive to IL-9 polarization. Transcription factor expression kinetics suggest that regulatory mechanisms of IL-9 expression are shared by iNKT and CD4 T cells, with Irf4 and Batf deficiency deeply affecting IL-9 production. Importantly, adoptive transfer of an enriched IL-9(+) iNKT cell population leads to exacerbated allergic inflammation in the airways upon intranasal immunization with house dust mite, confirming the ability of IL-9-producing iNKT cells to mediate proinflammatory effects in vivo, as previously reported. Taken together, our data show that peripheral iNKT cells retain the capacity of shaping their function in response to environmental cues, namely TGF-β and IL-4, adopting an IL-9-producing NKT cell phenotype able to mediate proinflammatory effects in vivo, namely granulocyte and mast cell recruitment to the lungs.This work was supported by Fundação Para a Ciência e Tecnologia, Portugal Grants PTDC/SAU-TOX/114424/2009 and HMSP-ICT/0034/2013 and the Novo Nordisk/European Foundation for the Study of Diabetes (to L.G.), as well as by grants from the Fundação Para a Ciência e Tecnologia, Portugal, the European Molecular Biology Organization, the European Research Council, and the U.S. National Blood Foundation (to H.V.-F.). A.A.-D., C.F.A., D.F.-P., and M.M. were supported by fellowships from the Fundação Para a Ciência e Tecnologia, Portugal.info:eu-repo/semantics/publishedVersio

Contribution of neural crest-derived cells in the embryonic and adult thymus

Abstract Neural crest (NC)-derived mesenchyme has previously been shown to play an important role in the development of fetal thymus. Using Wnt1-Cre and Sox10-Cre mice crossed to Rosa26eYfp reporter mice, we have revealed NC-derived mesenchymal cells in the adult murine thymus. We report that NC-derived cells infiltrate the thymus before day 13.5 of embryonic development (E13.5) and differentiate into cells with characteristics of smooth muscle cells associated with large vessels, and pericytes associated with capillaries. In the adult organ at 3 mo of age, these NC-derived perivascular cells continue to be associated with the vasculature, providing structural support to the blood vessels and possibly regulating endothelial cell function.</jats:p

Position effect variegation and imprinting of transgenes in lymphocytes

Sequences proximal to transgene integration sites are able to deregulate transgene expression resulting in complex position effect phenotypes. In addition, transgenes integrated as repeated arrays are susceptible to repeat-induced gene silencing. Using a Cre recombinase-based system we have addressed the influence of transgene copy number (CN) on expression of hCD2 transgenes. CN reduction resulted in a decrease, increase or no effect on variegation depending upon the site of integration. This finding argues that repeat-induced gene silencing is not the principle cause of hCD2 transgene variegation. These results also suggest that having more transgene copies can be beneficial at some integration sites. The transgenic lines examined in this report also exhibited a form of imprinting, which was manifested by decreased levels of expression and increased levels of variegation, upon maternal transmission; and this correlated with DNA hypermethylation and a reduction in epigenetic chromatin modifications normally associated with active genes

Extending and Applying Spartan to Perform Temporal Sensitivity Analyses for Predicting Changes in Influential Biological Pathways in Computational Models

Through integrating real time imaging, computational modelling, and statistical analysis approaches, previous work has suggested that the induction of and response to cell adhesion factors is the key initiating pathway in early lymphoid tissue development, in contrast to the previously accepted view that the process is triggered by chemokine mediated cell recruitment. These model derived hypotheses were developed using spartan, an open-source sensitivity analysis toolkit designed to establish and understand the relationship between a computational model and the biological system that model captures. Here, we extend the functionality available in spartan to permit the production of statistical analyses that contrast the behavior exhibited by a computational model at various simulated time-points, enabling a temporal analysis that could suggest whether the influence of biological mechanisms changes over time. We exemplify this extended functionality by using the computational model of lymphoid tissue development as a time-lapse tool. By generating results at twelve- hour intervals, we show how the extensions to spartan have been used to suggest that lymphoid tissue development could be biphasic, and predict the time-point when a switch in the influence of biological mechanisms might occur

Natural killer receptors: the burden of a name

A population of cells that expresses the NK cell receptor NKp46 and produces interleukin (IL)-22 have recently attracted considerable attention. The identity of these cells is still the subject of speculation, being variably defined as a novel NK cell subset or as a population containing conventional NK (cNK) cell precursors. In this issue, two studies shed light on this conundrum, demonstrating that NKp46+ IL-22+ cells and cNK cells belong to distinct lineages

Damage-responsive neuro-glial clusters coordinate the recruitment of dormant neural stem cells in Drosophila.

Recruitment of stem cells is crucial for tissue repair. Although stem cell niches can provide important signals, little is known about mechanisms that coordinate the engagement of disseminated stem cells across an injured tissue. In Drosophila, adult brain lesions trigger local recruitment of scattered dormant neural stem cells suggesting a mechanism for creating a transient stem cell activation zone. Here, we find that injury triggers a coordinated response in neuro-glial clusters that promotes the spread of a neuron-derived stem cell factor via glial secretion of the lipocalin-like transporter Swim. Strikingly, swim is induced in a Hif1-α-dependent manner in response to brain hypoxia. Mammalian Swim (Lcn7) is also upregulated in glia of the mouse hippocampus upon brain injury. Our results identify a central role of neuro-glial clusters in promoting neural stem cell activation at a distance, suggesting a conserved function of the HIF1-α/Swim/Wnt module in connecting injury-sensing and regenerative outcomes

Using argument notation to engineer biological simulations with increased confidence

The application of computational and mathematical modelling to explore the mechanics of biological systems is becoming prevalent. To significantly impact biological research, notably in developing novel therapeutics, it is critical that the model adequately represents the captured system. Confidence in adopting in silico approaches can be improved by applying a structured argumentation approach, alongside model development and results analysis. We propose an approach based on argumentation from safety-critical systems engineering, where a system is subjected to a stringent analysis of compliance against identified criteria. We show its use in examining the biological information upon which a model is based, identifying model strengths, highlighting areas requiring additional biological experimentation and providing documentation to support model publication. We demonstrate our use of structured argumentation in the development of a model of lymphoid tissue formation, specifically Peyer's Patches. The argumentation structure is captured using Artoo (www.york.ac.uk/ycil/software/artoo), our Web-based tool for constructing fitness-for-purpose arguments, using a notation based on the safety-critical goal structuring notation. We show how argumentation helps in making the design and structured analysis of a model transparent, capturing the reasoning behind the inclusion or exclusion of each biological feature and recording assumptions, as well as pointing to evidence supporting model-derived conclusions