Ecological Modelling with the Calculus of Wrapped Compartments

The Calculus of Wrapped Compartments is a framework based on stochastic multiset rewriting in a compartmentalised setting originally developed for the modelling and analysis of biological interactions. In this paper, we propose to use this calculus for the description of ecological systems and we provide the modelling guidelines to encode within the calculus some of the main interactions leading ecosystems evolution. As a case study, we model the distribution of height of Croton wagneri, a shrub constituting the endemic predominant species of the dry ecosystem in southern Ecuador. In particular, we consider the plant at different altitude gradients (i.e. at different temperature conditions), to study how it adapts under the effects of global climate change.Comment: A preliminary version of this paper has been presented in CMC13 (LNCS 7762, pp 358-377, 2013

A Process Calculus for Spatially-explicit Ecological Models

We propose PALPS, a Process Algebra with Locations for Population Systems. PALPS allows us to produce spatially-explicit, individual-based models and to reason about their behavior. Our calculus has two levels: at the first level we may define the behavior of an individual of a population while, at the second level, we may specify a system as the collection of individuals of various species located in space, moving through their life cycle while changing their location, if they so wish, and interacting with each other in various ways such as preying on each other. Furthermore, we propose a probabilistic temporal logic for reasoning about the behavior of PALPS processes. We illustrate our framework via models of dispersal in metapopulations.Comment: In Proceedings MeCBIC 2012, arXiv:1211.347

Rule-based multi-level modeling of cell biological systems

<p>Abstract</p> <p>Background</p> <p>Proteins, individual cells, and cell populations denote different levels of an organizational hierarchy, each of which with its own dynamics. Multi-level modeling is concerned with describing a system at these different levels and relating their dynamics. Rule-based modeling has increasingly attracted attention due to enabling a concise and compact description of biochemical systems. In addition, it allows different methods for model analysis, since more than one semantics can be defined for the same syntax.</p> <p>Results</p> <p>Multi-level modeling implies the hierarchical nesting of model entities and explicit support for downward and upward causation between different levels. Concepts to support multi-level modeling in a rule-based language are identified. To those belong rule schemata, hierarchical nesting of species, assigning attributes and solutions to species at each level and preserving content of nested species while applying rules. Further necessities are the ability to apply rules and flexibly define reaction rate kinetics and constraints on nested species as well as species that are nested within others. An example model is presented that analyses the interplay of an intracellular control circuit with states at cell level, its relation to cell division, and connections to intercellular communication within a population of cells. The example is described in ML-Rules - a rule-based multi-level approach that has been realized within the plug-in-based modeling and simulation framework JAMES II.</p> <p>Conclusions</p> <p>Rule-based languages are a suitable starting point for developing a concise and compact language for multi-level modeling of cell biological systems. The combination of nesting species, assigning attributes, and constraining reactions according to these attributes is crucial in achieving the desired expressiveness. Rule schemata allow a concise and compact description of complex models. As a result, the presented approach facilitates developing and maintaining multi-level models that, for instance, interrelate intracellular and intercellular dynamics.</p

Simulation and Verification in a Process Calculus for Spatially-Explicit Ecological Models

We propose PALPS, a Process Algebra with Locations for Population Systems. PALPS allows us to produce spatially-explicit individual-based ecological models and to reason about their behavior. PALPS has two abstraction levels: At the first level, we may define the behavior of an individual of a population and, at the second level, we may specify a system as the collection of individuals of various species located in space. In PALPS, the individuals move through their life cycle while changing their location and interact with each other in various ways such as predation, infection or mating. Furthermore, we propose a translation of a subset of PALPS into the probabilistic model checker PRISM. We illustrate our framework via models of dispersal in metapopulations and by applying PRISM on PALPS models for verifying temporal logic properties and conducting reachability and steady-state analysis

Toward Accessible Multilevel Modeling in Systems Biology: A Rule-based Language Concept

Promoted by advanced experimental techniques for obtaining high-quality data and the steadily accumulating knowledge about the complexity of life, modeling biological systems at multiple interrelated levels of organization attracts more and more attention recently. Current approaches for modeling multilevel systems typically lack an accessible formal modeling language or have major limitations with respect to expressiveness. The aim of this thesis is to provide a comprehensive discussion on associated problems and needs and to propose a concrete solution addressing them

Domain-specific languages for modeling and simulation

Simulation models and simulation experiments are increasingly complex. One way to handle this complexity is developing software languages tailored to specific application domains, so-called domain-specific languages (DSLs). This thesis explores the potential of employing DSLs in modeling and simulation. We study different DSL design and implementation techniques and illustrate their benefits for expressing simulation models as well as simulation experiments with several examples.Simulationsmodelle und -experimente werden immer komplexer. Eine Möglichkeit, dieser Komplexität zu begegnen, ist, auf bestimmte Anwendungsgebiete spezialisierte Softwaresprachen, sogenannte domänenspezifische Sprachen (\emph{DSLs, domain-specific languages}), zu entwickeln. Die vorliegende Arbeit untersucht, wie DSLs in der Modellierung und Simulation eingesetzt werden können. Wir betrachten verschiedene Techniken für Entwicklung und Implementierung von DSLs und illustrieren ihren Nutzen für das Ausdrücken von Simulationsmodellen und -experimenten anhand einiger Beispiele

General dynamics of the physical-chemical systems in mammals

Biodynamic regulator chain models for physical chemical systems in mammal

Hybrid Modeling of Cancer Drug Resistance Mechanisms

Cancer is a multi-scale disease and its overwhelming complexity depends upon the multiple interwind events occurring at both molecular and cellular levels, making it very difficult for therapeutic advancements in cancer research. The resistance to cancer drugs is a significant challenge faced by scientists nowadays. The roots of the problem reside not only at the molecular level, due to multiple type of mutations in a single tumor, but also at the cellular level of drug interactions with the tumor. Tumor heterogeneity is the term used by oncologists for the involvement of multiple mutations in the development of a tumor at the sub-cellular level. The mechanisms for tumor heterogeneity are rigorously being explored as a reason for drug resistance in cancer patients. It is important to observe cell interactions not only at intra-tumoral level, but it is also essential to study the drug and tumor cell interactions at cellular level to have a complete picture of the mechanisms underlying drug resistance. The multi-scale nature of cancer drug resistance problem require modeling approaches that can capture all the multiple sub-cellular and cellular interaction factors with respect to dierent scales for time and space. Hybrid modeling offers a way to integrate both discrete and continuous dynamics to overcome this challenge. This research work is focused on the development of hybrid models to understand the drug resistance behaviors in colorectal and lung cancers. The common thing about the two types of cancer is that they both have dierent mutations at epidermal growth factor receptors (EGFRs) and they are normally treated with anti-EGFR drugs, to which they develop resistances with the passage of time. The acquiring of resistance is the sign of relapse in both kind of tumors. The most challenging task in colorectal cancer research nowadays is to understand the development of acquired resistance to anti-EGFR drugs. The key reason for this problem is the KRAS mutations appearance after the treatment with monoclonal antibodies (moAb). A hybrid model is proposed for the analysis of KRAS mutations behavior in colorectal cancer with respect to moAb treatments. The colorectal tumor hybrid model is represented as a single state automata, which shows tumor progression and evolution by means of mathematical equations for tumor sub-populations, immune system components and drugs for the treatment. The drug introduction is managed as a discrete step in this model. To evaluate the drug performance on a tumor, equations for two types of tumors cells are developed, i.e KRAS mutated and KRAS wild-type. Both tumor cell populations were treated with a combination of moAb and chemotherapy drugs. It is observed that even a minimal initial concentration of KRAS mutated cells before the treatment has the ability to make the tumor refractory to the treatment. Moreover, a small population of KRAS mutated cells has a strong influence on a large number of wild-type cells by making them resistant to chemotherapy. Patient's immune responses are specifically taken into considerations and it is found that, in case of KRAS mutations, the immune strength does not affect medication efficacy. Finally, cetuximab (moAb) and irinotecan (chemotherapy) drugs are analyzed as first-line treatment of colorectal cancer with few KRAS mutated cells. Results show that this combined treatment could be only effective for patients with high immune strengths and it should not be recommended as first-line therapy for patients with moderate immune strengths or weak immune systems because of a potential risk of relapse, with KRAS mutant cells acquired resistance involved with them. Lung cancer is more complicated then colorectal cancer because of acquiring of multiple resistances to anti-EGFR drugs. The appearance of EGFR T790M and KRAS mutations makes tumor resistant to a geftinib and AZD9291 drugs, respectively. The hybrid model for lung cancer consists of two non-resistant and resistant states of tumor. The non-resistant state is treated with geftinib drug until resistance to this drug makes tumor regrowth leading towards the resistant state. The resistant state is treated with AZD9291 drug for recovery. In this model the complete resistant state due to KRAS mutations is ignored because of the unavailability of parameter information and patient data. Each tumor state is evaluated by mathematical differential equations for tumor growth and progression. The tumor model consists of four tumor sub-population equations depending upon the type of mutations. The drug administration in this model is also managed as a discrete step for exact scheduling and dosages. The parameter values for the model are obtained by experiments performed in the laboratory. The experimental data is only available for the tumor progression along with the geftinib drug. The model is then fine tuned for obtaining the exact tumor growth patterns as observed in clinic, only for the geftinib drug. The growth rate for EGFR T790M tumor sub-population is changed to obtain the same tumor progression patterns as observed in real patients. The growth rate of mutations largely depends upon the immune system strength and by manipulating the growth rates for different tumor populations, it is possible to capture the factor of immune strength of the patient. The fine tuned model is then used to analyze the effect of AZD9291 drug on geftinib resistant state of the tumor. It is observed that AZD9291 could be the best candidate for the treatment of the EGFR T790M tumor sub-population. Hybrid modeling helps to understand the tumor drug resistance along with tumor progression due to multiple mutations, in a more realistic way and it also provides a way for personalized therapy by managing the drug administration in a strict pattern that avoid the growth of resistant sub-populations as well as target other populations at the same time. The only key to avoid relapse in cancer is the personalized therapy and the proposed hybrid models promises to do that

Mathematical modelling of calcium signalling

Calcium (Ca2+) plays an integral role in a vast array of signalling pathways within both animals and plants. The study of these pathways has proven to be a fruitful avenue of research for experimental biologists and mathematical modellers. While the signalling processes have been well studied in animals, the same cannot be said of plants. This work takes a mathematical look at two important Ca2+ signalling pathways in plants, with a focus on how these signals are generated. Nuclear Ca2+ oscillations in legumes occur at a key step in the development of symbioses. The oscillations occur both inside the nucleus and in the perinuclear cytoplasm, and are temporally coordinated. We present and develop a model for simulating diffusion on the surface of the nucleus and relate the properties of this signalling to behaviour in the bulk. We show that diffusion of Ca2+ through the nuclear pore complexes provides a possible mechanism for this coordination and that this mechanism is robust to differences in Ca2+ diffusion rates in the two compartments or to different numbers of Ca2+ channels. Ca2+ has also been seen to propagate a wave travelling systemically through the root in response to salt stress. This wave is essential to the transcription of stress response genes in the leaves. We examine a range of di�erent models for propagation of the wave, demonstrating that a combined reactive oxygen species (ROS) and Ca2+ wave cooperatively propagate the signal. The presence of this accompanying ROS wave was confirmed in experiments by our collaborators. The present study highlights two very different Ca2+ signals and demonstrates the value of mathematical modelling for interpreting, understanding and furthering experimental investigations