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MOTIVATION: While there are software packages that analyze Boolean, ternary, or other multi-state models, none compute the complete state space of function-based models over any finite set. Results: We propose Cyclone, a simple light-weight software package which simulates the complete state space for a finite dynamical system over any finite set. AVAILABILITY AND IMPLEMENTATION: Source code is freely available at https://github.com/discretedynamics/cyclone under the Apache-2.0 license.
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Tormentas Ciclónicas , Simulación por Computador , Programas InformáticosRESUMEN
SUMMARY: We introduce SteadyCellPhenotype, a browser-based interface for the analysis of ternary biological networks. It includes tools for deterministically finding all steady states of a network, as well as the simulation and visualization of trajectories with publication quality graphics. Simulations allow us to approximate the size of the basin for attractors and deterministic simulations of trajectories nearby specified points allow us to explore the behavior of the system in that neighborhood. AVAILABILITY AND IMPLEMENTATION: https://github.com/knappa/steadycellphenotype MIT License.
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Internet , Programas Informáticos , Simulación por ComputadorRESUMEN
The abundance of actionable information available in a medicolegal suicide investigation is often inaccessible and underutilized in public health to the detriment of prevention efforts. Epidemiologists obtained the Washington County subset of the Oregon Violent Death Reporting System (OR-VDRS). To determine if additional information beyond the OR-VDRS was available through a standard death investigation, an epidemiologist shadowed medicolegal death investigators (MDIs) for nearly 2 years. The MDIs and epidemiologist developed a novel, real-time, MDI-entered surveillance system, the Suicide Risk Factor Surveillance System (SRFSS), to capture suicide risk factor data with greater timeliness and accuracy than available through the OR-VDRS. To evaluate the performance of each surveillance system, differences in the prevalence of suicide risk factor data from SRFSS were compared with the county OR-VDRS subset for the same 133 suicides occurring in 2014-2015. Across 27 suicide risk factors and circumstances, the median difference in prevalence was 10.5 percentage points between the OR-VDRS and the SRFSS, with the higher prevalence in SRFSS. The prevalence was significantly different between the 2 surveillance systems for 21 (78%) of 27 variables. This study demonstrates the truly exceptional data quality and timeliness of MDI information over traditional sources.
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Vigilancia de la Población , Suicidio/estadística & datos numéricos , Violencia/estadística & datos numéricos , Heridas y Lesiones/mortalidad , Recolección de Datos , Bases de Datos Factuales , Humanos , Almacenamiento y Recuperación de la Información , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
Aspergillus species are ubiquitous environmental moulds, with spores inhaled daily by most humans. Immunocompromised hosts can develop an invasive infection resulting in high mortality. There is, therefore, a pressing need for host-centric therapeutics for this infection. To address it, we created a multi-scale computational model of the infection, focused on its interaction with the innate immune system and iron, a critical nutrient for the pathogen. The model, parameterized using published data, was found to recapitulate a wide range of biological features and was experimentally validated in vivo. Conidial swelling was identified as critical in fungal strains with high growth, whereas the siderophore secretion rate seems to be an essential prerequisite for the establishment of the infection in low-growth strains. In immunocompetent hosts, high growth, high swelling probability and impaired leucocyte activation lead to a high conidial germination rate. Similarly, in neutropenic hosts, high fungal growth was achieved through synergy between high growth rate, high swelling probability, slow leucocyte activation and high siderophore secretion. In summary, the model reveals a small set of parameters related to fungal growth, iron acquisition and leucocyte activation as critical determinants of the fate of the infection.
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Aspergilosis , Aspergillus fumigatus , Aspergilosis/microbiología , Humanos , Hierro , Sideróforos , Esporas FúngicasRESUMEN
Iron is essential to the virulence of Aspergillus species, and restricting iron availability is a critical mechanism of antimicrobial host defense. Macrophages recruited to the site of infection are at the crux of this process, employing multiple intersecting mechanisms to orchestrate iron sequestration from pathogens. To gain an integrated understanding of how this is achieved in aspergillosis, we generated a transcriptomic time series of the response of human monocyte-derived macrophages to Aspergillus and used this and the available literature to construct a mechanistic computational model of iron handling of macrophages during this infection. We found an overwhelming macrophage response beginning 2 to 4 h after exposure to the fungus, which included upregulated transcription of iron import proteins transferrin receptor-1, divalent metal transporter-1, and ZIP family transporters, and downregulated transcription of the iron exporter ferroportin. The computational model, based on a discrete dynamical systems framework, consisted of 21 3-state nodes, and was validated with additional experimental data that were not used in model generation. The model accurately captures the steady state and the trajectories of most of the quantitatively measured nodes. In the experimental data, we surprisingly found that transferrin receptor-1 upregulation preceded the induction of inflammatory cytokines, a feature that deviated from model predictions. Model simulations suggested that direct induction of transferrin receptor-1 (TfR1) after fungal recognition, independent of the iron regulatory protein-labile iron pool (IRP-LIP) system, explains this finding. We anticipate that this model will contribute to a quantitative understanding of iron regulation as a fundamental host defense mechanism during aspergillosis. IMPORTANCE Invasive pulmonary aspergillosis is a major cause of death among immunosuppressed individuals despite the best available therapy. Depriving the pathogen of iron is an essential component of host defense in this infection, but the mechanisms by which the host achieves this are complex. To understand how recruited macrophages mediate iron deprivation during the infection, we developed and validated a mechanistic computational model that integrates the available information in the field. The insights provided by this approach can help in designing iron modulation therapies as anti-fungal treatments.