An introduction to Biomodel engineering, illustrated for signal transduction pathways

BioModel Engineering is the science of designing, constructing and analyzing computational models of biological systems. It is inspired by concepts from software engineering and computing science. This paper illustrates a major theme in BioModel Engineering, namely that identifying a quantitative model of a dynamic system means building the structure, finding an initial state, and parameter fitting. In our approach, the structure is obtained by piecewise construction of models from modular parts, the initial state is obtained by analysis of the structure and parameter fitting comprises determining the rate parameters of the kinetic equations. We illustrate this with an example in the area of intracellular signalling pathways

Hemodynamic study in a real intracranial aneurysm: an in vitro and in silico approach

Mestrado de dupla diplomação com o Centro Federal de Educação Tecnológica Celso Suckow da Fonseca - Cefet/RJIntracranial aneurysm (IA) is a cerebrovascular disease with high rates of mortality and morbidity when it ruptures. It is known that changes in the intra-aneurysmal hemodynamic load play a significant factor in the development and rupture of IA. However, these factors are not fully understood. In this sense, the main objective of this work is to study the hemodynamic behavior during the blood analogues flow inside an AI and to determine its influence on the evolution of this pathology. To this end, experimental and numerical studies were carried out, using a real AI model obtained using computerized angiography. In the experimental approach, it was necessary, in the initial phase, to develop and manufacture biomodels from medical images of real aneurysms. Two techniques were used to manufacture the biomodels: rapid prototyping and gravity casting. The materials used to obtain the biomodels were of low cost. After manufacture, the biomodels were compared to each other for their transparency and final structure and proved to be suitable for testing flow visualizations. Numerical studies were performed with the aid of the Ansys Fluent software, using computational fluid dynamics (CFD), using the finite volume method. Subsequently, flow tests were performed experimentally and numerically using flow rates calculated from the velocity curve of a patient's doppler test. The experimental and numerical tests, in steady-state, made it possible to visualize the three-dimensional behavior of the flow inside the aneurysm, identifying the vortex zones created throughout the cardiac cycle. Correlating the results obtained in the two analyzes, it was possible to identify that the areas of vortexes are characterized by low speed and with increasing the fluid flow, the vortexes are positioned closer to the wall. These characteristics are associated with the rupture of an intracranial aneurysm. There was also a good qualitative correlation between numerical and experimental results.O aneurisma intracraniano (AI) é uma patologia cerebrovascular com altas taxas de mortalidade e morbidade quando se rompe. Sabe-se que alterações na carga hemodinâmica intra-aneurismática exerce um fator significativo no desenvolvimento e ruptura de AI, porém, esses fatores não estão totalmente compreendidos. Nesse sentido, o objetivo principal deste trabalho é o de estudar o comportamento hemodinâmico durante o escoamento de fluidos análogos do sangue no interior de um AI e determinar a sua influência na evolução da patologia. Para tal, foram realizados estudos experimentais e numéricos, utilizando um modelo de AI real obtido por meio de uma angiografia computadorizada. Na abordagem experimental foi necessário, na fase inicial, desenvolver e fabricar biomodelos a partir de imagens médicas de um aneurisma real. No fabrico dos biomodelos foram utilizadas duas técnicas: a prototipagem rápida e o vazamento por gravidade. Os materiais utilizados para a obtenção dos biomodelos foram de baixo custo. Após a fabricação, os biomodelos foram comparados entre si quanto à sua transparência e estrutura final e verificou-se serem adequados para testes de visualizações do fluxo. Os estudos numéricos foram realizados com recurso ao software Ansys Fluent, utilizando a dinâmica dos fluidos computacional (CFD), através do método dos volumes finitos. Posteriormente, foram realizados testes de escoamento experimentais e numéricos, utilizando caudais determinados a partir da curva de velocidades do ensaio doppler de um paciente. Os testes experimentais e numéricos, em regime permanente, possibilitaram a visualização do comportamento tridimensional do fluxo no interior do aneurisma, identificando as zonas de vórtices criadas ao longo do ciclo cardíaco. Correlacionando os resultados obtidos nas duas análises, foi possível identificar que as áreas de vórtices são caracterizadas por uma baixa velocidade e com o aumento do caudal os vórtices posicionam-se mais próximos da parede. Essas características apresentadas estão associadas com a ruptura de aneurisma intracraniano. Verificou-se, também, uma boa correlação qualitativa entre os resultados numéricos e experimentais

Designing Predictive Mathematical Models for the Metabolic Pathways Associated with Polyhydroxybutyrate Synthesis in \u3ci\u3eEscherichia coli\u3c/i\u3e

Polyhydroxybutyrate (PHB) is a polyhydroxyalkanoate that has been extensively studied as a potential biodegradable replacement for petrochemically derived plastics. The synthesis pathway of PHB is native to Ralstonia eutropha, but the genes for the PHB pathway have successfully been introduced into Escherichia coli through plasmids such as the pBHR68 plasmid. However, the production of PHB needs to be more cost-effective before it can be commercially produced. A mathematical model for PHB synthesis was developed to identify target genes that could be genetically engineered to increase PHB production. The major metabolic pathways included in the model were glycolysis, acetyl coenzyme A (acetyl-CoA) synthesis, tricarboxylic acid (TCA) cycle, glyoxylate bypass, and PHB synthesis. Each reaction in the selected metabolic pathways was modeled using the kinetic mechanism identified for the associated enzyme. The promoters and transcription factors for each enzyme were incorporated into the model. The model was validated through comparison with other published models and experimental PHB production data. The predictive model identified 16 enzymes as having no effect on PHB production, 5 enzymes with a slight effect on PHB production, and 9 enzymes with large effects on PHB production. Decreasing the substrate affinity of the enzyme citrate synthase resulted in the largest increase in PHB synthesis. The second largest increase was observed from lowering the substrate affinity of glyceraldehyde-3-phosphate dehydrogenase. The predictive model also indicated that increasing the activity of the lac promoter in the pBHR68 plasmid resulted in the largest increase in the rate of PHB production. The predictive model successfully identified two genes and one promoter as targets for genetic engineering to create an optimized strain of E. coli for PHB production. The substrate-binding sites for the genes gltA (citrate synthase) and gapA (glyceraldehyde-3-phosphate dehydrogenase) should be genetically engineered to be less effective at binding the substrates. The lac promoter in the pBHR68 plasmid should be genetically engineered to more closely match the consensus sequence for binding to RNA polymerase. The model predicts that an optimized strain of E. coli for PHB production could be achieved by genetically altering gltA, gapA, and the lac promoter

09091 Abstracts Collection -- Formal Methods in Molecular Biology

From 23. February to 27. February 2009, the Dagstuhl Seminar 09091 ``Formal Methods in Molecular Biology \u27\u27 was held in Schloss Dagstuhl~--~Leibniz Center for Informatics. During the seminar, several participants presented their current research, and ongoing work and open problems were discussed. Abstracts of the presentations given during the seminar as well as abstracts of seminar results and ideas are put together in this paper. The first section describes the seminar topics and goals in general. Links to extended abstracts or full papers are provided, if available

StochSoCs: High performance biocomputing simulations for large scale Systems Biology

The stochastic simulation of large-scale biochemical reaction networks is of great importance for systems biology since it enables the study of inherently stochastic biological mechanisms at the whole cell scale. Stochastic Simulation Algorithms (SSA) allow us to simulate the dynamic behavior of complex kinetic models, but their high computational cost makes them very slow for many realistic size problems. We present a pilot service, named WebStoch, developed in the context of our StochSoCs research project, allowing life scientists with no high-performance computing expertise to perform over the internet stochastic simulations of large-scale biological network models described in the SBML standard format. Biomodels submitted to the service are parsed automatically and then placed for parallel execution on distributed worker nodes. The workers are implemented using multi-core and many-core processors, or FPGA accelerators that can handle the simulation of thousands of stochastic repetitions of complex biomodels, with possibly thousands of reactions and interacting species. Using benchmark LCSE biomodels, whose workload can be scaled on demand, we demonstrate linear speedup and more than two orders of magnitude higher throughput than existing serial simulators.Comment: The 2017 International Conference on High Performance Computing & Simulation (HPCS 2017), 8 page

Many-Core CPUs Can Deliver Scalable Performance to Stochastic Simulations of Large-Scale Biochemical Reaction Networks

Stochastic simulation of large-scale biochemical reaction networks is becoming essential for Systems Biology. It enables the in-silico investigation of complex biological system dynamics under different conditions and intervention strategies, while also taking into account the inherent "biological noise" especially present in the low species count regime. It is however a great computational challenge since in practice we need to execute many repetitions of a complex simulation model to assess the average and extreme cases behavior of the dynamical system it represents. The problem's work scales quickly, with the number of repetitions required and the number of reactions in the bio-model. The worst case scenario s when there is a need to run thousands of repetitions of a complex model with thousands of reactions. We have developed a stochastic simulation software framework for many- and multi-core CPUs. It is evaluated using Intel's experimental many-cores Single-chip Cloud Computer (SCC) CPU and the latest generation consumer grade Core i7 multi-core Intel CPU, when running Gillespie's First Reaction Method exact stochastic simulation algorithm. It is shown that emerging many-core NoC processors can provide scalable performance achieving linear speedup as simulation work scales in both dimensions

Design And Optimisation Of Microelectroelectromechanical System (MEMS) Cochlear Biomodel

The research and development of cochlear biomodelling has nowadays become one of the common interests in the biomedical research field. The main criterion of the developed cochlear biomodel is to have the ability to work within an audible range of human ear that is between 20 Hz to 20000 Hz. Microelectromechanical system (MEMS) is seen to have the potential to be utilised in mimicking the tonotopic organisation behavior of human ear. The developed MEMS cochlear biomodel is designed and simulated by using Comsol Multiphysics software to have the dimension of 0.5 μm thickness, 30 μm wide and length varying from 280 μm to 1000 μm. Five MEMS cochlear biomodel designs which are the Straight Bridge Beam (SBB), Straight Bridge Beam with Centered Diaphragm (SBBCD), Straight Bridge Beam with Centered Mass (SBBCM), Crab Legged and Serpentine, have been suggested in order to examine their resonant frequency performances. Four different materials have been considered which are Aluminium (Al), Copper (Cu), Tantalum (Ta) and Platinum (Pt). The design performance has been further tested in terms of its total surface displacement and capacitive ability. SBBCD MEMS cochlear biomodel that was developed with platinum as its base structure material and tantalum as the added mass material gives the highest resonant frequency performance of 92.87 % operating within the desired audible range. The design provides the total surface displacement ranging from 1.4370 nm to 0.0125 μm. The capacitance reading was also recorded to be 14.875 fF at the shortest beam structure and then increased to 53.125 fF towards the longest beam structure. In order to test its adaptivity, the structure was also tested with a voltage ranges from 0.1 V to 0.5 V. The resonant frequency tuning has been found to decrease in the range of 0.57 % to 4.65 % and the surface displacement has been amplified by ~4 to ~25 times bigger as the voltage increases. Relevant microfabrication steps have been suggested to fabricate SBBCM MEMS cochlear biomodel

Biomechanical Stress and Strain Analysis of Mandibular Human Region from Computed Tomography to Custom Implant Development

Currently computational tools are helping and improving the processes and testing procedures in several areas of knowledge. Computed tomography (CT) is a diagnostic tool already consolidated and now beginning to be used as a tool for something even more innovative, creating biomodels. Biomodels are anatomical physical copies of human organs and tissues that are used for diagnosis and surgical planning. The use of tomographic images in the creation of biomodels has been arousing great interest in the medical and bioengineering area. In addition to creating biomodels by computed tomography it is also possible, using this process, to create mathematical models to perform computer simulations and analyses of regions of interest. This paper discusses the creation of a biomodel of the skull-mandibular region of a patient from CT for study and evaluation of efforts in the area of the temporomandibular joint (TMJ) aiming at the design and development of a TMJ custom prosthesis. The evaluation of efforts in the TMJ region due to the forces of mastication was made using the finite element method and the results were corroborated by comparison with mandibular models studied in similar works

Numerical and experimental haemodynamic studies of stenotic coronary arteries

Dissertação de mestrado integrado em Engenharia Biomédica (área de especialização em Biomateriais, Reabilitação e Biomecânica)Cardiovascular diseases remain the most frequent cause of mortality worldwide and constitute a major healthcare challenge. Among them, coronary artery disease causes nearly half of the deaths and, thus it is of great interest to better understand its development and effects. This disease is characterized by the narrowing (stenosis) of coronary arteries due to plaque deposition at the arterial wall, a pathological process known as atherosclerosis. This dissertation aimed to study the hemodynamics in stenotic coronary arteries, in order to get a deeper understanding of the effects of this pathology on the blood flow behavior. For this purpose, both numerical and experimental studies were conducted using idealized models. The numerical research was carried out using Ansys® software by means of computational fluid dynamics which applies the finite volume method. The experimental approach was performed using a high-speed video microscopy system, to visualize and investigate the blood flow in the in vitro stenotic biomodels. Initially, the influence of roughness in flow visualizations was studied, and the best biomodel was the one printed with the lowest resolution having been, therefore, the selected to perform the hemodynamic studies. To compare those results with numerical data, the flow was set to be laminar and stationary and the fluid was considered Newtonian. In general, the numerical and experimental results were in good agreement, not only in the prediction of the flow behavior with the appearance of recirculation zones in the post-stenotic section, but also in the velocity profiles. In a posterior phase, a pulsatile inlet condition was applied to compare the use of laminar and turbulent assumptions, using the SST k- model. The results obtained allowed to conclude that the second one is more appropriate to simulate the blood flow. Subsequently, the main differences in hemodynamics were examined considering blood as a Newtonian and non-Newtonian fluid (Carreau model). For these models, the differences were very slight in terms of velocity fields, but more significant for the wall shear stress measurements, with the Newtonian model predicting lower values. The remaining simulations were performed using the Carreau model and a transient inlet flow, having observed an increase in the velocities and wall shear stress values with the degree of stenosis, which is associated with a greater risk of thrombosis.As doenças cardiovasculares continuam a ser a causa mais frequente de mortalidade em todo o mundo e constituem um grande desafio para a saúde. Entre elas, a doença arterial coronariana causa quase metade das mortes e, portanto, é de enorme interesse entender melhor o seu desenvolvimento e efeitos. Esta doença é caracterizada pelo estreitamento (estenose) das artérias coronárias devido à deposição de placas na parede arterial, um processo patológico conhecido como aterosclerose. Esta dissertação teve como objetivo estudar a hemodinâmica nas artérias coronárias estenóticas, a fim de obter uma compreensão mais profunda dos efeitos desta patologia no comportamento do fluxo sanguíneo. Para tal, foram realizados estudos numéricos e experimentais, utilizando modelos idealizados. A investigação numérica foi realizada no software Ansys®, através da dinâmica computacional dos fluidos, que aplica o método dos volumes finitos. A abordagem experimental foi realizada utilizando um sistema de microscopia de vídeo de alta velocidade, para visualizar e investigar o fluxo sanguíneo nos biomodelos estenóticos in vitro. Inicialmente, estudou-se a influência da rugosidade nas visualizações do escoamento, e o melhor biomodelo foi o impresso com menor resolução tendo sido, portanto, o selecionado para a realização dos estudos hemodinâmicos. Para comparar esses resultados com dados numéricos, o escoamento foi definido como laminar e estacionário e o fluído foi considerado Newtoniano. Em geral, os resultados numéricos e experimentais foram concordantes, não só na previsão do comportamento do fluxo com aparecimento de zonas de recirculação na zona pós-estenótica, mas também nos perfis de velocidade. Numa fase posterior, foi aplicada uma condição de entrada pulsátil para comparar o uso de simulações de natureza laminar e turbulenta, usando o modelo SST k-. Os resultados obtidos permitiram concluir que a segunda é mais apropriado para simular o fluxo sanguíneo. Posteriormente, foram examinadas as principais diferenças hemodinâmicas, considerando o sangue como fluído Newtoniano e não-Newtoniano (modelo de Carreau). Para estes modelos, as diferenças foram muito pequenas nos perfis de velocidade, mas mais significativas nas tensões de corte na parede medidas, com o modelo Newtoniano a prever valores mais baixos. As restantes simulações foram realizadas usando o modelo de Carreau e um escoamento de entrada transiente, tendo-se observado um aumento dos valores das velocidades e da tensão de corte na parede com o grau de estenose, o que está associado a um maior risco de trombose

骨モデルにおける切削特性に関する研究

Tohoku University太田信課