A method of Three-Dimensional Visualization of molecular processes of apoptosis (original) (raw)

Visualization of Biological Processes Described by Models of Apoptosis

2014

Visualization of biochemical processes is important for understanding various phenomena in living organisms. One of the famous biological processes is apoptosis. Apoptosis or programmed cell death plays an important role in many physiological states and diseases. Detection of apoptotic cells, tracing the development of apoptosis, drug development and regulation of apoptosis are an important parts of basic research in medicine. A large number of models have been developed that are based on differential equations of chemical kinetics, and can be expressed in a uniform notation using some XML-based languages. Here we briefly discuss the simulation and visual presentation models of apoptosis. We review modelling languages, such as SBML, FieldML and CellML and briefly describe the simulation environments and software libraries for these languages (SBMLeditor, libSBML, SBMLToolbox, MGSmodeller, OpenCell). These tools can display models schematically and output results is in the form of gr...

Mathematical modeling of the formation of apoptosome in intrinsic pathway of apoptosis

Systems and Synthetic Biology, 2008

Caspase-9 is the protease that mediates the intrinsic pathway of apoptosis, a type of cell death. Activation of caspase-9 is a multi-step process that requires dATP or ATP and involves at least two proteins, cytochrome c and Apaf-1. In this study, we mathematically model caspase-9 activation by using a system of ordinary differential equations (an ODE model) generated by a systems biology tool Simpathica-a simulation and reasoning system, developed to study biological pathways. A rudimentary version of ''model checking'' based on comparing simulation data with that obtained from a recombinant system of caspase-9 activation, provided several new insights into regulation of this protease. The model predicts that the activation begins with binding of dATP to Apaf-1, which initiates the interaction between Apaf-1 and cytochrome c, thus forming a complex that oligomerizes into an active caspase-9 holoenzyme via a linear binding model with cooperative interaction rather than through network formation.

In Silico Modeling and Simulation Approach for Apoptosis Caspase Pathways

2018

We revisit and improve in silico modeling and simulation approach of the apoptosis caspases pathways, initially developed for exploring and discovering the complex interaction patterns of apoptotic caspases and the mitochondrial role. Symbolic abstractions and algorithms of the in silico model were improved to allow dealing with crucial aspects of the cellular signal transduction such as cellular processes. Also, the particular model of extrinsic and intrinsic apoptotic signaling pathways was improved, increasing the number of reactions and using all kinetic parameters accurately calculated. Using the computational simulation tool BTSSOC-Cellulat, we were able to determine experimentally how the modulation of concentrations of proteins XIAP, cFLIPs and TRAIL/FASL, can cause the death of cancerous cells. Our results show how crucial were the improvements made in the in silico modeling approach, which in turn were reflected in the accuracy of the simulation and, therefore, in the sign...

Simulating apoptosis using discrete methods: a membrane system and a stochastic approach

2007

Membrane Systems provide an intriguing method for modeling biological systems at a molecular level. The hierarchical structure of Membrane Systems lends itself readily to mimic the nature and behavior of cells. We have refined a technique for modeling the type I and type II FAS-induced apoptosis signalling cascade. Improvements over our previous modeling work on apoptosis include increased efficiency for storing and sorting waiting times of reactions, a nondeterministic approach for handling reactions competing over limited reactants and improvements, and refinements of the model reactions. The modular nature of our systems provides flexibility with respect to future discoveries on the signal cascade. We provide a breakdown of our algorithms and explanations on improvements we have implemented. We also give an exhaustive comparison to an established ordinary differential equations technique. Based on the results of our simulations, we conclude that Membrane Systems are a useful simulation tool in Systems Biology that could provide new insight into the subcellular processes, and provide also the argument that Membrane Systems may outperform ordinary differential equation simulations when simulating cascades of reactions (as they are observed in cells).

Analysis of Cell Proliferation and Apoptosis in Virtual Model

Proceedings of the Bulgarian Academy of Sciences

Breast cancer is the second leading cause of cancer among women globally. Several treatments are involved in breast cancer like surgery, chemotherapy, radiotherapy, and hormone therapy; chemotherapy being used most often. Multicellular systems complications can be deeply understood by analyzing and studying how cells grow, move, divide, die and interact. To examine these factors, we use PhysiCell as our modelling platform. Virtual cell growth analysis is essential to view the cancer cell growth daily. PhysiCell physics-based multicellular simulator is an open-source agent-based simulator used to design a virtual model to analyze the changing cell cycle progression, volume, death, motility, mechanics and processes. Analysis was made on the cancer cell death rate, cell damage rate, and cell repair rate. Data were taken for every 6 hours of simulation and the result confirms that the chemotherapeutic agent kills 45% of cancer cells.

Model validation of biological pathways using Petri nets—demonstrated for apoptosis

Biosystems, 2004

This paper demonstrates the first steps of a new integrating methodology to develop and analyse models of biological pathways in a systematic manner using well established Petri net technologies. The whole approach comprises step-wise modelling, animation, model validation as well as qualitative and quantitative analysis for behaviour prediction. In this paper, the first phase is addressed how to develop and validate a qualitative model, which might be extended afterwards to a quantitative model.

Model reduction of the intracellular-signaling subsystem of apoptosis

Mathematical Biosciences, 2016

In recent few decades numerical treatment has become a standard tool in the system analysis and investigation of complex chemical reactions networks of reacting flows. The information about certain networks of biochemical reactions constantly increases. This leads to detailed descriptions of biochemical processes as a system of differential equations of high complexity and dimension. Nowadays methods, which are able automatically reduce the system dimension and complexity, are highly desirable. Recently several methods were developed for model reduction in combustion and chemical kinetics aiming at automatic numerical treatment and constructing the reduced system. The reduced system represents reliable description reproducing the detailed system behavior accurately enough. In this work the method of qualitative ODEs system analysis and the global quasi-linearization method (GQL) for kinetic mechanism reduction of combustion models are applied to the biochemical reaction network of the apoptosis. It is shown that the original model of the apoptosis can be essentially simplified firstly by using linear system integrals (9 dimensions) of the ODEs system, secondly the results of GQL analysis reveals the possibility of a further reduction (4 dimensions). It means that the final system dimension reaches 15 compare to the original 28 without any noticeable accuracy losses.

Computational Analysis of Dynamical Responses to the Intrinsic Pathway of Programmed Cell Death

Biophysical Journal, 2009

Multicellular organisms shape development and remove aberrant cells by programmed cell death ("apoptosis"). Because defective cell death (too little or too much) is implicated in various diseases (like cancer and autoimm unity), understanding how apoptosis is regulated is an important goal of molecular cell biologists. To this end, we propose a mathematical model of the intrinsic apoptotic pathway that captures three key dynamical features: a signal threshold to elicit cell death, irreversible commitment to the response, and a time delay that is inversely proportional to signal strength. Subdividing the intri nsic pathway into three modules (initiator, amplifier, executioner), we use computer simulation and bifurcation theory to attribute signal threshold and time delay to positive feedback in the initiator module and irreversible commitment to posit ive feedback in the executioner module. The model accounts for the behavior of mutants deficient in various genes a nd is used to design experiments that would test its basic assumptions. Finally, we apply the model to study p53-induced ce llular responses to DNA damage. Cells first undergo cell cycle arrest and DNA repair, and then apoptosis if the damage is beyond repair. T he model ascribes this cell-fate transition to a transformation of p53 from "helper" to "killer" fo rms.