scholarly journals Development of a Simple Kinetic Mathematical Model of Aggregation of Particles or Clustering of Receptors

Life ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 97
Author(s):  
Andrei K. Garzon Dasgupta ◽  
Alexey A. Martyanov ◽  
Aleksandra A. Filkova ◽  
Mikhail A. Panteleev ◽  
Anastasia N. Sveshnikova

The process of clustering of plasma membrane receptors in response to their agonist is the first step in signal transduction. The rate of the clustering process and the size of the clusters determine further cell responses. Here we aim to demonstrate that a simple 2-differential equation mathematical model is capable of quantitative description of the kinetics of 2D or 3D cluster formation in various processes. Three mathematical models based on mass action kinetics were considered and compared with each other by their ability to describe experimental data on GPVI or CR3 receptor clustering (2D) and albumin or platelet aggregation (3D) in response to activation. The models were able to successfully describe experimental data without losing accuracy after switching between complex and simple models. However, additional restrictions on parameter values are required to match a single set of parameters for the given experimental data. The extended clustering model captured several properties of the kinetics of cluster formation, such as the existence of only three typical steady states for this system: unclustered receptors, receptor dimers, and clusters. Therefore, a simple kinetic mass-action-law-based model could be utilized to adequately describe clustering in response to activation both in 2D and in 3D.

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1537 ◽  
Author(s):  
Mateusz Dębowski ◽  
Zuzanna Szymańska ◽  
Jacek Z. Kubiak ◽  
Mirosław Lachowicz

In this paper we propose a role for the CDC 6 protein in the entry of cells into mitosis. This has not been considered in the literature so far. Recent experiments suggest that CDC 6 , upon entry into mitosis, inhibits the appearance of active CDK 1 and cyclin B complexes. This paper proposes a mathematical model which incorporates the dynamics of kinase CDK 1 , its regulatory protein cyclin B, the regulatory phosphatase CDC 25 and the inhibitor CDC 6 known to be involved in the regulation of active CDK 1 and cyclin B complexes. The experimental data lead us to formulate a new hypothesis that CDC 6 slows down the activation of inactive complexes of CDK 1 and cyclin B upon mitotic entry. Our mathematical model, based on mass action kinetics, provides a possible explanation for the experimental data. We claim that the dynamics of active complexes CDK 1 and cyclin B have a similar nature to diauxic dynamics introduced by Monod in 1949. In mathematical terms we state it as the existence of more than one inflection point of the curve defining the dynamics of the complexes.


2021 ◽  
Vol 2 (5) ◽  
pp. 7493-7514
Author(s):  
Torres Jácome Julián ◽  
Martagon-Domínguez Juan Mauricio ◽  
Montes Pérez Areli ◽  
Montiel-Jaen Guadalupe ◽  
García-Garibay Otto ◽  
...  

In this work it proposes a mathematical model for ion channels based on two concepts, the Hodgkin and Huxley's as well as the Law of Mass Action in addition, we consider the kinetics of channels as a dynamic process of Markov`s chain. With the previous premises, a system of differential equations is proposed that when it is solved, all properties of the macroscopic currents are determined. The activation, deactivation, inactivation, and recovery of the inactivation concepts remain as processes that are part of a chemical reaction. With this system of equations, all the experimental protocols used in electrophysiology to characterize macroscopic currents can be modeled. Another advantage is that the model allows, with the same system of equations, to determine the properties of voltage-dependent channels regardless of the type of ion that pass through in the channel.


2018 ◽  
Vol 14 (1) ◽  
Author(s):  
Bahador Abolpour ◽  
M. Mehdi Afsahi ◽  
Ataallah Soltani Goharrizi

Abstract In this study, reduction of in-flight fine particles of magnetite ore concentrate by methane at a constant heat flux has been investigated both experimentally and numerically. A 3D turbulent mathematical model was developed to simulate the dynamic motion of these particles in a methane content reactor and experiments were conducted to evaluate the model. The kinetics of the reaction were obtained using an optimizing method as: [-Ln(1-X)]1/2.91 = 1.02 × 10−2dP−2.07CCH40.16exp(−1.78 × 105/RT)t. The model predictions were compared with the experimental data and the data had an excellent agreement.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 22-22 ◽  
Author(s):  
Joshuaine Toth ◽  
Guanfa Gan ◽  
Joanne van Ryn ◽  
Holly Dursema ◽  
Jennifer Isler ◽  
...  

Abstract Abstract 22 Background: The objective of this study is to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran (a small molecule thrombin inhibitor) and its antidote (a humanized Fab against dabigatran) in the monkey and to develop a combined mechanistic mathematical model to describe the data. Methods: There were three groups: control, antidote alone and dabigatran etexilate (DE) + antidote. Rhesus monkeys (n = 2/group) received either 12 mg/kg/day of DE or vehicle orally on Days 1–4, 15–18 and 29–32 with a single IV dose of the antidote administered 90 minutes after DE on Days 4, 18 and 32. Doses of the antidote were 30, 90 or 175 mg/kg, respectively. PK parameters of the antidote and sum dabigatran (dabigatran plus its glucuronides) were determined after measurements of plasma concentrations. Coagulation activity was measured using a diluted thrombin time assay to determine the activity of the unbound sum dabigatran. Results: The PK of the antidote were not affected by dabigatran. Clearance of the antidote was low (0.87 mL/min/kg) and steady-state volume of distribution was small (0.06 L/kg), indicating that the antidote was mostly restricted to plasma. The plasma profile of the antidote was bi-phasic with a short initial phase t1/2 of 0.4 hour (h) and a terminal phase t1/2 of 4.3 h. Immediately after antidote dosing, plasma concentrations of sum dabigatran increased, a consequence of the rapid redistribution of dabigatran and its glucuronides from tissue to plasma due to binding to the antidote. Complete reversal of dabigatran's anticoagulant activity was observed immediately after antidote dosing at all three dose levels, as measured by the diluted thrombin time assay, which indicates that all dabigatran was bound to the antidote. The degree to which this reversal effect was maintained over an extended period (24 h) was dose-dependent. A mechanistic ordinary differential equation model, based on the mass action kinetics for describing the distribution, binding and elimination of dabigatran and its antidote, was developed by combining the PK models for dabigatran and the antidote and adding the binding interaction (1:1 stoichiometry) between the two compounds. The distribution and elimination parameters of the dabigatran-antidote complex were assumed to be the same as those of the antidote, based on similar measured PK parameters of the antidote with and without dabigatran in the monkey. The combined PK/PD model of dabigatran and antidote was able to describe the in vivo PK/PD data observed in monkeys. Conclusion: The dabigatran-specific antidote successfully reversed the anticoagulant activity of dabigatran in the monkey in a dose-dependent manner, and our combined mathematical model accurately describes monkey PK/PD data of sum dabigatran and its antidote. Insights gained from this model will be used to guide model development for clinical trials. Disclosures: Toth: Boehringer Ingelheim: Employment. Gan:Boehringer Ingelheim: Employment. van Ryn:Boehringer Ingelheim: Employment. Dursema:Boehringer Ingelheim: Employment. Isler:Boehringer Ingelheim: Employment. Coble:Boehringer Ingelheim: Employment. Burke:Boehringer Ingelheim: Employment. Lalovic:Boehringer Ingelheim: Employment. Olson:Boehringer Ingelheim: Employment.


2021 ◽  
Author(s):  
Fabian Froehlich ◽  
Peter Karl Sorger

Motivation: Because they effectively represent mass action kinetics, ordinary differential equation models are widely used to describe biochemical processes. Optimization-based calibration of these models on experimental data can be challenging, even for low-dimensional problems. However, reliable model calibration is a prerequisite for many subsequent analysis steps, including uncertainty analysis, model selection and biological interpretation. Although multiple hypothesis have been advanced to explain why optimization based calibration of biochemical models is challenging, there are few comprehensive studies that test these hypothesis and tools for performing such studies are also lacking. Results: We implemented an established trust-region method as a modular python framework (fides) to enable structured comparison of different approaches to ODE model calibration involving Hessian approximation schemes and trust-region subproblem solvers. We evaluate fides on a set of benchmark problems that include experimental data. We find a high variability in optimizer performance among different implementations of the same algorithm, with fides performing more reliably that other implementations investigated. Our investigation of possible sources of poor optimizer performance identify shortcomings in the widely used Gauss-Newton approximation. We address these shortcomings by proposing a novel hybrid Hessian approximation scheme that enhances optimizer performance.


2021 ◽  
Author(s):  
Sara Hamis ◽  
Yury Kapelyukh ◽  
Aileen McLaren ◽  
Colin J. Henderson ◽  
C. Roland Wolf ◽  
...  

AbstractSimultaneous inhibition of multiple components of the BRAF-MEK-ERK cascade (vertical inhibition) has become a standard of care for treating BRAF-mutant melanoma. However, the molecular mechanisms of how vertical inhibition synergistically suppress intracellular ERK activity, and as a consequence cell proliferation, are yet to be fully elucidated.In this study, we develop a mechanistic mathematical model that describes how the mutant BRAF-inhibitor, dabrafenib, and the MEK-inhibitor, trametinib, affect signaling through the BRAFV600E-MEK-ERK cascade. We formulate a system of chemical reactions that describes cascade signaling dynamics and, using mass action kinetics, the chemical reactions are re-expressed as ordinary differential equations. Using model parameters obtained from in vitro data available in the literature, these equations are solved numerically to obtain the temporal evolution of the concentrations of the components in the signaling cascade.Our mathematical model provides a quantitative method to compute how dabrafenib and trametinib can be used in combination to synergistically inhibit ERK activity in BRAFV600E mutant melanoma cells. This work elucidates molecular mechanisms of vertical inhibition of the BRAFV600E-MEK-ERK cascade and delineates how elevated cellular BRAF concentrations generate drug resistance to dabrafenib and trametinib. In addition, the computational simulations suggest that elevated ATP levels could be a factor in drug resistance to dabrafenib. The mathematical model that is developed in this study will have generic application in the improved design of anticancer combination therapies that target BRAF-MEK-ERK pathways.


2020 ◽  
Vol 42 ◽  
pp. e8
Author(s):  
Paula De Almeida Rios ◽  
Ednilton Tavares De Andrade ◽  
Kátia Soares Moreira ◽  
Filipe Da Silva De Oliveira ◽  
Bárbara Lemes Outeiro Araújo

Dehydrated garlic is an important component both for culinary and medicinal purposes. However, there is a scarcity of studies that characterizes its drying kinetics. Thus, the objective of this work was to study the drying kinetics of Chinese garlic (Allium tuberosum), as well as to analyze the color effect resulting from each treatment. The garlic bulbs were cut into thin slices with a width of 2 and 3 mm, subjected to the drying air temperature of 35, 45, 55 and 70 °C in a mechanical dryer of a fixed layer with forced convection. Was performed a non-linear regression analysis by the Quasi-Newton method, for adjustment to 11 mathematical models to the experimental data of drying. The Midilli equation was the mathematical model that best characterized all the drying temperatures, for the experimental data. The diffusion coefficient presented values between 1.46 x 10-11 and 7.32 x 10-11 m2.s-1. The increase of the drying air temperature caused the dimming of the samples with a reduction of the L* coordinate and reduction of the yellow of the samples according to the coordinate results h*. The temperature of 70 °C was detrimental to the maintenance of the Chinese garlic coloration. 


Author(s):  
A. V. Komissarov ◽  
A. K. Nikiforov ◽  
S. N. Zadokhin ◽  
S. A. Eremin ◽  
O. A. Volokh ◽  
...  

Presented is mathematical model of kinetics of the process of O-antigen and cholera toxin synthesis during periodical submerged cultivation of V. cholerae 569В Inaba with limitation as regards carbonic substrate. The proposed model is based upon analysis of experimental data on V. cholerae 569В Inaba biomass and antigens accumulation, rate of growth and antigens release, and glucose utilization. Using Mathcad 15.0 software calculated are coefficients of differential equations entering into the mathematical model. Comparison of predicted and experimental data demonstrates that relative error of determination of concentrations of the synthesized substances, glucose and cholera vibrio is between 5 and 20 %. The proposed model permits to determine maximum output of final products and specify the parameters of cultivation process performance at different initial conditions.


Author(s):  
Ю.Н. Власов ◽  
Е.В. Нестерова ◽  
Е.Г. Хитров

В технике при изучении кинетики измельчения материалов пользуются математическими моделями в виде интегро-дифференциальных уравнений, решение которых трудоемко и не всегда приводит к получению наглядных результатов. Цель настоящей статьи разработать математическую модель, раскрывающую кинетику изменения фракционного состава измельчаемых древесных материалов, позволяющую на практике проводить оценку фракционного состава обрабатываемого сырья во времени. Методы исследования математический анализ, численные методы решения дифференциальных уравнений и обработки расчетных данных. Измельчение рассмотрено как многостадийный процесс, при котором фракции материала (узкие классы) под воздействием рабочего органа машины-измельчителя претерпевают превращения, происходящие как последовательно, так и параллельно, причем скорости превращений и доли вновь образованных узких классов материала определяются исходными размерами измельчаемых фракций и параметрами рабочего органа измельчителя. Предложена система дифференциальных уравнений, описывающая в общем превращения узких классов при измельчении, причем коэффициенты уравнений позволяют учесть произвольный вид функций скоростей измельчения фракций и выхода продуктов измельчения. Предложенная система является альтернативой интегро-дифференциальному уравнению балансовой модели измельчения. Выполнена оценка значений параметров математической модели на примере измельчения коры. По результатам сопоставления результатов моделирования с экспериментальными данными, полученными предыдущими исследователями, установлено, что предложенная дифференциальная модель изменения фракционного состава материала при принятых предпосылках к расчету ее параметров качественно и количественно описывает экспериментальных данные с высокой точностью. In techniques at study of kinetics of shredding of materials use mathematical models in the form of the integral-differential equations, which solution is laborious and not always leads to reception of evident results. The purpose of this article is to develop a mathematical model, which reveals the kinetics of change in fractional composition of wood materials being shredded, allowing in practice to evaluate the fractional composition of the processed raw materials in time. Methods of research include mathematical analysis, numerical methods for solving differential equations and processing of calculated data. Shredding is considered as multistage process at which fractions of a material (narrow classes) under the influence of a working body of the shredder machine undergo transformations occurring both consistently and in parallel, and rates of transformations and a share of again formed narrow classes of the material are defined by initial sizes of shredded fractions and parameters of the working body. The system of the differential equations describing in the general transformation of narrow classes at grinding is offered, and factors of the equations allow to consider any kind of functions of speeds of grinding of fractions and the output of shredding products. The proposed system is an alternative to the integral-differential equation of the balance shredding model. The estimation of values of parameters of the mathematical model on an example of bark shredding is carried out. By results of comparison of results of modeling with the experimental data received by previous researchers it is established that the offered differential model of change of fractional composition of the material at the accepted preconditions to calculation of its parameters qualitatively and quantitatively describes the experimental data with high accuracy.


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