RuleMonkey: software for stochastic simulation of rule-based models

<p>Abstract</p> <p>Background</p> <p>The system-level dynamics of many molecular interactions, particularly protein-protein interactions, can be conveniently represented using reaction rules, which can be specified using model-specification languages, such as the BioNetGen language (BNGL). A set of rules implicitly defines a (bio)chemical reaction network. The reaction network implied by a set of rules is often very large, and as a result, generation of the network implied by rules tends to be computationally expensive. Moreover, the cost of many commonly used methods for simulating network dynamics is a function of network size. Together these factors have limited application of the rule-based modeling approach. Recently, several methods for simulating rule-based models have been developed that avoid the expensive step of network generation. The cost of these "network-free" simulation methods is independent of the number of reactions implied by rules. Software implementing such methods is now needed for the simulation and analysis of rule-based models of biochemical systems.</p> <p>Results</p> <p>Here, we present a software tool called RuleMonkey, which implements a network-free method for simulation of rule-based models that is similar to Gillespie's method. The method is suitable for rule-based models that can be encoded in BNGL, including models with rules that have global application conditions, such as rules for intramolecular association reactions. In addition, the method is rejection free, unlike other network-free methods that introduce null events, i.e., steps in the simulation procedure that do not change the state of the reaction system being simulated. We verify that RuleMonkey produces correct simulation results, and we compare its performance against DYNSTOC, another BNGL-compliant tool for network-free simulation of rule-based models. We also compare RuleMonkey against problem-specific codes implementing network-free simulation methods.</p> <p>Conclusions</p> <p>RuleMonkey enables the simulation of rule-based models for which the underlying reaction networks are large. It is typically faster than DYNSTOC for benchmark problems that we have examined. RuleMonkey is freely available as a stand-alone application <url>http://public.tgen.org/rulemonkey</url>. It is also available as a simulation engine within GetBonNie, a web-based environment for building, analyzing and sharing rule-based models.</p

Time and length scales of autocrine signals in three dimensions

A model of autocrine signaling in cultures of suspended cells is developed on the basis of the effective medium approximation. The fraction of autocrine ligands, the mean and distribution of distances traveled by paracrine ligands before binding, as well as the mean and distribution of the ligand lifetime are derived. Interferon signaling by dendritic immune cells is considered as an illustration.Comment: 15 page

Modeling multivalent ligand-receptor interactions with steric constraints on configurations of cell surface receptor aggregates

Signal transduction generally involves multivalent protein-protein interactions, which can produce various protein complexes and post-translational modifications. The reaction networks that characterize these interactions tend to be so large as to challenge conventional simulation procedures. To address this challenge, a kinetic Monte Carlo (KMC) method has been developed that can take advantage of a model specification in terms of reaction rules for molecular interactions. A set of rules implicitly defines the reactions that can occur as a result of the interactions represented by the rules. With the rule-based KMC method, explicit generation of the underlying chemical reaction network implied by rules is avoided. Here, we apply and extend this method to characterize the interactions of a trivalent ligand with a bivalent cell-surface receptor. This system is also studied experimentally. We consider the following kinetic models: an equivalent-site model, an extension of this model, which takes into account steric constraints on the configurations of receptor aggregates, and finally, a model that accounts for cyclic receptor aggregates. Simulation results for the equivalent-site model are consistent with an equilibrium continuum model. Using these models, we investigate the effects of steric constraints and the formation of cyclic aggregates on the kinetics and equilibria of small and large aggregate formation and the percolation phase transition that occurs in this system

SARS-CoV-2 infection with bilateral intralabyrinthine hemorrhage

A 47-year-old woman presented with the complaint of sudden hearing loss associated with vertigo. Serological testing was positive for IgM and negative for IgG COVID-19 antibodies, with no other associated factors. Magnetic resonance imaging of the brain showed bilateral intralabyrinthine hemorrhage

Estudo estrutural da junta soldada dissimilar entre o aço inox austenítico AISI 347 e o aço carbono ferrítico ASTM A36 / Structural study of the dissimilar welded joint between AISI 347 austenitic stainless steel and ASTM A36 ferritic carbon steel

No presente trabalho investigou-se uma solda dissimilar, que são soldas feitas com a união entre materiais diferentes. Elas são utilizadas, em muitos segmentos da indústria, na construção de estruturas, das mais simples até as mais complexas. Nesse trabalho, foram usados o aço inoxidável austenítico AISI 347, soldado ao aço carbono ferrítico ASTM A36. A soldagem foi feita pelo processo a arco elétrico com eletrodo revestido, usando-se como metal de adição varetas de eletrodo E309L. O objetivo principal foi avaliar se a união desses metais atende aos requisitos de resistência mecânica e confiabilidade da junta soldada. Para se estudar essas propriedades, os corpos de prova tirados da junta foram submetidos a ensaios mecânicos de tração, dobramento, microdureza Vickers, macrografia e micrografias. Investigou-se também as tensões residuais geradas na junta soldada que podem influenciar na resistência e podem gerar o surgimento de trincas. Após análise dos resultados obtidos, permitiu-se concluir que a junta dissimilar soldada exibe boa confiabilidade na resistência mecânica e não comprometeram as características originais dos metais de base

Kinetic Monte Carlo Method for Rule-based Modeling of Biochemical Networks

We present a kinetic Monte Carlo method for simulating chemical transformations specified by reaction rules, which can be viewed as generators of chemical reactions, or equivalently, definitions of reaction classes. A rule identifies the molecular components involved in a transformation, how these components change, conditions that affect whether a transformation occurs, and a rate law. The computational cost of the method, unlike conventional simulation approaches, is independent of the number of possible reactions, which need not be specified in advance or explicitly generated in a simulation. To demonstrate the method, we apply it to study the kinetics of multivalent ligand-receptor interactions. We expect the method will be useful for studying cellular signaling systems and other physical systems involving aggregation phenomena.Comment: 18 pages, 5 figure

Mecânica da fratura aplicada em juntas soldadas do aço astm A672 GR B em tubulações de processo / Fracture mechanics applied to welded joints in astm A672 GR B steel in process pipes

Este trabalho avaliou a geração de trincas internas em juntas soldadas em tubulações industriais de aço ASTM A672 grau B. Nessa abordagem foi utilizado o Diagrama de Falhas – FAD, que avaliou descontinuidades planares da estrutura da solda através de ensaios não destrutivos. Foram estudados parâmetros envolvendo mecânica da fratura e os efeitos micro estruturais que contribuem para a avaliação da integridade estrutural. As amostras foram obtidas do Sistema de Flare Geral da Unidade de Hidrotratamento de Diesel localizada no Complexo Petroquímico do Estado do Rio de Janeiro – COMPERJ. Os resultados mostraram que, em juntas soldadas, novos critérios podem ser inseridos na avaliação de defeitos em relação às propriedades mecânicas do material. Após analisar as tensões por difração de raios X, foi possível se avaliar as condições de operação da tubulação, posição, geometria da trinca e as tensões atuantes que contribuem para a análise de peças que seriam reprovadas em testes. Os resultados mostraram também que as tensões geradas sempre relacionam as condições operacionais na linha, envolvendo pressão e temperatura, resultou em posicionamento no diagrama de falhas, em regiões seguras que demonstraram a inexistência de probabilidade de falha do material. 

Rule-based modelling provides an extendable framework for comparing candidate mechanisms underpinning clathrin polymerisation

Abstract Polymerisation of clathrin is a key process that underlies clathrin-mediated endocytosis. Clathrin-coated vesicles are responsible for cell internalization of external substances required for normal homeostasis and life –sustaining activity. There are several hypotheses describing formation of closed clathrin structures. According to one of the proposed mechanisms cage formation may start from a flat lattice buildup on the cellular membrane, which is later transformed into a curved structure. Creation of the curved surface requires rearrangement of the lattice, induced by additional molecular mechanisms. Different potential mechanisms require a modeling framework that can be easily modified to compare between them. We created an extendable rule-based model that describes polymerisation of clathrin molecules and various scenarios of cage formation. Using Global Sensitivity Analysis (GSA) we obtained parameter sets describing clathrin pentagon closure and the emergence/production and closure of large-size clathrin cages/vesicles. We were able to demonstrate that the model can reproduce budding of the clathrin cage from an initial flat array